U.S. patent application number 17/143602 was filed with the patent office on 2022-01-27 for salts and crystal forms of gaba-a positive allosteric modulator.
The applicant listed for this patent is Praxis Precision Medicines, Inc.. Invention is credited to Gabriel Martinez BOTELLA, Paul A. LASKAR, Nelson B. OLIVIER, Kiran REDDY, Magnus RONN.
Application Number | 20220024967 17/143602 |
Document ID | / |
Family ID | 1000005872084 |
Filed Date | 2022-01-27 |
United States Patent
Application |
20220024967 |
Kind Code |
A1 |
OLIVIER; Nelson B. ; et
al. |
January 27, 2022 |
SALTS AND CRYSTAL FORMS OF GABA-A POSITIVE ALLOSTERIC MODULATOR
Abstract
The invention relates to salts of Compound 1, crystalline forms
thereof, methods of their preparation, pharmaceutical compositions
thereof and methods of their use
Inventors: |
OLIVIER; Nelson B.;
(Stoughton, MA) ; REDDY; Kiran; (Charlestown,
MA) ; BOTELLA; Gabriel Martinez; (Wayland, MA)
; RONN; Magnus; (Melrose, MA) ; LASKAR; Paul
A.; (Napa, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Praxis Precision Medicines, Inc. |
Cambridge |
MA |
US |
|
|
Family ID: |
1000005872084 |
Appl. No.: |
17/143602 |
Filed: |
January 7, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
16698057 |
Nov 27, 2019 |
10927141 |
|
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17143602 |
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|
16517369 |
Jul 19, 2019 |
10562930 |
|
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16698057 |
|
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|
62725805 |
Aug 31, 2018 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07B 2200/13 20130101;
C07J 43/003 20130101; A61K 9/20 20130101; A61K 31/4164
20130101 |
International
Class: |
C07J 43/00 20060101
C07J043/00; A61K 9/20 20060101 A61K009/20 |
Claims
1. A citrate salt of Compound 1.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 16/698,057, filed Nov. 27, 2019, which is a continuation of
U.S. application Ser. No. 16/517,369, filed Jul. 19, 2019 (now U.S.
Pat. No. 10,562,930), which claims priority to U.S. Provisional
Application No. 62/725,805, filed Aug. 31, 2018, all of which are
hereby incorporated by reference in their entirety herein.
FIELD OF THE DISCLOSURE
[0002] The present disclosure relates to salts of
3.alpha.-hydroxy-3.beta.-methoxymethyl-21-(1'-imidazolyl)-5.alpha.-pregna-
n-20-one, crystal forms thereof and processes for preparing such
salts and crystal forms.
BACKGROUND OF THE DISCLOSURE
[0003]
3.alpha.-Hydroxy-3.beta.-methoxymethyl-21-(1'-imidazolyl)-5.alpha.--
pregnan-20-one (Compound 1) is a synthetic neuroactive steroid. Its
primary molecular target is the .gamma.-aminobutyric acid type A
(GABA.sub.A) receptor, where it acts as a positive allosteric
modulator (PAM) of channel function. The structural formula of
Compound 1 appears below.
##STR00001##
[0004] Neuroactive steroid GABA.sub.A PAMs have demonstrated
clinical efficacy in epilepsy, post-partum depression, and major
depression.
[0005] There is a need for isolable, stable and water-soluble
Compound 1 salts and processes for making the same.
SUMMARY OF THE DISCLOSURE
[0006] This disclosure provides salts of Compound 1 and methods of
making such salts. In some embodiments, the salts of Compound 1 are
crystalline. The disclosure also provides pharmaceutical
compositions comprising salts of Compound 1.
[0007] In some embodiments, the present disclosure provides
hydrobromide, citrate, malate, maleate, mesylate, phosphate,
tartrate, hydrochloride, tosylate, glucuronate, ethanesulfonate,
fumarate, sulfate, napthalene-2-sulfonate, ascorbate, oxalate,
napthalene-1,5-disulfonate, malonate, aminosalicylate,
benzenesulfonate, isethionate, gentisate, 1-hydroxy-2-napthoate,
dichloroacetate, cyclamate, and ethane-1,2-disulfonate salts of
Compound 1.
[0008] In some embodiments, the present disclosure provides
crystalline forms of hydrobromide, citrate, malate, maleate,
mesylate, phosphate, tartrate, hydrochloride, tosylate,
glucuronate, ethanesulfonate, fumarate, sulfate,
napthalene-2-sulfonate, ascorbate, oxalate,
napthalene-1,5-disulfonate, malonate, aminosalicylate,
benzenesulfonate, isethionate, gentisate, 1-hydroxy-2-napthoate,
dichloroacetate, cyclamate, and ethane-1,2-disulfonate salts of
Compound 1.
[0009] In some embodiments, the present disclosure provides
hydrobromide salts of Compound 1. In some embodiments, the present
disclosure provides crystalline forms of hydrobromide salts of
Compound 1 ("Compound 1 HBr"). In one embodiment, the present
disclosure provides Compound 1 HBr (Form A). In one embodiment, the
present disclosure provides Compound 1 HBr (Form B). In one
embodiment, the present disclosure provides Compound 1 HBr (Form
C). In one embodiment, the present disclosure provides Compound 1
HBr (Form D). In one embodiment, the present disclosure provides
Compound 1 HBr (Form E).
[0010] In some embodiments, the present disclosure provides citrate
salts of Compound 1. In some embodiments, the present disclosure
provides crystalline forms of citrate salts of Compound 1
("Compound 1 Citrate"). In one embodiment, the present disclosure
provides Compound 1 Citrate (Form A). In one embodiment, the
present disclosure provides Compound 1 Citrate (Form B). In one
embodiment, the present disclosure provides Compound 1 Citrate
(Form C).
[0011] The present disclosure provides methods of administering
salts of Compound 1. In some embodiments, the salts of Compound 1
are orally administered. The present disclosure also provides
methods of treating a disease, disorder, or condition comprising
administering a therapeutically effective amount of a salt of
Compound 1. In certain embodiments, the disease, disorder, or
condition is selected from epilepsy, post-partum depression, major
depressive disorder, bipolar disorder, treatment resistant
depression and anxiety.
DETAILED DESCRIPTION OF THE DRAWINGS
[0012] FIG. 1 shows an x-ray powder diffraction (XRPD) pattern of
Compound 1 free base (Pattern A).
[0013] FIG. 2 shows an XRPD pattern of Compound 1 HBr (Form A).
[0014] FIG. 3 shows a differential scanning calorimetry (DSC)
thermogram and a thermogravimetric analysis (TGA) thermogram of
Compound 1 HBr (Form A).
[0015] FIG. 4 shows a dynamic vapor sorption (DVS) isotherm plot
for Compound 1 HBr (Form A).
[0016] FIG. 5 shows an XRPD pattern of Compound 1 HBr (Form B).
[0017] FIG. 6 shows a differential scanning calorimetry (DSC)
thermogram and a thermogravimetric analysis (TGA) thermogram of
Compound 1 HBr (Form B).
[0018] FIG. 7 shows a dynamic vapor sorption (DVS) isotherm plot
for Compound 1 HBr (Form B).
[0019] FIG. 8 shows an XRPD pattern of Compound 1 HBr (Form C).
[0020] FIG. 9 shows a differential scanning calorimetry (DSC)
thermogram and a thermogravimetric analysis (TGA) thermogram of
Compound 1 HBr (Form C).
[0021] FIG. 10 shows a dynamic vapor sorption (DVS) isotherm plot
for Compound 1 HBr (Form C).
[0022] FIG. 11 shows an XRPD pattern of Compound 1 HBr (Form
D).
[0023] FIG. 12 shows a differential scanning calorimetry (DSC)
thermogram and a thermogravimetric analysis (TGA) thermogram of
Compound 1 HBr (Form D).
[0024] FIG. 13 shows an XRPD pattern of Compound 1 HBr (Form
E).
[0025] FIG. 14 shows a differential scanning calorimetry (DSC)
thermogram and a thermogravimetric analysis (TGA) thermogram of
Compound 1 HBr (Form E).
[0026] FIG. 15 shows an XRPD pattern of Compound 1 Citrate (Form
A).
[0027] FIG. 16 shows a DSC thermogram and a TGA thermogram of
Compound 1 Citrate (Form A).
[0028] FIG. 17 shows a DVS isotherm plot for Compound 1 Citrate
(Form A).
[0029] FIG. 18 shows an XRPD pattern of Compound 1 Citrate (Form
B).
[0030] FIG. 19 shows a DSC thermogram and a TGA thermogram of
Compound 1 Citrate (Form B).
[0031] FIG. 20 shows a DVS isotherm plot for Compound 1 Citrate
(Form B).
[0032] FIG. 21 shows an XRPD pattern of Compound 1 Citrate (Form
C).
[0033] FIG. 22 shows an XRPD pattern of Compound 1 Mesylate (Form
A).
[0034] FIG. 23 shows a DSC thermogram and a TGA thermogram of
Compound 1 Mesylate (Form A).
[0035] FIG. 24 shows a DVS isotherm plot for Compound 1 Mesylate
(Form A).
[0036] FIG. 25A shows an XRPD pattern of Compound 1 Mesylate (Form
B).
[0037] FIG. 25B shows an XRPD pattern of Compound 1 Mesylate (Form
C).
[0038] FIG. 26 shows an XRPD pattern of Compound 1 Mesylate (Form
D).
[0039] FIG. 27 shows an XRPD pattern of Compound 1 Phosphate (Form
A).
[0040] FIG. 28 shows a DSC thermogram and a TGA thermogram of
Compound 1 Phosphate (Form A).
[0041] FIG. 29 shows a DVS isotherm plot for Compound 1 Phosphate
(Form A).
[0042] FIG. 30 shows an XRPD pattern of Compound 1 L(+)-Tartrate
(Form A).
[0043] FIG. 31 shows a DSC thermogram and a TGA thermogram of
Compound 1 L(+)-Tartrate (Form A).
[0044] FIG. 32 shows a DVS isotherm plot for Compound 1
L(+)-Tartrate (Form A).
[0045] FIG. 33 shows an XRPD pattern of Compound 1 L(+)-Tartrate
(Form B).
[0046] FIG. 34 shows a DSC thermogram and a TGA thermogram of
Compound 1 L(+)-Tartrate (Form B).
[0047] FIG. 35 shows a DVS isotherm plot for Compound 1
L(+)-Tartrate (Form B).
[0048] FIG. 36 shows an XRPD pattern of Compound 1 Fumarate (Form
A).
[0049] FIG. 37 shows a DSC thermogram and a TGA thermogram of
Compound 1 Fumarate (Form A).
[0050] FIG. 38 shows an XRPD pattern of Compound 1 Fumarate (Form
B).
[0051] FIG. 39 shows a DSC thermogram and a TGA thermogram of
Compound 1 Fumarate (Form B).
[0052] FIG. 40 shows a DVS isotherm plot for Compound 1 Fumarate
(Form B).
[0053] FIG. 41 shows an XRPD pattern of Compound 1 Fumarate (Form
C).
[0054] FIG. 42 shows an XRPD pattern of Compound 1 Fumarate (Form
D).
[0055] FIG. 43 shows an XRPD pattern of Compound 1 Tosylate (Form
A).
[0056] FIG. 44 shows a DSC thermogram and a TGA thermogram of
Compound 1 Tosylate (Form A).
[0057] FIG. 45 shows a DVS isotherm plot for Compound 1 Tosylate
(Form A).
[0058] FIG. 46 shows an XRPD pattern of Compound 1 Tosylate (Form
B).
[0059] FIG. 47 shows an XRPD pattern of Compound 1 Tosylate (Form
C).
[0060] FIG. 48 shows an XRPD pattern of Compound 1 Glucuronate
(Form A).
[0061] FIG. 49 shows a DSC thermogram and a TGA thermogram of
Compound 1 Glucuronate (Form A).
[0062] FIG. 50 shows a DVS isotherm plot for Compound 1 Glucuronate
(Form A).
[0063] FIG. 51 shows an XRPD pattern of Compound 1 Glucuronate
(Form B).
[0064] FIG. 52 shows an XRPD pattern of Compound 1 Ethanesulfonate
(Form A).
[0065] FIG. 53 shows a DSC thermogram and a TGA thermogram of
Compound 1 Ethanesulfonate (Form A).
[0066] FIG. 54 shows a DVS isotherm plot for Compound 1
Ethanesulfonate (Form A).
[0067] FIG. 55 shows an XRPD pattern of Compound 1 Sulfate (Form
A).
[0068] FIG. 56 shows a DSC thermogram and a TGA thermogram of
Compound 1 Sulfate (Form A).
[0069] FIG. 57 shows a DVS isotherm plot for Compound 1 Sulfate
(Form A).
[0070] FIG. 58 shows an XRPD pattern of Compound 1 Ascorbate (Form
A).
[0071] FIG. 59 shows a DSC thermogram and a TGA thermogram of
Compound 1 Ascorbate (Form A).
[0072] FIG. 60 shows a DVS isotherm plot for Compound 1 Ascorbate
(Form A).
[0073] FIG. 61 shows an XRPD pattern of Compound 1 Ascorbate (Form
B).
[0074] FIG. 62 shows an XRPD pattern of Compound 1 Napadisylate
(Form A).
[0075] FIG. 63 shows a DSC thermogram and a TGA thermogram of
Compound 1 Napadisylate (Form A).
[0076] FIG. 64 shows a DVS isotherm plot for Compound 1
Napadisylate (Form A).
[0077] FIG. 65 shows an XRPD pattern of Compound 1 Napadisylate
(Form B).
[0078] FIG. 66 shows an XRPD pattern of Compound 1 Malonate (Form
A).
[0079] FIG. 67 shows a DSC thermogram and a TGA thermogram of
Compound 1 Malonate (Form A).
[0080] FIG. 68 shows an XRPD pattern of Compound 1 Besylate (Form
A).
[0081] FIG. 69 shows a DSC thermogram and a TGA thermogram of
Compound 1 Besylate (Form A).
[0082] FIG. 70 shows a DVS isotherm plot for Compound 1 Besylate
(Form A).
[0083] FIG. 71 shows an XRPD pattern of Compound 1 Besylate (Form
B).
[0084] FIG. 72 shows an XRPD pattern of Compound 1 Isethionate
(Form A).
[0085] FIG. 73 shows a DSC thermogram and a TGA thermogram of
Compound 1 Isethionate (Form A).
[0086] FIG. 74 shows a DVS isotherm plot for Compound 1 Isethionate
(Form A).
[0087] FIG. 75 shows an XRPD pattern of Compound 1 Isethionate
(Form B).
[0088] FIG. 76 shows an XRPD pattern of Compound 1 Gentisate (Form
A).
[0089] FIG. 77 shows a DSC thermogram and a TGA thermogram of
Compound 1 Gentisate (Form A).
[0090] FIG. 78 shows a DVS isotherm plot for Compound 1 Gentisate
(Form A).
[0091] FIG. 79 shows an XRPD pattern of Compound 1 Gentisate (Form
B).
[0092] FIG. 80 shows an XRPD pattern of Compound 1 Gentisate (Form
C).
[0093] FIG. 81 shows an XRPD pattern of Compound 1
1-Hydroxy-2-napthoate (Form A).
[0094] FIG. 82 shows a DSC thermogram and a TGA thermogram of
Compound 1 1-Hydroxy-2-napthoate (Form A).
[0095] FIG. 83 shows a DVS isotherm plot for Compound 1
1-Hydroxy-2-napthoate (Form A).
[0096] FIG. 84 shows an XRPD pattern of Compound 1
1-Hydroxy-2-napthoate (Form B).
[0097] FIG. 85 shows an XRPD pattern of Compound 1
1-Hydroxy-2-napthoate (Form C).
[0098] FIG. 86 shows an XRPD pattern of Compound 1
1-Hydroxy-2-napthoate (Form D).
[0099] FIG. 87 shows an XRPD pattern of Compound 1 Cyclamate (Form
A).
[0100] FIG. 88 shows a DSC thermogram and a TGA thermogram of
Compound 1 Cyclamate (Form A).
[0101] FIG. 89 shows a DVS isotherm plot for Compound 1 Cyclamate
(Form A).
[0102] FIG. 90 shows an XRPD pattern of Compound 1 Ethane-1,
2-disulfonate (Form A).
[0103] FIG. 91 shows a DSC thermogram and a TGA thermogram of
Compound 1 Ethane-1, 2-disulfonate (Form A).
[0104] FIG. 92 shows a DVS isotherm plot for Compound 1 Ethane-1,
2-disulfonate (Form A).
[0105] FIG. 93 shows an XRPD pattern of Compound 1 Ethane-1,
2-disulfonate (Form B).
[0106] FIG. 94 shows an XRPD pattern of Compound 1 Dichloroacetate
(Form A).
[0107] FIG. 95 shows a DSC thermogram and a TGA thermogram of
Compound 1 Dichloroacetate (Form A).
[0108] FIG. 96 shows a DVS isotherm plot for Compound 1
Dichloroacetate (Form A).
[0109] FIG. 97 shows an XRPD pattern of Compound 1 L-Malate (Form
A).
[0110] FIG. 98 shows a DSC thermogram and a TGA thermogram of
Compound 1 L-Malate (Form A).
[0111] FIG. 99 shows a DVS isotherm plot for Compound 1 L-Malate
(Form A).
[0112] FIG. 100 shows an XRPD pattern of Compound 1 L-Malate (Form
B).
[0113] FIG. 101 shows a DSC thermogram and a TGA thermogram of
Compound 1 L-Malate (Form B).
[0114] FIG. 102 shows a DVS isotherm plot for Compound 1 L-Malate
(Form B).
[0115] FIG. 103 shows an XRPD pattern of Compound 1 Hydrochloride
(Form A).
[0116] FIG. 104 shows a DSC thermogram and a TGA thermogram of
Compound 1 Hydrochloride (Form A).
[0117] FIG. 105 shows a DVS isotherm plot for Compound 1
Hydrochloride (Form A).
[0118] FIG. 106 shows an XRPD pattern of Compound 1 Hydrochloride
(Form B).
[0119] FIG. 107 shows a DSC thermogram and a TGA thermogram of
Compound 1 Hydrochloride (Form B).
[0120] FIG. 108 shows a DVS isotherm plot for Compound 1
Hydrochloride (Form B).
[0121] FIG. 109 shows an XRPD pattern of Compound 1 Hydrochloride
(Form C).
[0122] FIG. 110 shows a DSC thermogram and a TGA thermogram of
Compound 1 Hydrochloride (Form C).
[0123] FIG. 111 shows a DVS isotherm plot for Compound 1
Hydrochloride (Form C).
[0124] FIG. 112 shows an XRPD pattern of Compound 1 Napsylate (Form
A).
[0125] FIG. 113 shows a DSC thermogram and a TGA thermogram of
Compound 1 Napsylate (Form A).
[0126] FIG. 114 shows a DVS isotherm plot for Compound 1 Napsylate
(Form A).
[0127] FIG. 115 shows an XRPD pattern of Compound 1 Napsylate (Form
B).
[0128] FIG. 116 shows an XRPD pattern of Compound 1 Oxalate (Form
A).
[0129] FIG. 117 shows a DSC thermogram and a TGA thermogram of
Compound 1 Oxalate (Form A).
[0130] FIG. 118 shows a DVS isotherm plot for Compound 1 Oxalate
(Form A).
[0131] FIG. 119 shows an XRPD pattern of Compound 1 Oxalate (Form
B).
[0132] FIG. 120 shows an XRPD pattern of Compound 1
P-Aminosalicylate (Form A).
[0133] FIG. 121 shows a DSC thermogram and a TGA thermogram of
Compound 1 P-Aminosalicylate (Form A).
[0134] FIG. 122 shows a DVS isotherm plot for Compound 1
P-Aminosalicylate (Form A).
[0135] FIG. 123 shows an XRPD pattern of Compound 1
P-Aminosalicylate (Form B).
[0136] FIG. 124 shows an XRPD pattern of Compound 1 Maleate (Form
A).
DETAILED DESCRIPTION OF THE DISCLOSURE
Definitions
[0137] The term "about" when immediately preceding a numerical
value means a range (e.g., plus or minus 10% of that value). For
example, "about 50" can mean 45 to 55, "about 25,000" can mean
22,500 to 27,500, etc., unless the context of the disclosure
indicates otherwise, or is inconsistent with such an
interpretation. For example in a list of numerical values such as
"about 49, about 50, about 55, . . . ", "about 50" means a range
extending to less than half the interval(s) between the preceding
and subsequent values, e.g., more than 49.5 to less than 52.5.
Furthermore, the phrases "less than about" a value or "greater than
about" a value should be understood in view of the definition of
the term "about" provided herein. Similarly, the term "about" when
preceding a series of numerical values or a range of values (e.g.,
"about 10, 20, 30" or "about 10-30") refers, respectively to all
values in the series, or the endpoints of the range.
[0138] Throughout this disclosure, various patents, patent
applications and publications (including non-patent publications)
are referenced. The disclosures of these patents, patent
applications and publications in their entireties are incorporated
into this disclosure by reference for all purposes in order to more
fully describe the state of the art as known to those skilled
therein as of the date of this disclosure. This disclosure will
govern in the instance that there is any inconsistency between the
patents, patent applications and publications cited and this
disclosure.
[0139] For convenience, certain terms employed in the
specification, examples and claims are collected here. Unless
defined otherwise, all technical and scientific terms used in this
disclosure have the same meanings as commonly understood by one of
ordinary skill in the art to which this disclosure belongs.
[0140] The terms "administer," "administering" or "administration"
as used herein refer to either directly administering Compound 1 or
pharmaceutically acceptable salt thereof or a composition
comprising Compound 1 or pharmaceutically acceptable salt to a
patient.
[0141] The terms "aprotic solvent," "nonprotic solvent" or
"non-protic solvent" as used herein refers to an organic solvent or
a mixture of organic solvents that is not readily deprotonated in
the presence of a strongly basic reactant. Non-limiting examples of
non-protic solvents include ethers, dimethylformamide (DMF),
dimethylacetamide (DMAC),
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU),
1,3-dimethyl-2-imidazolidinone (DMI), N-methylpyrrolidinone (NMP),
formamide, N-methylacetamide, N-methylformamide, acetonitrile,
dimethyl sulfoxide, propionitrile, ethyl formate, methyl acetate,
methyl isobutyl ketone, hexachloroacetone, acetone, ethyl methyl
ketone, methyl ethyl ketone (MEK), ethyl acetate, isopropyl
acetate, sulfolane, N,N-dimethylpropionamide, tetramethylurea,
nitromethane, nitrobenzene, or hexamethylphosphoramide,
diethoxymethane, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, furan,
diethyl ether, tetrahydropyran, diisopropyl ether, dibutyl ether,
ethylene glycol dimethyl ether, ethylene glycol diethyl ether,
diethylene glycol dimethyl ether, diethylene glycol diethyl ether,
triethylene glycol dimethyl ether, anisole, t-butyl methyl ether,
and the like.
[0142] The term "carrier" as used herein encompasses carriers,
excipients, and diluents, meaning a material, composition or
vehicle, such as a liquid or solid filler, diluent, excipient,
solvent or encapsulating material involved in carrying or
transporting a pharmaceutical agent from one organ, or portion of
the body, to another organ or portion of the body.
[0143] The term "disorder" is used in this disclosure to mean, and
is used interchangeably with, the terms disease, condition, or
illness, unless otherwise indicated.
[0144] The terms "effective amount" and "therapeutically effective
amount" are used interchangeably in this disclosure and refer to an
amount of a compound, or a salt, solvate or ester thereof, that,
when administered to a patient, is capable of performing the
intended result. For example, an effective amount of a salt of
Compound 1 is that amount that is required to reduce at least one
symptom of depression in a patient. The actual amount that
comprises the "effective amount" or "therapeutically effective
amount" will vary depending on a number of conditions including,
but not limited to, the severity of the disorder, the size and
health of the patient, and the route of administration. A skilled
medical practitioner can readily determine the appropriate amount
using methods known in the medical arts.
[0145] The term "isomer" refers to compounds having the same
chemical formula but may have different stereochemical formula,
structural formula, or special arrangements of atoms. Examples of
isomers include stereoisomers, diastereomers, enantiomers,
conformational isomers, rotamers, geometric isomers, and
atropisomers.
[0146] The term "peak" refers to a line having a substantial
intensity in the XRPD diffractogram (or pattern) obtained from a
sample using standard XRPD collection techniques. For example, a
peak is a line in the XRPD diffractogram having an intensity that
is, for example, at least about 10% of the intensity of the largest
peak in the XRPD diffractogram.
[0147] The phrase "pharmaceutically acceptable" as used herein
refers to those compounds, materials, compositions, and/or dosage
forms which are, within the scope of sound medical judgment,
suitable for use in contact with the tissues of human beings and
animals without excessive toxicity, irritation, allergic response,
or other problem or complication, commensurate with a reasonable
benefit/risk ratio.
[0148] The term "protic solvent" as used herein refers to a solvent
or a solvent mixture that is capable of functioning as an acid for
purposes of protonating any unreacted, strongly basic reaction
intermediates. Non-limiting examples of protic solvents include
water, methanol, ethanol, 2-nitroethanol, 2-fluoroethanol,
2,2,2-trifluoroethanol, ethylene glycol, 1-propanol, 2-propanol,
2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl
alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol,
neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl
ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl
alcohol, phenol, glycerol, and the like.
[0149] The term "salts" as used herein embraces pharmaceutically
acceptable salts commonly used to form addition salts of free
bases. The nature of the salt is not critical provided that it is
pharmaceutically acceptable. The term "salts" also includes
solvates of addition salts, such as hydrates, as well as polymorphs
of addition salts. Suitable pharmaceutically acceptable acid
addition salts can be prepared from an inorganic acid or from an
organic acid. In a salt, proton transfer occurs between Compound 1
free base and an organic acid or an inorganic acid. However, in
some cases proton transfer is incomplete. In such cases, Compound 1
and the "co-former" molecules in the solid (i.e., "co-crystal")
interact through non-ionic forces such as hydrogen bonding.
[0150] Where an acid co-former is a solid at about 23.degree. C.
(i.e., room temperature) and there is no, or partial, proton
transfer between Compound 1 and the acid co-former, a co-crystal of
the co-former and Compound 1 is provided. As used herein, the term
"salt" encompasses co-crystal forms of Compound 1.
[0151] The term "substantially similar" as used herein means an
analytical spectrum, such as XRPD pattern, DSC thermogram, etc.,
which resembles the reference spectrum to a great degree in both
the peak locations and their intensity.
[0152] The term "treating" as used herein with regard to a patient,
refers to improving at least one symptom of the patient's disorder.
Treating can be curing, improving, or at least partially
ameliorating a disorder.
[0153] The term "therapeutic effect" as used herein refers to a
desired or beneficial effect provided by the method and/or the
composition. For example, the method for treating depression
provides a therapeutic effect when the method reduces at least one
symptom of depression in a patient.
[0154] As used herein, the symbol ".ltoreq." means "not more than"
or "equal to or less than"; "<" means "less than"; ".gtoreq."
means "not less than" or "equal to or more than"; and ">" means
"more than". Furthermore, the numerical numbers, when used herein
in connection with purity or impurity content, include not only the
exact number but also the approximate range around the number. For
example, the phrase "purity of 99.0%" denotes a purity of about
99.0%.
Salts of Compound 1
[0155] Compound 1 is a neuroactive steroid GABA-A positive
allosteric modulator (PAM) with high potency similar to clinical
stage neuroactive steroids (allopregnanolone, ganaxolone, SAGE-217,
alphaxolone). Compound 1 is poorly soluble at the pH found in the
lower GI tract, which may limit Compound 1's oral
bioavailability.
[0156] The synthesis of Compound 1 is described in U.S. Publication
Nos. 2004/034002 and 2009/0118248; crystalline polymorph of
Compound 1 free base is described in U.S. Publication No.
2006/0074059 and pharmaceutical compositions containing Compound 1
are described in U.S. Publication No. 2009/0131383, which are
hereby incorporated by reference in their entirety for all
purposes.
[0157] The present disclosure provides salts of Compound 1 and
crystalline forms thereof.
Crystalline Salts of Compound 1
[0158] In some embodiments, the present disclosure provides
crystalline forms of a salt of Compound 1. Polymorphism can be
characterized as the ability of a compound to crystallize into
different crystal forms while maintaining the same structural
formula (i.e., the covalent bonds in the compound are the same in
different crystal forms). A crystalline polymorph of a given drug
substance is chemically identical to any other crystalline
polymorph of that drug substance in containing the same atoms
bonded to one another in the same way, but differs in its crystal
forms, which can affect one or more physical properties, such as
stability, solubility, melting point, bulk density, flow
properties, etc., or pharmacological properties such as
bioavailability, etc.
[0159] In some embodiments, the crystalline forms are characterized
by the interlattice plane intervals determined by an X-ray powder
diffraction pattern (XRPD). The XRPD diffractogram is typically
represented by a diagram plotting the intensity of the peaks versus
the location of the peaks, i.e., diffraction angle 2.theta.
(two-theta) in degrees. The characteristic peaks of a given XRPD
diffractogram can be selected according to the peak locations and
their relative intensity to conveniently distinguish this
crystalline structure from others. The % intensity of the peaks
relative to the most intense peak may be represented as I/Io.
[0160] Those skilled in the art recognize that the measurements of
the XRPD peak locations and/or intensity for a given crystalline
form of the same compound will vary within a margin of error. The
values of degree 2.theta. allow appropriate error margins.
Typically, the error margins are represented by ".+-.". For
example, the degree 20 of about "8.716.+-.0.3" denotes a range from
about 8.716+0.3, i.e., about 9.016, to about 8.716-0.3, i.e., about
8.416. Depending on the sample preparation technique, the
calibration technique applied to the instrument, human operational
variation, and etc., those skilled in the art recognize that the
appropriate error of margins for an XRPD can be about .+-.0.7;
.+-.0.6; .+-.0.5; .+-.0.4; .+-.0.3; .+-.0.2; .+-.0.1; .+-.0.05; or
less.
[0161] Additional details of the methods and equipment used for the
XRPD analysis are described in the Examples section.
[0162] In some embodiments, the crystalline forms are characterized
by Differential Scanning calorimetry (DSC). The DSC thermogram is
typically expressed by a diagram plotting the normalized heat flow
in units of Watts/gram ("W/g") versus the measured sample
temperature in degree C. The DSC thermogram is usually evaluated
for extrapolated onset and end (outset) temperatures, peak
temperature, and heat of fusion. A peak characteristic value of a
DSC thermogram is often used as the characteristic peak to
distinguish this crystalline structure from others.
[0163] Those skilled in the art recognize that the measurements of
the DSC thermogram for a given crystalline form of the same
compound will vary within a margin of error. The values of a single
peak characteristic value, expressed in degree C., allow
appropriate error margins. Typically, the error margins are
represented by ".+-.". For example, the single peak characteristic
value of about "53.09.+-.2.0" denotes a range from about 53.09+2,
i.e., about 55.09, to about 53.09-2, i.e., about 51.09. Depending
on the sample preparation techniques, the calibration techniques
applied to the instruments, human operational variations, and etc.,
those skilled in the art recognize that the appropriate error of
margins for a single peak characteristic value can be .+-.2.5;
.+-.2.0; .+-.1.5; .+-.1.0; .+-.0.5; or less.
[0164] Additional details of the methods and equipment used for the
DSC thermogram analysis are described in the Examples section.
Hydrobromide Salt
[0165] In some embodiments, the present disclosure provides a
hydrobromide salt of Compound 1 ("Compound 1 HBr"). In some
embodiments, the present disclosure provides a crystalline form of
Compound 1 HBr.
[0166] In one embodiment, the present disclosure provides Compound
1 HBr (Form A). In some embodiments, the Compound 1 HBr (Form A)
exhibits an XRPD comprising one or more peaks at about 7.6, 15.2,
16.3, 19.8 and 22.9 degrees two-theta with the margin of error of
about .+-.0.5; about .+-.0.4; about .+-.0.3; about .+-.0.2; about
.+-.0.1; about .+-.0.05; or less. In another embodiment, the XRPD
of the Compound 1 HBr (Form A) further comprises one or more peaks
at about 15.5, 19.2, 20.6, 26.1, and 31.3 degrees two-theta with
the margin of error of about .+-.0.5; about .+-.0.4; about .+-.0.3;
about .+-.0.2; about .+-.0.1; about .+-.0.05; or less. In yet
another embodiment, the Compound 1 HBr (Form A) exhibits an XRPD
comprising peaks shown in Table 1 below:
TABLE-US-00001 TABLE 1 XRPD Table of Compound 1 HBr (Form A)
2-Theta Intensity % 7.6 100 9.6 11.4 11.6 3.1 11.9 2.8 13.2 2.8
13.9 5.6 15.2 47.9 15.5 24.4 16.3 82.8 18.5 2.0 19.2 11.6 19.8 28.8
20.6 15.0 21.2 2.9 22.3 3.3 22.9 53.3 23.2 3.4 23.7 11.1 24.6 3.7
25.4 1.6 26.1 20.7 26.4 4.8 27.0 4.4 27.4 2.5 28.0 2.0 28.9 6.0
30.3 3.1 30.7 4.7 31.3 15.6 31.7 2.1 32.5 1.5 33.0 4.4 33.6 1.5
34.0 2.1 34.7 3.9 35.6 2.2 39.1 4.8
[0167] Some embodiments provide Compound 1 HBr (Form A), wherein in
the range from 15.2.+-.0.2 to 16.3.+-.0.2 degrees two-theta in the
XRPD pattern, the Form A exhibits only three peaks.
[0168] In some embodiments, the Compound 1 HBr (Form A) exhibits an
XRPD that is substantially similar to FIG. 2.
[0169] In some embodiments, the Compound 1 HBr (Form A) exhibits a
DSC thermogram comprising a sharp endotherm at about 243.1.degree.
C. with the error of margin of about .+-.2.5; about .+-.2.0; about
.+-.1.5; about .+-.1.0; about .+-.0.5; or less. In some
embodiments, the Compound 1 HBr (Form A) exhibits a DSC thermogram
that is substantially similar to FIG. 3.
[0170] In some embodiments, the Compound 1 HBr (Form A) exhibits a
TGA thermogram that is substantially similar to FIG. 3. In other
embodiments, the TGA thermogram of the Compound 1 HBr (Form A)
exhibits a weight loss of about 0.0 to 1.9% in the temperature
range of 25 to 230.degree. C.
[0171] In some embodiments, the Compound 1 HBr (Form A) exhibits a
DVS isotherm plot that is substantially similar to FIG. 4. In other
embodiments, the Compound 1 HBr (Form A) exhibits a gravimetric
moisture sorption of about 1.1% (by weight) at 80% Relative
Humidity.
[0172] In one embodiment, the present disclosure provides Compound
1 HBr (Form B). In some embodiments, the Compound 1 HBr (Form B)
exhibits an XRPD comprising one or more peaks at about 3.6, 16.3,
17.7, 21.4 and 23.5 degrees two-theta with the margin of error of
about .+-.0.5; about .+-.0.4; about .+-.0.3; about .+-.0.2; about
.+-.0.1; about .+-.0.05; or less. In another embodiment, the XRPD
of the Compound 1 HBr (Form B) further comprises one or more peaks
at about 14.4, 18.7, 24.8, 27.3 and 28.2 degrees two-theta with the
margin of error of about .+-.0.5; about .+-.0.4; about .+-.0.3;
about .+-.0.2; about .+-.0.1; about .+-.0.05; or less. In yet
another embodiment, the Compound 1 HBr (Form B) exhibits an XRPD
comprising peaks shown in Table 2 below:
TABLE-US-00002 TABLE 2 XRPD Table of Compound 1 HBr (Form B)
2-Theta Intensity % 3.6 51 8.9 18.8 14.1 17.8 14.4 37.5 16.3 52.6
16.7 19.8 17.7 100 18.7 32.2 19.3 23.6 19.5 20 21.4 76 21.8 17.6
22.8 14.8 23.5 41.8 24.3 14.4 24.8 30.7 25.7 23.9 25.9 11.4 26.6 14
27.3 29.2 27.7 11.2 28.2 28.6 30.2 5.4 30.3 7.5 30.9 12.5 33.8 12.7
34.5 11 35.0 13.1 35.9 11.6
[0173] In some embodiments, the Compound 1 HBr (Form B) exhibits an
XRPD that is substantially similar to FIG. 5.
[0174] In some embodiments, the Compound 1 HBr (Form B) exhibits a
DSC thermogram comprising an endotherm at about 121.degree. C. with
the error of margin of about .+-.2.5; about .+-.2.0; about .+-.1.5;
about .+-.1.0; about .+-.0.5; or less. In some embodiments, the
Compound 1 HBr (Form B) exhibits a DSC thermogram that is
substantially similar to FIG. 6.
[0175] In some embodiments, the Compound 1 HBr (Form B) exhibits a
TGA thermogram that is substantially similar to FIG. 6. In other
embodiments, the TGA thermogram of the Compound 1 HBr (Form B)
exhibits a weight loss of about 0.0 to 3.4% in the temperature
range of 25 to 120.degree. C.
[0176] In some embodiments, the Compound 1 HBr (Form B) exhibits a
DVS isotherm plot that is substantially similar to FIG. 7. In other
embodiments, the Compound 1 HBr (Form B) exhibits a gravimetric
moisture sorption of about 0.2% (by weight) at 80% Relative
Humidity.
[0177] In some embodiments, the Compound 1 HBr (Form B) is defined
by unit cell parameters substantially similar to the following:
a=9.3 (4) .ANG.; b=10.8 (4) .ANG.; c=25.2 (11) .ANG.; .alpha.=90';
.beta.=90.degree.; .gamma.=90'; Space group P2.sub.12.sub.12.sub.1;
Molecules/asymmetric unit 1, wherein the crystalline form is at
about 120 K.
[0178] In one embodiment, the present disclosure provides Compound
1 HBr (Form C). In some embodiments, the Compound 1 HBr (Form C)
exhibits an XRPD comprising one or more peaks at about 6.9, 13.8,
20.8, 21.6 and 27.7 degrees two-theta with the margin of error of
about .+-.0.5; about .+-.0.4; about .+-.0.3; about .+-.0.2; about
.+-.0.1; about .+-.0.05; or less. In another embodiment, the XRPD
of the Compound 1 HBr (Form C) further comprises one or more peaks
at about 8.8, 25.6, 27.5, 36.2 and 37.3 degrees two-theta with the
margin of error of about .+-.0.5; about .+-.0.4; about .+-.0.3;
about .+-.0.2; about .+-.0.1; about .+-.0.05; or less. In yet
another embodiment, the Compound 1 HBr (Form C) exhibits an XRPD
comprising peaks shown in Table 3 below:
TABLE-US-00003 TABLE 3 XRPD Table of Compound 1 HBr (Form C)
2-Theta Intensity % 3.4 8.3 6.9 62.4 8.8 10.2 10.9 7.0 13.8 32.4
16.3 3.2 17.7 8.9 19.3 5.0 20.8 100 21.6 20.5 23.6 8.5 23.8 3.2
25.6 14.1 27.5 14.8 27.7 70.1 34.8 8.4 36.2 10.2 37.3 14.3
[0179] In some embodiments, the Compound 1 HBr (Form C) exhibits an
XRPD that is substantially similar to FIG. 8.
[0180] In some embodiments, the Compound 1 HBr (Form C) exhibits a
DSC thermogram comprising a sharp endotherm at about 141.degree. C.
with the error of margin of about .+-.2.5; about .+-.2.0; about
.+-.1.5; about .+-.1.0; about .+-.0.5; or less. In some
embodiments, the Compound 1 HBr (Form C) exhibits a DSC thermogram
that is substantially similar to FIG. 9.
[0181] In some embodiments, the Compound 1 HBr (Form C) exhibits a
TGA thermogram that is substantially similar to FIG. 9. In other
embodiments, the TGA thermogram of the Compound 1 HBr (Form C)
exhibits a weight loss of about 0.0 to 4.1% in the temperature
range of 25 to 170.degree. C.
[0182] In some embodiments, the Compound 1 HBr (Form C) exhibits a
DVS isotherm plot that is substantially similar to FIG. 10. In
other embodiments, the Compound 1 HBr (Form C) exhibits a
gravimetric moisture sorption of about 0.25% (by weight) at 80%
Relative Humidity.
[0183] In one embodiment, the present disclosure provides Compound
1 HBr (Form D). In some embodiments, the Compound 1 HBr (Form D)
exhibits an XRPD comprising one or more peaks at about 14.7, 15.2,
15.6, 16.4, and 23.1 degrees two-theta with the margin of error of
about .+-.0.5; about .+-.0.4; about .+-.0.3; about .+-.0.2; about
.+-.0.1; about .+-.0.05; or less. In another embodiment, the XRPD
of the Compound 1 HBr (Form D) further comprises one or more peaks
at about 18.2, 19.9, 21.3, 22.2, and 23.4 degrees two-theta with
the margin of error of about .+-.0.5; about .+-.0.4; about .+-.0.3;
about .+-.0.2; about .+-.0.1; about .+-.0.05; or less. In yet
another embodiment, the Compound 1 HBr (Form D) exhibits an XRPD
comprising peaks shown in Table 4 below:
TABLE-US-00004 TABLE 4 XRPD Table of Compound 1 HBr (Form D)
2-Theta Intensity % 7.7 27.7 9.1 2.6 9.7 12.1 11.9 12.0 12.7 14.5
13.3 6.6 14.0 12.4 14.7 51.5 15.2 100.0 15.6 55.3 16.1 27.9 16.4
52.4 17.9 31.1 18.2 40.0 18.8 34.9 19.4 36.2 19.9 47.0 20.7 23.5
21.3 41.0 22.2 39.1 23.1 56.6 23.4 48.2 23.8 30.7 24.2 24.6 24.8
21.8 26.2 31.4 26.6 20.1 27.5 16.4 29.0 11.3 29.5 18.7 29.7 21.6
30.4 21.1 31.4 14.1 32.7 12.4 33.5 9.7 35.3 10.2 39.3 10.3
[0184] In some embodiments, the Compound 1 HBr (Form D) exhibits an
XRPD that is substantially similar to FIG. 11.
[0185] In some embodiments, the Compound 1 HBr (Form D) exhibits a
DSC thermogram comprising a sharp endotherm at about 248.degree. C.
with the error of margin of about .+-.2.5; about .+-.2.0; about
.+-.1.5; about .+-.1.0; about .+-.0.5; or less. In some
embodiments, the Compound 1 HBr (Form D) exhibits a DSC thermogram
that is substantially similar to FIG. 12.
[0186] In some embodiments, the Compound 1 HBr (Form D) exhibits a
TGA thermogram that is substantially similar to FIG. 12. In other
embodiments, the TGA thermogram of the Compound 1 HBr (Form D)
exhibits a weight loss of about 0.0 to 1.7% in the temperature
range of 29 to 150.degree. C.
[0187] In some embodiments, the present disclosure provides
Compound 1 HBr (Form E). In some embodiments, the Compound 1 HBr
(Form E) exhibits an XRPD comprising one or more peaks at about
7.6, 15.2, 16.3, 22.9 and 23.2 degrees two-theta with the margin of
error of about .+-.0.5; about .+-.0.4; about .+-.0.3; about
.+-.0.2; about .+-.0.1; about .+-.0.05; or less. In another
embodiment, the XRPD of the Compound 1 HBr (Form E) further
comprises one or more peaks at about 9.6, 17.4, 22.4, 23.6 and 31.2
degrees two-theta with the margin of error of about .+-.0.5; about
.+-.0.4; about .+-.0.3; about .+-.0.2; about .+-.0.1; about
.+-.0.05; or less. In yet another embodiment, the Compound 1 HBr
(Form E) exhibits an XRPD comprising peaks shown in Table 5
below:
TABLE-US-00005 TABLE 5 XRPD Table of Compound 1 HBr (Form E)
2-Theta Intensity % 7.6 100 9.6 6.1 11.7 1.4 12.3 4.5 12.8 2.3 13.1
1.9 14 2.3 15.2 58.3 16.3 53.5 17.4 14 19.2 1.6 19.9 4 20.1 5.8
21.2 1.8 22.4 6.8 22.9 47.9 23.2 19.9 23.6 8.2 23.9 2.1 24.8 1.7
25.4 3.5 25.8 2.6 26.2 5.5 26.5 5.2 26.7 1.7 27.4 2.7 28.4 3.2 29.9
4.6 30.6 5 31.2 9 33.5 2.1 35.1 3.5 36.5 2.2 39 3.1 39.5 1.6
[0188] Some embodiments provide Compound 1 HBr (Form E), wherein in
the range from 15.2.+-.0.2 to 16.3.+-.0.2 degrees two-theta in the
XRPD pattern, the Form E exhibits only two peaks.
[0189] In some embodiments, the Compound 1 HBr (Form E) exhibits an
XRPD that is substantially similar to FIG. 13.
[0190] In some embodiments, the Compound 1 HBr (Form E) exhibits a
DSC thermogram comprising a sharp endotherm at about 245.degree. C.
with the error of margin of about .+-.2.5; about .+-.2.0; about
.+-.1.5; about .+-.1.0; about .+-.0.5; or less. In some
embodiments, the Compound 1 HBr (Form E) exhibits a DSC thermogram
that is substantially similar to FIG. 14.
[0191] In some embodiments, the Compound 1 HBr (Form E) exhibits a
TGA thermogram that is substantially similar to FIG. 14. In other
embodiments, the TGA thermogram of the Compound 1 HBr (Form E)
exhibits a weight loss of about 0.0 to 0.5% in the temperature
range of 28 to 150.degree. C.
[0192] In some embodiments, the Compound 1 HBr (Form E) is defined
by unit cell parameters substantially similar to the following:
a=7.5 (10) .ANG.; b=15.0 (2) .ANG.; c=23.0 (2) .ANG.;
.alpha.=90.degree.; .beta.=90.degree.; .gamma.=90.degree.; Space
group P2.sub.12.sub.12.sub.1; Molecules/asymmetric unit 1, wherein
the crystalline form is at about 120 K.
[0193] In some embodiments, the Compound 1 HBr (Form E) is defined
by unit cell parameters substantially similar to the following:
a=23.3 (5) .ANG.; b=15.0 (3) .ANG.; c=7.5 (10) .ANG.;
.alpha.=90.degree.; .beta.=90.degree.; .gamma.=90.degree.; Space
group P2.sub.12.sub.12.sub.1; Molecules/asymmetric unit 1, wherein
the crystalline form is at about 298 K.
Citrate Salt
[0194] In some embodiments, the present disclosure provides a
citrate salt of Compound 1 ("Compound 1 Citrate"). In some
embodiments, the present disclosure provides a crystalline form of
Compound 1 Citrate.
[0195] In one embodiment, the present disclosure provides Compound
1 Citrate (Form A). In some embodiments, the Compound 1 Citrate
(Form A) exhibits an XRPD comprising one or more peaks at about
5.7, 11.9, 17.1, 20.1, and 20.3 degrees two-theta with the margin
of error of about .+-.0.5; about .+-.0.4; about .+-.0.3; about
.+-.0.2; about .+-.0.1; about .+-.0.05; or less. In another
embodiment, the XRPD of the Compound 1 Citrate (Form A) further
comprises one or more peaks at about 12.7, 13.0, 13.6, 15.3, and
16.8 degrees two-theta with the margin of error of about .+-.0.5;
about .+-.0.4; about .+-.0.3; about .+-.0.2; about .+-.0.1; about
.+-.0.05; or less. In yet another embodiment, the Compound 1
Citrate (Form A) exhibits an XRPD comprising peaks shown in Table 6
below:
TABLE-US-00006 TABLE 6 XRPD Table of Compound 1 Citrate (Form A)
2-Theta Intensity (%) 5.7 100 8.2 18.5 10.3 4.3 10.6 12 11.4 12.6
11.9 38 12.5 19 12.7 19.6 13.0 22.4 13.6 21.2 13.9 14.1 14.1 14.2
14.7 5 15.3 21.8 16.8 30.6 17.1 39.7 17.5 11.4 18.0 14.1 18.7 10.6
19.0 18.3 19.4 14.5 19.7 12.1 20.1 37.7 20.3 63.7 20.7 11.8 21.3
12.7 21.6 9.9 22.4 11.3 22.8 13.2 23.4 7 23.9 5.2 24.6 5.7 25.0 4.6
25.8 19.3 26.2 6.3 26.5 6.8 27.2 4.8 28.2 6.5 28.6 5.8 29.5 6.7
30.5 5.4 31.3 5.8 32.8 4.6 37.1 5.9
[0196] In some embodiments, the Compound 1 Citrate (Form A)
exhibits an XRPD comprising peaks at about: 5.7.+-.0.2; 12.5.+-.0.2
and 13.0.+-.0.2; or 5.7.+-.0.2, 12.5.+-.0.2 and 20.1.+-.0.2; or
5.7.+-.0.2; 12.5.+-.0.2 and 20.3.+-.0.2; or 5.7.+-.0.2; 12.7.+-.0.2
and 13.0.+-.0.2; or 5.7.+-.0.2; 12.7.+-.0.2 and 20.3.+-.0.2; or
5.7.+-.0.2, 13.0.+-.0.2 and 20.3.+-.0.2; or 5.7.+-.0.2, 16.8.+-.0.2
and 20.1.+-.0.2; or 5.7.+-.0.2; 20.1.+-.0.2 and 20.3.+-.0.2; or
12.5.+-.0.2, 13.0.+-.0.2 and 20.3.+-.0.2; or 12.7.+-.0.2,
13.0.+-.0.2 and 20.3.+-.0.2; or 16.8.+-.0.2, 20.1.+-.0.2 and
20.3.+-.0.2 degrees two-theta.
[0197] In some embodiments, the Compound 1 Citrate (Form A)
exhibits an XRPD that is substantially similar to FIG. 15.
[0198] In some embodiments, the Compound 1 Citrate (Form A)
exhibits a DSC thermogram comprising a endotherm at about
89.0.degree. C. with the error of margin of about .+-.2.5; about
.+-.2.0; about .+-.1.5; about .+-.1.0; about .+-.0.5; or less. In
another embodiment, the Compound 1 Citrate (Form A) exhibits a DSC
thermogram comprising a sharp endotherm at about 139.5.degree. C.
with the error of margin of about .+-.2.5; about .+-.2.0; about
.+-.1.5; about .+-.1.0; about .+-.0.5; or less. In some
embodiments, the Compound 1 Citrate (Form A) exhibits a DSC
thermogram that is substantially similar to FIG. 16.
[0199] In some embodiments, the Compound 1 Citrate (Form A)
exhibits a TGA thermogram that is substantially similar to FIG. 16.
In other embodiments, the TGA thermogram of the Compound 1 Citrate
(Form A) exhibits a weight loss of 0.0 to 2.6% in the temperature
range of 25 to 65.degree. C.
[0200] In some embodiments, the Compound 1 Citrate (Form A)
exhibits a DVS isotherm plot that is substantially similar to FIG.
17. In other embodiments, the Compound 1-citrate (Form A) exhibits
a gravimetric moisture sorption of about 3.6% (by weight) at 80%
Relative Humidity.
[0201] In some embodiments, the Compound 1 Citrate (Form A) is
defined by unit cell parameters substantially similar to the
following: a=8.9 (10) .ANG.; b=12.2 (10) .ANG.; c=16.5 (10) .ANG.;
.alpha.=73.7 (10.degree.); .beta.=76.6 (10.degree.); .gamma.=83.2
(10.degree.); Space group P1; Molecules/asymmetric unit 2, wherein
the crystalline form is at about 120.00 K.
[0202] In one embodiment, the present disclosure provides Compound
1 Citrate (Form B). In some embodiments, the Compound 1 Citrate
(Form B) exhibits an XRPD comprising one or more peaks at about
5.5, 5.7, 10.9, 16.3 and 20.5 degrees two-theta with the margin of
error of about .+-.0.5; about .+-.0.4; about .+-.0.3; about
.+-.0.2; about .+-.0.1; about .+-.0.05; or less. In another
embodiment, the XRPD of the Compound 1 Citrate (Form B) further
comprises one or more peaks at about 3.4, 11.8, 14.6, 17.2 and 21.1
degrees two-theta with the margin of error of about .+-.0.5; about
.+-.0.4; about .+-.0.3; about .+-.0.2; about .+-.0.1; about
.+-.0.05; or less. In yet another embodiment, the Compound 1
Citrate (Form B) exhibits an XRPD comprising peaks shown in Table 7
below:
TABLE-US-00007 TABLE 7 XRPD Table of Compound 1 Citrate (Form B)
2-Theta Intensity % 3.4 4.8 5.5 58.1 5.7 42.3 10.9 32.1 11.4 4.3
11.8 8.9 13.6 4.5 14.6 9.7 14.8 3.1 16.0 2.4 16.3 100 17.2 13.3
20.5 29.8 21.1 7.5 25.6 3.2 25.9 4 27.3 4.4 30.9 1.6
[0203] In some embodiments, the Compound 1 Citrate (Form B)
exhibits an XRPD that is substantially similar to FIG. 18.
[0204] In some embodiments, the Compound 1 Citrate (Form B)
exhibits a DSC thermogram comprising an endotherm at about
77.7.degree. C. with the error of margin of about .+-.2.5; about
.+-.2.0; about .+-.1.5; about .+-.1.0; about .+-.0.5; or less. In
some embodiments, the Compound 1 Citrate (Form B) exhibits a DSC
thermogram comprising an endotherm at about 121.5.degree. C. with
the error of margin of about .+-.2.5; about .+-.2.0; about .+-.1.5;
about .+-.1.0; about .+-.0.5; or less. In some embodiments, the
Compound 1 Citrate (Form B) exhibits a DSC thermogram comprising an
endotherm at about 136.6.degree. C. with the error of margin of
about .+-.2.5; about .+-.2.0; about .+-.1.5; about .+-.1.0; about
.+-.0.5; or less. In some embodiments, the Compound 1 Citrate (Form
B) exhibits a DSC thermogram that is substantially similar to FIG.
19.
[0205] In some embodiments, the Compound 1 Citrate (Form B)
exhibits a TGA thermogram that is substantially similar to FIG. 19.
In other embodiments, the TGA thermogram of the Compound 1 Citrate
(Form B) exhibits a weight loss of about 0.0 to 4.5% in the
temperature range of 25 to 120.degree. C.
[0206] In some embodiments, the Compound 1 Citrate (Form B)
exhibits a DVS isotherm plot that is substantially similar to FIG.
20. In other embodiments, the Compound 1 Citrate (Form B) exhibits
a gravimetric moisture sorption of about 2.8% (by weight) at 80%
Relative Humidity.
[0207] In one embodiment, the present disclosure provides Compound
1 Citrate (Form C). In some embodiments, the Compound 1 Citrate
(Form C) exhibits an XRPD comprising one or more peaks at about
15.4, 18.7, 19.7, 20.6 and 27.1 degrees two-theta with the margin
of error of about .+-.0.5; about .+-.0.4; about .+-.0.3; about
.+-.0.2; about .+-.0.1; about .+-.0.05; or less. In another
embodiment, the XRPD of the Compound 1 Citrate (Form C) further
comprises one or more peaks at about 13.5, 15.5, 16.2, 17.0 and
22.1 degrees two-theta with the margin of error of about .+-.0.5;
about .+-.0.4; about .+-.0.3; about .+-.0.2; about .+-.0.1; about
.+-.0.05; or less. In yet another embodiment, the Compound 1
Citrate (Form C) exhibits an XRPD comprising peaks shown in Table 8
below.
TABLE-US-00008 TABLE 8 XRPD Table of Compound 1 Citrate (Form C)
2-Theta Intensity % 5.1 23.1 5.6 7.8 8.2 6.5 10.3 16.4 11.3 9.3
11.9 9.8 13.5 46.3 14.5 21.6 15.0 40.2 15.4 82.4 15.5 66.9 16.2
49.5 17.0 49.5 17.8 42.7 18.7 78.7 19.7 74.8 20.6 100.0 22.1 60.4
23.4 28.7 24.1 11.8 24.7 16.6 25.8 25.3 26.6 23.8 27.1 83.0 27.7
11.5 28.4 21.5 29.6 5.9 30.2 13.4 31.3 7.0 31.7 10.3 32.2 9.7 32.8
7.1 33.7 4.0 34.2 8.2 34.8 8.5 35.6 6.2 36.6 9.3 37.0 7.5 37.4 8.8
38.4 7.9 39.2 8.8
[0208] In some embodiments, the Compound 1 Citrate (Form C)
exhibits an XRPD that is substantially similar to FIG. 21.
Mesylate Salt
[0209] In some embodiments, the present disclosure provides a
mesylate salt of Compound 1 ("Compound 1 Mesylate"). In some
embodiments, the present disclosure provides a crystalline form of
Compound 1 Mesylate.
[0210] In one embodiment, the present disclosure provides Compound
1 Mesylate (Form A). In some embodiments, the Compound 1 Mesylate
(Form A) exhibits an XRPD comprising one or more peaks at about
3.6, 7.1, 14.2, 19.1 and 25.9 degrees two-theta with the margin of
error of about .+-.0.5; about .+-.0.4; about .+-.0.3; about
.+-.0.2; about .+-.0.1; about .+-.0.05; or less. In another
embodiment, the XRPD of the Compound 1 Mesylate (Form A) further
comprises one or more peaks at about 7.7, 12.7, 17.8, 19.4, and
21.4 degrees two-theta with the margin of error of about .+-.0.5;
about .+-.0.4; about .+-.0.3; about .+-.0.2; about .+-.0.1; about
.+-.0.05; or less. In yet another embodiment, the Compound 1
Mesylate (Form A) exhibits an XRPD comprising peaks shown in Table
9 below:
TABLE-US-00009 TABLE 9 XRPD Table of Compound 1 Mesylate (Form A)
2-Theta Intensity % 3.6 14.5 7.1 100 7.7 9.4 12.0 3.7 12.7 8.7 13.4
3.3 14.2 24.3 17.5 2.8 17.8 7.4 19.1 35.4 19.4 10.1 21.4 8.1 23.6
2.2 25.4 4.2 25.9 10.3
[0211] In some embodiments, the Compound 1 Mesylate (Form A)
exhibits an XRPD that is substantially similar to FIG. 22.
[0212] In some embodiments, the Compound 1 Mesylate (Form A)
exhibits a DSC thermogram comprising an endotherm at about
170.9.degree. C. with the error of margin of about .+-.2.5; about
.+-.2.0; about .+-.1.5; about .+-.1.0; about .+-.0.5; or less. In
some embodiments, the Compound 1 Mesylate (Form A) exhibits a DSC
thermogram comprising a sharp endotherm at about 209.7.degree. C.
with the error of margin of about .+-.2.5; about .+-.2.0; about
.+-.1.5; about .+-.1.0; about .+-.0.5; or less. In some
embodiments, the Compound 1 Mesylate (Form A) exhibits a DSC
thermogram that is substantially similar to FIG. 23.
[0213] In some embodiments, the Compound 1 Mesylate (Form A)
exhibits a TGA thermogram that is substantially similar to FIG. 23.
In other embodiments, the TGA thermogram of the Compound 1 Mesylate
(Form A) exhibits a weight loss of 0.0 to 0.5% in the temperature
range of 25 to 150.degree. C.
[0214] In some embodiments, the Compound 1 Mesylate (Form A)
exhibits a DVS isotherm plot that is substantially similar to FIG.
24. In other embodiments, the Compound 1 Mesylate (Form A) exhibits
a gravimetric moisture sorption of about 3.4% (by weight) at 80%
Relative Humidity.
[0215] In one embodiment, the present disclosure provides Compound
1 Mesylate (Form B). In some embodiments, the Compound 1 Mesylate
(Form B) exhibits an XRPD comprising one or more peaks at about
7.1, 14.3, 15.9, 21.4, and 22.6 degrees two-theta with the margin
of error of about .+-.0.5; about .+-.0.4; about .+-.0.3; about
.+-.0.2; about .+-.0.1; about .+-.0.05; or less. In another
embodiment, the Compound 1 Mesylate (Form B) exhibits an XRPD
comprising peaks shown in Table 10A below:
TABLE-US-00010 TABLE 10A XRPD Table of Compound 1 Mesylate (Form B)
2-Theta Intensity % 7.1 100 14.3 25.8 15.9 11.3 19.0 3.5 21.4 9.1
22.6 6.1
[0216] In some embodiments, the Compound 1 Mesylate (Form B)
exhibits an XRPD that is substantially similar to FIG. 25A.
[0217] In some embodiments, the present disclosure provides
Compound 1 Mesylate (Form C). In some embodiments, the Compound 1
Mesylate (Form C) exhibits an XRPD comprising one or more peaks at
about 7.5, 15.0, 19.4, 22.5, and 30.2 degrees two-theta with the
margin of error of about .+-.0.5; about .+-.0.4; about .+-.0.3;
about .+-.0.2; about .+-.0.1; about .+-.0.05; or less. In yet
another embodiment, the Compound 1 Mesylate (Form C) exhibits an
XRPD comprising peaks shown in Table 10B below:
TABLE-US-00011 TABLE 10B XRPD Table of Compound 1 Mesylate (Form C)
2-Theta Intensity % 7.5 100 15.0 33.1 19.4 3.1 22.5 13.3 30.2 3
[0218] In some embodiments, the Compound 1 Mesylate (Form C)
exhibits an XRPD that is substantially similar to FIG. 25B.
[0219] In one embodiment, the present disclosure provides Compound
1 Mesylate (Form D). In some embodiments, the Compound 1 Mesylate
(Form D) exhibits an XRPD comprising one or more peaks at about
7.4, 15.0, and 22.6 degrees two-theta with the margin of error of
about .+-.0.5; about .+-.0.4; about .+-.0.3; about .+-.0.2; about
.+-.0.1; about .+-.0.05; or less. In yet another embodiment, the
Compound 1 Mesylate (Form D) exhibits an XRPD comprising peaks
shown in Table 11 below:
TABLE-US-00012 TABLE 11 XRPD Table of Compound 1 Mesylate (Form D)
2-Theta Intensity % 7.4 100 15.0 21.1 22.6 10
[0220] In some embodiments, the Compound 1 Mesylate (Form D)
exhibits an XRPD that is substantially similar to FIG. 26.
Phosphate Salt
[0221] In some embodiments, the present disclosure provides a
phosphate salt of Compound 1 ("Compound 1 Phosphate"). In some
embodiments, the present disclosure provides a crystalline form of
Compound 1 Phosphate.
[0222] In one embodiment, the present disclosure provides Compound
1 Phosphate (Form A). In some embodiments, the Compound 1 Phosphate
(Form A) exhibits an XRPD comprising one or more peaks at about
3.3, 3.6, 5.4, 9.9, and 13.1 degrees two-theta with the margin of
error of about .+-.0.5; about .+-.0.4; about .+-.0.3; about
.+-.0.2; about .+-.0.1; about .+-.0.05; or less. In another
embodiment, the XRPD of the Compound 1 Phosphate (Form A) further
comprises one or more peaks at about 16.1, 17.9, 20.9, 23.7, and
26.4 degrees two-theta with the margin of error of about .+-.0.5;
about .+-.0.4; about .+-.0.3; about .+-.0.2; about .+-.0.1; about
.+-.0.05; or less. In yet another embodiment, the Compound 1
Phosphate (Form A) exhibits an XRPD comprising peaks shown in Table
12 below:
TABLE-US-00013 TABLE 12 XRPD Table of Compound 1 Phosphate (Form A)
2-Theta Intensity % 3.3 100 3.6 7.8 5.4 7.2 6.6 1.9 9.9 14.2 13.1
12.7 15.7 1.8 16.1 5.4 16.4 1.7 17.9 3.8 19.0 1.4 20.4 1.9 20.9 2.6
23.7 2.9 26.4 2.3 26.5 1.1 29.6 1.1 31.0 1.3
[0223] In some embodiments, the Compound 1 Phosphate (Form A)
exhibits an XRPD that is substantially similar to FIG. 27.
[0224] In some embodiments, the Compound 1 Phosphate (Form A)
exhibits a DSC thermogram comprising a sharp endotherm at about
217.6.degree. C. with the error of margin of about .+-.2.5; about
.+-.2.0; about .+-.1.5; about .+-.1.0; about .+-.0.5; or less. In
some embodiments, the Compound 1 Phosphate (Form A) exhibits a DSC
thermogram that is substantially similar to FIG. 28.
[0225] In some embodiments, the Compound 1 Phosphate (Form A)
exhibits a TGA thermogram that is substantially similar to FIG. 28.
In other embodiments, the TGA thermogram of the Compound 1
Phosphate (Form A) exhibits a weight loss of 0.0 to 1.7% in the
temperature range of 25 to 204.degree. C.
[0226] In some embodiments, the Compound 1 Phosphate (Form A)
exhibits a DVS isotherm plot that is substantially similar to FIG.
29. In other embodiments, the Compound 1 Phosphate (Form A)
exhibits a gravimetric moisture sorption of about 2.1% (by weight)
at 80% Relative Humidity.
Tartrate Salt
[0227] In some embodiments, the present disclosure provides a
tartrate salt of Compound 1 ("Compound 1 Tartrate"). In some
embodiments, the present disclosure provides a D(-)-tartrate salt
of Compound 1 ("Compound 1 D(-)-Tartrate"). In some embodiments,
the present disclosure provides an L(+)-tartrate salt of Compound 1
("Compound 1 L(+)-Tartrate").
[0228] In some embodiments, the present disclosure provides a
crystalline form of Compound 1 Tartrate. In some embodiments, the
present disclosure provides a crystalline form of Compound 1
D(-)-Tartrate. In some embodiments, the present disclosure provides
a crystalline form of Compound 1 L(+)-Tartrate.
[0229] In one embodiment, the present disclosure provides Compound
1 L(+)-Tartrate (Form A). In some embodiments, the Compound 1
L(+)-Tartrate (Form A) exhibits an XRPD comprising one or more
peaks at about 3.6, 4.7, 13.9, 18.6, and 22.8 degrees two-theta
with the margin of error of about .+-.0.5; about .+-.0.4; about
.+-.0.3; about .+-.0.2; about .+-.0.1; about .+-.0.05; or less. In
another embodiment, the XRPD of the Compound 1 L(+)-Tartrate (Form
A) further comprises one or more peaks at about 14.6, 17.8 and 18.1
degrees two-theta with the margin of error of about .+-.0.5; about
.+-.0.4; about .+-.0.3; about .+-.0.2; about .+-.0.1; about
.+-.0.05; or less. In yet another embodiment, the Compound 1
L(+)-Tartrate (Form A) exhibits an XRPD comprising peaks shown in
Table 13 below:
TABLE-US-00014 TABLE 13 XRPD Table of Compound 1 L(+)-Tartrate
(Form A) 2-Theta Intensity % 3.6 13.6 4.7 100 13.9 82.1 14.6 5.1
17.8 7.6 18.1 3.1 18.6 13 22.8 50.7
[0230] In some embodiments, the Compound 1 L(+)-Tartrate (Form A)
exhibits an XRPD that is substantially similar to FIG. 30.
[0231] In some embodiments, the Compound 1 L(+)-Tartrate (Form A)
exhibits a DSC thermogram comprising a sharp endotherm at about
207.6.degree. C. with the error of margin of about .+-.2.5; about
.+-.2.0; about .+-.1.5; about .+-.1.0; about .+-.0.5; or less. In
some embodiments, the Compound 1 L(+)-Tartrate (Form A) exhibits a
DSC thermogram that is substantially similar to FIG. 31.
[0232] In some embodiments, the Compound 1 L(+)-Tartrate (Form A)
exhibits a TGA thermogram that is substantially similar to FIG. 31.
In other embodiments, the TGA thermogram of the Compound 1
L(+)-Tartrate (Form A) exhibits a weight loss of 0.0 to 1.2% in the
temperature range of 25 to 189.degree. C.
[0233] In some embodiments, the Compound 1 L(+)-Tartrate (Form A)
exhibits a DVS isotherm plot that is substantially similar to FIG.
32. In other embodiments, the Compound 1 L(+)-Tartrate (Form A)
exhibits a gravimetric moisture sorption of about 1.6% (by weight)
at 80% Relative Humidity.
[0234] In one embodiment, the present disclosure provides Compound
1 L(+)-Tartrate (Form B). In some embodiments, the Compound 1
L(+)-Tartrate (Form B) exhibits an XRPD comprising one or more
peaks at about 3.6, 4.6, 12.4, 13.9, and 22.7 degrees two-theta
with the margin of error of about .+-.0.5; about .+-.0.4; about
.+-.0.3; about .+-.0.2; about .+-.0.1; about .+-.0.05; or less. In
another embodiment, the XRPD of the Compound 1 L(+)-Tartrate (Form
B) further comprises one or more peaks at about 14.8, 18.3 and 18.5
degrees two-theta with the margin of error of about .+-.0.5; about
.+-.0.4; about .+-.0.3; about .+-.0.2; about .+-.0.1; about
.+-.0.05; or less. In yet another embodiment, the Compound 1
L(+)-Tartrate (Form B) exhibits an XRPD comprising peaks shown in
Table 14 below:
TABLE-US-00015 TABLE 14 XRPD Table of Compound 1 L(+)-Tartrate
(Form B) 2-Theta Intensity % 3.6 65 4.6 100 12.4 22 13.9 50.8 14.8
17.1 18.3 16.9 18.5 20.9 22.7 54.9
[0235] In some embodiments, the Compound 1 L(+)-Tartrate (Form B)
exhibits an XRPD that is substantially similar to FIG. 33.
[0236] In some embodiments, the Compound 1 L(+)-Tartrate (Form B)
exhibits a DSC thermogram comprising a sharp endotherm at about
207.3.degree. C. with the error of margin of about .+-.2.5; about
.+-.2.0; about .+-.1.5; about .+-.1.0; about .+-.0.5; or less. In
some embodiments, the Compound 1 L(+)-Tartrate (Form B) exhibits a
DSC thermogram that is substantially similar to FIG. 34.
[0237] In some embodiments, the Compound 1 L(+)-Tartrate (Form B)
exhibits a TGA thermogram that is substantially similar to FIG. 34.
In other embodiments, the TGA thermogram of the Compound 1
L(+)-Tartrate (Form B) exhibits a weight loss of 0.0 to 0.6% in the
temperature range of 25 to 180.degree. C.
[0238] In some embodiments, the Compound 1 L(+)-Tartrate (Form B)
exhibits a DVS isotherm plot that is substantially similar to FIG.
35. In other embodiments, the Compound 1 L(+)-Tartrate (Form B)
exhibits a gravimetric moisture sorption of about 1.7% (by weight)
at 80% Relative Humidity.
Fumarate Salt
[0239] In some embodiments, the present disclosure provides a
fumarate salt of Compound 1 ("Compound 1 Fumarate"). In some
embodiments, the present disclosure provides a crystalline form of
Compound 1 Fumarate.
[0240] In one embodiment, the present disclosure provides Compound
1 Fumarate (Form A). In some embodiments, the Compound 1 Fumarate
(Form A) exhibits an XRPD comprising one or more peaks at about 3.5
and 16.0 degrees two-theta with the margin of error of about
.+-.0.5; about .+-.0.4; about .+-.0.3; about .+-.0.2; about
.+-.0.1; about .+-.0.05; or less. In yet another embodiment, the
Compound 1 Fumarate (Form A) exhibits an XRPD comprising peaks
shown in Table 15 below:
TABLE-US-00016 TABLE 15 XRPD Table of Compound 1 Fumarate (Form A)
2-Theta Intensity % 3.5 100 16.0 13.4
[0241] In some embodiments, the Compound 1 Fumarate (Form A)
exhibits an XRPD that is substantially similar to FIG. 36.
[0242] In some embodiments, the Compound 1 Fumarate (Form A)
exhibits a DSC thermogram comprising a sharp endotherm at about
87.0.degree. C. with the error of margin of about .+-.2.5; about
.+-.2.0; about .+-.1.5; about .+-.1.0; about .+-.0.5; or less. In
some embodiments, the Compound 1 Fumarate (Form A) exhibits a DSC
thermogram that is substantially similar to FIG. 37.
[0243] In some embodiments, the Compound 1 Fumarate (Form A)
exhibits a TGA thermogram that is substantially similar to FIG. 37.
In other embodiments, the TGA thermogram of the Compound 1 Fumarate
(Form A) exhibits a weight loss of 0.0 to 0.9% in the temperature
range of 25 to 75.degree. C.
[0244] In some embodiments, the present disclosure provides
Compound 1 Fumarate (Form B). In some embodiments, the Compound 1
Fumarate (Form B) exhibits an XRPD comprising one or more peaks at
about 3.6, 11.0, 16.2, and 17.5 degrees two-theta with the margin
of error of about .+-.0.5; about .+-.0.4; about .+-.0.3; about
.+-.0.2; about .+-.0.1; about .+-.0.05; or less. In yet another
embodiment, the Compound 1 Fumarate (Form B) exhibits an XRPD
comprising peaks shown in Table 16 below:
TABLE-US-00017 TABLE 16 XRPD Table of Compound 1 Fumarate (Form B)
2-Theta Intensity % 3.6 100 11.0 12.8 16.2 23.4 17.5 13.1
[0245] In some embodiments, the Compound 1 Fumarate (Form B)
exhibits an XRPD that is substantially similar to FIG. 38.
[0246] In some embodiments, the Compound 1 Fumarate (Form B)
exhibits a DSC thermogram comprising a sharp endotherm at about
89.9.degree. C. with the error of margin of about .+-.2.5; about
.+-.2.0; about .+-.1.5; about .+-.1.0; about .+-.0.5; or less. In
some embodiments, the Compound 1 Fumarate (Form B) exhibits a DSC
thermogram that is substantially similar to FIG. 39.
[0247] In some embodiments, the Compound 1 Fumarate (Form B)
exhibits a TGA thermogram that is substantially similar to FIG. 39.
In other embodiments, the TGA thermogram of the Compound 1 Fumarate
(Form B) exhibits a weight loss of 0.0 to 1.85% in the temperature
range of 25 to 150.degree. C.
[0248] In some embodiments, the Compound 1 Fumarate (Form B)
exhibits a DVS isotherm plot that is substantially similar to FIG.
40. In other embodiments, the Compound 1 Fumarate (Form B) exhibits
a gravimetric moisture sorption of about 7.2% (by weight) at 80%
Relative Humidity.
[0249] In one embodiment, the present disclosure provides Compound
1 Fumarate (Form C). In some embodiments, the Compound 1 Fumarate
(Form C) exhibits an XRPD comprising one or more peaks at about
14.5, 15.4, 16.7, 17.6, and 28.8 degrees two-theta with the margin
of error of about .+-.0.5; about .+-.0.4; about .+-.0.3; about
.+-.0.2; about .+-.0.1; about .+-.0.05; or less. In another
embodiment, the XRPD of the Compound 1 Fumarate (Form C) further
comprises one or more peaks at about 8.4, 19.7, 20.5, 22.9, and
38.1 degrees two-theta with the margin of error of about .+-.0.5;
about .+-.0.4; about .+-.0.3; about .+-.0.2; about .+-.0.1; about
.+-.0.05; or less. In yet another embodiment, the Compound 1
Fumarate (Form C) exhibits an XRPD comprising peaks shown in Table
17 below:
TABLE-US-00018 TABLE 17 XRPD Table of Compound 1 Fumarate (Form C)
2-Theta Intensity % 8.4 26.2 9.8 8.9 12.9 10.2 14.5 46.3 15.4 100
16.7 36.6 17.6 44.4 19.7 21.7 20.5 27.9 21.5 12.6 22.9 20.6 23.3
8.2 25.2 15.8 25.7 12.1 27.4 14.5 28.8 41.6 38.1 28.8
[0250] In some embodiments, the Compound 1 Fumarate (Form C)
exhibits an XRPD that is substantially similar to FIG. 41.
[0251] In one embodiment, the present disclosure provides Compound
1 Fumarate (Form D). In some embodiments, the Compound 1 Fumarate
(Form D) exhibits an XRPD comprising one or more peaks at about
5.2, 12.2, 15.2, 15.5, and 19.9 degrees two-theta with the margin
of error of about .+-.0.5; about .+-.0.4; about .+-.0.3; about
.+-.0.2; about .+-.0.1; about .+-.0.05; or less. In another
embodiment, the XRPD of the Compound 1 Fumarate (Form D) further
comprises one or more peaks at about 10.4, 13.6, 14.2, 21.2, and
22.3 degrees two-theta with the margin of error of about .+-.0.5;
about .+-.0.4; about .+-.0.3; about .+-.0.2; about .+-.0.1; about
.+-.0.05; or less. In yet another embodiment, the Compound 1
Fumarate (Form D) exhibits an XRPD comprising peaks shown in Table
18 below:
TABLE-US-00019 TABLE 18 XRPD Table of Compound 1 Fumarate (Form D)
2-Theta Intensity % 5.2 29.5 10.4 23.5 12.2 100 13.6 27.9 14.2 28.8
15.2 42 15.5 40 16.5 19.6 16.9 13.5 17.2 9.6 19.1 11 19.9 40.9 20.5
19.2 21.2 27.9 22.3 21.2 22.9 17.1 23.5 17.4 24.0 21.2 24.6 13.5
26.2 18.5 26.9 14.4 28.9 15.1
[0252] In some embodiments, the Compound 1 Fumarate (Form D)
exhibits an XRPD that is substantially similar to FIG. 42.
Tosylate Salt
[0253] In some embodiments, the present disclosure provides a
tosylate salt of Compound 1 ("Compound 1 Tosylate"). In some
embodiments, the present disclosure provides a crystalline form of
Compound 1 Tosylate.
[0254] In one embodiment, the present disclosure provides Compound
1 Tosylate (Form A). In some embodiments, the Compound 1 Tosylate
(Form A) exhibits an XRPD comprising one or more peaks at about
3.4, 9.8, 10.3, 12.5, and 15.3 degrees two-theta with the margin of
error of about .+-.0.5; about .+-.0.4; about .+-.0.3; about
.+-.0.2; about .+-.0.1; about .+-.0.05; or less. In another
embodiment, the XRPD of the Compound 1 Tosylate (Form A) further
comprises one or more peaks at about 17.4, 17.9, 19.6, 23.2 and
26.0 degrees two-theta with the margin of error of about .+-.0.5;
about .+-.0.4; about .+-.0.3; about .+-.0.2; about .+-.0.1; about
.+-.0.05; or less.
[0255] In yet another embodiment, the Compound 1 Tosylate (Form A)
exhibits an XRPD comprising peaks shown in Table 19 below:
TABLE-US-00020 TABLE 19 XRPD Table of Compound 1 Tosylate (Form A)
2-Theta Intensity % 3.4 100 9.8 3.1 10.3 3 12.5 7 15.3 6.3 15.8 1.1
16.5 0.9 16.9 1.1 17.4 2.2 17.9 1.8 19.0 1.4 19.6 2.6 20.7 1.3 21.4
1.5 23.2 1.7 23.6 1.1 26.0 1.9 27.2 1.1 27.5 1.3 28.7 1 29.6 0.7
30.7 0.9
[0256] In some embodiments, the Compound 1 Tosylate (Form A)
exhibits an XRPD that is substantially similar to FIG. 43.
[0257] In some embodiments, the Compound 1 Tosylate (Form A)
exhibits a DSC thermogram comprising a sharp endotherm at about
186.2.degree. C. with the error of margin of about .+-.2.5; about
.+-.2.0; about .+-.1.5; about .+-.1.0; about .+-.0.5; or less. In
some embodiments, the Compound 1 Tosylate (Form A) exhibits a DSC
thermogram that is substantially similar to FIG. 44.
[0258] In some embodiments, the Compound 1 Tosylate (Form A)
exhibits a TGA thermogram that is substantially similar to FIG. 44.
In other embodiments, the TGA thermogram of the Compound 1 Tosylate
(Form A) exhibits a weight loss of 0.0 to 0.9% in the temperature
range of 25 to 175.degree. C.
[0259] In some embodiments, the Compound 1 Tosylate (Form A)
exhibits a DVS isotherm plot that is substantially similar to FIG.
45. In other embodiments, the Compound 1 Tosylate (Form A) exhibits
a gravimetric moisture sorption of about 1.5% (by weight) at 80%
Relative Humidity.
[0260] In one embodiment, the present disclosure provides Compound
1 Tosylate (Form B). In some embodiments, the Compound 1 Tosylate
(Form B) exhibits an XRPD comprising one or more peaks at about
10.0, 15.2, 15.5, 17.2, and 19.4 degrees two-theta with the margin
of error of about .+-.0.5; about .+-.0.4; about .+-.0.3; about
.+-.0.2; about .+-.0.1; about .+-.0.05; or less. In another
embodiment, the XRPD of the Compound 1 Tosylate (Form B) further
comprises one or more peaks at about 10.3, 16.7, 19.1, 20.1 and
20.8 degrees two-theta with the margin of error of about .+-.0.5;
about .+-.0.4; about .+-.0.3; about .+-.0.2; about .+-.0.1; about
.+-.0.05; or less.
[0261] In yet another embodiment, the Compound 1 Tosylate (Form B)
exhibits an XRPD comprising peaks shown in Table 20 below:
TABLE-US-00021 TABLE 20 XRPD Table of Compound 1 Tosylate (Form B)
2-Theta Intensity % 6.8 16.7 9.1 24.4 10.0 100 10.3 39.9 11.0 12.8
11.9 23.8 12.2 25.9 13.0 15.5 13.5 19.3 15.2 58.3 15.5 65.5 16.2
27.1 16.7 35.1 17.2 47.9 18.5 23.2 19.1 29.2 19.4 41.7 19.8 28.0
20.1 32.1 20.8 40.2 21.7 25.6 22.2 25.3 23.2 21.7 24.4 20.5 25.6
26.8 26.2 26.8 27.2 18.5 28.4 17.9 29.0 12.8
[0262] In some embodiments, the Compound 1 Tosylate (Form B)
exhibits an XRPD that is substantially similar to FIG. 46.
[0263] In one embodiment, the present disclosure provides Compound
1 Tosylate (Form C). In some embodiments, the Compound 1 Tosylate
(Form C) exhibits an XRPD comprising one or more peaks at about
7.4, 10.2, 12.5, 18.3, and 19.7 degrees two-theta with the margin
of error of about .+-.0.5; about .+-.0.4; about .+-.0.3; about
.+-.0.2; about .+-.0.1; about .+-.0.05; or less. In another
embodiment, the XRPD of the Compound 1 Tosylate (Form C) further
comprises one or more peaks at about 9.8, 14.7, 16.6, 17.8, and
23.2 degrees two-theta with the margin of error of about .+-.0.5;
about .+-.0.4; about .+-.0.3; about .+-.0.2; about .+-.0.1; about
.+-.0.05; or less.
[0264] In yet another embodiment, the Compound 1 Tosylate (Form C)
exhibits an XRPD comprising peaks shown in Table 21 below:
TABLE-US-00022 TABLE 21 XRPD Table of Compound 1 Tosylate (Form C)
2-Theta Intensity % 7.4 70 9.8 28.2 10.2 46.9 10.8 16.4 11.4 21.8
12.5 100 13.1 15.6 13.8 17.1 14.7 34.2 15.3 16.7 16.6 40.2 16.9 16
17.4 16.2 17.8 41.6 18.3 65.1 19.7 85.6 20.3 8 20.7 14.2 21.1 18.9
21.4 16 22.2 26.7 22.8 9.3 23.2 46.4 23.6 14.9 24.2 11.8 24.7 16.9
25.9 21.6 27.2 11.3 27.5 20.9 28.6 17.8 30.5 16.2 30.8 13.8 31.2
12.4 37.8 11.1
[0265] In some embodiments, the Compound 1 Tosylate (Form C)
exhibits an XRPD that is substantially similar to FIG. 47.
Glucuronate Salt
[0266] In some embodiments, the present disclosure provides a
glucuronate salt of Compound 1 ("Compound 1 Glucuronate"). In some
embodiments, the present disclosure provides a D-glucuronate salt
of Compound 1 ("Compound 1 D-Glucuronate"). In some embodiments,
the present disclosure provides L-glucuronate salt of Compound 1
("Compound 1 L-Glucuronate").
[0267] In some embodiments, the present disclosure provides a
crystalline form of Compound 1 Glucuronate. In some embodiments,
the present disclosure provides a crystalline form of Compound 1
D-Glucuronate. In some embodiments, the present disclosure provides
a crystalline form of Compound 1 L-Glucuronate.
[0268] In one embodiment, the present disclosure provides Compound
1 D-Glucuronate (Form A). In some embodiments, the Compound 1
D-Glucuronate (Form A) exhibits an XRPD comprising one or more
peaks at about 4.3, 12.9, 16.8, 20.2 and 20.9 degrees two-theta
with the margin of error of about .+-.0.5; about .+-.0.4; about
.+-.0.3; about .+-.0.2; about .+-.0.1; about .+-.0.05; or less. In
another embodiment, the XRPD of the Compound 1 D-Glucuronate (Form
A) further comprises one or more peaks at about 3.3, 14.7, 17.3,
21.6, and 24.8 degrees two-theta with the margin of error of about
.+-.0.5; about .+-.0.4; about .+-.0.3; about .+-.0.2; about
.+-.0.1; about .+-.0.05; or less.
[0269] In yet another embodiment, the Compound 1 D-Glucuronate
(Form A) exhibits an XRPD comprising peaks shown in Table 22
below:
TABLE-US-00023 TABLE 22 XRPD Table of Compound 1 D-Glucuronate
(Form A) 2-Theta Intensity % 3.3 30.3 4.3 100 11.6 8.8 12.9 51.1
13.8 11.1 14.7 24.3 15.0 8.3 15.4 18.7 16.8 62.1 17.3 38.5 20.2
49.3 20.9 99.8 21.6 20.9 22.4 8 24.2 20 24.8 20.5 25.7 5.7 28.2 9.1
28.8 5.7 30.8 9.1 32.5 11.3
[0270] In some embodiments, the Compound 1 D-Glucuronate (Form A)
exhibits an XRPD that is substantially similar to FIG. 48.
[0271] In some embodiments, the Compound 1 D-Glucuronate (Form A)
exhibits a DSC thermogram comprising a endotherm at about
116.2.degree. C. with the error of margin of about .+-.2.5; about
.+-.2.0; about .+-.1.5; about .+-.1.0; about .+-.0.5; or less. In
another embodiment, the Compound 1 D-Glucuronate (Form A) exhibits
a DSC thermogram comprising a endotherm at about 139.3.degree. C.
with the error of margin of about .+-.2.5; about .+-.2.0; about
.+-.1.5; about .+-.1.0; about .+-.0.5; or less. In some
embodiments, the Compound 1 D-Glucuronate (Form A) exhibits a DSC
thermogram that is substantially similar to FIG. 49.
[0272] In some embodiments, the Compound 1 D-Glucuronate (Form A)
exhibits a TGA thermogram that is substantially similar to FIG. 49.
In other embodiments, the TGA thermogram of the Compound 1
D-Glucuronate (Form A) exhibits a weight loss of 0.0 to 3.0% in the
temperature range of 25 to 120.degree. C.
[0273] In some embodiments, the Compound 1 D-Glucuronate (Form A)
exhibits a DVS isotherm plot that is substantially similar to FIG.
50. In other embodiments, the Compound 1 D-Glucuronate (Form A)
exhibits a gravimetric moisture sorption of about 1.4% (by weight)
at 80% Relative Humidity.
[0274] In one embodiment, the present disclosure provides Compound
1 D-Glucuronate (Form B). In some embodiments, the Compound 1
D-Glucuronate (Form B) exhibits an XRPD comprising one or more
peaks at about 14.7, 16.7, 17.0, 20.0 and 20.4 degrees two-theta
with the margin of error of about .+-.0.5; about .+-.0.4; about
.+-.0.3; about .+-.0.2; about .+-.0.1; about .+-.0.05; or less. In
another embodiment, the XRPD of the Compound 1 D-Glucuronate (Form
B) further comprises one or more peaks at about 8.5, 15.0, 19.5,
22.5 and 24.3 degrees two-theta with the margin of error of about
.+-.0.5; about .+-.0.4; about .+-.0.3; about .+-.0.2; about
.+-.0.1; about .+-.0.05; or less.
[0275] In yet another embodiment, the Compound 1 D-Glucuronate
(Form B) exhibits an XRPD comprising peaks shown in Table 23
below:
TABLE-US-00024 TABLE 23 XRPD Table of Compound 1 D-Glucuronate
(Form B) 2-Theta Intensity % 8.5 16.1 11.7 7.1 14.7 100 15.0 24.8
16.7 45.2 17.0 67.7 19.1 4.7 19.5 18.7 20.0 32.9 20.4 42.3 21.7
11.1 22.5 15.6 22.9 8.5 24.3 18 24.8 7.4 25.4 11.2 25.6 14.2 26.2
14.2 28.0 4.1 28.8 3.8 30.1 6.2 30.6 13.6 35.2 9.1 35.8 6.5 38.3
5.1 39.2 5
[0276] In some embodiments, the Compound 1 D-Glucuronate (Form B)
exhibits an XRPD that is substantially similar to FIG. 51.
Ethanesulfonate Salt
[0277] In some embodiments, the present disclosure provides an
ethanesulfonate salt of Compound 1 ("Compound 1 Ethanesulfonate").
In some embodiments, the present disclosure provides a crystalline
form of Compound 1 Ethanesulfonate.
[0278] In one embodiment, the present disclosure provides Compound
1 Ethanesulfonate (Form A). In some embodiments, the Compound 1
Ethanesulfonate (Form A) exhibits an XRPD comprising one or more
peaks at about 3.4, 3.7, 7.6, 15.3, and 23.0 degrees two-theta with
the margin of error of about .+-.0.5; about .+-.0.4; about .+-.0.3;
about .+-.0.2; about .+-.0.1; about .+-.0.05; or less. In another
embodiment, the XRPD of the Compound 1 Ethanesulfonate (Form A)
further comprises one or more peaks at about 23.3 and 30.8 degrees
two-theta with the margin of error of about .+-.0.5; about .+-.0.4;
about .+-.0.3; about .+-.0.2; about .+-.0.1; about .+-.0.05; or
less.
[0279] In yet another embodiment, the Compound 1 Ethanesulfonate
(Form A) exhibits an XRPD comprising peaks shown in Table 24
below:
TABLE-US-00025 TABLE 24 XRPD Table of Compound 1 Ethanesulfonate
(Form A) 2-Theta Intensity % 3.4 22.4 3.7 11.7 7.6 100 15.3 70.3
23.0 21.6 23.3 1.6 30.8 4.3
[0280] In some embodiments, the Compound 1 Ethanesulfonate (Form A)
exhibits an XRPD that is substantially similar to FIG. 52.
[0281] In some embodiments, the Compound 1 Ethanesulfonate (Form A)
exhibits a DSC thermogram comprising a endotherm at about
177.9.degree. C. with the error of margin of about .+-.2.5; about
.+-.2.0; about .+-.1.5; about .+-.1.0; about .+-.0.5; or less. In
another embodiment, the Compound 1 Ethanesulfonate (Form A)
exhibits a DSC thermogram comprising a endotherm at about
207.0.degree. C. with the error of margin of about .+-.2.5; about
.+-.2.0; about .+-.1.5; about .+-.1.0; about .+-.0.5; or less. In
some embodiments, the Compound 1 Ethanesulfonate (Form A) exhibits
a DSC thermogram that is substantially similar to FIG. 53.
[0282] In some embodiments, the Compound 1 Ethanesulfonate (Form A)
exhibits a TGA thermogram that is substantially similar to FIG. 53.
In other embodiments, the TGA thermogram of the Compound 1
Ethanesulfonate (Form A) exhibits a weight loss of 0.0 to 2.9% in
the temperature range of 25 to 180.degree. C.
[0283] In some embodiments, the Compound 1 Ethanesulfonate (Form A)
exhibits a DVS isotherm plot that is substantially similar to FIG.
54. In other embodiments, the Compound 1 Ethanesulfonate (Form A)
exhibits a gravimetric moisture sorption of about 1.4% (by weight)
at 80% Relative Humidity.
Sulfate Salt
[0284] In some embodiments, the present disclosure provides a
sulfate salt of Compound 1 ("Compound 1 Sulfate"). In some
embodiments, the present disclosure provides a crystalline form of
Compound 1 Sulfate.
[0285] In one embodiment, the present disclosure provides Compound
1 Sulfate (Form A). In some embodiments, the Compound 1 Sulfate
(Form A) exhibits an XRPD comprising one or more peaks at about
3.6, 5.2, 7.8, 8.1, and 15.1 degrees two-theta with the margin of
error of about .+-.0.5; about .+-.0.4; about .+-.0.3; about
.+-.0.2; about .+-.0.1; about .+-.0.05; or less. In another
embodiment, the XRPD of the Compound 1 Sulfate (Form A) further
comprises one or more peaks at about 14.7, 17.4, 18.2, 18.4, and
19.7 degrees two-theta with the margin of error of about .+-.0.5;
about .+-.0.4; about .+-.0.3; about .+-.0.2; about .+-.0.1; about
.+-.0.05; or less. In some embodiments, the Compound 1 Sulfate
(Form A) exhibits an XRPD comprising peaks shown in Table 25
below:
TABLE-US-00026 TABLE 25 XRPD Table of Compound 1 Sulfate (Form A)
2-Theta Intensity % 3.6 100 5.2 39 7.8 50 8.1 16.4 14.2 9 14.7 9.6
15.1 13.6 17.4 10.3 18.2 10.6 18.4 9.4 19.7 11.3 20.8 9 21.6 8.2
24.0 8.8
[0286] In some embodiments, the Compound 1 Sulfate (Form A)
exhibits an XRPD that is substantially similar to FIG. 55.
[0287] In some embodiments, the Compound 1 Sulfate (Form A)
exhibits a DSC thermogram comprising a endotherm at about
167.1.degree. C. with the error of margin of about .+-.2.5; about
.+-.2.0; about .+-.1.5; about .+-.1.0; about .+-.0.5; or less. In
some embodiments, the Compound 1 Sulfate (Form A) exhibits a DSC
thermogram that is substantially similar to FIG. 56.
[0288] In some embodiments, the Compound 1 Sulfate (Form A)
exhibits a TGA thermogram that is substantially similar to FIG. 56.
In other embodiments, the TGA thermogram of the Compound 1 Sulfate
(Form A) exhibits a weight loss of 0.0 to 1.0% in the temperature
range of 25 to 120.degree. C.
[0289] In some embodiments, the Compound 1 Sulfate (Form A)
exhibits a DVS isotherm plot that is substantially similar to FIG.
57. In other embodiments, the Compound 1 Sulfate (Form A) exhibits
a gravimetric moisture sorption of about 6.2% (by weight) at 80%
Relative Humidity.
Ascorbate Salt
[0290] In some embodiments, the present disclosure provides an
ascorbate salt of Compound 1 ("Compound 1 Ascorbate"). In some
embodiments, the present disclosure provides a crystalline form of
Compound 1 Ascorbate.
[0291] In one embodiment, the present disclosure provides Compound
1 Ascorbate (Form A). In some embodiments, the Compound 1 Ascorbate
(Form A) exhibits an XRPD comprising one or more peaks at about
3.6, 5.6, 16.6, 19.6, and 19.8 degrees two-theta with the margin of
error of about .+-.0.5; about .+-.0.4; about .+-.0.3; about
.+-.0.2; about .+-.0.1; about .+-.0.05; or less. In another
embodiment, the XRPD of the Compound 1 Ascorbate (Form A) further
comprises one or more peaks at about 11.5, 11.9, 21.6, 24.1, and
24.5 degrees two-theta with the margin of error of about .+-.0.5;
about .+-.0.4; about .+-.0.3; about .+-.0.2; about .+-.0.1; about
.+-.0.05; or less.
[0292] In some embodiments, the Compound 1 Ascorbate (Form A)
exhibits an XRPD comprising peaks shown in Table 26 below:
TABLE-US-00027 TABLE 26 XRPD Table of Compound 1 Ascorbate (Form A)
2-Theta Intensity % 3.6 28.5 5.6 31.7 9.6 9.7 11.0 8.8 11.5 13.8
11.9 13.3 14.5 12.9 16.6 100 18.9 6.3 19.6 31.9 19.8 22.5 21.6 14.7
22.1 5.1 22.9 6 23.2 10.6 24.1 15.1 24.5 21.1
[0293] In some embodiments, the Compound 1 Ascorbate (Form A)
exhibits an XRPD that is substantially similar to FIG. 58.
[0294] In some embodiments, the Compound 1 Ascorbate (Form A)
exhibits a DSC thermogram comprising a endotherm at about
46.3.degree. C. with the error of margin of about .+-.2.5; about
.+-.2.0; about .+-.1.5; about .+-.1.0; about .+-.0.5; or less. In
some embodiments, the Compound 1 Ascorbate (Form A) exhibits a DSC
thermogram comprising a endotherm at about 124.3.degree. C. with
the error of margin of about .+-.2.5; about .+-.2.0; about .+-.1.5;
about .+-.1.0; about .+-.0.5; or less. In some embodiments, the
Compound 1 Ascorbate (Form A) exhibits a DSC thermogram that is
substantially similar to FIG. 59.
[0295] In some embodiments, the Compound 1 Ascorbate (Form A)
exhibits a TGA thermogram that is substantially similar to FIG. 59.
In other embodiments, the TGA thermogram of the Compound 1
Ascorbate (Form A) exhibits a weight loss of 0.0 to 5.6% in the
temperature range of 25 to 120.degree. C.
[0296] In some embodiments, the Compound 1 Ascorbate (Form A)
exhibits a DVS isotherm plot that is substantially similar to FIG.
60. In other embodiments, the Compound 1 Ascorbate (Form A)
exhibits a gravimetric moisture sorption of about 5.7% (by weight)
at 80% Relative Humidity.
[0297] In one embodiment, the present disclosure provides Compound
1 Ascorbate (Form B). In some embodiments, the Compound 1 Ascorbate
(Form B) exhibits an XRPD comprising one or more peaks at about
5.5, 16.6, 19.7, 20.1, and 28.3 degrees two-theta with the margin
of error of about .+-.0.5; about .+-.0.4; about .+-.0.3; about
.+-.0.2; about .+-.0.1; about .+-.0.05; or less. In another
embodiment, the XRPD of the Compound 1 Ascorbate (Form B) further
comprises one or more peaks at about 14.7 and 23.6 degrees
two-theta with the margin of error of about .+-.0.5; about .+-.0.4;
about .+-.0.3; about .+-.0.2; about .+-.0.1; about .+-.0.05; or
less.
[0298] In some embodiments, the Compound 1 Ascorbate (Form B)
exhibits an XRPD comprising peaks shown in Table 27 below:
TABLE-US-00028 TABLE 27 XRPD Table of Compound 1 Ascorbate (Form B)
2-Theta Intensity % 5.5 74.9 14.7 21.2 16.6 100 19.7 29.6 20.1 38
23.6 22.9 28.3 39.7
[0299] In some embodiments, the Compound 1 Ascorbate (Form B)
exhibits an XRPD that is substantially similar to FIG. 61.
Napadisylate Salt
[0300] In some embodiments, the present disclosure provides a
napadisylate salt of Compound 1 ("Compound 1 Napadisylate"). In
some embodiments, the present disclosure provides a crystalline
form of Compound 1 Napadisylate.
[0301] In one embodiment, the present disclosure provides Compound
1 Napadisylate (Form A). In some embodiments, the Compound 1
Napadisylate (Form A) exhibits an XRPD comprising one or more peaks
at about 3.3, 9.4, 14.2, 16.4, and 17.8 degrees two-theta with the
margin of error of about .+-.0.5; about .+-.0.4; about .+-.0.3;
about .+-.0.2; about .+-.0.1; about .+-.0.05; or less. In another
embodiment, the XRPD of the Compound 1 Napadisylate (Form A)
further comprises one or more peaks at about 9.7, 17.3, 20.3, 24.4,
and 26.1 degrees two-theta with the margin of error of about
.+-.0.5; about .+-.0.4; about .+-.0.3; about .+-.0.2; about
.+-.0.1; about .+-.0.05; or less. In some embodiments, the Compound
1 Napadisylate (Form A) exhibits an XRPD comprising peaks shown in
Table 28 below:
TABLE-US-00029 TABLE 28 XRPD Table of Compound 1 Napadisylate (Form
A) 2-Theta Intensity % 3.3 70.6 3.6 18.5 4.7 15.3 7.1 7.7 9.4 38.1
9.7 35.7 14.2 52 16.4 100 17.3 23.3 17.8 77.6 19.6 22.9 20.3 24.5
20.8 19.9 22.1 12.6 22.6 6.6 23.0 17.3 24.4 23.7 25.5 6.2 26.1 37.4
27.3 19.7 28.3 7.6
[0302] In some embodiments, the Compound 1 Napadisylate (Form A)
exhibits an XRPD that is substantially similar to FIG. 62.
[0303] In some embodiments, the Compound 1 Napadisylate (Form A)
exhibits a DSC thermogram comprising a endotherm at about
41.7.degree. C. with the error of margin of about .+-.2.5; about
.+-.2.0; about .+-.1.5; about .+-.1.0; about .+-.0.5; or less. In
some embodiments, the Compound 1 Napadisylate (Form A) exhibits a
DSC thermogram that is substantially similar to FIG. 63.
[0304] In some embodiments, the Compound 1 Napadisylate (Form A)
exhibits a TGA thermogram that is substantially similar to FIG. 63.
In other embodiments, the TGA thermogram of the Compound 1
Napadisylate (Form A) exhibits a weight loss of 0.0 to 0.7% in the
temperature range of 25 to 120.degree. C.
[0305] In some embodiments, the Compound 1 Napadisylate (Form A)
exhibits a DVS isotherm plot that is substantially similar to FIG.
64. In other embodiments, the Compound 1 Napadisylate exhibits a
gravimetric moisture sorption of about 3.1% (by weight) at 80%
Relative Humidity.
[0306] In some embodiments, the present disclosure provides
Compound 1 Napadisylate (Form B). In some embodiments, the Compound
1 Napadisylate (Form B) exhibits an XRPD comprising one or more
peaks at about 6.0, 14.2, 18.1, 19.0, and 20.3 degrees two-theta
with the margin of error of about .+-.0.5; about .+-.0.4; about
.+-.0.3; about .+-.0.2; about .+-.0.1; about .+-.0.05; or less. In
another embodiment, the XRPD of the Compound 1 Napadisylate (Form
B) further comprises one or more peaks at about 12.0, 16.9, 18.4,
19.4, and 24.1 degrees two-theta with the margin of error of about
.+-.0.5; about .+-.0.4; about .+-.0.3; about .+-.0.2; about
.+-.0.1; about .+-.0.05; or less.
[0307] In some embodiments, the Compound 1 Napadisylate (Form B)
exhibits an XRPD comprising peaks shown in Table 29 below:
TABLE-US-00030 TABLE 29 XRPD Table of Compound 1 Napadisylate (Form
B) 2-Theta Intensity % 6.0 100 12.0 18.2 13.3 14.8 13.5 12.4 14.2
33.8 16.9 23.6 18.1 51.1 18.4 22.9 19.0 26.3 19.4 17 20.3 39.9 21.7
10.5 24.1 22.4 25.8 11.2
[0308] In some embodiments, the Compound 1 Napadisylate (Form B)
exhibits an XRPD that is substantially similar to FIG. 65.
Malonate Salt
[0309] In some embodiments, the present disclosure provides a
malonate salt of Compound 1 ("Compound 1 Malonate"). In some
embodiments, the present disclosure provides a crystalline form of
Compound 1 Malonate.
[0310] In one embodiment, the present disclosure provides Compound
1 Malonate (Form A). In some embodiments, the Compound 1 Malonate
(Form A) exhibits an XRPD comprising one or more peaks at about
15.1, 18.0, 18.8, 23.4, and 23.8 degrees two-theta with the margin
of error of about .+-.0.5; about .+-.0.4; about .+-.0.3; about
.+-.0.2; about .+-.0.1; about .+-.0.05; or less. In another
embodiment, the XRPD of the Compound 1 Malonate (Form A) further
comprises one or more peaks at about 3.6, 13.8, 15.6, 21.4, and
27.6 degrees two-theta with the margin of error of about .+-.0.5;
about .+-.0.4; about .+-.0.3; about .+-.0.2; about .+-.0.1; about
.+-.0.05; or less.
[0311] In some embodiments, the Compound 1 Malonate (Form A)
exhibits an XRPD comprising peaks shown in Table 30 below:
TABLE-US-00031 TABLE 30 XRPD Table of Compound 1 Malonate (Form A)
2-Theta Intensity % 3.6 26.7 10.9 13.6 11.7 6.7 12.1 17.6 13.8 25
14.6 15 15.1 60.1 15.6 29.2 16.7 7.4 18.0 100 18.8 85.6 20.6 18.3
21.4 24.8 21.7 24.1 23.1 17.8 23.4 43.3 23.8 56.3 25.0 8.2 25.6 8.3
27.6 37.3 29.4 17.5
[0312] In some embodiments, the Compound 1 Malonate (Form A)
exhibits an XRPD that is substantially similar to FIG. 66.
[0313] In some embodiments, the Compound 1 Malonate (Form A)
exhibits a DSC thermogram comprising a endotherm at about
36.9.degree. C. with the error of margin of about .+-.2.5; about
.+-.2.0; about .+-.1.5; about .+-.1.0; about .+-.0.5; or less. In
some embodiments, the Compound 1 Malonate (Form A) exhibits a DSC
thermogram comprising a endotherm at about 124.6.degree. C. with
the error of margin of about .+-.2.5; about .+-.2.0; about .+-.1.5;
about .+-.1.0; about .+-.0.5; or less. In some embodiments, the
Compound 1 Malonate (Form A) exhibits a DSC thermogram that is
substantially similar to FIG. 67.
[0314] In some embodiments, the Compound 1 Malonate (Form A)
exhibits a TGA thermogram that is substantially similar to FIG. 67.
In other embodiments, the TGA thermogram of the Compound 1 Malonate
(Form A) exhibits a weight loss of 0.0 to 1.9% in the temperature
range of 25 to 120.degree. C.
Besylate Salt
[0315] In some embodiments, the present disclosure provides a
besylate salt of Compound 1 ("Compound 1 Besylate"). In some
embodiments, the present disclosure provides a crystalline form of
Compound 1 Besylate.
[0316] In one embodiment, the present disclosure provides Compound
1 Besylate (Form A). In some embodiments, the Compound 1 Besylate
(Form A) exhibits an XRPD comprising one or more peaks at about
14.7, 15.8, 22.1, 23.2, and 26.6 degrees two-theta with the margin
of error of about .+-.0.5; about .+-.0.4; about .+-.0.3; about
.+-.0.2; about .+-.0.1; about .+-.0.05; or less. In another
embodiment, the XRPD of the Compound 1 Besylate (Form A) further
comprises one or more peaks at about 3.7, 16.2, 17.8, 19.5, and
30.4 degrees two-theta with the margin of error of about .+-.0.5;
about .+-.0.4; about .+-.0.3; about .+-.0.2; about .+-.0.1; about
.+-.0.05; or less.
[0317] In some embodiments, the Compound 1 Besylate (Form A)
exhibits an XRPD comprising peaks shown in Table 31 below:
TABLE-US-00032 TABLE 31 XRPD Table of Compound 1 Besylate (Form A)
2-Theta Intensity % 3.3 21.9 3.7 7 7.4 100 14.7 41.9 15.8 3.5 16.2
19.3 17.2 5.7 17.8 9.1 19.5 9.3 22.1 21.4 23.2 20.6 26.6 3.8 29.6
3.6 30.4 7.3
[0318] In some embodiments, the Compound 1 Besylate (Form A)
exhibits an XRPD that is substantially similar to FIG. 68.
[0319] In some embodiments, the Compound 1 Besylate (Form A)
exhibits a DSC thermogram comprising a sharp endotherm at about
194.2.degree. C. with the error of margin of about .+-.2.5; about
.+-.2.0; about .+-.1.5; about .+-.1.0; about .+-.0.5; or less. In
some embodiments, the Compound 1 Besylate (Form A) exhibits a DSC
thermogram that is substantially similar to FIG. 69.
[0320] In some embodiments, the Compound 1 Besylate (Form A)
exhibits a TGA thermogram that is substantially similar to FIG. 69.
In other embodiments, the TGA thermogram of the Compound 1 Besylate
(Form A) exhibits a weight loss of 0.0 to 3.3% in the temperature
range of 25 to 120.degree. C.
[0321] In some embodiments, the Compound 1 Besylate (Form A)
exhibits a DVS isotherm plot that is substantially similar to FIG.
70. In other embodiments, the Compound 1 Besylate (Form A) exhibits
a gravimetric moisture sorption of about 4.0% (by weight) at 80%
Relative Humidity.
[0322] In one embodiment, the present disclosure provides Compound
1 Besylate (Form B).
[0323] In some embodiments, the Compound 1 Besylate (Form B)
exhibits an XRPD comprising one or more peaks at about 7.3, 14.7,
22.1, 23.2, and 29.6 degrees two-theta with the margin of error of
about .+-.0.5; about .+-.0.4; about .+-.0.3; about .+-.0.2; about
.+-.0.1; about .+-.0.05; or less. In another embodiment, the XRPD
of the Compound 1 Besylate (Form B) further comprises one or more
peaks at about 7.9, 16.2, 16.4, 17.2, and 30.4 degrees two-theta
with the margin of error of about .+-.0.5; about .+-.0.4; about
.+-.0.3; about .+-.0.2; about .+-.0.1; about .+-.0.05; or less.
[0324] In some embodiments, the Compound 1 Besylate (Form B)
exhibits an XRPD comprising peaks shown in Table 32 below:
TABLE-US-00033 TABLE 32 XRPD Table of Compound 1 Besylate (Form B)
2-Theta Intensity % 7.3 100 7.9 0.5 14.7 51.7 16.2 3.4 16.4 3.0
17.2 2.7 22.1 24.5 23.2 7.7 29.6 4.4 30.4 2.7
[0325] In some embodiments, the Compound 1 Besylate (Form B)
exhibits an XRPD that is substantially similar to FIG. 71.
Isethionate Salt
[0326] In some embodiments, the present disclosure provides an
isethionate salt of Compound 1 ("Compound 1 Isethionate"). In some
embodiments, the present disclosure provides a crystalline form of
Compound 1 Isethionate.
[0327] In one embodiment, the present disclosure provides Compound
1 Isethionate (Form A).
[0328] In some embodiments, the Compound 1 Isethionate (Form A)
exhibits an XRPD comprising one or more peaks at about 5.6, 16.7,
16.9, 18, and 20.9 degrees two-theta with the margin of error of
about .+-.0.5; about .+-.0.4; about .+-.0.3; about .+-.0.2; about
.+-.0.1; about .+-.0.05; or less. In another embodiment, the XRPD
of the Compound 1 Isethionate (Form A) further comprises one or
more peaks at about 3.7, 15.7, 16.2, 20.7, and 25.1 degrees
two-theta with the margin of error of about .+-.0.5; about .+-.0.4;
about .+-.0.3; about .+-.0.2; about .+-.0.1; about .+-.0.05; or
less.
[0329] In some embodiments, the Compound 1 Isethionate (Form A)
exhibits an XRPD comprising peaks shown in Table 33 below:
TABLE-US-00034 TABLE 33 XRPD Table of Compound 1 Isethionate (Form
A) 2-Theta Intensity % 3.7 23.7 5.6 26.4 9.6 5 10.0 10.8 11.2 6.8
13.1 17 14.1 9.8 14.6 7.7 14.7 7 15.7 24.8 16.2 18.5 16.7 100 16.9
46.9 18.1 26.1 19.2 10.1 19.5 6.6 20.1 7.1 20.3 12.5 20.7 19.2 20.9
45.1 22.4 7.2 25.1 23.1 25.6 8.7 26.1 7.9 27.7 12.8 28.0 7.5
[0330] In some embodiments, the Compound 1 Isethionate (Form A)
exhibits an XRPD that is substantially similar to FIG. 72.
[0331] In some embodiments, the Compound 1 Isethionate (Form A)
exhibits a DSC thermogram comprising a sharp endotherm at about
153.3.degree. C. with the error of margin of about .+-.2.5; about
.+-.2.0; about .+-.1.5; about .+-.1.0; about .+-.0.5; or less. In
some embodiments, the Compound 1 Isethionate (Form A) exhibits a
DSC thermogram that is substantially similar to FIG. 73.
[0332] In some embodiments, the Compound 1 Isethionate (Form A)
exhibits a TGA thermogram that is substantially similar to FIG. 73.
In other embodiments, the TGA thermogram of the Compound 1
Isethionate (Form A) exhibits a weight loss of 0.0 to 0.0% in the
temperature range of 25 to 120.degree. C.
[0333] In some embodiments, the Compound 1 Isethionate (Form A)
exhibits a DVS isotherm plot that is substantially similar to FIG.
74. In other embodiments, the Compound 1 Isethionate (Form A)
exhibits a gravimetric moisture sorption of about 4.9% (by weight)
at 80% Relative Humidity.
[0334] In one embodiment, the present disclosure provides Compound
1 Isethionate (Form B). In some embodiments, the Compound 1
Isethionate (Form B) exhibits an XRPD comprising one or more peaks
at about 14.5, 15.8, 17.9, 18.1, and 18.6 degrees two-theta with
the margin of error of about .+-.0.5; about .+-.0.4; about .+-.0.3;
about .+-.0.2; about .+-.0.1; about .+-.0.05; or less. In another
embodiment, the XRPD of the Compound 1 Isethionate (Form B) further
comprises one or more peaks at about 11.4, 13.1, 14.2, 15.0, and
17.0 degrees two-theta with the margin of error of about .+-.0.5;
about .+-.0.4; about .+-.0.3; about .+-.0.2; about .+-.0.1; about
.+-.0.05; or less.
[0335] In some embodiments, the Compound 1 Isethionate (Form B)
exhibits an XRPD comprising peaks shown in Table 34 below:
TABLE-US-00035 TABLE 34 XRPD Table of Compound 1 Isethionate (Form
B) 2-Theta Intensity % 8.5 15.7 11.4 27.1 13.1 29.2 14.2 26.5 14.5
71.4 15.0 23.4 15.8 30.5 17.0 24.0 17.9 100 18.1 54.8 18.6 75.1
19.5 14.8 22.1 14.8 24.2 16.9 27.2 15.4 27.5 10.5
[0336] In some embodiments, the Compound 1 Isethionate (Form B)
exhibits an XRPD that is substantially similar to FIG. 75.
Gentisate Salt
[0337] In some embodiments, the present disclosure provides a
gentisate salt of Compound 1 ("Compound 1 Gentisate"). In some
embodiments, the present disclosure provides a crystalline form of
Compound 1 Gentisate.
[0338] In one embodiment, the present disclosure provides Compound
1 Gentisate (Form A). In some embodiments, the Compound 1 Gentisate
(Form A) exhibits an XRPD comprising one or more peaks at about
3.4, 3.6, 7.0, 14.6, and 21.4 degrees two-theta with the margin of
error of about .+-.0.5; about .+-.0.4; about .+-.0.3; about
.+-.0.2; about .+-.0.1; about .+-.0.05; or less. In another
embodiment, the XRPD of the Compound 1 Gentisate (Form A) further
comprises one or more peaks at about 16.0, 18.0, 18.5, 19.5, and
21.1 degrees two-theta with the margin of error of about .+-.0.5;
about .+-.0.4; about .+-.0.3; about .+-.0.2; about .+-.0.1; about
.+-.0.05; or less.
[0339] In some embodiments, the Compound 1 Gentisate (Form A)
exhibits an XRPD comprising peaks shown in Table 35 below:
TABLE-US-00036 TABLE 35 XRPD Table of Compound 1 Gentisate (Form A)
2-Theta Intensity % 3.4 100 3.6 54.6 5.3 10.1 7.0 88.3 7.6 5.8 8.1
12.3 9.0 8.2 10.9 20 14.0 18.5 14.6 42.3 16.0 30.1 16.3 25.7 18.0
40.3 18.5 28.1 19.5 31.7 19.8 11.8 21.1 39.1 21.4 48 21.8 6.8 22.8
22.4 23.3 7.8
[0340] In some embodiments, the Compound 1 Gentisate (Form A)
exhibits an XRPD that is substantially similar to FIG. 76.
[0341] In some embodiments, the Compound 1 Gentisate (Form A)
exhibits a DSC thermogram comprising a sharp endotherm at about
117.7.degree. C. with the error of margin of about .+-.2.5; about
.+-.2.0; about .+-.1.5; about .+-.1.0; about .+-.0.5; or less. In
some embodiments, the Compound 1 Gentisate (Form A) exhibits a DSC
thermogram that is substantially similar to FIG. 77.
[0342] In some embodiments, the Compound 1 Gentisate (Form A)
exhibits a TGA thermogram that is substantially similar to FIG. 77.
In other embodiments, the TGA thermogram of the Compound 1
Gentisate (Form A) exhibits a weight loss of 0.0 to 9.0% in the
temperature range of 25 to 200.degree. C.
[0343] In some embodiments, the Compound 1 Gentisate (Form A)
exhibits a DVS isotherm plot that is substantially similar to FIG.
78. In other embodiments, the Compound 1 Gentisate (Form A)
exhibits a gravimetric moisture sorption of about 3.1% (by weight)
at 80% Relative Humidity.
[0344] In one embodiment, the present disclosure provides Compound
1 Gentisate (Form B). In some embodiments, the Compound 1 Gentisate
(Form B) exhibits an XRPD comprising one or more peaks at about
5.5, 10.9, 16.4, 21.9, and 22.8 degrees two-theta with the margin
of error of about .+-.0.5; about .+-.0.4; about .+-.0.3; about
.+-.0.2; about .+-.0.1; about .+-.0.05; or less. In another
embodiment, the XRPD of the Compound 1 Gentisate (Form B) further
comprises one or more peaks at about 9.2, 13.0, 17.2, 18.7, and
27.8 degrees two-theta with the margin of error of about .+-.0.5;
about .+-.0.4; about .+-.0.3; about .+-.0.2; about .+-.0.1; about
.+-.0.05; or less.
[0345] In some embodiments, the Compound 1 Gentisate (Form B)
exhibits an XRPD comprising peaks shown in Table 36 below:
TABLE-US-00037 TABLE 36 XRPD Table of Compound 1 Gentisate (Form B)
2-Theta Intensity % 5.5 100 9.2 12.5 10.9 25.5 11.6 2.7 13.0 5.4
14.8 3.1 16.4 70.6 17.2 11.2 18.3 5.2 18.7 11.2 20.5 1.7 21.9 12.8
22.8 20.9 23.2 4.5 23.8 2.6 26.0 1.5 26.2 2.1 27.2 2.7 27.5 2.6
27.8 5.6 28.7 1.8 28.9 2.3
[0346] In some embodiments, the Compound 1 Gentisate (Form B)
exhibits an XRPD that is substantially similar to FIG. 79.
[0347] In one embodiment, the present disclosure provides Compound
1 Gentisate (Form C). In some embodiments, the Compound 1 Gentisate
(Form C) exhibits an XRPD comprising one or more peaks at about
5.3, 15.2, 15.9, 21.4, and 26.6 degrees two-theta with the margin
of error of about .+-.0.5; about .+-.0.4; about .+-.0.3; about
.+-.0.2; about .+-.0.1; about .+-.0.05; or less. In another
embodiment, the XRPD of the Compound 1 Gentisate (Form C) further
comprises one or more peaks at about 7.6, 10.6, 13.8, 16.9, and
19.8 degrees two-theta with the margin of error of about .+-.0.5;
about .+-.0.4; about .+-.0.3; about .+-.0.2; about .+-.0.1; about
.+-.0.05; or less.
[0348] In some embodiments, the Compound 1 Gentisate (Form C)
exhibits an XRPD comprising peaks shown in Table 37 below:
TABLE-US-00038 TABLE 37 XRPD Table of Compound 1 Gentisate (Form C)
2-Theta Intensity % 5.3 71.5 7.6 39.3 10.6 28.0 12.1 16.7 13.8 37.8
15.2 63.5 15.9 100 16.2 19.8 16.9 24.4 19.8 27.7 21.4 78.3 22.7 4.0
23.7 4.6 24.0 7.3 26.6 49.6 28.9 7.4
[0349] In some embodiments, the Compound 1 Gentisate (Form C)
exhibits an XRPD that is substantially similar to FIG. 80.
1-Hydroxy-2-napthoate Salt
[0350] In some embodiments, the present disclosure provides a
1-hydroxy-2-napthoate salt of Compound 1 ("Compound 1
1-Hydroxy-2-napthoate"). In some embodiments, the present
disclosure provides a crystalline form of Compound 1
1-Hydroxy-2-napthoate.
[0351] In one embodiment, the present disclosure provides Compound
1 1-Hydroxy-2-napthoate (Form A). In some embodiments, the Compound
1 1-Hydroxy-2-napthoate (Form A) exhibits an XRPD comprising one or
more peaks at about 3.2, 6.2, 13.8, 21.2, and 21.6 degrees
two-theta with the margin of error of about .+-.0.5; about .+-.0.4;
about .+-.0.3; about .+-.0.2; about .+-.0.1; about .+-.0.05; or
less. In another embodiment, the XRPD of the Compound 1
1-Hydroxy-2-napthoate (Form A) further comprises one or more peaks
at about 13.4, 16.2, 19.9, 20.2, and 24.7 degrees two-theta with
the margin of error of about .+-.0.5; about .+-.0.4; about .+-.0.3;
about .+-.0.2; about .+-.0.1; about .+-.0.05; or less.
[0352] In some embodiments, the Compound 1 1-Hydroxy-2-napthoate
(Form A) exhibits an XRPD comprising peaks shown in Table 38
below:
TABLE-US-00039 TABLE 38 XRPD Table of Compound 1
1-Hydroxy-2-napthoate (Form A) 2-Theta Intensity % 3.2 100 6.2 17.9
10.6 7.3 10.8 8.9 13.4 16.2 13.8 21.9 16.2 14.2 16.7 5.5 18.2 7.1
19.9 14.7 20.2 10.3 21.2 29.4 21.6 22.6 22.8 5.8 24.7 9.6
[0353] In some embodiments, the Compound 1 1-Hydroxy-2-napthoate
(Form A) exhibits an XRPD that is substantially similar to FIG.
81.
[0354] In some embodiments, the Compound 1 1-Hydroxy-2-napthoate
(Form A) exhibits a DSC thermogram comprising a endotherm at about
57.7.degree. C. with the error of margin of about .+-.2.5; about
.+-.2.0; about .+-.1.5; about .+-.1.0; about .+-.0.5; or less. In
some embodiments, the Compound 1 1-Hydroxy-2-napthoate (Form A)
exhibits a DSC thermogram comprising a endotherm at about
79.1.degree. C. with the error of margin of about .+-.2.5; about
.+-.2.0; about .+-.1.5; about .+-.1.0; about .+-.0.5; or less. In
some embodiments, the Compound 1 1-Hydroxy-2-napthoate (Form A)
exhibits a DSC thermogram comprising a endotherm at about
116.1.degree. C. with the error of margin of about .+-.2.5; about
.+-.2.0; about .+-.1.5; about .+-.1.0; about .+-.0.5; or less. In
some embodiments, the Compound 1 1-Hydroxy-2-napthoate (Form A)
exhibits a DSC thermogram comprising a endotherm at about
164.7.degree. C. with the error of margin of about .+-.2.5; about
.+-.2.0; about .+-.1.5; about .+-.1.0; about .+-.0.5; or less. In
some embodiments, the Compound 1 1-Hydroxy-2-napthoate (Form A)
exhibits a DSC thermogram that is substantially similar to FIG.
82.
[0355] In some embodiments, the Compound 1 1-Hydroxy-2-napthoate
(Form A) exhibits a TGA thermogram that is substantially similar to
FIG. 82. In other embodiments, the TGA thermogram of the Compound 1
1-Hydroxy-2-napthoate (Form A) exhibits a weight loss of 0.0 to
3.6% in the temperature range of 25 to 120.degree. C.
[0356] In some embodiments, the Compound 1 1-Hydroxy-2-napthoate
(Form A) exhibits a DVS isotherm plot that is substantially similar
to FIG. 83. In other embodiments, the Compound 1
1-Hydroxy-2-napthoate (Form A) exhibits a gravimetric moisture
sorption of about 4.6% (by weight) at 80% Relative Humidity.
[0357] In one embodiment, the present disclosure provides Compound
1 1-Hydroxy-2-napthoate (Form B). In some embodiments, the Compound
1 1-Hydroxy-2-napthoate (Form B) exhibits an XRPD comprising one or
more peaks at about 8.0, 8.6, 13.5, 13.8, and 20.6 degrees
two-theta with the margin of error of about .+-.0.5; about .+-.0.4;
about .+-.0.3; about .+-.0.2; about .+-.0.1; about .+-.0.05; or
less. In another embodiment, the XRPD of the Compound 1
1-Hydroxy-2-napthoate (Form B) further comprises one or more peaks
at about 14.4, 15.2, 16.1, 21.4, and 23.8 degrees two-theta with
the margin of error of about .+-.0.5; about .+-.0.4; about .+-.0.3;
about .+-.0.2; about .+-.0.1; about .+-.0.05; or less.
[0358] In some embodiments, the Compound 1 1-Hydroxy-2-napthoate
(Form B) exhibits an XRPD comprising peaks shown in Table 39
below:
TABLE-US-00040 TABLE 39 XRPD Table of Compound 1
1-Hydroxy-2-napthoate (Form B) 2-Theta Intensity % 8.0 34.8 8.6
37.1 10.6 6.9 11.8 15 13.5 57.4 13.8 37 14.4 20.9 15.2 15.9 15.6
11.1 16.1 17.7 16.5 7.3 17.2 7.7 18.3 9.5 19.3 8.5 19.6 7 20.0 6.8
20.6 100 21.4 26.6 22.4 8.9 23.3 5.5 23.8 19.9 24.9 7 25.1 6.3 26.0
4.4 26.4 4.6 27.0 10.7 27.5 8.4 27.9 6.6 28.3 14.4 28.7 5.5 34.3
4.7 36.4 4.2 38.3 4.6 38.6 3.7
[0359] In some embodiments, the Compound 1 1-Hydroxy-2-napthoate
(Form B) exhibits an XRPD that is substantially similar to FIG.
84.
[0360] In one embodiment, the present disclosure provides Compound
1 1-Hydroxy-2-napthoate (Form C). In some embodiments, the Compound
1 1-Hydroxy-2-napthoate (Form C) exhibits an XRPD comprising one or
more peaks at about 8.5, 13.7, 14.2, 17.3, and 21.4 degrees
two-theta with the margin of error of about .+-.0.5; about .+-.0.4;
about .+-.0.3; about .+-.0.2; about .+-.0.1; about .+-.0.05; or
less. In another embodiment, the XRPD of the Compound 1
1-Hydroxy-2-napthoate (Form C) further comprises one or more peaks
at about 7.7, 15.4, 20.2, 20.6, and 21.1 degrees two-theta with the
margin of error of about .+-.0.5; about .+-.0.4; about .+-.0.3;
about .+-.0.2; about .+-.0.1; about .+-.0.05; or less.
[0361] In some embodiments, the Compound 1 1-Hydroxy-2-napthoate
(Form C) exhibits an XRPD comprising peaks shown in Table 40
below:
TABLE-US-00041 TABLE 40 XRPD Table of Compound 1
1-Hydroxy-2-napthoate (Form C) 2-Theta Intensity % 5.0 20.3 5.4
22.3 7.7 43.6 8.0 27.8 8.5 77.3 10.5 17.5 10.7 18.6 11.0 15.1 12.5
25.1 13.7 80.1 14.2 100 15.4 62.2 16.1 22.7 17.3 72.9 17.6 28.5
17.8 18.2 18.2 22.7 19.2 13.4 20.2 35.1 20.6 42.3 20.8 29.2 21.1 46
21.4 70.4 27.5 15.5
[0362] In some embodiments, the Compound 1 1-Hydroxy-2-napthoate
(Form C) exhibits an XRPD that is substantially similar to FIG.
85.
[0363] In one embodiment, the present disclosure provides Compound
1 1-Hydroxy-2-napthoate (Form D). In some embodiments, the Compound
1 1-Hydroxy-2-napthoate (Form D) exhibits an XRPD comprising one or
more peaks at about 10.4, 12.9, 13.5, 20.4, and 20.9 degrees
two-theta with the margin of error of about .+-.0.5; about .+-.0.4;
about .+-.0.3; about .+-.0.2; about .+-.0.1; about .+-.0.05; or
less. In another embodiment, the XRPD of the Compound 1
1-Hydroxy-2-napthoate (Form D) further comprises one or more peaks
at about 6.3, 9.1, 11.2, 13.2, and 19.9 degrees two-theta with the
margin of error of about .+-.0.5; about .+-.0.4; about .+-.0.3;
about .+-.0.2; about .+-.0.1; about .+-.0.05; or less.
[0364] In some embodiments, the Compound 1 1-Hydroxy-2-napthoate
(Form D) exhibits an XRPD comprising peaks shown in Table 41
below:
TABLE-US-00042 TABLE 41 XRPD Table of Compound 1
1-Hydroxy-2-napthoate (Form D) 2-Theta Intensity % 6.3 20.2 9.1
14.6 10.4 46.3 11.2 16.5 12.1 11.3 12.9 29.9 13.2 22.5 13.5 40.5
19.5 14.4 19.9 21.1 20.4 40.1 20.9 100 22.6 7.7 28.2 6.1 31.5
5.6
[0365] In some embodiments, the Compound 1 1-Hydroxy-2-napthoate
(Form D) exhibits an XRPD that is substantially similar to FIG.
86.
Cyclamate Salt
[0366] In some embodiments, the present disclosure provides a
cyclamate salt of Compound 1 ("Compound 1 Cyclamate"). In some
embodiments, the present disclosure provides a crystalline form of
Compound 1 Cyclamate.
[0367] In one embodiment, the present disclosure provides Compound
1 Cyclamate (Form A). In some embodiments, the Compound 1 Cyclamate
(Form A) exhibits an XRPD comprising one or more peaks at about
6.6, 7.2, 18.5, 19.5, and 21.6 degrees two-theta with the margin of
error of about .+-.0.5; about .+-.0.4; about .+-.0.3; about
.+-.0.2; about .+-.0.1; about .+-.0.05; or less. In another
embodiment, the XRPD of the Compound 1 Cyclamate (Form A) further
comprises one or more peaks at about 14.3, 14.8, 17.2, 17.6, and
18.2 degrees two-theta with the margin of error of about .+-.0.5;
about .+-.0.4; about .+-.0.3; about .+-.0.2; about .+-.0.1; about
.+-.0.05; or less.
[0368] In some embodiments, the Compound 1 Cyclamate (Form A)
exhibits an XRPD comprising peaks shown in Table 42 below:
TABLE-US-00043 TABLE 42 XRPD Table of Compound 1 Cyclamate (Form A)
2-Theta Intensity % 6.6 100 7.2 42.7 8.6 9.3 14.3 19.8 14.8 18.7
17.2 11.3 17.6 12.9 18.2 24.9 18.5 28.8 19.5 27 20.9 6.1 21.6 35.6
26.1 5
[0369] In some embodiments, the Compound 1 Cyclamate (Form A)
exhibits an XRPD that is substantially similar to FIG. 87.
[0370] In some embodiments, the Compound 1 Cyclamate (Form A)
exhibits a DSC thermogram comprising a endotherm at about
60.1.degree. C. with the error of margin of about .+-.2.5; about
.+-.2.0; about .+-.1.5; about .+-.1.0; about .+-.0.5; or less. In
some embodiments, the Compound 1 Cyclamate (Form A) exhibits a DSC
thermogram comprising a endotherm at about 168.5.degree. C. with
the error of margin of about .+-.2.5; about .+-.2.0; about .+-.1.5;
about .+-.1.0; about .+-.0.5; or less. In some embodiments, the
Compound 1 Cyclamate (Form A) exhibits a DSC thermogram that is
substantially similar to FIG. 88.
[0371] In some embodiments, the Compound 1 Cyclamate (Form A)
exhibits a TGA thermogram that is substantially similar to FIG. 88.
In other embodiments, the TGA thermogram of the Compound 1
Cyclamate (Form A) exhibits a weight loss of 0.0 to 5.1% in the
temperature range of 25 to 180.degree. C.
[0372] In some embodiments, the Compound 1 Cyclamate (Form A)
exhibits a DVS isotherm plot that is substantially similar to FIG.
89. In other embodiments, the Compound 1 Cyclamate (Form A)
exhibits a gravimetric moisture sorption of about 7.3% (by weight)
at 80% Relative Humidity.
Ethane-1, 2-disulfonate Salt
[0373] In some embodiments, the present disclosure provides an
ethane-1, 2-disulfonate salt of Compound 1 ("Compound 1
Ethane-1,2-disulfonate"). In some embodiments, the present
disclosure provides a crystalline form of Compound 1
Ethane-1,2-disulfonate.
[0374] In one embodiment, the present disclosure provides Compound
1 Ethane-1,2-disulfonate (Form A). In some embodiments, the
Compound 1 Ethane-1,2-disulfonate (Form A) exhibits an XRPD
comprising one or more peaks at about 16.2, 16.5, 17.5, 20.7, and
21.3 degrees two-theta with the margin of error of about .+-.0.5;
about .+-.0.4; about .+-.0.3; about .+-.0.2; about .+-.0.1; about
.+-.0.05; or less. In another embodiment, the XRPD of the Compound
1 Ethane-1,2-disulfonate (Form A) further comprises one or more
peaks at about 3.7, 5.5, 13.8, 14.7, and 26.0 degrees two-theta
with the margin of error of about .+-.0.5; about .+-.0.4; about
.+-.0.3; about .+-.0.2; about .+-.0.1; about .+-.0.05; or less.
[0375] In some embodiments, the Compound 1 Ethane-1,2-disulfonate
(Form A) exhibits an XRPD comprising peaks shown in Table 43
below:
TABLE-US-00044 TABLE 43 XRPD Table of Compound 1
Ethane-1,2-disulfonate (Form A) 2-Theta Intensity % 3.7 55.6 5.5
38.8 11.0 16.4 11.4 11 13.8 50.4 14.7 38 15.8 10.3 16.2 58 16.5
93.5 17.5 100 18.2 6.8 19.3 27.4 19.6 34.6 20.7 90.4 21.3 62.5 22.0
13.3 23.7 21.2 26.0 40.4 27.2 23.7 34.2 5.9 38.5 5.8
[0376] In some embodiments, the Compound 1 Ethane-1,2-disulfonate
(Form A) exhibits an XRPD that is substantially similar to FIG.
90.
[0377] In some embodiments, the Compound 1 Ethane-1,2-disulfonate
(Form A) exhibits a DSC thermogram comprising a endotherm at about
59.0.degree. C. with the error of margin of about .+-.2.5; about
.+-.2.0; about .+-.1.5; about .+-.1.0; about .+-.0.5; or less. In
some embodiments, the Compound 1 Ethane-1,2-disulfonate (Form A)
exhibits a DSC thermogram comprising a endotherm at about
154.8.degree. C. with the error of margin of about .+-.2.5; about
.+-.2.0; about .+-.1.5; about .+-.1.0; about .+-.0.5; or less. In
some embodiments, the Compound 1 Ethane-1, 2-disulfonate (Form A)
exhibits a DSC thermogram that is substantially similar to FIG.
91.
[0378] In some embodiments, the Compound 1 Ethane-1,2-disulfonate
(Form A) exhibits a TGA thermogram that is substantially similar to
FIG. 91. In other embodiments, the TGA thermogram of the Compound 1
Ethane-1,2-disulfonate (Form A) exhibits a weight loss of 0.0 to
0.7% in the temperature range of 25 to 120.degree. C.
[0379] In some embodiments, the Compound 1 Ethane-1,2-disulfonate
(Form A) exhibits a DVS isotherm plot that is substantially similar
to FIG. 92. In other embodiments, the Compound 1
Ethane-1,2-disulfonate (Form A) exhibits a gravimetric moisture
sorption of about 12.9% (by weight) at 80% Relative Humidity.
[0380] In one embodiment, the present disclosure provides Compound
1 Ethane-1,2-disulfonate (Form B). In some embodiments, the
Compound 1 Ethane-1,2-disulfonate (Form B) exhibits an XRPD
comprising one or more peaks at about 5.5, 16.4, 17.4, 17.6, and
20.7 degrees two-theta with the margin of error of about .+-.0.5;
about .+-.0.4; about .+-.0.3; about .+-.0.2; about .+-.0.1; about
.+-.0.05; or less. In another embodiment, the XRPD of the Compound
1 Ethane-1,2-disulfonate (Form B) further comprises one or more
peaks at about 10.9, 13.7, 14.6, 21.2, and 22.1 degrees two-theta
with the margin of error of about .+-.0.5; about .+-.0.4; about
.+-.0.3; about .+-.0.2; about .+-.0.1; about .+-.0.05; or less
[0381] In some embodiments, the Compound 1 Ethane-1,2-disulfonate
(Form B) exhibits an XRPD comprising peaks shown in Table 44
below:
TABLE-US-00045 TABLE 44 XRPD Table of Compound 1
Ethane-1,2-disulfonate (Form B) 2-Theta Intensity % 5.5 33.4 10.9
15.5 11.4 11.1 13.7 22.1 14.6 25.3 15.0 7.4 15.2 6.3 15.7 8.1 16.0
7.5 16.4 100 17.4 36.4 17.6 29.9 19.6 10.2 20.7 42.5 21.0 6.1 21.2
16.9 22.1 16.8 24.7 5.8 25.9 14.7 26.2 5.4 27.1 5.3 27.4 5.4 27.9
5.2
[0382] In some embodiments, the Compound 1 Ethane-1,2-disulfonate
(Form B) exhibits an XRPD that is substantially similar to FIG.
93.
Dichloroacetate Salt
[0383] In some embodiments, the present disclosure provides a
dichloroacetate salt of Compound 1 ("Compound 1 Dichloroacetate").
In some embodiments, the present disclosure provides a crystalline
form of Compound 1 Dichloroacetate.
[0384] In one embodiment, the present disclosure provides Compound
1 Dichloroacetate (Form A). In some embodiments, the Compound 1
Dichloroacetate (Form A) exhibits an XRPD comprising one or more
peaks at about 3.4, 3.6, 16.2, 17.1 and 19.5 degrees two-theta with
the margin of error of about .+-.0.5; about .+-.0.4; about .+-.0.3;
about .+-.0.2; about .+-.0.1; about .+-.0.05; or less. In another
embodiment, the XRPD of the Compound 1 Dichloroacetate (Form A)
further comprises one or more peaks at about 8.1, 11.4, 12.8, 16.7
and 20.0 degrees two-theta with the margin of error of about
.+-.0.5; about .+-.0.4; about .+-.0.3; about .+-.0.2; about
.+-.0.1; about .+-.0.05; or less.
[0385] In some embodiments, the Compound 1 Dichloroacetate (Form A)
exhibits an XRPD comprising peaks shown in Table 45 below:
TABLE-US-00046 TABLE 45 XRPD Table of Compound 1 Dichloroacetate
(Form A) 2-Theta Intensity % 3.4 100 3.6 49.1 8.1 37.7 11.0 9.6
11.4 11.6 12.8 10.8 14.7 7.7 16.2 42.9 16.7 9.8 17.1 58.4 17.5 7.1
19.5 43.2 20.0 14.3 21.9 8.5 22.7 7.3 25.5 9.3 25.8 9.1 26.6 8.2
27.2 5.1 31.0 6.6
[0386] In some embodiments, the Compound 1 Dichloroacetate (Form A)
exhibits an XRPD that is substantially similar to FIG. 94.
[0387] In some embodiments, the Compound 1 Dichloroacetate (Form A)
exhibits a DSC thermogram comprising a sharp endotherm at about
117.7.degree. C. with the error of margin of about .+-.2.5; about
.+-.2.0; about .+-.1.5; about .+-.1.0; about .+-.0.5; or less. In
some embodiments, the Compound 1 Dichloroacetate (Form A) exhibits
a DSC thermogram that is substantially similar to FIG. 95.
[0388] In some embodiments, the Compound 1 Dichloroacetate (Form A)
exhibits a TGA thermogram that is substantially similar to FIG. 95.
In other embodiments, the TGA thermogram of the Compound 1
Dichloroacetate (Form A) exhibits a weight loss of 0.0 to 3.7% in
the temperature range of 25 to 150.degree. C.
[0389] In some embodiments, the Compound 1 Dichloroacetate (Form A)
exhibits a DVS isotherm plot that is substantially similar to FIG.
96. In other embodiments, the Compound 1 Dichloroacetate (Form A)
exhibits a gravimetric moisture sorption of about 1.8% (by weight)
at 80% Relative Humidity.
Malate Salt
[0390] In some embodiments, the present disclosure provides a
malate salt of Compound 1 ("Compound 1 Malate"). In some
embodiments, the present disclosure provides a D-malate salt of
Compound 1 ("Compound 1 D-Malate"). In some embodiments, the
present disclosure provides an L-malate salt of Compound 1
("Compound 1 L-malate").
[0391] In some embodiments, the present disclosure provides a
crystalline form of Compound 1 Malate. In some embodiments, the
present disclosure provides a crystalline form of Compound 1
D-Malate. In some embodiments, the present disclosure provides a
crystalline form of Compound 1 L-Malate.
[0392] In one embodiment, the present disclosure provides Compound
1 L-Malate (Form A). In some embodiments, the Compound 1 L-Malate
(Form A) exhibits an XRPD comprising one or more peaks at about
3.2, 12.5, 14.4, 15.7, and 18.4 degrees two-theta with the margin
of error of about .+-.0.5; about .+-.0.4; about .+-.0.3; about
.+-.0.2; about .+-.0.1; about .+-.0.05; or less. In another
embodiment, the XRPD of the Compound 1 L-Malate (Form A) further
comprises one or more peaks at about 3.6, 6.1, 13.2, 18.9, and 21.1
degrees two-theta with the margin of error of about .+-.0.5; about
.+-.0.4; about .+-.0.3; about .+-.0.2; about .+-.0.1; about
.+-.0.05; or less.
[0393] In some embodiments, the Compound 1 L-Malate (Form A)
exhibits an XRPD comprising peaks shown in Table 46 below:
TABLE-US-00047 TABLE 46 XRPD Table of Compound 1 L-Malate (Form A)
2-Theta Intensity % 3.2 93.3 3.6 45.4 6.1 42.2 8.4 9.8 10.4 5.9
10.6 6.2 11.1 14.2 12.2 19.5 12.5 68.8 13.2 47.8 14.1 7.2 14.4 53.1
15.5 16.6 15.7 63.1 16.9 12.3 17.1 27.8 17.8 7.6 18.0 9.5 18.4 100
18.9 43.6 19.2 11.5 20.7 16.7 21.1 32.6 21.2 17.9 22.6 7.7 23.1 6.3
23.4 20.3 23.9 8.8 24.5 8.9 24.9 6 26.0 8.5 26.4 13.8 26.8 6.9 27.4
5.5 28.5 3.5 28.9 4.6 29.2 3 29.9 4.5 32.3 3.9 32.6 6.3 33.0
2.4
[0394] In some embodiments, the Compound 1 L-Malate (Form A)
exhibits an XRPD that is substantially similar to FIG. 97.
[0395] In some embodiments, the Compound 1 L-Malate (Form A)
exhibits a DSC thermogram comprising a sharp endotherm at about
120.9.degree. C. with the error of margin of about .+-.2.5; about
.+-.2.0; about .+-.1.5; about .+-.1.0; about .+-.0.5; or less. In
some embodiments, the Compound 1 L-Malate (Form A) exhibits a DSC
thermogram comprising a sharp endotherm at about 142.3.degree. C.
with the error of margin of about .+-.2.5; about .+-.2.0; about
.+-.1.5; about .+-.1.0; about .+-.0.5; or less. In some
embodiments, the Compound 1 L-Malate (Form A) exhibits a DSC
thermogram that is substantially similar to FIG. 98.
[0396] In some embodiments, the Compound 1 L-Malate (Form A)
exhibits a TGA thermogram that is substantially similar to FIG. 98.
In other embodiments, the TGA thermogram of the Compound 1 L-Malate
(Form A) exhibits a weight loss of 0.0 to 0.7% in the temperature
range of 25 to 105.degree. C.
[0397] In some embodiments, the Compound 1 L-Malate (Form A)
exhibits a DVS isotherm plot that is substantially similar to FIG.
99. In other embodiments, the Compound 1 L-Malate (Form A) exhibits
a gravimetric moisture sorption of about 2.0% (by weight) at 80%
Relative Humidity.
[0398] In one embodiment, the present disclosure provides Compound
1 L-Malate (Form B). In some embodiments, the Compound 1 L-Malate
(Form B) exhibits an XRPD comprising one or more peaks at about
5.6, 13.4, 17.3, 20.8 and 23.2 degrees two-theta with the margin of
error of about .+-.0.5; about .+-.0.4; about .+-.0.3; about
.+-.0.2; about .+-.0.1; about .+-.0.05; or less. In another
embodiment, the XRPD of the Compound 1 L-Malate (Form B) further
comprises one or more peaks at about 3.7, 11.2, 14.4, 14.9 and 17.8
degrees two-theta with the margin of error of about .+-.0.5; about
.+-.0.4; about .+-.0.3; about .+-.0.2; about .+-.0.1; about
.+-.0.05; or less.
[0399] In some embodiments, the Compound 1 L-Malate (Form B)
exhibits an XRPD comprising peaks shown in Table 47 below:
TABLE-US-00048 TABLE 47 XRPD Table of Compound 1 L-Malate (Form B)
2-Theta Intensity % 3.7 57.5 5.6 100 6.0 23.7 8.3 12.1 9.2 19.4
11.2 56.7 11.9 14.1 13.4 63.7 14.4 44.5 14.9 53.1 16.0 39.4 16.6 34
17.3 83.5 17.8 62.3 18.6 14.3 19.2 28.2 20.0 13.7 20.8 77.2 21.3
44.5 23.2 69 25.7 10.6 26.1 29.5
[0400] In some embodiments, the Compound 1 L-Malate (Form B)
exhibits an XRPD that is substantially similar to FIG. 100.
[0401] In some embodiments, the Compound 1 L-Malate (Form B)
exhibits a DSC thermogram comprising an endotherm at about
108.7.degree. C. with the error of margin of about .+-.2.5; about
.+-.2.0; about .+-.1.5; about .+-.1.0; about .+-.0.5; or less. In
some embodiments, the Compound 1 L-Malate (Form B) exhibits a DSC
thermogram comprising a sharp endotherm at about 143.3.degree. C.
with the error of margin of about .+-.2.5; about .+-.2.0; about
.+-.1.5; about .+-.1.0; about .+-.0.5; or less. In some
embodiments, the Compound 1 L-Malate (Form B) exhibits a DSC
thermogram that is substantially similar to FIG. 101.
[0402] In some embodiments, the Compound 1 L-Malate (Form B)
exhibits a TGA thermogram that is substantially similar to FIG.
101. In other embodiments, the TGA thermogram of the Compound 1
L-Malate (Form B) exhibits a weight loss of 0.0 to 1.2% in the
temperature range of 25 to 120.degree. C.
[0403] In some embodiments, the Compound 1 L-Malate (Form B)
exhibits a DVS isotherm plot that is substantially similar to FIG.
102. In other embodiments, the Compound 1 L-Malate (Form B)
exhibits a gravimetric moisture sorption of about 3.5% (by weight)
at 80% Relative Humidity.
Hydrochloride Salt
[0404] In some embodiments, the present disclosure provides a
hydrochloride salt of Compound 1 ("Compound 1 Hydrochloride"). In
some embodiments, the present disclosure provides a crystalline
form of Compound 1 Hydrochloride.
[0405] In one embodiment, the present disclosure provides Compound
1 Hydrochloride (Form A). In some embodiments, the Compound 1
Hydrochloride (Form A) exhibits an XRPD comprising one or more
peaks at about 3.6, 5.2, 14.2, 17.4 and 17.7 degrees two-theta with
the margin of error of about .+-.0.5; about .+-.0.4; about .+-.0.3;
about .+-.0.2; about .+-.0.1; about .+-.0.05; or less. In another
embodiment, the XRPD of the Compound 1 Hydrochloride (Form A)
further comprises one or more peaks at about 12.8, 13.4, 14.9, 18.9
and 20.4 degrees two-theta with the margin of error of about
.+-.0.5; about .+-.0.4; about .+-.0.3; about .+-.0.2; about
.+-.0.1; about .+-.0.05; or less.
[0406] In some embodiments, the Compound 1 Hydrochloride (Form A)
exhibits an XRPD comprising peaks shown in Table 48 below:
TABLE-US-00049 TABLE 48 XRPD Table of Compound 1 Hydrochloride
(Form A) 2-Theta Intensity % 3.6 88 5.2 100 8.7 11.2 12.1 15.1 12.8
22.6 13.4 19.5 13.8 10.1 14.2 57.8 14.9 29.7 15.5 9.8 16.1 11.2
17.1 13.7 17.4 79.6 17.7 54.6 18.3 10.6 18.9 16.4 20.4 21.1 21.2 9
22.0 15.9 22.5 6.1 28.2 8.7
[0407] In some embodiments, the Compound 1 Hydrochloride (Form A)
exhibits an XRPD that is substantially similar to FIG. 103.
[0408] In some embodiments, the Compound 1 Hydrochloride (Form A)
exhibits a DSC thermogram comprising an endotherm at about
225.0.degree. C. with the error of margin of about .+-.2.5; about
.+-.2.0; about .+-.1.5; about .+-.1.0; about .+-.0.5; or less. In
some embodiments, the Compound 1 Hydrochloride (Form A) exhibits a
DSC thermogram comprising an endotherm at about 232.7.degree. C.
with the error of margin of about .+-.2.5; about .+-.2.0; about
.+-.1.5; about .+-.1.0; about .+-.0.5; or less. In some
embodiments, the Compound 1 Hydrochloride (Form A) exhibits a DSC
thermogram that is substantially similar to FIG. 104.
[0409] In some embodiments, the Compound 1 Hydrochloride (Form A)
exhibits a TGA thermogram that is substantially similar to FIG.
104. In other embodiments, the TGA thermogram of the Compound 1
Hydrochloride (Form A) exhibits a weight loss of 0.0 to 1.2% in the
temperature range of 25 to 150.degree. C.
[0410] In some embodiments, the Compound 1 Hydrochloride (Form A)
exhibits a DVS isotherm plot that is substantially similar to FIG.
105. In other embodiments, the Compound 1 Hydrochloride (Form A)
exhibits a gravimetric moisture sorption of about 3.6% (by weight)
at 80% Relative Humidity.
[0411] In one embodiment, the present disclosure provides Compound
1 Hydrochloride (Form B). In some embodiments, the Compound 1
Hydrochloride (Form B) exhibits an XRPD comprising one or more
peaks at about 3.3, 7.8, 15.4, 16.6 and 23.2 degrees two-theta with
the margin of error of about .+-.0.5; about .+-.0.4; about .+-.0.3;
about .+-.0.2; about .+-.0.1; about .+-.0.05; or less. In another
embodiment, the XRPD of the Compound 1 Hydrochloride (Form B)
further comprises one or more peaks at about 15.0, 18.8, 20.4,
23.5, and 26.5 degrees two-theta with the margin of error of about
.+-.0.5; about .+-.0.4; about .+-.0.3; about .+-.0.2; about
.+-.0.1; about .+-.0.05; or less.
[0412] In some embodiments, the Compound 1 Hydrochloride (Form B)
exhibits an XRPD comprising peaks shown in Table 49 below:
TABLE-US-00050 TABLE 49 XRPD Table of Compound 1 Hydrochloride
(Form B) 2-Theta Intensity % 3.3 58.7 4.9 12.3 7.8 34.4 9.8 14.2
15.0 25.8 15.4 100 16.6 57.7 17.6 7.3 18.8 16.1 20.4 14.6 22.7 5.8
23.2 59.2 23.5 32.2 26.5 15.4 26.9 8.4 28.4 5.8 31.7 9.3
[0413] In some embodiments, the Compound 1 Hydrochloride (Form B)
exhibits an XRPD that is substantially similar to FIG. 106.
[0414] In some embodiments, the Compound 1 Hydrochloride (Form B)
exhibits a DSC thermogram comprising an endotherm at about
87.1.degree. C. with the error of margin of about .+-.2.5; about
.+-.2.0; about .+-.1.5; about .+-.1.0; about .+-.0.5; or less. In
some embodiments, the Compound 1 Hydrochloride (Form B) exhibits a
DSC thermogram comprising a sharp endotherm at about 207.3.degree.
C. with the error of margin of about .+-.2.5; about .+-.2.0; about
.+-.1.5; about .+-.1.0; about .+-.0.5; or less. In some
embodiments, the Compound 1 Hydrochloride (Form B) exhibits a DSC
thermogram that is substantially similar to FIG. 107.
[0415] In some embodiments, the Compound 1 Hydrochloride (Form B)
exhibits a TGA thermogram that is substantially similar to FIG.
107. In other embodiments, the TGA thermogram of the Compound 1
Hydrochloride (Form B) exhibits a weight loss of 0.0 to 0.7% in the
temperature range of 25 to 120.degree. C.
[0416] In some embodiments, the Compound 1 Hydrochloride (Form B)
exhibits a DVS isotherm plot that is substantially similar to FIG.
108. In other embodiments, the Compound 1 Hydrochloride (Form B)
exhibits a gravimetric moisture sorption of about 2.9% (by weight)
at 80% Relative Humidity.
[0417] In one embodiment, the present disclosure provides Compound
1 Hydrochloride (Form C). In some embodiments, the Compound 1
Hydrochloride (Form C) exhibits an XRPD comprising one or more
peaks at about 14.6, 16.5, 18.0, 21.5, and 21.9 degrees two-theta
with the margin of error of about .+-.0.5; about .+-.0.4; about
.+-.0.3; about .+-.0.2; about .+-.0.1; about .+-.0.05; or less. In
another embodiment, the XRPD of the Compound 1 Hydrochloride (Form
C) further comprises one or more peaks at about 3.6, 18.8, 19.9,
22.1, and 23.7 degrees two-theta with the margin of error of about
.+-.0.5; about .+-.0.4; about .+-.0.3; about .+-.0.2; about
.+-.0.1; about .+-.0.05; or less.
[0418] In some embodiments, the Compound 1 Hydrochloride (Form C)
exhibits an XRPD comprising peaks shown in Table 50 below:
TABLE-US-00051 TABLE 50 XRPD Table of Compound 1 Hydrochloride
(Form C) 2-Theta Intensity % 3.6 36.5 9.1 13.5 10.8 8.4 12.0 16.4
13.3 24.3 14.2 27.6 14.6 62.6 16.1 9.1 16.5 100 16.9 30.1 18.0 46.2
18.8 32.2 19.6 17.7 19.9 31.3 20.5 16.4 21.5 94.7 21.9 61.3 22.1
41.1 22.9 7.1 23.7 32 24.4 8.9
[0419] In some embodiments, the Compound 1 Hydrochloride (Form C)
exhibits an XRPD that is substantially similar to FIG. 109.
[0420] In some embodiments, the Compound 1 Hydrochloride (Form C)
exhibits a DSC thermogram comprising an endotherm at about
132.9.degree. C. with the error of margin of about .+-.2.5; about
.+-.2.0; about .+-.1.5; about .+-.1.0; about .+-.0.5; or less. In
some embodiments, the Compound 1 Hydrochloride (Form C) exhibits a
DSC thermogram that is substantially similar to FIG. 110.
[0421] In some embodiments, the Compound 1 Hydrochloride (Form C)
exhibits a TGA thermogram that is substantially similar to FIG.
110. In other embodiments, the TGA thermogram of the Compound 1
Hydrochloride (Form C) exhibits a weight loss of 0.0 to 3.8% in the
temperature range of 25 to 120.degree. C.
[0422] In some embodiments, the Compound 1 Hydrochloride (Form C)
exhibits a DVS isotherm plot that is substantially similar to FIG.
111. In other embodiments, the Compound 1 Hydrochloride (Form C)
exhibits a gravimetric moisture sorption of about 0.7% (by weight)
at 80% Relative Humidity.
Napsylate Salt
[0423] In some embodiments, the present disclosure provides a
napsylate salt of Compound 1 ("Compound 1 Napsylate"). In some
embodiments, the present disclosure provides a crystalline form of
Compound 1 Napsylate.
[0424] In one embodiment, the present disclosure provides Compound
1 Napsylate (Form A). In some embodiments, the Compound 1 Napsylate
(Form A) exhibits an XRPD comprising one or more peaks at about
3.4, 9.5, 16.6, 17.0, and 17.5 degrees two-theta with the margin of
error of about .+-.0.5; about .+-.0.4; about .+-.0.3; about
.+-.0.2; about .+-.0.1; about .+-.0.05; or less. In another
embodiment, the XRPD of the Compound 1 Napsylate (Form A) further
comprises one or more peaks at about 8.3, 8.7, 19.8, 25.0, and 25.5
degrees two-theta with the margin of error of about .+-.0.5; about
.+-.0.4; about .+-.0.3; about .+-.0.2; about .+-.0.1; about
.+-.0.05; or less.
[0425] In some embodiments, the Compound 1 Napsylate (Form A)
exhibits an XRPD comprising peaks shown in Table 51 below:
TABLE-US-00052 TABLE 51 XRPD Table of Compound 1 Napsylate (Form A)
2-Theta Intensity % 3.4 100 8.3 5.3 8.7 5.1 9.5 5.8 16.6 22 17.0
31.5 17.5 11.5 19.8 4.4 25.0 4.5 25.5 5.4
[0426] In some embodiments, the Compound 1 Napsylate (Form A)
exhibits an XRPD that is substantially similar to FIG. 112.
[0427] In some embodiments, the Compound 1 Napsylate (Form A)
exhibits a DSC thermogram comprising an endotherm at about
100.1.degree. C. with the error of margin of about .+-.2.5; about
.+-.2.0; about .+-.1.5; about .+-.1.0; about .+-.0.5; or less. In
some embodiments, the Compound 1 Napsylate (Form A) exhibits a DSC
thermogram comprising a sharp endotherm at about 202.3.degree. C.
with the error of margin of about .+-.2.5; about .+-.2.0; about
.+-.1.5; about .+-.1.0; about .+-.0.5; or less. In some
embodiments, the Compound 1 Napsylate exhibits a DSC thermogram
that is substantially similar to FIG. 113.
[0428] In some embodiments, the Compound 1 Napsylate (Form A)
exhibits a TGA thermogram that is substantially similar to FIG.
113. In other embodiments, the TGA thermogram of the Compound 1
Napsylate exhibits a weight loss of 0.0 to 1.7% in the temperature
range of 25 to 180.degree. C.
[0429] In some embodiments, the Compound 1 Napsylate (Form A)
exhibits a DVS isotherm plot that is substantially similar to FIG.
114. In other embodiments, the Compound 1 Napsylate (Form A)
exhibits a gravimetric moisture sorption of about 3.9% (by weight)
at 80% Relative Humidity.
[0430] In one embodiment, the present disclosure provides Compound
1 Napsylate (Form B). In some embodiments, the Compound 1 Napsylate
(Form B) exhibits an XRPD comprising one or more peaks at about
9.1, 15.6, 16.1, 18.2, and 19.7 degrees two-theta with the margin
of error of about .+-.0.5; about .+-.0.4; about .+-.0.3; about
.+-.0.2; about .+-.0.1; about .+-.0.05; or less. In another
embodiment, the XRPD of the Compound 1 Napsylate (Form B) further
comprises one or more peaks at about 8.6, 12.9, 17.1, 25.8, and
26.2 degrees two-theta with the margin of error of about .+-.0.5;
about .+-.0.4; about .+-.0.3; about .+-.0.2; about .+-.0.1; about
.+-.0.05; or less.
[0431] In some embodiments, the Compound 1 Napsylate (Form B)
exhibits an XRPD comprising peaks shown in Table 52 below:
TABLE-US-00053 TABLE 52 XRPD Table of Compound 1 Napsylate (Form B)
2-Theta Intensity % 8.6 29.7 9.1 100 12.9 34.5 15.6 87.2 16.1 62.8
17.1 54.1 18.2 85.8 19.7 64.9 21.4 22.3 25.8 25.7 26.2 35.1
[0432] In some embodiments, the Compound 1 Napsylate (Form B)
exhibits an XRPD that is substantially similar to FIG. 115.
Oxalate Salt
[0433] In some embodiments, the present disclosure provides an
oxalate salt of Compound 1 ("Compound 1 Oxalate"). In some
embodiments, the present disclosure provides a crystalline form of
Compound 1 Oxalate.
[0434] In one embodiment, the present disclosure provides Compound
1 Oxalate (Form A). In some embodiments, the Compound 1 Oxalate
(Form A) exhibits an XRPD comprising one or more peaks at about
6.1, 18.2, 19.1, 19.8, and 24.3 degrees two-theta with the margin
of error of about .+-.0.5; about .+-.0.4; about .+-.0.3; about
.+-.0.2; about .+-.0.1; about .+-.0.05; or less. In another
embodiment, the XRPD of the Compound 1 Oxalate (Form A) further
comprises one or more peaks at about 12.1, 13.9, 21.1, 21.7, and
24.7 degrees two-theta with the margin of error of about .+-.0.5;
about .+-.0.4; about .+-.0.3; about .+-.0.2; about .+-.0.1; about
.+-.0.05; or less.
[0435] In some embodiments, the Compound 1 Oxalate (Form A)
exhibits an XRPD comprising peaks shown in Table 53 below:
TABLE-US-00054 TABLE 53 XRPD Table of Compound 1 Oxalate (Form A)
2-Theta Intensity % 6.1 32.9 9.9 5.3 11.4 8.9 12.1 13.7 13.5 12.1
13.9 23.6 14.5 12.6 15.8 6.2 16.2 5.8 17.0 8.5 18.2 52.7 19.1 26.2
19.8 100 21.1 23.9 21.7 14.1 24.3 28.3 24.7 13.6 25.6 10.7 25.9
10.9 29.9 7.2 31.8 5.3 33.7 6 38.7 5.8
[0436] In some embodiments, the Compound 1 Oxalate (Form A)
exhibits an XRPD that is substantially similar to FIG. 116.
[0437] In some embodiments, the Compound 1 Oxalate (Form A)
exhibits a DSC thermogram comprising an endotherm at about
163.8.degree. C. with the error of margin of about .+-.2.5; about
.+-.2.0; about .+-.1.5; about .+-.1.0; about .+-.0.5; or less. In
some embodiments, the Compound 1 Oxalate (Form A) exhibits a DSC
thermogram comprising a sharp endotherm at about 198.6.degree. C.
with the error of margin of about .+-.2.5; about .+-.2.0; about
.+-.1.5; about .+-.1.0; about .+-.0.5; or less. In some
embodiments, the Compound 1 Oxalate exhibits a DSC thermogram that
is substantially similar to FIG. 117.
[0438] In some embodiments, the Compound 1 Oxalate (Form A)
exhibits a TGA thermogram that is substantially similar to FIG.
117. In other embodiments, the TGA thermogram of the Compound 1
Oxalate exhibits a weight loss of 0.0 to 0.4% in the temperature
range of 25 to 150.degree. C.
[0439] In some embodiments, the Compound 1 Oxalate (Form A)
exhibits a DVS isotherm plot that is substantially similar to FIG.
118. In other embodiments, the Compound 1 Oxalate (Form A) exhibits
a gravimetric moisture sorption of about 1.4% (by weight) at 80%
Relative Humidity.
[0440] In one embodiment, the present disclosure provides Compound
1 Oxalate (Form B). In some embodiments, the Compound 1 Oxalate
(Form B) exhibits an XRPD comprising one or more peaks at about
6.0, 6.3, 18.2, 18.8, and 20.0 degrees two-theta with the margin of
error of about .+-.0.5; about .+-.0.4; about .+-.0.3; about
.+-.0.2; about .+-.0.1; about .+-.0.05; or less. In another
embodiment, the XRPD of the Compound 1 Oxalate (Form B) further
comprises one or more peaks at about 12.1, 12.5, 17.8, 20.7, and
23.5 degrees two-theta with the margin of error of about .+-.0.5;
about .+-.0.4; about .+-.0.3; about .+-.0.2; about .+-.0.1; about
.+-.0.05; or less.
[0441] In some embodiments, the Compound 1 Oxalate (Form B)
exhibits an XRPD comprising peaks shown in Table 54 below:
TABLE-US-00055 TABLE 54 XRPD Table of Compound 1 Oxalate (Form B)
2-Theta Intensity % 6.0 37.1 6.3 56.6 9.7 13.9 9.9 13.2 12.1 27.1
12.5 34.1 13.4 23.2 14.0 22.5 14.9 22.5 16.9 21.6 17.8 30.4 18.2
47.3 18.8 100 19.8 23.4 20.0 42.9 20.7 28.3 22.7 16 23.5 33.6 25.5
9 29.5 10.2 29.9 7
[0442] In some embodiments, the Compound 1 Oxalate (Form B)
exhibits an XRPD that is substantially similar to FIG. 119.
P-Aminosalicylate Salt
[0443] In some embodiments, the present disclosure provides a
p-aminosalicylate salt of Compound 1 ("Compound 1
P-Aminosalicylate"). In some embodiments, the present disclosure
provides a crystalline form of Compound 1 P-Aminosalicylate.
[0444] In one embodiment, the present disclosure provides Compound
1 P-Aminosalicylate (Form A). In some embodiments, the Compound 1
P-Aminosalicylate (Form A) exhibits an XRPD comprising one or more
peaks at about 5.4, 13.8, 15.7, 20.7, and 21.2 degrees two-theta
with the margin of error of about .+-.0.5; about .+-.0.4; about
.+-.0.3; about .+-.0.2; about .+-.0.1; about .+-.0.05; or less. In
another embodiment, the XRPD of the Compound 1 P-Aminosalicylate
(Form A) further comprises one or more peaks at about 12.5, 13.5,
15.3, 19.2, and 27.6 degrees two-theta with the margin of error of
about .+-.0.5; about .+-.0.4; about .+-.0.3; about .+-.0.2; about
.+-.0.1; about .+-.0.05; or less.
[0445] In some embodiments, the Compound 1 P-Aminosalicylate (Form
A) exhibits an XRPD comprising peaks shown in Table 55 below:
TABLE-US-00056 TABLE 55 XRPD Table of Compound 1 P-Aminosalicylate
(Form A) 2-Theta Intensity % 5.4 46.7 7.0 8.2 9.9 6.4 12.5 27.2
13.0 18.7 13.5 18.8 13.8 42.3 14.9 5.6 15.3 20.5 15.7 32.9 16.6
18.3 17.5 5.7 18.5 10.8 18.9 10.9 19.2 25.3 19.9 10.9 20.7 91.8
21.2 100 21.8 9.1 22.1 9 23.0 9.1 23.3 8.9 24.2 13.3 27.6 29.6 28.1
15.2
[0446] In some embodiments, the Compound 1 P-Aminosalicylate (Form
A) exhibits an XRPD that is substantially similar to FIG. 120.
[0447] In some embodiments, the Compound 1 P-Aminosalicylate (Form
A) exhibits a DSC thermogram comprising an endotherm at about
97.1.degree. C. with the error of margin of about .+-.2.5; about
.+-.2.0; about .+-.1.5; about .+-.1.0; about .+-.0.5; or less. In
some embodiments, the Compound 1 P-Aminosalicylate (Form A)
exhibits a DSC thermogram comprising a endotherm at about
146.8.degree. C. with the error of margin of about .+-.2.5; about
.+-.2.0; about .+-.1.5; about .+-.1.0; about .+-.0.5; or less. In
some embodiments, the Compound 1 P-Aminosalicylate (Form A)
exhibits a DSC thermogram that is substantially similar to FIG.
121.
[0448] In some embodiments, the Compound 1 P-Aminosalicylate (Form
A) exhibits a TGA thermogram that is substantially similar to FIG.
121. In other embodiments, the TGA thermogram of the Compound 1
P-Aminosalicylate (Form A) exhibits a weight loss of 0.0 to 4.0% in
the temperature range of 25 to 120.degree. C.
[0449] In some embodiments, the Compound 1 P-Aminosalicylate (Form
A) exhibits a DVS isotherm plot that is substantially similar to
FIG. 122. In other embodiments, the Compound 1 P-Aminosalicylate
(Form A) exhibits a gravimetric moisture sorption of about 4.0% (by
weight) at 80% Relative Humidity.
[0450] In one embodiment, the present disclosure provides Compound
1 P-Aminosalicylate (Form B). In some embodiments, the Compound 1
P-Aminosalicylate (Form B) exhibits an XRPD comprising one or more
peaks at about 12.3, 15.2, 17.3, 19.9, and 22.9 degrees two-theta
with the margin of error of about .+-.0.5; about .+-.0.4; about
.+-.0.3; about .+-.0.2; about .+-.0.1; about .+-.0.05; or less. In
another embodiment, the XRPD of the Compound 1 P-Aminosalicylate
(Form B) further comprises one or more peaks at about 6.3, 12.5,
14.8, 16.4, and 20.7 degrees two-theta with the margin of error of
about .+-.0.5; about .+-.0.4; about .+-.0.3; about .+-.0.2; about
.+-.0.1; about .+-.0.05; or less.
[0451] In some embodiments, the Compound 1 P-Aminosalicylate (Form
B) exhibits an XRPD comprising peaks shown in Table 56 below:
TABLE-US-00057 TABLE 56 XRPD Table of Compound 1 P-Aminosalicylate
(Form B) 2-Theta Intensity % 6.3 47.2 12.3 100 12.5 44.8 14.0 18
14.8 42.6 15.2 83.7 16.4 47.8 16.9 31.3 17.3 66.8 18.3 17.9 18.9
17.7 19.5 41.3 19.9 84.9 20.7 42.4 22.0 19.9 22.9 65.1 23.2 31.9
25.9 21.4 28.1 19.6 29.1 23
[0452] In some embodiments, the Compound 1 P-Aminosalicylate (Form
B) exhibits an XRPD that is substantially similar to FIG. 123.
Maleate Salt
[0453] In some embodiments, the present disclosure provides a
maleate salt of Compound 1 ("Compound 1 Maleate"). In some
embodiments, the present disclosure provides a crystalline form of
Compound 1 maleate.
[0454] In one embodiment, the present disclosure provides Compound
1 Maleate (Form A). In some embodiments, the Compound 1 Maleate
(Form A) exhibits an XRPD comprising one or more peaks at about
6.4, 9.5, 11.2, 13.1, 15.0, and 17.6 degrees two-theta with the
margin of error of about .+-.0.5; about .+-.0.4; about .+-.0.3;
about .+-.0.2; about .+-.0.1; about .+-.0.05; or less. In another
embodiment, the XRPD of the Compound 1 Maleate (Form A) further
comprises one or more peaks at about 11.2, 12.6, 14.0, 16.7, and
19.2 degrees two-theta with the margin of error of about .+-.0.5;
about .+-.0.4; about .+-.0.3; about .+-.0.2; about .+-.0.1; about
.+-.0.05; or less.
[0455] In some embodiments, the Compound 1 Maleate (Form A)
exhibits an XRPD comprising peaks shown in Table 57 below:
TABLE-US-00058 TABLE 57 XRPD Table of Compound 1 Maleate (Form A)
2-Theta Intensity % 6.4 100 8.1 24.2 9.5 74.6 11.2 54.4 11.6 24.6
12.6 31.0 13.1 57.1 14.0 39.7 15.0 86.5 16.7 46.4 17.6 65.1 19.2
44.4 23.6 21.0 24.2 16.3 24.8 15.9
[0456] In some embodiments, the Compound 1 Maleate (Form A)
exhibits an XRPD that is substantially similar to FIG. 124.
Methods of Preparing Salts of Compound 1
[0457] Salts of Compound 1 (and crystalline forms thereof) may be
prepared, for example, by mixing Compound 1 free base and an acid
(such as hydrochloric acid) in a suitable solvent to provide the
Compound 1 salt as a suspension in the suitable solvent. In some
embodiments, the Compound 1 salts may be prepared by slow
evaporation, slow cooling or antisolvent addition to the mixture of
Compound 1 free base and an acid.
[0458] In some embodiments, the present disclosure provides methods
of making crystalline forms of salts of Compound 1. In some
embodiments, a salt of Compound 1 is suspended in a suitable
solvent for a time sufficient to provide a suspension of a
crystalline form of the salt of Compound 1.
[0459] In some embodiments, a salt of Compound 1 is dissolved in a
suitable solvent to provide a solution and a crystalline form of
the salt of Compound 1 is precipitated from the solution. In some
further embodiments, the salt of Compound 1 is dissolved by heating
a mixture of a salt of Compound 1 and a suitable solvent. In some
further embodiments, a crystalline form of the salt of Compound 1
is precipitated from the solution by cooling the solution. In other
further embodiments, the crystalline form of the salt of Compound 1
is precipitated from the solution by adding an anti-solvent (i.e.,
a solvent that decreases the solubility of the crystalline form of
the salt of Compound 1) the solution. In still other further
embodiments, a crystalline form of the salt of Compound 1 is
precipitated from the solution by evaporating a portion of the
suitable solvent from the solution. In certain further embodiments,
the suitable solvent comprises water.
[0460] In some embodiments, a salt of Compound 1 is heated to
provide a melt and the melt is cooled to provide a crystalline form
of the salt of Compound 1. In some embodiments, a salt of Compound
1 is compressed at a pressure and for a time sufficient (for
example, 5 mPa for 5 minutes) to provide a crystalline form of the
salt of Compound 1. In some embodiments, a salt of Compound 1 is
ground (for example, using a mortar and pestle or a mill) to
provide a crystalline form of the salt of Compound 1. In some
further embodiments, a salt of Compound 1 is ground in the presence
of a suitable solvent to provide crystalline form of the salt of
Compound 1. In some embodiments, a salt of Compound 1 is subjected
to a relative humidity and temperature (for example, 75% relative
humidity at 45.degree. C.), for a time sufficient to provide a
crystalline form of the salt of Compound 1.
[0461] In some embodiments, the suitable solvent comprises a
non-protic solvent. In some embodiments, the non-protic solvent
comprises at least one solvent selected from dimethylformamide
(DMF), dimethylacetamide (DMAC),
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU),
1,3-dimethyl-2-imidazolidinone (DMI), N-methylpyrrolidinone (NMP),
formamide, N-methylacetamide, N-methylformamide, acetonitrile,
dimethyl sulfoxide, propionitrile, ethyl formate, methyl acetate,
methyl ethyl ketone (MEK), hexachloroacetone, acetone, ethyl methyl
ketone, ethyl acetate, sulfolane, N,N-dimethylpropionamide,
tetramethylurea, nitromethane, nitrobenzene, or
hexamethylphosphoramide, diethoxymethane, tetrahydrofuran, toluene,
1,3-dioxane, 1,4-dioxane, furan, diethyl ether, tetrahydropyran,
diisopropyl ether, dibutyl ether, ethylene glycol dimethyl ether,
ethylene glycol diethyl ether, diethylene glycol dimethyl ether,
diethylene glycol diethyl ether, triethylene glycol dimethyl ether,
anisole, t-butyl methyl ether. In some embodiments, the non-protic
solvent is acetone. In some embodiments, the non-protic solvent is
ethyl acetate. In some embodiments, the non-protic solvent is
acetonitrile.
[0462] In some embodiments, the suitable solvent comprises protic
solvent. In some embodiments, the protic solvent comprises at least
one solvent selected from water, methanol, ethanol, 2-nitroethanol,
2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol,
1-propanol, 2-propanol, 2-methoxyethanol, 1-butanol, 2-butanol,
i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene
glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl
alcohol, diethylene glycol monomethyl ether, diethylene glycol
monoethyl ether, cyclohexanol, benzyl alcohol, phenol, and
glycerol. In some embodiments, the protic solvent comprises a
mixture of 2-propanol and water.
[0463] In some embodiments, the suitable solvent is a single
solvent. In some embodiments, the solvent is a mixture of solvents.
In some embodiments, the suitable solvent is a mixture of a protic
solvent and a non-protic solvent.
[0464] In certain embodiments, the Compound 1 salts (or crystalline
forms of the salts) are isolated after they are prepared. The
isolation of the salts (or crystalline forms of the salts) may be
accomplished using methods such as filtration, decantation,
centrifugation or other suitable separation technique.
[0465] In certain embodiments, the isolated salts (or crystalline
forms of the salts) are optionally washed with a liquid such as an
anti-solvent, acetonitrile, methanol, ethanol, ethyl acetate,
methyl ethyl ketone, acetone, tetrahydrofuran, or a combination
thereof.
[0466] In certain embodiments, the salts of Compound 1 prepared by
the embodiments above are substantially pure. For example, in some
embodiments, the chemical purity of the salt of Compound 1 (for
example Compound 1 Hydrochloride) may comprise at least about
99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about
99.4%, about 99.3%, about 99.2%, about 99.1%, about 99.0%, about
98%, about 97%, about 96%, or about 95% of the salt of Compound 1.
Chemical purity may be determined using methods known to those
skilled in the area (for example, HPLC chromatography with a
suitable solvent and column detecting a wavelength of 210 nm). In
some embodiments, the substantial purity is determined on a weight
percent basis. In some embodiments, the substantial purity is
determined on an area under the curve basis.
[0467] In some embodiments, the salts of Compound 1 prepared by the
embodiments above are crystalline. In certain embodiments, the
crystalline salts of Compound 1 prepared by the embodiments above
are substantially pure. For example, in some embodiments, the
polymorphic purity of the crystalline salt of Compound 1 (for
example Compound 1 Hydrochloride) may comprise at least about
99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about
99.4%, about 99.3%, about 99.2%, about 99.1%, about 99.0%, about
98%, about 97%, about 96%, about 95%, about 94%, about 93%, about
92%, about 91%, about 90%, about 85%, about 80%, about 75%, about
70%, about 65%, about 60%, about 55% or about 50% of a single
crystalline form (for example, Compound 1 Hydrochloride (Form A)).
Polymorphic purity may be determined using methods known to those
skilled in the art (including, among others, X-ray powder
crystallography as described in Shah, B., et al., Analytical
techniques for quantification of amorphous/crystalline phases in
pharmaceutical solids, J. Pharm. Sci. 2006, 95(8), pages 1641-1665
which is hereby incorporated by reference in its entirety).
[0468] In some embodiments, the salts of Compound 1 prepared by the
embodiments above are epimerically enriched at one or more
positions compared to the epimeric purity of the Compound 1 free
base starting material. For example, in some embodiments, the salt
of Compound 1 may comprise at least about 8:1, about 9:1, about
10:1, about 11:1, about 12:1, about 13:1, about 14:1, about 15:1,
or about 20:1 of 17-.beta.: 17.alpha. epimer of Compound 1. In some
embodiments, the salt of Compound 1 may comprise at least about
8:1, about 9:1, about 10:1, about 11:1, about 12:1, about 13:1,
about 14:1, about 15:1, or about 20:1 of 3.alpha.-hydroxy:
3.beta.-hydroxy of Compound 1. In other embodiments, the epimeric
purity of the salts of Compound 1 as described herein is
substantially the same as the epimeric purity of the Compound 1
free base starting material.
[0469] Pharmaceutical Compositions
[0470] In one aspect, the present disclosure provides a
pharmaceutical composition comprising a salt of Compound 1. In some
embodiments, the salt of Compound 1 is Compound 1 Hydrobromide,
Compound 1 Citrate, Compound 1 L-Malate, Compound 1 Mesylate,
Compound 1 Phosphate, Compound 1 L(+)-Tartrate, Compound 1
Hydrochloride, Compound 1 Tosylate, Compound 1 Glucuronate, or
Compound 1 Ethanesulfonate. In some embodiments, the salt of
Compound 1 is Compound 1 Hydrobromide (Form A). In some
embodiments, the salt of Compound 1 is Compound 1 Hydrobromide
(Form B). In some embodiments, the salt of Compound 1 is Compound 1
Hydrobromide (Form C). In some embodiments, the salt of Compound 1
is Compound 1 Hydrobromide (Form D). In some embodiments, the salt
of Compound 1 is Compound 1 Hydrobromide (Form E). In some
embodiments, the salt of Compound 1 is Compound 1 Citrate (Form A).
In some embodiments, the salt of Compound 1 is Compound 1 Citrate
(Form B). In some embodiments, the salt of Compound 1 is Compound 1
Citrate (Form C).
[0471] The compositions may be administered by a suitable route,
including, but not limited to, orally, parenterally, rectally,
topically and locally. The compositions may be in liquid,
semi-liquid or solid form and may be formulated using methods known
to those skilled in the art in a manner suitable for each route of
administration.
[0472] Orally administered dosage forms include, for example, solid
dosage forms (such as tablets, capsules, pills, granules, and the
like) and liquid dosage forms (such as oral solutions, oral
suspensions, syrups and the like).
[0473] In some embodiments, the pharmaceutical composition
comprises a therapeutically effective amount of a salt of Compound
1 or solvate thereof and a pharmaceutically acceptable
excipient.
[0474] Methods of Use
[0475] In one aspect, the present invention provides methods of
treating a disease or condition in a subject in need thereof
comprising administering to the subject a therapeutically effective
amount of a salt of Compound 1.
[0476] In some embodiments, the disease or condition is depression.
In some embodiments, the disease or condition is treatment
resistant depression. In some embodiments, the disease or condition
is post-partum depression. In some embodiments, the disease or
condition is major depressive disorder. In some embodiments, the
disease or condition is bipolar disorder. In some embodiments, the
disease or condition is epilepsy. In some embodiments, the disease
or condition is anxiety.
EXAMPLES
[0477] The present invention is further illustrated by reference to
the following Examples. However, it is noted that these Examples,
like the embodiments described above, are illustrative and are not
to be construed as restricting the scope of the invention in any
way.
[0478] "EtOAc" means ethyl acetate. "(m)DSC" means (modulated)
differential scanning calorimetry. "ACN" means acetonitrile. "AR"
means analytically pure. "DCM" means dichloromethane. "DMF" means
dimethyl formamide. "DMSO" means dimethylsulfoxide. "DI" means
distilled. "DSC" means differential scanning calorimetry. "DVS"
means dynamic vapor sorption. "e.q." means equivalents. "EtOH"
means ethyl alcohol. "FaSSIF" means fasted state simulated
intestinal fluids. "FeSSIF" means fed state simulated intestinal
fluids. "1H-NMR" means proton nuclear magnetic resonance. "IPA"
means isopropanol. "IPAC" means isopropyl acetate. "IPE" means
diisopropyl ether. "LC" means low crystallinity. "MEK" means methyl
ethyl ketone. "MeOH" means methyl alcohol. "MIBK" means methyl
isobutyl ketone. "MTBE" means Methyl Tert-Butyl ether. "NMR" means
nuclear magnetic resonance. "PLM" means polarized light microscope.
"RH" means relative humidity. "RRT" means relative retention time.
"RT" means Room temperature. "RT(min)" means Retention time. "SGF"
means simulated gastric fluids. "TGA" means Thermal gravimetric
analysis. "THF" means Tetrahydrofuran. "UPLC" means ultra
performance liquid chromatography. "XRPD" means X-ray Powder
Diffractometer.
[0479] In some instances, the ratio of Compound 1: acid in the
Compound 1 salts described herein was determined by the ion
chromatography (IC) using the following method: 25 ut of 10.0
.mu.g/mL sample or standard were injected into a Dionex IonPac AG18
column with a flow rate of 1.0 mL/min and detected by a Thermo
ICS-2100 Conductivity detector. ASRS-4 mm suppressor was set at 38
mA and the column temperature was 30.degree. C. The chromatographic
elution was 15 mM KOH with a total run time of 20 minutes.
[0480] X-Ray Powder Diffraction patterns were collected on a Rigaku
D/Max-2200/PC or a Bruker D8 Advance powder diffractometer. The
samples were irradiated with copper K-alpha X-rays (.lamda.=1.54179
.ANG.) with the generator operated at 40 kV/40 mA. The samples were
scanned in continuous mode from 3.degree. to 40.degree. with a
sample rotation speed of 15 rpm and a scanning rate of
10.degree./min.
[0481] Single crystal x-ray analysis: The single crystal X-ray
diffraction data were obtained was using Rigaku XtaLAB
Synergy-R(Cu) (Micro-Max007HF Cu mode, CuK.alpha.: .lamda.=1.54184
.ANG., Hypix6000HE detector) diffractometer.
[0482] The following SCXRD Instrument parameters were used:
TABLE-US-00059 Instrument Rigaku XtaLAB Synergy R X-Ray sources
generator MicroMax-007HF X-ray source (Cu/k.alpha.: 1.54184 .ANG.)
Detector HyPix 6000HE detector Goniometer Four-circle Kappa
Goniometer Low Temperature Devices Cryostream-700 (Oxford
Cryosystems) Software package CrysAlisPro (V1.171.40.14e)
[0483] A suitable single crystal with good diffraction quality was
separated out of the block-like crystal sample and was wrapped with
Paratone-N(an oil based cryoprotectant). The crystal was mounted on
a mylar loop in a random orientation and immersed in a stream of
nitrogen at the temperature specified in the Example, below.
Preliminary examination and data collection were performed on a
Rigaku XtaLAB Synergy R (CuK.alpha. radiation, .lamda.=1.54184
.ANG.) diffractometer and analyzed with the CrysAlisPro (Rigaku,
V1.171.40.14e, 2018) software package.
[0484] Structures were solved in the ShelXT (Sheldrick, G. M. Acta
Cryst. 2015, A71, 3-8.) structure solution program using Intrinsic
Phasing and refined with ShelXL (Version 2017/1; Sheldrick, G. M.
Acta Cryst. 2015, C71, 3-8) refinement package using full-matrix
least-squares on F.sup.2 contained in OLEX2 (Dolomanov, O. V.,
Bourhis, L. J., Gildea, R. J, Howard, J.A.K. & Puschmann, H. J.
Appl. Cryst. 2009, 42, 339-341). All non-hydrogen atoms were
refined anisotropically. The positions of the hydrogen atoms
connected with the carbon atoms were calculated geometrically and
refined using the riding model, but the hydrogen atoms connected
with nitrogen atom and oxygen atom were refined freely based on the
Difference Fourier Map.
[0485] DSC data were collected on a TA Q2000. For each sample
analyzed approximately 1 mg of the sample was placed in a hermetic
aluminum pan containing a pinhole and heated from 25.degree. C. to
250.degree. C. ramped at 10.degree. C./min.
[0486] TGA data were collected on TA Q5000. For each sample
analyzed approximately 4 mg of material was placed in an open
platinum pan and heated from 30.degree. C. to 300.degree. C. or
weight %<80% at a rate of 10.degree. C./min.
[0487] Dynamic Vapor Sorption (DVS) were collected conducted using
an SMS DVS Advantage 1 system. For each sample analyzed
approximately 10 mg of material was transferred into the DVS
instrument and recorded the weight change with respect to the
atmospheric humidity at 25.degree. C. using the following
parameters: Equilibrium dm/dt: 0.01%/min, (for min: 10 min and max:
180 min); drying setting were 0% RH for 120 min; RH (%) measurement
step at 10% and RH (%) measurement step scope of 0-90-0%.
[0488] .sup.1H-NMR were collected on a Bruker 400 MHz magnet. For
each sample analyzed, approximately 6 mg of material was dissolved
in 0.6 mL of d.sub.6-DMSO for analysis. As is known to those
skilled in the art, the relative ppm shift and integration values
for .sup.1H-NMR resonances may vary depending on various sample
factors, including, for example, water content in the d.sub.6-DMSO,
ion concentration in the sample, etc. Thus, the .sup.1H-NMR values
reported in the following examples should not be considered
characteristic for the respective salt and polymorphic form.
[0489] UPLC data were collected by injecting a 0.5 .mu.L of sample
or standard into a Waters Acquity UPLC Shield RP18 column with a
flow rate of 0.8 mL/min by an Agilent 1290 UPLC (detection
wavelength: 210 nm). The column was equilibrated with mobile phase
A which consisted of 0.1% H.sub.3PO.sub.4 in water. Mobile phase B
was acetonitrile (ACN). The chromatographic elution was programed
as follows with an additional minute after for re-equilibration and
a total run time of 6 minutes:
TABLE-US-00060 Time (mm) A(%) B(%) 0 90 10 4 10 90 5 10 90
[0490] The crystalline salts described herein were characterized by
polarized light microscopy. In some embodiments, the crystalline
salts described herein exhibit birefringence, which indicates
crystallinity.
Example 1: Preparation of Hydrobromide Salt of Compound 1
[0491] Hydrobromide Salts of Compound 1 may be prepared from
Compound 1 using the following exemplary methods.
Compound 1 HBr (Form A):
[0492] 500 mg of Compound 1 (Pattern A, see XRPD in FIG. 1) was
dissolved in 16.0 mL of acetone at 60.degree. C. while stirring at
500 rpm and held at 60.degree. C. for 1.5 hrs. 1.1 e.q. hydrobromic
acid in acetone (2.565 mL, 0.5 mol/L) was then added into the
Compound 1 solution and incubated at 60.degree. C. for 3 hrs, then
cooled to 25.degree. C. and held at 25.degree. C. for overnight.
This suspension was centrifuged and the precipitate collected and
washed with acetone. The obtained wet product was vacuum dried at
25.degree. C. for 72 hrs resulting in 532.16 mg of powder with a
yield of 72.05%.
[0493] The resulting solid is Compound 1 HBr (Form A). The ratio of
Compound 1:HBr in Compound 1 HBr (Form A) is 1:1.02 as determined
by ion chromatography. The XPRD is shown in FIG. 2; the DSC and TGA
are shown in FIG. 3; and the DVS is shown in FIG. 4.
[0494] Compound 1 HBr (Form B):
[0495] 1 g of Compound 1 HBr (Form A) was suspended in 20 mL of
0.603 water activity solution (14.5% water in acetone, v/v) to
generate a suspension of 50 mg/mL. The suspension was stirred at
700 rpm and held at 50.degree. C. for 26 hours. The suspension was
centrifuged and the precipitate collected. The obtained wet product
was vacuum dried at 30.degree. C. for three days resulting in
powder with yield of 70.82%. The ratio of Compound 1:HBr in
Compound 1 HBr (Form B) is 1:1.01 as determined by ion
chromatography. The XPRD is shown in FIG. 5; the DSC and TGA are
shown in FIG. 6; and the DVS is shown in FIG. 7.
[0496] Compound 1 HBr (Form C):
[0497] 500 mg of Compound 1 HBr (Form A) was dissolved in 4.5 mL of
DMSO to generate a clear solution, then 31.5 mL of water
(anti-solvent) was added to the DMSO solution. The solution was
left at room temperature for seven days. Afterward, the
precipitated material was isolated. The obtained wet product was
vacuum dried at 30.degree. C. for three days resulting in powder
with yield of 66.1%. The ratio of Compound 1:HBr in Compound 1 HBr
(Form C) is 1:1.09 as determined by ion chromatography. The XPRD is
shown in FIG. 8; the DSC and TGA are shown in FIG. 9; and the DVS
is shown in FIG. 10.
[0498] Compound 1 HBr (Form D):
[0499] Form D is observed by VT-XRPD when heating Form B to
160.degree. C. The XRPD is shown in FIG. 11; the TGA and DSC are
shown in FIG. 12.
[0500] Compound 1 HBr (Form E):
[0501] In a 20 mL vial with stir bar, Compound 1 (1.00 g, 1.0
equiv.) in EtOH (5 mL) was stirred at 60.degree. C. for 30 mins.
HBr (48% w/w in water, 0.3 mL, 1.1 equiv.) was added to the mixture
and stirred at 60.degree. C. for 1 hr. The reaction mixture was
cooled to 25.degree. C. and ethyl acetate anti-solvent (5 mL) was
added to the reaction mixture and stirred for 1 hr. The mixture was
kept in an ice bath for 30 mins followed by filtration and solids
were collected and dried under vacuum at 25.degree. C. overnight to
afford Compound 1 HBr (876 mg, 73.7% yield). The XRPD is shown in
FIG. 13; the DSC and TGA are shown in FIG. 14.
[0502] General Procedures to Prepare Compound 1 HBr
[0503] The following general procedures were conducted to prepare
Compound 1 HBr.
[0504] General Procedure 1
[0505] In a 20 mL vial with stir bar, Compound 1 (1.00 g, 1.0
equiv.) in solvent (15 mL, 15 mL/g Compound 1), was stirred at
60.degree. C. for 30 mins. HBr (48% w/w in water, 0.3 mL, 1.1
equiv.) was added to the reaction and stirred at 60.degree. C. for
1 hr. The reaction was cooled to 25.degree. C. and stirred for 1
hr. The mixture was kept in ice bath for 30 mins (procedure 1-2 was
kept at 25.degree. C.) followed by filtration and solids were
collected and dried under vacuum at 25.degree. C. overnight to
afford Compound 1 HBr.
[0506] General Procedure 2
[0507] In a 20 mL vial with stir bar, Compound 1 (1.00 g, 1.0
equiv.) in solvent (3.5 mL, 3.5 mL/g Compound 1), was stirred at
60.degree. C. for 30 mins. HBr (48% w/w in water, 0.3 mL, 1.1
equiv.) in acetone (3.5 mL, 3.5 mL/g Compound 1) was added to the
reaction and stirred at 60.degree. C. for 1 hr. The reaction was
cooled to 25.degree. C. and stirred for 1 hr. The mixture was kept
in ice bath for 30 mins followed by filtration and solids were
collected and dried under vacuum at 25.degree. C. overnight to
afford Compound 1 HBr.
[0508] General Procedure 3
[0509] In a 20 mL vial with stir bar, Compound 1 (1.00 g, 1.0
equiv.) in EtOH (5 mL, 5 mL/g Compound 1), was stirred at
60.degree. C. for 30 mins. HBr (48% w/w in water, 0.3 mL, 1.1
equiv.) was added to the mixture and stirred at 60.degree. C. for 1
hr. The reaction mixture was cooled to 25.degree. C., then
anti-solvent (5 mL, 5 mL/g Compound 1) was added to the reaction
mixture and stirred for 1 hr. The mixture was kept in an ice bath
for 30 mins followed by filtration and solids were collected and
dried under vacuum at 25.degree. C. overnight to afford Compound 1
HBr.
[0510] The following table summarizes preparations of Compound 1
HBr according to these general procedures:
TABLE-US-00061 General Procedure 1-2 1-2 1 1 1 3 Solvent Acetone 2-
EtOH EtOH/H.sub.2O MeOH EtOH/ (mL/g (15X) propanol (15X) (1:1, 15X)
(15X) EtOAc Compound 1) (15X) (1:1, 14X) Weight 88.1% 66.0% 50.9%
48.0% 38.0% 73.7% Yield Purity 98.5% 99.2% 99.1% 98.0% 99.6% 99.0%
Form by Form A Form A Form A Form A Form A + E Form E XRPD General
Procedure 1 1-2 2 2 3 3 Solvent MeOH/ EtOH/ EtOH/ EtOH/ EtOH/ EtOH/
(mL/g Acetone Acetone Acetone Acetone IPE EtOAc Compound 1) (1:1,
15X) (1:1, 15X) (1:2, 10.5X) (1:4, 17.5X) (1:2, 10.5X) (1:1, 20X)
Weight 48.2% 64.7% 77.4% 80.2% 80.3% 65.1% Yield Purity 99.8% 99.7%
99.7% 99.6% 99.7% 99.4% Form by Form E Form A Form A Form A Form A
+ E Form E XRPD General Procedure 3 3 3 3 3 3 Solvent EtOH/ EtOH/
EtOH/ EtOH/ EtOH/ EtOH/ (mL/g IPE EtOAc IPAc MTBE MIBK Toluene
Compound 1) (1:4, 17.5X) (1:1, 10X) (1:1 ,10X) (1:1, 10X) (1:1, 10X
(1:1, 10X) Weight 86.8% 74.4% 79.2% 82.0% 77.2% 64.4% Yield Purity
99.6% 99.7% 99.8% 99.8 % 99.8% 99.9% Form by Form Form E Form Form
Form E Form XRPD A + E A + E A + E A + E
[0511] Chemical and Physical Stability Test
[0512] For each salt, approximately 5 mg compound was added into an
8 mL glass vial with a multi-hole aluminum foil cap, and kept at
60.degree. C., 40.degree. C./75% RH for 1 week. For photostability
test, the compound in vial without cap was kept in photo-stability
chamber and exposed to a total illumination of 1.2 million lux-hrs,
while the sample in vial covered with aluminum foil completely was
considered as the dark control. Appearance by visual observation
were recorded followed by purity assessment and XPRD data
collection on the residual solids.
[0513] The chemical and physical stability test results for
Compound 1 HBr (Form A), Compound 1 HBr (Form B), Compound 1 HBr
(Form C) and Compound 1 free base are shown in the following
table:
TABLE-US-00062 XRPD Final Test Material Conditions pattern purity
Compound 1 60.degree. C., 1 w Pattern A 98.2 40.degree. C./75% RH,
1 w Pattern A 98.2 1.2 million lux-hrs Pattern A 97.9 Dark control
Pattern A 98.3 Hydrobromide 60.degree. C., 1 w Form A 98.0 (Form A)
40.degree. C./75% RH, 1 w Form A 98.2 1.2 million lux-hrs Form A
98.2 Dark control Form A 97.9 Hydrobromide 60.degree. C., 1 w Form
B 98.8 (Form B) 40.degree. C./75% RH, 1 w Form B 98.9 1.2 million
lux-hrs Form B 98.4 Dark control Form B 97.8 Hydrobromide
60.degree. C., 1 w Form C + B 98.1 (Form C) 40.degree. C./75% RH, 1
w Form C + B 98.4 1.2 million lux-hrs Form C + B 98.1 Dark control
Form C + B 98.0
Solubility Tests in Simulated Gastric and Intestinal Fluids
[0514] For each salt, between about 4-6 mg of Compound 1 or the
salt was added into a 2-mL vial in triplicate. Then 1 mL of
bio-relevant media (SGF, FaSSIF or FeSSIF) was added into the vial.
All the vials were placed on the thermo-mixer and kept at
37.degree. C. while shaking at 700 rpm. If the compounds were
completely dissolved in the media, then more compound was added
until the system became a suspension, no additional material was
added if the concentration of the compound exceeded 25 mg/mL. After
shaking at 37.degree. C. for 24 hrs, 300 .mu.L of suspension from
each system were isolated for analysis. The samples were
centrifuged at 12000 rpm for 5 mins and the supernatant were
analyzed by UPLC after dilution by ACN:H.sub.2O (4/1, V/V) for 10
times. The final pH values of bio-relevant media were measured and
recorded. The solubility results (mg/mL) in bio-relevant solutions
for Compound 1 HBr (Form A), Compound 1 HBr (Form B), Compound 1
HBr (Form C) and Compound 1 free base are shown in the following
table:
TABLE-US-00063 SGF FaSSIF FeSSIF (original (original (original pH =
1.82) pH = 6.51) pH = 4.99) Final Final Final Solute tested 24 h pH
24 h pH 24 h pH Compound 1 4.44 3.10 0.05 6.48 0.84 5.11
Hydrobromide 2.60 1.91 1.04 4.11 0.88 5.01 (Form A) Hydrobromide
1.28 1.89 0.09 5.51 0.74 4.89 (Form B) Hydrobromide 1.32 1.99 0.42
4.90 0.41 5.05 (Form C)
[0515] Single Crystal X-Ray Analysis of Compound 1 HBr Form B
[0516] The block-like single crystal of Compound 1 Hydrobromide
Form B used for SCXRD characterization were crystallized from
MeOH/MEK (1:3, v/v) solvent mixture by slow evaporation method.
[0517] Characterization of the salt by PLM and XRPD showed it to be
Compound 1 HBr Form B.
[0518] Cell parameters and an orientation matrix for data
collection were retrieved and refined (least-squares refinement) by
CrysAlisPro (Rigaku, V1.171.40.14e, 2018) software using the
setting angles of 45416 reflections in the range
3.4880.degree.<.theta.<75.8360.degree.. The data were
collected to a minimum diffraction angle (.theta.) of 3.506.degree.
and a maximum diffraction angle (.theta.) of 68.243.degree. at
120.00 K. The final completeness is 100%. The mean I/.sigma. of the
data is 91.7 and the maximum resolution that was achieved was 0.83
.ANG..
[0519] SCXRD data obtained by the methods described herein is
provided in the table below.
TABLE-US-00064 Temperature 120.00 (10) K a 9.28522 (4) .ANG. b
10.84366 (4) .ANG. c 25.21443 (11) .ANG. .alpha. 90.degree. .beta.
90.degree. .gamma. 90.degree. Space group P2.sub.12.sub.12.sub.1
Crystal system Orthorhombic Volume 2538.734 (18) .ANG..sup.3
Empirical formula C.sub.26H.sub.41BrN.sub.2O.sub.3H.sub.2O
[0520] Single Crystal X-Ray Analysis of Compound 1 HBr Form E
[0521] The block-like single crystal of Compound 1 Hydrobromide
Form E used for SCXRD characterization were crystallized from
MeOH/MEK (1:3, v/v) solvent mixture by slow evaporation method.
Characterization of the salt by PLM and XRPD showed it to be
Compound 1 HBr Form E.
[0522] Data collection at 120 K: Cell parameters and an orientation
matrix for data collection were retrieved and refined
(least-squares refinement) by CrysAlisPro (Rigaku, V1.171.40.14e,
2018) software using the setting angles of 10196 reflections in the
range 3.4990.degree.<.theta.<75.6570.degree.. The data were
collected to a minimum diffraction angle (.theta.) of 3.508.degree.
and a maximum diffraction angle (.theta.) of 66.553.degree. at
120.00 (10) K. The final completeness is 100%. The mean I/.sigma.
of the data is 19.3 and the maximum resolution that was achieved
was 0.84 .ANG..
[0523] Data collection at Room Temperature: Cell parameters and an
orientation matrix for data collection were retrieved and refined
(least-squares refinement) by CrysAlisPro (Rigaku, V1.171.40.14e,
2018) software using the setting angles of 17551 reflections in the
range 3.4830.degree.<.theta.<75.8250.degree.. The data were
collected to a minimum diffraction angle (.theta.) of 3.496.degree.
and a maximum diffraction angle (.theta.) of 66.597.degree. at room
temperature. The final completeness is 99.8%. The mean I/.sigma. of
the data is 40.0 and the maximum resolution that was achieved was
0.84 .ANG..
[0524] SCXRD data obtained by the methods described herein is
provided in the table below.
TABLE-US-00065 Temperature 120.00 (10) K Room Temperature a 7.49140
(10) .ANG. 23.3046 (5) .ANG. b 15.0483 (2) .ANG. 15.0483 (3) .ANG.
c 23.0349 (2) .ANG. 7.53530 (10) .ANG. .alpha. 90.degree.
90.degree. .beta. 90.degree. 90.degree. .gamma. 90.degree.
90.degree. Space group P2.sub.12.sub.12.sub.1
P2.sub.12.sub.12.sub.1 Crystal system Orthorhombic Orthorhombic
Volume 2596.79 (5) .ANG..sup.3 2642.59 (8) .ANG..sup.3 Empirical
formula C.sub.26H.sub.41BrN.sub.2O.sub.3
C.sub.26H.sub.41BrN.sub.2O.sub.3
Example 2: Preparation of Citrate Salt of Compound 1
[0525] Citrate Salts of Compound 1 may be prepared from Compound 1
using the following exemplary methods.
[0526] Compound 1 Citrate (Form A):
[0527] 200 mg of Compound 1 was dissolved in 10.0 mL of acetone at
60.degree. C. while stirring at 500 rpm and held at 60.degree. C.
for 1.5 hrs. 1.1 e.q. Citric acid in acetone (1.027 mL, 0.5 mol/L)
was then added into the Compound 1 solution and incubated at
60.degree. C. for 3 hrs, then cooled to 25.degree. C. and held at
25.degree. C. for 20 hrs. The solution was evaporated by nitrogen
to remove the organic solvent. The obtained wet product was vacuum
dried at 25.degree. C. for 42 hrs resulting in 218.85 mg of powder
with a yield of 71.1%.
[0528] The resulting solid is Compound 1 Citrate (Form A). The
ratio of Compound 1: citric acid in Compound 1 Citrate (Form A) is
1:1.23 as determined by ion chromatography. The XPRD is shown in
FIG. 15; the DSC and TGA are shown in FIG. 16; and the DVS is shown
in FIG. 17.
[0529] Compound 1 Citrate (Form A) was analyzed by .sup.1H-NMR in
deuterated DMSO resulting in the following chemical shifts: .sup.1H
NMR (400 MHz, DMSO-d.sub.6): .delta. 0.48-0.88 (m, 7H) 2.03-2.22
(m, 2H) 2.46-2.86 (m, 28H) 3.00-3.17 (m, 3H) 3.19-3.46 (m, 5H)
4.74-5.35 (m, 2H) 7.09 (s, 1H) 7.19 (s, 1H) 7.86 (s, 1H).
[0530] Compound 1 Citrate (Form B):
[0531] 500 mg of Compound 1 Citrate (Form A) was dissolved in 4.0
mL of 0.901 water activity solution (65% water in acetone, v/v) to
generate a suspension targeting 125 mg/mL. The suspension was
stirred at 300 rpm and held at 50.degree. C. for 3 days. The
suspension was centrifuged and the precipitate collected. The wet
crude product was vacuum dried at 30.degree. C. for one day
resulting in powder with yield of 56.9%. The ratio of Compound 1:
citric acid in Compound 1 Citrate (Form B) is 1:1.17 as determined
by ion chromatography. The XPRD is shown in FIG. 18; the DSC and
TGA are shown in FIG. 19; and the DVS is shown in FIG. 20. Compound
1 Citrate (Form B) was analyzed by .sup.1H-NMR in deuterated DMSO
resulting in the following chemical shifts: .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 0.53-0.79 (m, 7H) 0.85-1.76 (m, 24H)
1.99-2.14 (m, 3H) 2.32-2.35 (m, 1H) 2.61-2.74 (m, 6H) 3.00-3.09 (m,
2H) 4.89-5.13 (m, 1H) 6.99 (s, 1H) 7.11 (s, 1H) 7.74 (s, 1H).
[0532] Compound 1 Citrate (Form C):
[0533] A sample of Compound 1 Citrate Form A was stirred as a
suspension in acetonitrile at 50.degree. C. The resultant solids
were isolated by filtration.
[0534] General Procedures to Prepare Compound 1 Citrate
[0535] The following general procedures were conducted to prepare
Compound 1 Citrate.
[0536] General Procedure A
[0537] To a 20 mL vial equipped with stir bar, Compound (1.00 g,
1.0 equiv.) and solvent or co-solvent were charged. The resulting
mixture was heated to 60.degree. C. for 30 mins. To the mixture was
added citric acid monohydrate (0.54 g, 1.1 equiv.) in solvent or
co-solvent (pre-heated to dissolution) at 60.degree. C. and stirred
for 1 hr. The reaction was cooled to 25.degree. C. and stirred
overnight. The suspension was filtered and the wet cake was washed
with acetone. The solids were collected and dried under vacuum at
25.degree. C. overnight to afford Compound 1 Citrate.
[0538] General Procedure A-2
[0539] To a 20 mL vial equipped with stir bar, Compound 1 (1.00 g,
1.0 equiv.) and co-solvent (10 mL, 10 mL/g Compound 1) were
charged. The resulting mixture was heated to 60.degree. C. for 30
mins. To the mixture was added citric acid monohydrate (0.54 g, 1.1
equiv.) in co-solvent (2 mL, 2 mL/g Compound 1) (pre-heated to
dissolution) at 60.degree. C. and stirred for 1 hr. The reaction
was cooled to 0.degree. C. (no ppt.). The mixture was dried under
vacuum and added co-solvent (3 mL, 3 mL/g Compound 1) at 60.degree.
C. The reaction was cooled to 25.degree. C. and stirred overnight.
The suspension was filtered and the wet cake was washed with
acetone. The solids were collected and dried under vacuum at
25.degree. C. overnight to afford Compound 1 Citrate.
[0540] General Procedure B
[0541] To a 20 mL vial equipped with stir bar, Compound 1 (1.00 g,
1.0 equiv.) and EtOH (3.5 mL, 3.5 mL/g Compound 1) were charged.
The resulting mixture was heated to 60.degree. C. for 30 mins. To
the mixture was added citric acid monohydrate (0.54 g, 1.1 equiv.)
in EtOH (1.5 mL, 1.5 mL/g Compound 1) (pre-heated to dissolution)
at 60.degree. C. and stirred for 1 hr. The reaction was cooled to
25.degree. C. and added anti-solvent (5 mL, 5 mL/g Compound 1) at
25.degree. C. The reaction was cooled to 0.degree. C. and then
stirred for 1 hr. The mixture was stirred at 25.degree. C.
overnight. The reaction was cooled to 0.degree. C. and then stirred
for 1 hr. The suspension was filtered and the wet cake was washed
with acetone. The solids were collected and dried under vacuum at
25.degree. C. overnight to afford Compound 1 Citrate.
[0542] General Procedure C
[0543] To a four-neck 250 mL flask equipped with a mechanical
stirrer (5.5 cm paddle; 100 rpm), thermometer, and N2 inlet,
Compound 1 (5.00 g, 1.0 equiv.) and EtOH/IPAc (1:1, 40 mL, 8 mL/g
Compound 1) were charged. The resulting mixture was heated to
60.degree. C. for 30 mins. To the mixture was added citric acid
monohydrate (2.73 g, 1.1 equiv.) in EtOH/IPAc (1:1, 10 mL, 2 mL/g
Compound 1) (pre-heated to dissolution) at 60.degree. C., and
stirred for 1 hr. The reaction was cooled to 25.degree. C. and then
stirred for 1 hr. The reaction was cooled to 0.degree. C. and then
stirred for 30 mins. The suspension was filtered and the wet cake
was washed with acetone. The solids were collected and dried under
vacuum at 50.degree. C. overnight to afford Compound 1 Citrate.
[0544] The following table summarizes preparations of Compound 1
Citrate according to these general procedures:
TABLE-US-00066 Preparation General 1 2 3 4 5 6 7 Procedure A C A A
A A-2 B Solvent Acetone EtOH/ 10-20% 1- EtOH EtOH/ EtOH/ (mL/g
(30X) IPAc EtOH butanol (5X) Acetone EtOAc Compound 1) (1:1, 10X)
in H.sub.2O (10X) (1:1, (1:1, 10X) (20X) 12X.fwdarw.3X) Weight
Yield 67.0% 90.0% 60.7% 75.1% 66.1% 63.8% 67.5% Purity 99.0% 99.6 %
98.2% 99.01% 99.4% 99.6 % 99.6 % Form by Form A Form A Form C Form
A Form A Form A Form A XRPD Preparation General 8 9 10 11 12 13 14
Procedure B B B B B B B Solvent EtOH/ EtOH/ EtOH/ EtOH/ EtOH/ EtOH/
EtOH/ (mL/g IPE IPAc IPAc MTBE MIBK Toluene H.sub.2O Compound 1)
(1:1, 10X) (1:1, 10X) (1:1, 10X) (1:1, 10X) (1:1, 10X) (1:1, 10X)
(1:1, 10X) Weight Yield 82.2% 74.8% 76.2% 75.2% 71.5% 66.0% 47.7%
Purity 99.0% 99.1% 99.80% 99.0% 99.2% 99.7% 99.4% Form by Form A
Form A Form A Form A Form A Form A Form A XRPD N.R. means that free
base was recovered from the experiment.
Chemical and Physical Stability Test
[0545] Chemical and physical stability testing was carried out
using the procedures set forth in Example 1. The chemical and
physical stability test results for Compound 1 Citrate (Form A),
Compound 1 Citrate (Form B) and Compound 1 free base are shown in
the following table:
TABLE-US-00067 XRPD Final Test Material Conditions patterns purity
Compound 1 60.degree. C., 1 w Pattern A 99.3 40.degree. C./75% RH,
1 w Pattern A 99.1 1.2 million lux-hrs Pattern A 99.2 Dark control
Pattern A 99.1 Citrate 60.degree. C., 1 w Form A 99.5 (Form A)
40.degree. C./75% RH, 1 w Form A 99.4 1.2 million lux-hrs Form A
99.5 Dark control Form A 99.5 Citrate 60.degree. C., 1 w Form B
97.7 (Form B) 40.degree. C./75% RH, 1 w Form B 98.3 1.2 million
lux-hrs Form B 99.3 Dark control Form B 99.1
Solubility Tests in Simulated Gastric and Intestinal Fluids
[0546] Solubility Tests in Simulated Gastric and Intestinal Fluids
was carried out using the procedures set forth in Example 1. The
solubility results (mg/mL) in bio-relevant solutions for Compound 1
Citrate (Form A), Compound 1 Citrate (Form B) and Compound 1 free
base are shown in the following table:
TABLE-US-00068 SGF FaSSIF FeSSIF (original pH = 1.82) (original pH
= 6.50) (original pH = 4.99) Solute tested 1 h 24 h Final pH 1 h 24
h Final pH 1 h 24 h Final pH Compound 1 3.41 2.81 2.07 0.03 0.03
6.47 0.87 0.95 5.00 Citrate 4.23 4.27 3.00 0.18 0.16 4.85 2.18 0.38
4.71 (Form A) Citrate N/A 8.00 2.79 N/A 0.33 5.05 N/A 0.37 5.13
(Form B)
[0547] Single Crystal X-Ray Structure of Compound 1 Citrate Form
A
[0548] A block-like single crystal sample Compound 1 Citrate Form A
used for SCXRD characterization was crystallized from THF solvent
by slow evaporation method.
[0549] Characterization of the salt by PLM and XRPD showed it to be
Compound 1 Citrate Form A.
[0550] Cell parameters and an orientation matrix for data
collection were retrieved and refined (least-squares refinement) by
CrysAlisPro (Rigaku, V1.171.40.14e, 2018) software using the
setting angles of 64393 reflections in the range
3.7580.degree.<.theta.<75.8720.degree.. The data were
collected to a minimum diffraction angle (.theta.) of 3.785.degree.
and a maximum diffraction angle (.theta.) of 66.597.degree. at
120.00 K. The final completeness is 99.3%. The mean I/.sigma. of
the data is 81.3 and the maximum resolution that was achieved was
0.84 .ANG..
[0551] SCXRD data obtained by the methods described herein is
provided in the table below.
TABLE-US-00069 Temperature 120.00 (10) K a 8.85550 (10) .ANG. b
12.18980 (10) .ANG. c 16.49670 (10) .ANG. .alpha. 73.6770
(10).degree. .beta. 76.5960 (10).degree. .gamma. 83.2390
(10).degree. Space group P1 Crystal system Triclinic Volume 1659.80
(3) .ANG..sup.3 Empirical formula
(C.sub.26H.sub.42N.sub.2O.sub.3).sup.+(C.sub.6H.sub.6O.sub.7).sup.-H.sub.-
2O
Example 3: Preparation of Mesylate Salt of Compound 1
[0552] A Mesylate Salt of Compound 1 may be prepared from Compound
1 using the following exemplary methods.
Compound 1 Mesylate (Form A):
[0553] 200 mg of Compound 1 was dissolved in 10.0 mL of EtOAc at
60.degree. C. while stirring at 500 rpm and held at 60.degree. C.
for 1 hr. 1.1 e.q. methanesulfonic acid in EtOAc (1.027 mL, 0.5
mol/L) was then added into the Compound 1 solution and incubated at
60.degree. C. for 3 hrs, then cooled to 25.degree. C. and held at
25.degree. C. for 20 hrs. This suspension was centrifuged and the
precipitate collected and washed with EtOAc. The obtained wet
product was vacuum dried at 35.degree. C. for 22 hrs resulting in
234.52 mg of powder with a yield of 94.1%.
[0554] The resulting solid is Compound 1 Mesylate (Form A). The
ratio of Compound 1: methanesulfonic acid in Compound 1 Mesylate
(Form A) is 1:1.08 as determined by ion chromatography. The XPRD is
shown in FIG. 22; the DSC and TGA are shown in FIG. 23; and the DVS
is shown in FIG. 24.
[0555] Compound 1 Mesylate (Form A) was analyzed by .sup.1H-NMR in
deuterated DMSO resulting in the following chemical shifts: .sup.1H
NMR (400 MHz, DMSO-d.sub.6): .delta. 0.54-0.81 (m, 7H) 0.84 (t,
J=7.44 Hz, 1H) 1.84-2.17 (m, 3H) 2.31 (s, 3H) 2.41-2.59 (m, 20H)
2.65-2.83 (m, 1H) 3.05 (s, 2H) 3.22-3.48 (m, 1H) 3.23-3.51 (m, 6H)
4.96-5.52 (m, 1H) 4.96-5.52 (m, 1H) 7.62 (s, 1H) 7.55-7.64 (m, 1H)
7.62-7.77 (m, 1H) 9.01 (s, 1H).
Compound 1 Mesylate (Form B):
[0556] 200 mg of Compound 1 was dissolved in 10.0 mL of EtOAc at
60.degree. C. while stirring at 500 rpm and held at 60.degree. C.
for 1 hr. 1.1 e.q. methane sulfonic acid in EtOAc (1.027 mL, 0.5
mol/L) was then added into the Compound 1 solution and incubated at
60.degree. C. for 3 hrs, then cooled to 25.degree. C. and held at
25.degree. C. for 20 hrs. This suspension was centrifuged and the
precipitate collected and washed with EtOAc. The obtained wet
product was vacuumed dried at 35.degree. C. for 22 hrs resulting in
234.52 mg powder with a yield of 94.1%.
[0557] The resulting solid is Compound 1 Mesylate (Form B). The
XPRD is shown in FIG. 25A.
Compound 1 Mesylate (Form C):
[0558] Compound 1 Mesylate (Form C) was prepared using solvent ACN
solvent and methane sulfonic acid. For liquid counter-ion, 50 mg
Compound 1 was weighed into 2 mL vials, and 743 .mu.L solvents were
added in the vials subsequently. Then 1.1 e.g. counter-ions
solutions of corresponding solvent (257 .mu.L, concentration: 0.5
mol/L) was added to the vial. The vial was placed on the
thermo-mixer with a stirrer bar and heated to 50.degree. C. After
keeping at 50.degree. C. under stirring at 900 rpm for 18 hrs, the
vial was then cooled to 25.degree. C. After keeping at 25.degree.
C. for 1 hr, the solids in suspensions were isolated by
centrifugation and dried in the vacuum oven at 30.degree. C.
overnight.
[0559] The resulting solid is Compound 1 Mesylate (Form C). The
XPRD is shown in FIG. 25B.
Compound 1 Mesylate (Form D):
[0560] Approximately 5 mg Compound 1 Mesylate (Form A) was added
into an 8 mL glass vial with a multi-hole aluminum foil cap, and
kept at 60.degree. C., 40.degree. C./75% RH for 1 week. Appearance
by visual observation were recorded followed by purity assessment
and XPRD data collection on the residual solids. The resulting
solid is Compound 1 Mesylate (Form D). The dried solids were
characterized by PLM and XRPD.
The XPRD is shown in FIG. 26.
Chemical and Physical Stability Test
[0561] Chemical and physical stability testing was carried out
using the procedures set forth in Example 1. The chemical and
physical stability test results for Compound 1 Mesylate (Form A)
and Compound 1 free base are shown in the following table:
TABLE-US-00070 XRPD Final Test material Conditions patterns purity
Compound 1 60.degree. C., 1 w Pattern A 99.3 40.degree. C./75% RH,
1 w Pattern A 99.1 1.2 million lux-hrs Pattern A 99.2 Dark control
Pattern A 99.1 Mesylate 60.degree. C., 1 w Form A 99.4 (Form A)
40.degree. C./75% RH, 1 w Form D 99.4 (see FIG. 26) 1.2 million
lux-hrs Form A 99.3 Dark control Form A 99.4
Solubility Tests in Simulated Gastric and Intestinal Fluids
[0562] Solubility Tests in Simulated Gastric and Intestinal Fluids
was carried out using the procedures set forth in Example 1. The
solubility results (mg/mL) in bio-relevant solutions for Compound 1
Mesylate (Form A) and Compound 1 free base are shown in the
following table:
TABLE-US-00071 SGF FaSSIF FeSSIF (original pH = 1.82) (original pH
= 6.50) (original pH = 4.99) Solute tested 1 h 24 h Final pH 1 h 24
h Final pH 1 h 24 h Final pH Compound 1 3.41 2.81 2.07 0.03 0.03
6.47 0.87 0.95 5.00 Mesylate >29.38 >26.49 2.07 0.10 0.09
5.16 1.66 0.004 5.05 (Form A)
Example 4: Preparation of Phosphate Salt of Compound 1
[0563] A Phosphate Salt of Compound 1 may be prepared from Compound
1 using the following exemplary method.
[0564] 200 mg of Compound 1 was dissolved in 10.0 mL of acetone at
60.degree. C. while stirring at 500 rpm and held at 60.degree. C.
for 1.5 hrs. 1.1 e.q. phosphoric acid in acetone (1.027 mL, 0.5
mol/L) was then added into the Compound 1 solution and incubated at
60.degree. C. for 3 hrs, then cooled to 25.degree. C. and held at
25.degree. C. for 20 hrs. This suspension was centrifuged and the
precipitate collected and washed with acetone. The obtained wet
product was vacuum dried at 30.degree. C. for 42 hrs resulting in
233.51 mg of powder with a yield of 93.3%.
[0565] The resulting solid is Compound 1 Phosphate (Form A). The
ratio of Compound 1: phosphoric acid in Compound 1 Phosphate (Form
A) is 1:0.9 as determined by ion chromatography. The XPRD is shown
in FIG. 27; the DSC and TGA are shown in FIG. 28; and the DVS is
shown in FIG. 29.
Chemical and Physical Stability Test
[0566] Chemical and physical stability testing was carried out
using the procedures set forth in Example 1. The chemical and
physical stability test results for Compound 1 Phosphate (Form A)
and Compound 1 free base are shown in the following table:
TABLE-US-00072 XRPD Final Test Material Conditions patterns purity
Compound 1 60.degree. C., 1 w Pattern A 99.3 40.degree. C./75% RH,
1 w Pattern A 99.1 1.2 million lux-hrs Pattern A 99.2 Dark control
Pattern A 99.1 Phosphate 60.degree. C., 1 w Form A 99.2 (Form A)
40.degree. C./75% RH, 1 w Form A 99.2 1.2 million lux-hrs Form A
98.9 Dark control Form A 99.2
[0567] Solubility Tests in Simulated Gastric and Intestinal
Fluids
[0568] Solubility Tests in Simulated Gastric and Intestinal Fluids
was carried out using the procedures set forth in Example 1. The
solubility results (mg/mL) in bio-relevant solutions for Compound 1
Phosphate (Form A) and Compound 1 free base are shown in the
following table:
TABLE-US-00073 SGF FaSSIF FeSSIF (original pH = 1.82) (original pH
= 6.50) (original pH = 4.99) Solute tested 1 h 24 h Final pH 1 h 24
h Final pH 1 h 24 h Final pH Compound 1 3.41 2.81 2.07 0.03 0.03
6.47 0.87 0.95 5.00 Phosphate 18.94 14.26 2.47 0.72 0.70 4.28 1.62
0.004 4.94 (Form A)
Example 5: Preparation of L(+)-Tartrate Salt of Compound 1
[0569] L(+)-Tartrate Salts of Compound 1 may be prepared from
Compound 1 using the following exemplary methods.
Compound 1 L(+)-Tartrate (Form A):
[0570] 200 mg of Compound 1 was dissolved in 10.0 mL of acetone at
60.degree. C. while stirring at 500 rpm and held at 60.degree. C.
for 1.5 hrs. 1.1 e.q. L(+)-tartaric acid powder (77 mg, 0.5 mmol)
was then added into the Compound 1 solution and incubated at
60.degree. C. for 3 hrs, then cooled to 25.degree. C. and held at
25.degree. C. for 20 hrs. The suspension was centrifuged and the
precipitate collected and washed with acetone. The obtained wet
product was vacuum dried at 30.degree. C. for 42 hrs resulting in
237.95 mg of powder with a yield of 85.9%.
[0571] The resulting solid is Compound 1 L(+)-Tartrate (Form A).
The ratio of Compound 1: tartaric acid in Compound 1 L(+)-Tartrate
(Form A) is 1:1.15 as determined by ion chromatography. The XPRD is
shown in FIG. 30; the DSC and TGA are shown in FIG. 31; and the DVS
is shown in FIG. 32.
[0572] Compound 1 L(+)-Tartrate (Form A) was analyzed by
.sup.1H-NMR in deuterated DMSO resulting in the following chemical
shifts: .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 0.49-0.84 (m,
7H) 0.90-1.75 (m, 21H) 1.94-2.21 (m, 3H) 2.35-2.58 (m, 14H)
2.66-2.80 (m, 1H) 3.10 (s, 2H) 3.23-3.34 (m, 3H) 4.24-4.39 (m, 2H)
4.80-5.19 (m, 2H) 6.98 (s, 1H) 7.12 (s, 1H) 7.67 (s, 1H).
Compound 1 L(+)-Tartrate (Form B):
[0573] 200 mg of Compound 1 was dissolved in 10.0 mL of EtOAc at
60.degree. C. while stirring at 500 rpm and held at 60.degree. C.
for 1 hr. 1.1 e.q. L(+)-tartaric acid powder (77 mg, 0.5 mmol) was
then added into the RX-0001175 solution and incubated at 60.degree.
C. for 3 hrs, then cooled to 25.degree. C. and held at 25.degree.
C. for 20 hrs. The suspension was centrifuged and the precipitate
collected and washed with EtOAc. The obtained wet product was
vacuum dried at 35.degree. C. for 22 hrs resulting in 254.08 mg of
powder with a yield of 91.7%.
[0574] The resulting solid is Compound 1 L(+)-Tartrate (Form B).
The ratio of Compound 1: tartaric acid in Compound 1 L(+)-Tartrate
(Form B) is 1:1.19 as determined by ion chromatography. The XPRD is
shown in FIG. 33; the DSC and TGA are shown in FIG. 34; and the DVS
is shown in FIG. 35.
[0575] Compound 1 L(+)-Tartrate (Form B) was analyzed by
.sup.1H-NMR in deuterated DMSO resulting in the following chemical
shifts: .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 0.50-0.82 (m,
6H) 1.91-2.22 (m, 2H) 3.03 (s, 2H) 3.24 (s, 2H) 3.14-3.53 (m, 1H)
4.27 (s, 2H) 4.54-5.21 (m, 2H) 6.71-7.18 (m, 2H) 7.59 (s, 1H).
[0576] Chemical and Physical Stability Test
[0577] Chemical and physical stability testing was carried out
using the procedures set forth in Example 1. The chemical and
physical stability test results for Compound 1 L(+)-Tartrate (Form
A), Compound 1 L(+)-Tartrate (Form B), and Compound 1 free base are
shown in the following table:
TABLE-US-00074 Starting XRPD Final materials Conditions patterns
purity Compound 1 60.degree. C., 1 w Pattern A 99.3 40.degree.
C./75% RH, 1 w Pattern A 99.1 1.2 million lux-hrs Pattern A 99.2
Dark control Pattern A 99.1 L(+)-Tartrate 60.degree. C., 1 w Form A
99.3 (Form A) 40.degree. C./75% RH, 1 w Form A 99.3 1.2 million
lux-hrs Form A 99.4 Dark control Form A 99.2 L(+)-Tartrate
60.degree. C., 1 w Form B 99.2 (Form B) 40.degree. C./75% RH, 1 w
Form B 99.2 1.2 million lux-hrs Form B 99.3 Dark control Form B
99.2
Solubility Tests in Simulated Gastric and Intestinal Fluids
[0578] Solubility Tests in Simulated Gastric and Intestinal Fluids
was carried out using the procedures set forth in Example 1. The
solubility results (mg/mL) in bio-relevant solutions for Compound 1
L(+)-Tartrate (Form A), Compound 1 L(+)-Tartrate (Form B), and
Compound 1 free base are shown in the following table:
TABLE-US-00075 SGF FaSSIF FeSSIF (original pH = 1.82) (original pH
= 6.50) (original pH = 4.99) Solute tested 1 h 24 h Final pH 1 h 24
h Final pH 1 h 24 h Final pH Compound 1 3.41 2.81 2.07 0.03 0.03
6.47 0.87 0.95 5.00 L(+)- 5.76 5.82 2.91 0.58 0.54 4.32 1.98 1.07
4.79 Tartrate (Form A) L(+)- 6.03 5.42 2.77 0.61 0.56 4.35 2.11
0.98 4.79 Tartrate (Form B)
Example 6: Preparation of Fumarate of Compound 1
[0579] Fumarate Salts of Compound 1 may be prepared from Compound 1
using the following exemplary method.
Compound 1 Fumarate (Form A):
[0580] 200 mg of Compound 1 was dissolved in 10.0 mL of acetone at
60.degree. C. while stirring at 500 rpm and held at 60.degree. C.
for 1.5 hrs. 1.1 e.q. fumaric acid powder (60 mg, 0.51 mmol) was
then added into the Compound 1 solution and incubated at 60.degree.
C. for 3 hrs, then cooled to 25.degree. C. and held at 25.degree.
C. for 20 hrs. A 2-fold volume of heptane was then added to the
acetone mixture which produced a suspension. This suspension was
centrifuged and the precipitate collected, then vacuum dried at
25.degree. C. for 42 hrs resulting in 75.58 mg of powder with a
yield of 29.1%.
[0581] The resulting solid is Compound 1 Fumarate (Form A). The
ratio of Compound 1: fumaric acid in Compound 1 Fumarate (Form A)
is 1:1.37 as determined by ion chromatography. The XPRD is shown in
FIG. 36 and the DSC and TGA are shown in FIG. 37.
[0582] Compound 1 Fumarate (Form A) was analyzed by .sup.1H-NMR in
deuterated DMSO resulting in the following chemical shifts: .sup.1H
NMR (400 MHz, DMSO-d.sub.6): .delta. 0.45-0.80 (m, 7H) 1.97-2.13
(m, 3H) 2.47-2.58 (m, 12H) 2.63-2.78 (m, 1H) 2.63-2.78 (m, 1H) 3.04
(s, 2H) 3.25 (s, 3H) 4.80-5.14 (m, 1H) 4.80-5.14 (m, 1H) 6.63 (s,
3H) 6.91 (s, 1H) 7.05 (s, 1H) 7.52-7.69 (m, 1H).
Compound 1 Fumarate (Form B):
[0583] 200 mg of Compound 1 was dissolved in 10.0 mL of ethyl
acetate at 60.degree. C. while stirring at 500 rpm and held at
60.degree. C. for 1 hr. 1.1 e.g. fumaric acid powder (60 mg, 0.51
mmol) was added into the Compound 1 solution. The solution was held
at 60.degree. C. for 3 hrs, then cooled to 25.degree. C. and held
at 25.degree. C. for 20 hrs. During the cooling process, the clear
solution became suspension. This suspension was subsequently
centrifuged and the precipitate collected and vacuumed dried at
35.degree. C. for 22 hrs resulting in 156.78 mg of powder with a
yield of 60.4%.
[0584] The resulting solid is Compound 1 Fumarate (Form B). The
ratio of Compound 1: fumaric acid in Compound 1 Fumarate (Form B)
is 1:1.55 as determined by ion chromatography. The XPRD is shown in
FIG. 38; the DSC and TGA are shown in FIG. 39; and the DVS is FIG.
40.
[0585] .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 0.43-0.79 (m,
8H) 1.88-2.13 (m, 2H) 3.03 (s, 2H) 3.10-3.39 (m, 4H) 4.38-5.21 (m,
3H) 6.61 (s, 2H) 6.59-6.64 (m, 1H) 6.74-7.16 (m, 2H) 7.56 (s,
1H).
Compound 1 Fumarate (Form C):
[0586] 50 mg Compound 1 and 1.1 e.g. counter ion of fumaric acid in
solid form were weighed into 2 mL vials individually, followed by
adding 1 mL solvent ACN into the vial. The vial was placed on the
thermo-mixer with a stir bar and heated to 50.degree. C. After
keeping at 50.degree. C. under constant stirring at 900 rpm for 18
hrs, the vial was then cooled to 25.degree. C. After keeping at
25.degree. C. for 1 hr, the solids in suspension were isolated by
centrifugation and dried in the vacuum oven at 30.degree. C. for 48
hrs.
[0587] The resulting solid is Compound 1 Fumarate (Form C). The
dried solids were characterized by PLM and XRPD.
[0588] The XPRD is shown in FIG. 41.
Compound 1 Fumarate (Form D):
[0589] Approximately 5 mg Compound 1 Fumarate (Form A) was added
into an 8 mL glass vial with a multi-hole aluminum foil cap, and
kept at 60.degree. C., 40.degree. C./75% RH for 1 week. Appearance
by visual observation were recorded followed by purity assessment
and XPRD data collection on the residual solids. The resulting
solid is Compound 1 Fumarate (Form D). The dried solids were
characterized by PLM and XRPD. The XPRD is shown in FIG. 42.
Chemical and Physical Stability Test
[0590] Chemical and physical stability testing was carried out
using the procedures set forth in Example 1. The chemical and
physical stability test results for Compound 1 Fumarate (Form A),
and Compound 1 free base are shown in the following table:
TABLE-US-00076 XRPD Final Start material Condition pattern purity
Compound 1 60.degree. C., 1 w Pattern A 99.3 40.degree. C./75% RH,
1 w Pattern A 99.1 1.2 million lux-hrs Pattern A 99.2 Dark control
Pattern A 99.1 Fumarate 60.degree. C., 1 w Form A 88.4 (Form A)
40.degree. C./75% RH, 1 w Form D 97.9 (see FIG. 42) 1.2 million
lux-hrs Form A 97.7 Dark control Form A 97.1
Solubility Tests in Simulated Gastric and Intestinal Fluids
[0591] Solubility Tests in Simulated Gastric and Intestinal Fluids
was carried out using the procedures set forth in Example 1. The
solubility results (mg/mL) in bio-relevant solutions for Compound 1
Fumarate (Form A), and Compound 1 free base are shown in the
following table:
TABLE-US-00077 SGF FaSSIF FeSSIF Solute (original pH = 1.82)
(original pH = 6.50) (original pH = 4.99) tested 1 h 24 h Final pH
1 h 24 h Final pH 1 h 24 h Final pH Compound 1 3.41 2.81 2.07 0.03
0.03 6.47 0.87 0.95 5.00 Fumarate 2.90 3.03 2.39 0.25 0.32 4.63
2.06 0.72 4.58 (Form A)
Example 7: Preparation of Tosylate Salt of Compound 1
[0592] A Tosylate Salt of Compound 1 may be prepared from Compound
1 using the following exemplary methods.
Compound 1 Tosylate (Form A):
[0593] 200 mg of Compound 1 was dissolved in 10.0 mL of ACN at
60.degree. C. while stirring at 500 rpm and held at 60.degree. C.
for 1 hr. 1.1 e.q. p-toluenesulfonic acid in ACN (1.027 mL, 0.5
mol/L) was then added into the Compound 1 solution and incubated at
60.degree. C. for 3 hrs, then cooled to 25.degree. C. and held at
25.degree. C. for 20 hrs. The suspension was centrifuged and the
precipitate collected and washed with ACN. The obtained wet product
was vacuum dried at 35.degree. C. for 22 hrs resulting in 141.85 mg
of powder with a yield of 49.2%.
[0594] The resulting solid is Compound 1 Tosylate (Form A). The
ratio of Compound 1: toluenesulfonic acid in Compound 1 Tosylate
(Form A) is 1:1.09 as determined by ion chromatography. The XPRD is
shown in FIG. 43; the DSC and TGA are shown in FIG. 44; and the DVS
is shown in FIG. 45.
[0595] Compound 1 Tosylate (Form A) was analyzed by .sup.1H-NMR in
deuterated DMSO resulting in the following chemical shifts: .sup.1H
NMR (400 MHz, DMSO-d.sub.6): .delta. 0.50-0.79 (m, 7H) 1.98-2.15
(m, 3H) 2.28 (s, 4H) 2.49 (s, 23H) 2.60-2.76 (m, 1H) 3.03 (s, 2H)
3.21-3.34 (m, 5H) 4.85-5.45 (m, 2H) 7.10 (d, J=7.78 Hz, 2H) 7.45
(s, 1H) 7.46-7.73 (m, 3H) 8.99 (s, 1H).
Compound 1 Tosylate (Form B):
[0596] 50 mg Compound 1 and 1.1 e.g. counter ion of
para-toluenesulfonic acid in solid form were weighed into 2 mL
vials individually, and then 1 mL EtOAc solvent was added into the
vial. The vial was placed on the thermo-mixer with a stir bar and
heated to 50.degree. C. After keeping at 50.degree. C. under
constant stirring at 900 rpm for 18 hrs, the vial was then cooled
to 25.degree. C. After keeping at 25.degree. C. for 1 hr, the
solids in suspension were isolated by centrifugation and dried in
the vacuum oven at 30.degree. C. overnight.
[0597] The resulting solid is Compound 1 Tosylate (Form B). The
XPRD is shown in FIG. 46.
Compound 1 Tosylate (Form C):
[0598] Approximately 5 mg Compound 1 Tosylate (Form A) was added
into an 8 mL glass vial with a multi-hole aluminum foil cap, and
kept at 60.degree. C., 40.degree. C./75% RH for 1 week. Appearance
by visual observation were recorded followed by purity assessment
and XPRD data collection on the residual solids. The resulting
solid is Compound 1 Tosylate (Form C). The dried solids were
characterized by PLM and XRPD.
[0599] The resulting solid is Compound 1 Tosylate (Form C). The
XPRD is shown in FIG. 47.
Chemical and Physical Stability Test
[0600] Chemical and physical stability testing was carried out
using the procedures set forth in Example 1. The chemical and
physical stability test results for Compound 1 Tosylate (Form A)
and Compound 1 free base are shown in the following table:
TABLE-US-00078 Starting XRPD Final materials Conditions patterns
purity Compound 1 60.degree. C., 1 w Pattern A 99.3 40.degree.
C./75% RH, 1 w Pattern A 99.1 1.2 million lux-hrs Pattern A 99.2
Dark control Pattern A 99.1 Tosylate 60.degree. C., 1 w Form A 99.5
(Form A) 40.degree. C./75% RH, 1 w Form C 99.5 (see FIG. 47) 1.2
million lux-hrs Form A 99.0 Dark control Form A 99.5
Solubility Tests in Simulated Gastric and Intestinal Fluids
[0601] Solubility Tests in Simulated Gastric and Intestinal Fluids
was carried out using the procedures set forth in Example 1. The
solubility results (mg/mL) in bio-relevant solutions for Compound 1
Tosylate (Form M and Compound 1 free base are shown in the
following table:
TABLE-US-00079 SGF FaSSIF FeSSIF (original pH = 1.82) (original pH
= 6.50) (original pH = 4.99) Solute tested 1 h 24 h Final pH 1 h 24
h Final pH 1 h 24 h Final pH Compound 1 3.41 2.81 2.07 0.03 0.03
6.47 0.87 0.95 5.00 Tosylate 0.64 0.62 2.10 0.02 0.03 6.33 1.61
1.69 4.94 (Form A)
Example 8: Preparation of Glucuronate Salt of Compound 1
[0602] A Glucuronate Salt of Compound 1 may be prepared from
Compound 1 using the following exemplary method.
Compound 1 Glucuronate (Form A)
[0603] 500 mg of Compound 1 was dissolved in 16.0 mL of acetone at
60.degree. C. while stirring at 500 rpm and held at 60.degree. C.
for 1.5 hrs. 1.1 e.q. D-glucuronic acid solid (248.62 mg) was then
added into the Compound 1 solution and incubated at 60.degree. C.
for 3 hrs, then cooled to 25.degree. C. and held at 25.degree. C.
for overnight. This suspension was centrifuged and the precipitate
collected and washed with acetone. The obtained wet product was
vacuum dried at 25.degree. C. for 72 hrs resulting in 739.32 mg of
powder with a yield of 98.76%.
[0604] The resulting solid is Compound 1 Glucuronate (Form A). The
ratio of Compound 1: glucuronic acid in Compound 1 Glucuronate
(Form A) is 1:1.09 as determined by ion chromatography. The XPRD is
shown in FIG. 48; the DSC and TGA are shown in FIG. 49; and the DVS
is shown in FIG. 50.
[0605] Compound 1 Glucuronate (Form A) was analyzed by .sup.1H-NMR
in deuterated DMSO resulting in the following chemical shifts:
.sup.1H NMR (400 MHz, DMSO-d6) .delta. ppm 0.49-0.81 (m, 7H)
0.83-1.73 (m, 22H) 1.98-2.13 (m, 2H) 2.68 (br t, J=8.76 Hz, 1H)
2.90-3.08 (m, 3H) 3.10-3.20 (m, 2H) 3.57 (d, J=9.76 Hz, 1H)
3.95-4.14 (m, 2H) 4.33 (d, J=7.75 Hz, 1H) 4.78-5.11 (m, 4H) 6.51
(br s, 1H) 6.88 (s, 1H) 7.03 (s, 1H) 7.54 (s, 1H).
Chemical and Physical Stability Test
[0606] Chemical and physical stability testing was carried out
using the procedures set forth in Example 1. The chemical and
physical stability test results for Compound 1 Glucuronate (Form A)
and Compound 1 free base are shown in the following table:
TABLE-US-00080 Starting XRPD Final materials Conditions patterns
purity Compound 1 60.degree. C., 1 w Pattern A 98.2 40.degree.
C./75% RH, 1 w Pattern A 98.2 1.2 million lux-hrs Pattern A 97.9
Dark control Pattern A 98.3 Glucoronate 60.degree. C., 1 w Form A
96.7 (Form A) 40.degree. C./75% RH, 1 w Form A 98.0 1.2 million
lux-hrs Form A 97.5 Dark control Form A 97.5
Solubility Tests in Simulated Gastric and Intestinal Fluids
[0607] Solubility Tests in Simulated Gastric and Intestinal Fluids
was carried out using the procedures set forth in Example 1. The
solubility results (mg/mL) in bio-relevant solutions for Compound 1
Glucuronate (Form A) and Compound 1 free base are shown in the
following table:
TABLE-US-00081 SGF FaSSIF FeSSIF (original (original (original pH =
1.82) pH = 6.51) pH = 4.99) Solute Final Final Final tested 24 h pH
24 h pH 24 h pH Compound 1 4.44 3.10 0.05 6.48 0.84 5.11
Glucuronate 5.40 2.82 0.65 4.28 0.47 4.97 (Form A)
Compound 1 Glucuronate (Form B)
[0608] 50 mg Compound 1 and 1.1 e.q. counter ion of D-Glucuronic
acid in solid form were weighed into 2 mL vials individually, and
then 1 mL solvent EtOAc/ACN was added into the vial. The vial was
placed on the thermo-mixer with a stir bar and heated to 50.degree.
C. After keeping at 50.degree. C. under constant stirring at 900
rpm for 18 hrs, the vial was then cooled to 25.degree. C. After
keeping at 25.degree. C. for 1 hr, the solids in suspension were
isolated by centrifugation and dried in the vacuum oven at
30.degree. C. for 18 hrs.
[0609] The dried solids were characterized by PLM and XRPD (FIG.
51).
Example 9: Preparation of Ethanesulfonate Salt of Compound 1
[0610] An Ethanesulfonate Salt of Compound 1 may be prepared from
Compound 1 using the following exemplary method.
[0611] 500 mg of Compound 1 was dissolved in 16.0 mL of acetone at
60.degree. C. while stirring at 500 rpm and held at 60.degree. C.
for 1.5 hrs. 1.1 e.q. ethanesulfonic acid in acetone (2.565 mL, 0.5
mol/L) was then added into the Compound 1 solution and incubated at
60.degree. C. for 3 hrs, then cooled to 25.degree. C. and held at
25.degree. C. for overnight. This suspension was centrifuged and
the precipitate collected and washed with acetone. The obtained wet
product was vacuum dried at 25.degree. C. for 72 hrs resulting in
546.88 mg of powder with a yield of 84.68%.
[0612] The resulting solid is Compound 1 Ethanesulfonate (Form A).
The ratio of Compound 1: ethanesulfonic acid in Compound 1
Ethanesulfonate (Form A) is 1:1.17 as determined by ion
chromatography. The XPRD is shown in FIG. 52; the DSC and TGA are
shown in FIG. 53; and the DVS is shown in FIG. 54.
[0613] Compound 1 Ethanesulfonate (Form A) was analyzed by
.sup.1H-NMR in deuterated DMSO resulting in the following chemical
shifts: .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 0.52-0.81
(m, 7H) 0.83-1.78 (m, 25H) 1.99-2.17 (m, 3H) 2.39 (q, J=7.42 Hz,
2H) 2.69-2.80 (m, 1H) 3.05 (s, 2H) 3.43 (br s, 4H) 5.11-5.46 (m,
2H) 7.54-7.77 (m, 2H) 9.02 (s, 1H).
Chemical and Physical Stability Test
[0614] Chemical and physical stability testing was carried out
using the procedures set forth in Example 1. The chemical and
physical stability test results for Compound 1 Ethanesulfonate
(Form A) and Compound 1 free base are shown in the following
table:
TABLE-US-00082 Starting XRPD Final materials Conditions patterns
purity Compound 1 60.degree. C., 1 w Pattern A 98.2 40.degree.
C./75% RH, 1 w Pattern A 98.2 1.2 million lux-hrs Pattern A 97.9
Dark control Pattern A 98.3 Ethanesulfonate 60.degree. C., 1 w Form
A 98.2 (Form A) 40.degree. C./75% RH, 1 w Form A 98.0 1.2 million
lux-hrs Form A 97.7 Dark control Form A 97.4
Solubility Tests in Simulated Gastric and Intestinal Fluids
[0615] Solubility Tests in Simulated Gastric and Intestinal Fluids
was carried out using the procedures set forth in Example 1. The
solubility results (mg/mL) in bio-relevant solutions for Compound 1
Ethanesulfonate (Form A) and Compound 1 free base are shown in the
following table:
TABLE-US-00083 SGF FaSSIF FeSSIF (original (original (original pH =
1.82) pH = 6.51) pH = 4.99) Solute tested 24 h Final pH 24 h Final
pH 24 h Final pH Compound 1 4.44 3.10 0.05 6.48 0.84 5.11
Ethanesulfonate 5.85 1.88 0.39 4.59 0.76 5.02 (Form A)
Example 10: Preparation of Sulfate Salt of Compound 1
[0616] A Sulfate Salt of Compound 1 may be prepared from Compound 1
using the following exemplary method.
[0617] 200 mg of Compound 1 was dissolved in 10.0 mL of ACN at
60.degree. C. while stirring at 500 rpm and held at 60.degree. C.
for 1 hr. 1.1 e.q. sulfuric acid in ACN (1.027 mL, 0.5 mol/L) was
then added into the Compound 1 solution and incubated at 60.degree.
C. for 3 hrs, then cooled to 25.degree. C. and held at 25.degree.
C. for 20 hrs. The suspension was centrifuged and the precipitate
collected and washed with ACN. The obtained wet product was vacuum
dried at 35.degree. C. for 22 hrs resulting in 177.38 mg of powder
with a yield of 70.9%.
[0618] The resulting solid is Compound 1 Sulfate (Form A). The
ratio of Compound 1: sulfuric acid in Compound 1 Sulfate (Form A)
is 1:1.03 as determined by ion chromatography. The XPRD is shown in
FIG. 55; the DSC and TGA are shown in FIG. 56; and the DVS is shown
in FIG. 57.
Chemical and Physical Stability Test
[0619] Chemical and physical stability testing was carried out
using the procedures set forth in Example 1. The chemical and
physical stability test results for Compound 1 Sulfate (Form A) and
Compound 1 free base are shown in the following table:
TABLE-US-00084 Starting XRPD Final materials Conditions patterns
purity Compound 1 60.degree. C., 1 w Pattern A 99.3 40.degree.
C./75% RH, 1 w Pattern A 99.1 1.2 million lux-hrs Pattern A 99.2
Dark control Pattern A 99.1 Sulfate 60.degree. C., 1 w Form A 96.2
(Form A) 40.degree. C./75% RH, 1 w Form A 97.5 1.2 million lux-hrs
Form A 97.1 Dark control Form A 97.6
Solubility Tests in Simulated Gastric and Intestinal Fluids
[0620] Solubility Tests in Simulated Gastric and Intestinal Fluids
was carried out using the procedures set forth in Example 1. The
solubility results (mg/mL) in bio-relevant solutions for Compound 1
Sulfate (Form A) and Compound 1 free base are shown in the
following table:
TABLE-US-00085 SGF FaSSIF FeSSIF (original pH = 1.82) (original pH
= 6.50) (original pH = 4.99) Solute tested 1 h 24 h Final pH 1 h 24
h Final pH 1 h 24 h Final pH Compound 1 3.41 2.81 2.07 0.03 0.03
6.47 0.87 0.95 5.00 Sulfate 1.95 1.75 1.75 2.27 1.55 2.33 0.98 0.64
4.77 (Form A)
Example 11: Preparation of Ascorbate Salt of Compound 1
[0621] An Ascorbate Salt of Compound 1 may be prepared from
Compound 1 using the following exemplary method.
Compound 1 Ascorbate (Form A):
[0622] 500 mg of Compound 1 was dissolved in 16.0 mL of acetone at
60.degree. C. while stirring at 500 rpm and held at 60.degree. C.
for 1.5 hrs. 1.1 e.q. ascorbic acid powder (226 mg) was then added
into the Compound 1 solution and incubated at 60.degree. C. for 3
hrs, then cooled to 25.degree. C. and held at 25.degree. C. for
overnight. This suspension was centrifuged and the precipitate
collected and washed with acetone. The obtained wet product was
vacuum dried at 25.degree. C. for 72 hrs resulting in 264.1 mg of
powder with a yield of 36.3%.
[0623] The resulting solid is Compound 1 Ascorbate (Form A). The
ratio of Compound 1: ascorbic acid in Compound 1 Ascorbate (Form A)
is 1:0.98 as determined by ion chromatography. The XPRD is shown in
FIG. 58; the DSC and TGA are shown in FIG. 59; and the DVS is shown
in FIG. 60.
[0624] Compound 1 Ascorbate (Form A) was analyzed by .sup.1H-NMR in
deuterated DMSO resulting in the following chemical shifts: .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 0.51-0.81 (m, 7H) 0.83-1.76
(m, 22H) 1.98-2.14 (m, 4H) 2.33 (br s, 1H) 2.64-2.72 (m, 1H) 3.04
(s, 2H) 3.25 (s, 3H) 3.41-3.45 (m, 3H) 3.73 (br t, J=7.65 Hz, 1H)
4.71 (d, J=1.51 Hz, 1H) 4.87-5.11 (m, 3H) 6.98 (s, 1H) 7.10 (s, 1H)
7.71 (s, 1H).
Chemical and Physical Stability Test
[0625] Chemical and physical stability testing was carried out
using the procedures set forth in Example 1. The chemical and
physical stability test results for Compound 1 Ascorbate (Form A)
and Compound 1 free base are shown in the following table:
TABLE-US-00086 Starting XRPD Final materials Conditions patterns
purity Compound 1 60.degree. C., 1 w Pattern A 98.2 40.degree.
C./75% RH, 1 w Pattern A 98.2 1.2 million lux-hrs Pattern A 97.9
Dark control Pattern A 98.3 Ascorbate 60.degree. C., 1 w Form A
95.7 (Form A) 40.degree. C./75% RH, 1 w Form A 96.4 1.2 million
lux-hrs Form A 96.8 Dark control Form A 96.8
Solubility Tests in Simulated Gastric and Intestinal Fluids
[0626] Solubility Tests in Simulated Gastric and Intestinal Fluids
was carried out using the procedures set forth in Example 1. The
solubility results (mg/mL) in bio-relevant solutions for Compound 1
Ascorbate (Form A) and Compound 1 free base are shown in the
following table:
TABLE-US-00087 SGF FaSSIF FeSSIF (original (original (original pH =
1.82) pH = 6.51) pH = 4.99) Solute tested 24 h Final pH 24 h Final
pH 24 h Final pH Compound 1 4.44 3.10 0.05 6.48 0.84 5.11 Ascorbate
4.34 2.56 0.48 5.06 1.86 4.58 (Form A)
Compound 1 Ascorbate (Form B):
[0627] 50 mg Compound 1 and 1.1 e.q. counter ion of ascorbic acid
in solid form were weighed into 2 mL vials individually, and then 1
mL ACN solvent was added into the vial. The vial was placed on the
thermo-mixer with a stir bar and heated to 50.degree. C. After
keeping at 50.degree. C. under constant stirring at 500 rpm for 21
hrs, the vial was then cooled to 25.degree. C. After keeping at
25.degree. C. for 1 hr, the solids in suspension were isolated by
centrifugation and dried in the vacuum oven at 30.degree. C. for 18
hrs.
[0628] The obtained dried solids were characterized by PLM and XRPD
(FIG. 61).
Example 12: Preparation of Napadisylate Salt of Compound 1
[0629] A Napadisylate Salt of Compound 1 may be prepared from
Compound 1 using the following exemplary method.
Compound 1 Napadisylate (Form A)
[0630] 500 mg of Compound 1 was dissolved in 16.0 mL of acetone at
60.degree. C. while stirring at 500 rpm and held at 60.degree. C.
for 1.5 hrs. 1.1 e.q. naphthalene-1,5-disulfonic acid tetrahydrate
in acetone (2.565 mL, 0.5 mol/L) was then added into the Compound 1
solution and incubated at 60.degree. C. for 3 hrs, then cooled to
25.degree. C. and held at 25.degree. C. for overnight. This
suspension was centrifuged and the precipitate collected and washed
with acetone. The obtained wet product was vacuum dried at
25.degree. C. for 72 hrs resulting in 675.62 mg of light pink
powder with a yield of 69.38%.
[0631] The resulting solid is Compound 1 Napadisylate (Form A). The
ratio of Compound 1: naphthalene-1, 5-disulfonic acid in Compound 1
Napadisylate (Form A) is 1:0.7 as determined by ion chromatography.
The XPRD is shown in FIG. 62; the DSC and TGA are shown in FIG. 63;
and the DVS is shown in FIG. 64.
[0632] Compound 1 Napadisylate (Form A) was analyzed by .sup.1H-NMR
in deuterated DMSO resulting in the following chemical shifts:
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 0.51-0.81 (m, 7H)
0.85-1.76 (m, 21H) 2.00-2.15 (m, 2H) 2.34 (s, 1H) 2.64-2.78 (m, 1H)
3.05 (s, 2H) 3.25 (s, 4H) 5.16-5.38 (m, 2H) 7.37-7.45 (m, 1H) 7.62
(s, 1H) 7.68 (s, 1H) 7.93 (d, J=6.88 Hz, 1H) 8.86 (d, J=8.63 Hz,
1H) 9.01 (s, 1H).
Chemical and Physical Stability Test
[0633] Chemical and physical stability testing was carried out
using the procedures set forth in Example 1. The chemical and
physical stability test results for Compound 1 Napadisylate (Form
A) and Compound 1 free base are shown in the following table:
TABLE-US-00088 Starting XRPD Final materials Conditions patterns
purity Compound 1 60.degree. C., 1 w Pattern A 98.2 40.degree.
C./75% RH, 1 w Pattern A 98.2 1.2 million lux-hrs Pattern A 97.9
Dark control Pattern A 98.3 Napadisylate 60.degree. C., 1 w Form A
96.6 (Form A) 40.degree. C./75% RH, 1 w Form A 97.4 1.2 million
lux-hrs Form A 98.0 Dark control Form A 97.8
Solubility Tests in Simulated Gastric and Intestinal Fluids
[0634] Solubility Tests in Simulated Gastric and Intestinal Fluids
was carried out using the procedures set forth in Example 1. The
solubility results (mg/mL) in bio-relevant solutions for Compound 1
Napadisylate (Form A) and Compound 1 free base are shown in the
following table:
TABLE-US-00089 SGF FaSSIF FeSSIF (original (original (original pH =
1.82) pH = 6.51) pH = 4.99) Solute tested 24 h Final pH 24 h Final
pH 24 h Final pH Compound 1 4.44 3.10 0.05 6.48 0.84 5.11
Napadisylate 0.13 1.88 0.10 5.61 1.06 5.59 (Form A)
Compound 1 Napadisylate (Form B)
[0635] 50 mg Compound 1 and 1.1 e.q. counter ion of
naphthalene-1,5-disulfonic acid tetrahydrate in solid form were
weighed into 2 mL vials individually, and then 1 mL solvent
IPA/water (95/5, V/V) was added into the vial. The vial was placed
on the thermo-mixer with a stir bar and heated to 50.degree. C.
After keeping at 50.degree. C. under constant stirring at 500 rpm
for 21 hrs, the vial was then cooled to 25.degree. C. After keeping
at 25.degree. C. for 1 hr, the solids in suspension were isolated
by centrifugation and dried in the vacuum oven at 30.degree. C. for
18 hrs.
[0636] The dried solids were characterized by PLM and XRPD (FIG.
65).
Example 13: Preparation of Malonate Salt of Compound 1
[0637] A Malonate Salt of Compound 1 may be prepared from Compound
1 using the following exemplary method.
[0638] 500 mg of Compound 1 was dissolved in 16.0 mL of acetone at
60.degree. C. while stirring at 500 rpm and held at 60.degree. C.
for 1.5 hrs. 1.1 e.q. malonic acid in acetone (2.565 mL, 0.5 mol/L)
was then added into the Compound 1 solution and incubated at
60.degree. C. for 3 hrs, then cooled to 25.degree. C. and held at
25.degree. C. for overnight. This suspension was centrifuged and
the precipitate collected and washed with acetone. The obtained wet
product was vacuum dried at 25.degree. C. for 72 hrs.
[0639] The resulting solid is Compound 1 Malonate (Form A). The
ratio of Compound 1: malonic acid in Compound 1 Malonate (Form A)
is 1:1.28 as determined by ion chromatography. The XPRD is shown in
FIG. 66; and the DSC and TGA are shown in FIG. 67.
[0640] Compound 1 Malonate (Form A) was analyzed by .sup.1H-NMR in
deuterated DMSO resulting in the following chemical shifts: .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 0.50-0.79 (m, 7H) 0.84-1.75
(m, 20H) 1.91 (s, 1H) 2.00-2.12 (m, 2H) 2.65-2.73 (m, 1H) 3.04 (s,
2H) 3.13 (s, 3H) 4.92-5.15 (m, 2H) 7.03-7.20 (m, 2H) 7.91 (s,
1H).
Chemical and Physical Stability Test
[0641] Chemical and physical stability testing was carried out
using the procedures set forth in Example 1. The chemical and
physical stability test results for Compound 1 Malonate (Form A)
and Compound 1 free base are shown in the following table:
TABLE-US-00090 Starting XRPD Final materials Conditions patterns
purity Compound 1 60.degree. C., 1 w Pattern A 98.2 40.degree.
C./75% RH, Pattern A 98.2 1 w 1.2 million lux- Pattern A 97.9 hrs
Dark control Pattern A 98.3 Malonate (Form 60.degree. C., 1 w Form
A 97.0 A) 40.degree. C./75% RH, Form A 98.5 1 w 1.2 million lux-
Form A 98.2 hrs Dark control Form A 99.0
Solubility Tests in Simulated Gastric and Intestinal Fluids
[0642] Solubility Tests in Simulated Gastric and Intestinal Fluids
was carried out using the procedures set forth in Example 1. The
solubility results (mg/mL) in bio-relevant solutions for Compound 1
Malonate (Form A) and Compound 1 free base are shown in the
following table:
TABLE-US-00091 SGF FaSSIF FeSSIF (original (original (original pH =
1.82) pH = 6.51) pH = 4.99) Solute tested 24 h Final pH 24 h Final
pH 24 h Final pH Compound 1 4.44 3.10 0.05 6.48 0.84 5.11 Malonate
4.99 2.26 0.80 4.30 2.42 4.96 (Form A)
Example 14: Preparation of Besylate Salt of Compound 1
[0643] A Besylate Salt of Compound 1 may be prepared from Compound
1 using the following exemplary method.
Compound 1 Besylate (Form A)
[0644] 500 mg of Compound 1 was dissolved in 16.0 mL of acetone at
60.degree. C. while stirring at 500 rpm and held at 60.degree. C.
for 1.5 hrs. 1.1 e.q. benzenesulfonic acid in acetone (2.565 mL,
0.5 mol/L) was then added into the Compound 1 solution and
incubated at 60.degree. C. for 3 hrs, then cooled to 25.degree. C.
and held at 25.degree. C. for overnight. This suspension was
centrifuged and the precipitate collected and washed with acetone.
The obtained wet product was vacuum dried at 25.degree. C. for 72
hrs resulting in 654.68 mg of powder with a yield of 92.56%.
[0645] The resulting solid is Compound 1 Besylate (Form A). The
ratio of Compound 1: benzenesulfonic acid in Compound 1 Besylate
(Form A) is 1:0.94 as determined by ion chromatography. The XPRD is
shown in FIG. 68; the DSC and TGA are shown in FIG. 69; and the DVS
is shown in FIG. 70.
[0646] Compound 1 Besylate (Form A) was analyzed by .sup.1H-NMR in
deuterated DMSO resulting in the following chemical shifts: .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 0.53-0.80 (m, 7H) 0.83-1.78
(m, 21H) 1.99-2.15 (m, 3H) 2.29-2.36 (m, 1H) 2.56 (br s, 1H)
2.66-2.77 (m, 1H) 3.05 (s, 2H) 3.25 (s, 4H) 4.03 (br s, 1H)
5.15-5.39 (m, 2H) 7.27-7.36 (m, 3H) 7.55-7.70 (m, 4H) 8.97 (s,
1H).
Chemical and Physical Stability Test
[0647] Chemical and physical stability testing was carried out
using the procedures set forth in Example 1. The chemical and
physical stability test results for Compound 1 Besylate (Form A)
and Compound 1 free base are shown in the following table:
TABLE-US-00092 Starting XRPD Final materials Conditions patterns
purity Compound 1 60.degree. C., 1 w Pattern A 98.2 40.degree.
C./75% RH, Pattern A 98.2 1 w 1.2 million lux- Pattern A 97.9 hrs
Dark control Pattern A 98.3 Besylate (Form 60.degree. C., 1 w Form
A 98.3 A) 40.degree. C./75% RH, Form A 98.3 1 w 1.2 million lux-
Form A 98.7 hrs Dark control Form A 98.4
Solubility Tests in Simulated Gastric and Intestinal Fluids
[0648] Solubility Tests in Simulated Gastric and Intestinal Fluids
was carried out using the procedures set forth in Example 1. The
solubility results (mg/mL) in bio-relevant solutions for Compound 1
Besylate (Form A) and Compound 1 free base are shown in the
following table:
TABLE-US-00093 SGF FaSSIF FeSSIF (original (original (original pH =
1.82) pH = 6.51) pH = 4.99) Solute tested 24 h Final pH 24 h Final
pH 24 h Final pH Compound 1 4.44 3.10 0.05 6.48 0.84 5.11 Besylate
(Form A) 0.85 1.84 0.28 4.78 0.78 5.04
Compound 1 Besylate (Form B)
[0649] 50 mg Compound 1 and 1.1 e.g. counter ion of benzenesulfonic
acid in solid form were weighed into 2 mL vials individually, and
then 1 mL ACN solvent was added into the vial. The vial was placed
on the thermo-mixer with a stir bar and heated to 50.degree. C.
After keeping at 50.degree. C. under constant stirring at 500 rpm
for 21 hrs, the vial was then cooled to 25.degree. C. After keeping
at 25.degree. C. for 1 hr, the solids in suspension were isolated
by centrifugation and dried in the vacuum oven at 30.degree. C. for
18 hrs.
[0650] The obtained dried solids were characterized by PLM and XRPD
(FIG. 71).
Example 15: Preparation of Isethionate Salt of Compound 1
[0651] An Isethionate Salt of Compound 1 may be prepared from
Compound 1 using the following exemplary method.
Compound 1 Isethionate (Form A)
[0652] 500 mg of Compound 1 was dissolved in 16.0 mL of acetone at
60.degree. C. while stirring at 500 rpm and held at 60.degree. C.
for 1.5 hrs. 1.1 e.q. 2-hydroxyethanesulphonic acid in acetone
(2.565 mL, 0.5 mol/L) was then added into the Compound 1 solution
and incubated at 60.degree. C. for 3 hrs, then cooled to 25.degree.
C. and held at 25.degree. C. for overnight. This suspension was
centrifuged and the precipitate collected and washed with acetone.
The obtained wet product was vacuum dried at 25.degree. C. for 72
hrs resulting in 493.12 mg of powder with a yield of 74.64%.
[0653] The resulting solid is Compound 1 Isethionate (Form A). The
ratio of Compound 1: 2-hydroxyethanesulphonic acid in Compound 1
Isethionate (Form A) is 1:1.09 as determined by ion chromatography.
The XPRD is shown in FIG. 72; the DSC and TGA are shown in FIG. 73;
and the DVS is shown in FIG. 74.
[0654] Compound 1 Isethionate (Form A) was analyzed by .sup.1H-NMR
in deuterated DMSO resulting in the following chemical shifts:
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 0.53-0.81 (m, 7H)
0.84-1.78 (m, 22H) 2.01-2.15 (m, 3H) 2.34 (br s, 1H) 2.61 (t,
J=6.82 Hz, 2H) 2.66-2.78 (m, 1H) 3.05 (s, 2H) 3.25 (s, 3H) 3.63 (t,
J=6.75 Hz, 2H) 5.14-5.38 (m, 2H) 7.58-7.69 (m, 2H) 8.99 (s,
1H).
Chemical and Physical Stability Test
[0655] Chemical and physical stability testing was carried out
using the procedures set forth in Example 1. The chemical and
physical stability test results for Compound 1 Isethionate (Form A)
and Compound 1 free base are shown in the following table:
TABLE-US-00094 Starting XRPD Final materials Conditions patterns
purity Compound 1 60.degree. C., 1 w Pattern A 98.2 40.degree.
C./75% RH, Pattern A 98.2 1 w 1.2 million lux- Pattern A 97.9 hrs
Dark control Pattern A 98.3 Isethionate 60.degree. C., 1 w Form A
98.7 (Form A) 40.degree. C./75% RH, Form A 98.5 1 w 1.2 million
lux- Form A 98.9 hrs Dark control Form A 98.8
Solubility Tests in Simulated Gastric and Intestinal Fluids
[0656] Solubility Tests in Simulated Gastric and Intestinal Fluids
was carried out using the procedures set forth in Example 1. The
solubility results (mg/mL) in bio-relevant solutions for Compound 1
Isethionate (Form A) and Compound 1 free base are shown in the
following table:
TABLE-US-00095 SGF FaSSIF FeSSIF (original (original (original pH =
1.82) pH = 6.51) pH = 4.99) Solute tested 24 h Final pH 24 h Final
pH 24 h Final pH Compound 1 4.44 3.10 0.05 6.48 0.84 5.11
Isethionate (Form 4.45 1.93 1.12 4.05 0.76 4.98 A)
Compound 1 Isethionate (Form B)
[0657] 50 mg Compound 1 was weighed into 2 mL vials, and 743 .mu.L
solvent IPA/water (95/5, V/V) was added in the vials subsequently.
Then 1.1 e.q. counter-ion of 2-hydroxyethanesulphonic acid (257
.mu.L, concentration: 0.5 mol/L) was added to the vial. The vial
was placed on the thermo-mixer with a stir bar and heated to
50.degree. C. After keeping at 50.degree. C. under constant
stirring at 500 rpm for 21 hrs, the vial was then cooled to
25.degree. C. After keeping at 25.degree. C. for 1 hr, the vial
showed a clear solution. The solvent was evaporated by vacuum oven
at 30.degree. C.
[0658] The resulting solids were characterized by PLM and XRPD
(FIG. 75).
Example 16: Preparation of Gentisate Salt of Compound 1
[0659] A Gentisate Salt of Compound 1 may be prepared from Compound
1 using the following exemplary method.
Compound 1 Gentisate (Form A)
[0660] 500 mg of Compound 1 was dissolved in 16.0 mL of acetone at
60.degree. C. while stirring at 500 rpm and held at 60.degree. C.
for 1.5 hrs. 1.1 e.q. gentisic acid in acetone (2.565 mL, 0.5
mol/L) was then added into the Compound 1 solution and incubated at
60.degree. C. for 3 hrs, then cooled to 25.degree. C. and held at
25.degree. C. for overnight. This suspension was centrifuged and
the precipitate collected and washed with acetone. The obtained wet
product was vacuum dried at 25.degree. C. for 72 hrs resulting in
281.5 mg of powder with a yield of 31.39%.
[0661] The resulting solid is Compound 1 Gentisate (Form A). The
ratio of Compound 1: gentisic acid in Compound 1 Gentisate (Form A)
is 1:1.03 as determined by ion chromatography. The XPRD is shown in
FIG. 76; the DSC and TGA are shown in FIG. 77; and the DVS is shown
in FIG. 78.
[0662] Compound 1 Gentisate (Form A) was analyzed by .sup.1H-NMR in
deuterated DMSO resulting in the following chemical shifts: .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 0.53-0.80 (m, 7H) 0.85-1.72
(m, 20H) 2.00-2.13 (m, 5H) 2.66-2.74 (m, 1H) 3.04 (s, 2H) 4.02 (br
s, 1H) 4.90-5.12 (m, 2H) 6.71 (d, J=8.76 Hz, 1H) 6.88 (dd, J=8.82,
3.06 Hz, 1H) 7.03 (s, 1H) 7.13-7.17 (m, 2H) 7.78-7.86 (m, 1H) 7.81
(s, 1H) 9.01 (br s, 1H).
Chemical and Physical Stability Test
[0663] Chemical and physical stability testing was carried out
using the procedures set forth in Example 1. The chemical and
physical stability test results for Compound 1 Gentisate (Form A)
and Compound 1 free base are shown in the following table:
TABLE-US-00096 XRPD Final Starting materials Conditions patterns
purity Compound 1 60.degree. C., 1 w Pattern A 98.2 40.degree.
C./75% RH, Pattern A 98.2 1 w 1.2 million ltvc- Pattern A 97.9 hrs
Dark control Pattern A 98.3 Gentisate 60.degree. C., 1 w Form A
97.0 salt (Form A) 40.degree. C./75% RH, 1 w Form A 97.6 1.2
million lux- Form A 96.0 hrs Dark control Form A 97.6
Compound 1 Gentisate (Form B)
[0664] 50 mg Compound 1 and 1.1 e.q. counter ion of gentisic acid
in solid form were weighed into 2 mL vials individually, and then 1
mL EtOAc solvent was added into the vial. The vial was placed on
the thermo-mixer with a stir bar and heated to 50.degree. C. After
keeping at 50.degree. C. under constant stirring at 900 rpm for 18
hrs, the vial was then cooled to 25.degree. C. After keeping at
25.degree. C. for 1 hr, the solids in suspension were isolated by
centrifugation and dried in the vacuum oven at 30.degree. C. for 18
hrs.
[0665] The dried solids were characterized by PLM and XRPD (FIG.
79).
Compound 1 Gentisate (Form C)
[0666] 50 mg Compound 1 and 1.1 e.q. counter ion of gentisic acid
in solid form were weighed into 2 mL vials individually, and then 1
mL IPA/water (95/5, V/V) solvent was added into the vial. The vial
was placed on the thermo-mixer with a stir bar and heated to
50.degree. C. After keeping at 50.degree. C. under constant
stirring at 900 rpm for 18 hrs, the vial was then cooled to
25.degree. C. After keeping at 25.degree. C. for 1 hr, the solids
in suspension were isolated by centrifugation and dried in the
vacuum oven at 30.degree. C. for 18 hrs.
[0667] The dried solids were characterized by PLM and XRPD (FIG.
80).
Solubility Tests in Simulated Gastric and Intestinal Fluids
[0668] Solubility Tests in Simulated Gastric and Intestinal Fluids
was carried out using the procedures set forth in Example 1. The
solubility results (mg/mL) in bio-relevant solutions for Compound 1
Gentisate (Form A) and Compound 1 free base are shown in the
following table:
TABLE-US-00097 SGF FaSSIF FeSSIF (original (original (original pH =
1.82) pH = 6.51) pH = 4.99) Solute tested 24 h Final pH 24 h Final
pH 24 h Final pH Compound 1 4.44 3.10 0.05 6.48 0.84 5.11 Gentisate
(Form A) 1.16 1.93 0.15 5.23 1.20 5.01
Example 17: Preparation of 1-Hydroxy-2-Napthoate Salt of Compound
1
[0669] A 1-Hydroxy-2-Napthoate Salt of Compound 1 may be prepared
from Compound 1 using the following exemplary method.
Compound 1 1-Hydroxy-2-Napthoate (Form A)
[0670] 500 mg of Compound 1 was dissolved in 16.0 mL of acetone at
60.degree. C. while stirring at 500 rpm and held at 60.degree. C.
for 1.5 hrs. 1.1 e.q. 1-hydroxy-2-napthoic acid in acetone (2.565
mL, 0.5 mol/L) was then added into the Compound 1 solution and
incubated at 60.degree. C. for 3 hrs, then cooled to 25.degree. C.
and held at 25.degree. C. for overnight. This suspension was
centrifuged and the precipitate collected and washed with acetone.
The obtained wet product was vacuum dried at 25.degree. C. for 72
hrs resulting in 675.36 mg of powder with a yield of 68.15%.
[0671] The resulting solid is Compound 1 1-Hydroxy-2-Napthoate
(Form A). The ratio of Compound 1: 1-Hydroxy-2-Napthoic acid in
Compound 1 1-Hydroxy-2-Napthoate (Form A) is 1:1.15 as determined
by ion chromatography. The XPRD is shown in FIG. 81; the DSC and
TGA are shown in FIG. 82; and the DVS is shown in FIG. 83.
[0672] Compound 1 1-Hydroxy-2-Napthoate (Form A) was analyzed by
.sup.1H-NMR in deuterated DMSO resulting in the following chemical
shifts: .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 0.49-0.79
(m, 7H) 0.82-1.76 (m, 22H) 1.96-2.16 (m, 4H) 2.63-2.76 (m, 1H)
2.95-3.11 (m, 2H) 4.98-5.22 (m, 2H) 7.19-7.32 (m, 3H) 7.46-7.62 (m,
2H) 7.72-7.86 (m, 2H) 8.16-8.29 (m, 2H).
Chemical and Physical Stability Test
[0673] Chemical and physical stability testing was carried out
using the procedures set forth in Example 1. The chemical and
physical stability test results for Compound 1
1-Hydroxy-2-Napthoate (Form A) and Compound 1 free base are shown
in the following table:
TABLE-US-00098 XRPD Final Starting materials Conditions patterns
purity Compound 1 60.degree. C., 1 w Pattern A 98.15 40.degree.
C./75% RH, Pattern A 98.23 1 w 1.2 million lux- Pattern A 97.92 hrs
Dark control Pattern A 98.30 1-hydroxy-2- 60.degree. C., 1 w Form A
88.91 napthoate 40.degree. C./75% RH, 1 w Form A 92.64 (Form A) 1.2
million lux- Form A 92.64 hrs Dark control Form A 91.96
Solubility Tests in Simulated Gastric and Intestinal Fluids
[0674] Solubility Tests in Simulated Gastric and Intestinal Fluids
was carried out using the procedures set forth in Example 1. The
solubility results (mg/mL) in bio-relevant solutions for Compound 1
1-Hydroxy-2-Napthoate (Form A) and Compound 1 free base are shown
in the following table:
TABLE-US-00099 SGF FaSSIF FeSSIF (original (original (original pH =
1.82) pH = 6.51) pH = 4.99) Solute tested 24 h Final pH 24 h Final
pH 24 h Final pH Compound 1 4.44 3.10 0.05 6.48 0.84 5.11
1-hydroxy-2-napthoate 1.04 2.05 0.08 5.74 2.32 4.98 (Form A)
Compound 1 1-Hydroxy-2-Napthoate (Form B)
[0675] 50 mg Compound 1 and 1.1 e.g. counter ion of
1-hydroxy-2-napthoic acid in solid form were weighed into 2 mL
vials individually, and then 1 mL EtOAc solvent was added into the
vial. The vial was placed on the thermo-mixer with a stir bar and
heated to 50.degree. C. After keeping at 50.degree. C. under
constant stirring at 900 rpm for 18 hrs, the vial was then cooled
to 25.degree. C. After keeping at 25.degree. C. for 1 hr, the
solids in suspension were isolated by centrifugation and dried in
the vacuum oven at 30.degree. C. for 18 hrs.
[0676] The dried solids were characterized by PLM and XRPD (FIG.
84).
Compound 1 1-Hydroxy-2-Napthoate (Form C)
[0677] 50 mg Compound 1 and 1.1 e.g. counter ion of
1-hydroxy-2-napthoic acid in solid form were weighed into 2 mL
vials individually, and then 1 mL ACN solvent was added into the
vial. The vial was placed on the thermo-mixer with a stir bar and
heated to 50.degree. C. After keeping at 50.degree. C. under
constant stirring at 900 rpm for 18 hrs, the vial was then cooled
to 25.degree. C. After keeping at 25.degree. C. for 1 hr, the
solids in suspension were isolated by centrifugation and dried in
the vacuum oven at 30.degree. C. for 18 hrs.
[0678] The dried solids were characterized by PLM and XRPD (FIG.
85).
Compound 1 1-Hydroxy-2-Napthoate (Form D)
[0679] 50 mg Compound 1 and 1.1 e.g. counter ion of
1-hydroxy-2-napthoic acid in solid form were weighed into 2 mL
vials individually, and then 1 mL solvent IPA/water (95/5, V/V) was
added into the vial. The vial was placed on the thermo-mixer with a
stir bar and heated to 50.degree. C. After keeping at 50.degree. C.
under constant stirring at 900 rpm for 18 hrs, the vial was then
cooled to 25.degree. C. After keeping at 25.degree. C. for 1 hr,
the solids in suspension were isolated by centrifugation and dried
in the vacuum oven at 30.degree. C. for 18 hrs.
[0680] The dried solids were characterized by PLM and XRPD (FIG.
86).
Example 18: Preparation of Cyclamate Salt of Compound 1
[0681] A Cyclamate Salt of Compound 1 may be prepared from Compound
1 using the following exemplary method.
[0682] 500 mg of Compound 1 was dissolved in 16.0 mL of acetone at
60.degree. C. while stirring at 500 rpm and held at 60.degree. C.
for 1.5 hrs. 1.1 e.q. cyclamic acid in acetone (2.565 mL, 0.5
mol/L) was then added into the Compound 1 solution and incubated at
60.degree. C. for 3 hrs, then cooled to 25.degree. C. and held at
25.degree. C. for overnight. This suspension was centrifuged and
the precipitate collected and washed with acetone. The obtained wet
product was vacuum dried at 25.degree. C. for 72 hrs resulting in
715.81 mg of powder with a yield of 74.48%.
[0683] The resulting solid is Compound 1 Cyclamate (Form A). The
ratio of Compound 1: cyclamic acid in Compound 1 Cyclamate (Form A)
is 1:1.00 as determined by ion chromatography. The XPRD is shown in
FIG. 87; the DSC and TGA are shown in FIG. 88; and the DVS is shown
in FIG. 89.
[0684] Compound 1 Cyclamate (Form A) was analyzed by .sup.1H-NMR in
deuterated DMSO resulting in the following chemical shifts: .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 0.49-0.80 (m, 7H) 0.84-1.77
(m, 30H) 1.83-2.14 (m, 5H) 2.65-2.74 (m, 1H) 2.90-3.09 (m, 3H)
3.35-3.60 (m, 2H) 4.03 (br s, 1H) 4.87-5.16 (m, 2H) 6.97-7.18 (m,
2H) 7.54-7.91 (m, 3H).
Chemical and Physical Stability Test
[0685] Chemical and physical stability testing was carried out
using the procedures set forth in Example 1. The chemical and
physical stability test results for Compound 1 Cyclamate (Form A)
and Compound 1 free base are shown in the following table:
TABLE-US-00100 XRPD Final Starting materials Conditions patterns
purity Compound 1 60.degree. C., 1 w Pattern A 98.2 40.degree.
C./75% RH, Pattern A 98.2 1 w 1.2 million lux- Pattern A 97.9 hrs
Dark control Pattern A 98.3 Cyclamate 60.degree. C., 1 w Form A
97.6 (Form A) 40.degree. C./75% RH, 1 w Form A 97.5 1.2 million
lux- Form A 97.2 hrs Dark control Form A 97.5
Solubility Tests in Simulated Gastric and Intestinal Fluids
[0686] Solubility Tests in Simulated Gastric and Intestinal Fluids
was carried out using the procedures set forth in Example 1. The
solubility results (mg/mL) in bio-relevant solutions for Compound 1
Cyclamate (Form A) and Compound 1 free base are shown in the
following table:
TABLE-US-00101 SGF FaSSIF FeSSIF (original (original (original pH =
1.82) pH = 6.51) pH = 4.99) Solute tested 24 h Final pH 24 h Final
pH 24 h Final pH Compound 1 4.44 3.10 0.05 6.48 0.84 5.11 Cyclamate
(Form A) 1.99 2.05 0.57 4.50 0.83 5.00
Example 19: Preparation of Ethane-1,2-Disulfonate Salt of Compound
1
[0687] A Ethane-1,2-Disulfonate Salt of Compound 1 may be prepared
from Compound 1 using the following exemplary method.
Compound 1 Ethane-1,2-Disulfonate (Form A)
[0688] 500 mg of Compound 1 was dissolved in 16.0 mL of acetone at
60.degree. C. while stirring at 500 rpm and held at 60.degree. C.
for 1.5 hrs. 1.1 e.q. ethane-1,2-disulfonic acid in acetone (2.565
mL, 0.5 mol/L) was then added into the Compound 1 solution and
incubated at 60.degree. C. for 3 hrs, then cooled to 25.degree. C.
and held at 25.degree. C. for overnight. This suspension was
centrifuged and the precipitate collected and washed with acetone.
The obtained wet product was vacuum dried at 25.degree. C. for 72
hrs resulting in 704.45 mg of powder with a yield of 71.61%.
[0689] The resulting solid is Compound 1 Ethane-1,2-Disulfonate
(Form A). The ratio of Compound 1: Ethane-1,2-Disulfonic acid in
Compound 1 Ethane-1,2-Disulfonate (Form A) is 1:2.4 as determined
by ion chromatography. The XPRD is shown in FIG. 90; the DSC and
TGA are shown in FIG. 91; and the DVS is shown in FIG. 92.
[0690] Compound 1 Ethane-1,2-Disulfonate (Form A) was analyzed by
.sup.1H-NMR in deuterated DMSO resulting in the following chemical
shifts: .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 0.52-0.79
(m, 7H) 0.82-1.77 (m, 22H) 1.97-2.15 (m, 2H) 2.58-2.78 (m, 4H) 3.03
(s, 2H) 3.23 (s, 4H) 5.13-5.40 (m, 2H) 7.56-7.71 (m, 2H) 9.00 (s,
1H).
Chemical and Physical Stability Test
[0691] Chemical and physical stability testing was carried out
using the procedures set forth in Example 1. The chemical and
physical stability test results for Compound 1
Ethane-1,2-Disulfonate (Form A) and Compound 1 free base are shown
in the following table:
TABLE-US-00102 XRPD Final Starting materials Conditions patterns
purity Compound 1 60.degree. C., 1 w Pattern A 98.2 40.degree.
C./75% RH, Pattern A 98.2 1 w 1.2 million lux- Pattern A 97.9 hrs
Dark control Pattern A 98.3 Ethane-1,2- 60.degree. C., 1 w Form A
95.6 disulfonate salt 40.degree. C./75% RH, 1 w Form A 96.0 (Form
A) 1.2 million lux- Form A 96.6 hrs Dark control Form A 96.8
Compound 1 Ethane-1,2-Disulfonate (Form B)
[0692] 50 mg Compound 1 and 1.1 e.q. counter ion of
ethane-1,2-disulfonic acid in solid form were weighed into 2 mL
vials individually, and then 1 mL solvent EtOAc/IPA/water (95/5,
V/V) was added into the vial. The vial was placed on the
thermo-mixer with a stir bar and heated to 50.degree. C. After
keeping at 50.degree. C. under constant stirring at 900 rpm for 18
hrs, the vial was then cooled to 25.degree. C. After keeping at
25.degree. C. for 1 hr, the solids in suspension were isolated by
centrifugation and dried in the vacuum oven at 30.degree. C. for 18
hrs.
[0693] The dried solids were characterized by PLM and XRPD (FIG.
93).
Solubility Tests in Simulated Gastric and Intestinal Fluids
[0694] Solubility Tests in Simulated Gastric and Intestinal Fluids
was carried out using the procedures set forth in Example 1. The
solubility results (mg/mL) in bio-relevant solutions for Compound 1
Ethane-1,2-Disulfonate (Form A) and Compound 1 free base are shown
in the following table:
TABLE-US-00103 SGF FaSSIF FeSSIF (original (original (original pH =
1.82) pH = 6.51) pH = 4.99) Solute tested 24 h Final pH 24 h Final
pH 24 h Final pH Compound 1 4.44 3.10 0.05 6.48 0.84 5.11
Ethane-1,2-disulfonate 1.66 1.86 0.55 4.53 0.06 4.97 (Form A)
Example 20: Preparation of Dichloroacetate Salt of Compound 1
[0695] A Dichloroacetate Salt of Compound 1 may be prepared from
Compound 1 using the following exemplary method.
[0696] 500 mg of Compound 1 was dissolved in 16.0 mL of acetone at
60.degree. C. while stirring at 500 rpm and held at 60.degree. C.
for 1.5 hrs. 1.1 e.q. dichloroacetic acid in acetone (2.565 mL, 0.5
mol/L) was then added into the Compound 1 solution and incubated at
60.degree. C. for 3 hrs, then cooled to 25.degree. C. and held at
25.degree. C. for overnight. This suspension was centrifuged and
the precipitate collected and washed with acetone. The obtained wet
product was vacuum dried at 25.degree. C. for 72 hrs resulting in
559.98 mg of powder with a yield of 83.41%.
[0697] The resulting solid is Compound 1 Dichloroacetate (Form A).
The ratio of Compound 1: Dichloroacetic acid in Compound 1
Dichloroacetate (Form A) is 1:1.14 as determined by ion
chromatography. The XPRD is shown in FIG. 94; the DSC and TGA are
shown in FIG. 95; and the DVS is shown in FIG. 96.
[0698] Compound 1 Dichloroacetate (Form A) was analyzed by
.sup.1H-NMR in deuterated DMSO resulting in the following chemical
shifts: .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 0.46-0.79
(m, 7H) 0.82-1.75 (m, 21H) 1.96-2.15 (m, 2H) 2.62-2.75 (m, 1H) 3.02
(s, 2H) 4.98-5.27 (m, 3H) 6.30 (s, 1H) 7.31 (d, J=12.80 Hz, 2H)
8.32 (s, 1H).
Chemical and Physical Stability Test
[0699] Chemical and physical stability testing was carried out
using the procedures set forth in Example 1. The chemical and
physical stability test results for Compound 1 Dichloroacetate
(Form A) and Compound 1 free base are shown in the following
table:
TABLE-US-00104 XRPD Final Starting materials Conditions patterns
purity Compound 1 60.degree. C., 1 w Pattern A 98.2 40.degree.
C./75% RH, Pattern A 98.2 1 w 1.2 million lux- Pattern A 97.9 hrs
Dark control Pattern A 98.3 Dichloroacetate 60.degree. C., 1 w Form
A 96.3 (Form A) 40.degree. C./75% RH, 1 w Form A 98.0 1.2 million
lux- Form A 96.4 hrs Dark control Form A 97.3
Solubility Tests in Simulated Gastric and Intestinal Fluids
[0700] Solubility Tests in Simulated Gastric and Intestinal Fluids
was carried out using the procedures set forth in Example 1. The
solubility results (mg/mL) in bio-relevant solutions for Compound 1
Dichloroacetate (Form A) and Compound 1 free base are shown in the
following table:
TABLE-US-00105 SGF FaSSIF FeSSIF (original (original (original pH =
1.82) pH = 6.51) pH = 4.99) Solute tested 24 h Final pH 24 h Final
pH 24 h Final pH Compound 1 4.44 3.10 0.05 6.48 0.84 5.11
Dichloroacetate 5.96 1.90 0.60 4.41 1.20 4.00 (Form A)
Example 21: Preparation of L-Malate Salt of Compound 1
[0701] L-Malate Salts of Compound 1 may be prepared from Compound 1
using the following exemplary method.
Compound 1 L-Malate (Form A):
[0702] 200 mg of Compound 1 was dissolved in 10.0 mL of acetone at
60.degree. C. while stirring at 500 rpm and held at 60.degree. C.
for 1.5 hrs. 1.1 e.q. L-malic acid in acetone (1.027 mL, 0.5 mol/L)
was then added into the Compound 1 solution and incubated at
60.degree. C. for 3 hrs, then cooled to 25.degree. C. and held at
25.degree. C. for 20 hrs. The solution was evaporated by nitrogen
to remove the organic solvent. The obtained wet product was vacuum
dried at 25.degree. C. for 42 hrs resulting in 230.93 mg of powder
with a yield of 85.9%.
[0703] The resulting solid is Compound 1 L-Malate (Form A). The
ratio of Compound 1: Malic acid in Compound 1 L-Malate (Form A) is
1:1.35 as determined by ion chromatography. The XPRD is shown in
FIG. 97; the DSC and TGA are shown in FIG. 98; and the DVS is shown
in FIG. 99.
[0704] Compound 1 L-Malate (Form A) was analyzed by .sup.1H-NMR in
deuterated DMSO resulting in the following chemical shifts: .sup.1H
NMR (400 MHz, DMSO-d.sub.6): .delta. 0.57-0.86 (m, 4H) 0.70-0.86
(m, 4H) 0.89-1.79 (m, 21H) 2.00-2.21 (m, 3H) 2.33-2.78 (m, 13H)
3.10 (s, 2H) 3.31 (s, 3H) 4.28 (dd, J=7.32, 5.44 Hz, 1H) 4.85-5.19
(m, 2H) 7.00 (s, 1H) 7.13 (s, 1H) 7.53-7.84 (m, 1H).
Compound 1 L-Malate (Form B):
[0705] 10 g of Compound 1 was suspended in 350 mL of acetone at
60.degree. C. while stirring at 200 rpm and held at 60.degree. C.
for 0.5 hrs. 1.1 e.q. L-malic acid in acetone (50 mL, 0.5 mol/L)
was then added into the Compound 1 suspension and incubated at
60.degree. C. for 3 hrs, then cooled to 25.degree. C. and held at
25.degree. C. for 72 hrs with vial openly. The suspension was
centrifuged and the precipitate was collected and vacuum dried at
30.degree. C. for 24 hrs resulting in 4.44 g of powder with a yield
of 33.86%.
[0706] The resulting solid is Compound 1 L-Malate (Form B). The
ratio of Compound 1: Malic acid in Compound 1 L-Malate (Form B) is
1:1.26 as determined by ion chromatography. The XPRD is shown in
FIG. 100; the DSC and TGA are shown in FIG. 101; and the DVS is
shown in FIG. 102.
[0707] Compound 1 L-Malate (Form B) was analyzed by .sup.1H-NMR in
deuterated DMSO resulting in the following chemical shifts: .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 0.45-0.79 (m, 7H) 0.83-1.73
(m, 20H) 1.98-2.12 (m, 2H) 2.43 (dd, J=15.69, 7.40 Hz, 1H)
2.56-2.72 (m, 2H) 3.04 (s, 2H) 4.22 (dd, J=7.28, 5.52 Hz, 1H)
4.86-5.10 (m, 2H) 6.94 (s, 1H) 7.07 (s, 1H) 7.65 (s, 1H).
Chemical and Physical Stability Test
[0708] Chemical and physical stability testing was carried out
using the procedures set forth in Example 1. The chemical and
physical stability test results for Compound 1 L-Malate (Form A),
Compound 1 L-Malate (Form B), and Compound 1 free base are shown in
the following table:
TABLE-US-00106 Starting XRPD Final materials Conditions patterns
purity Compound 1 60.degree. C., 1 w Pattern A 99.3 40.degree.
C./75% RH, Pattern A 99.1 1 w 1.2 million lux- Pattern A 99.2 hrs
Dark control Pattern A 99.1 L-Malate (Form 60.degree. C., 1 w Form
A 99.6 A) 40.degree. C./75% RH, Form A 99.2 1 w 1.2 million lux-
Form A 99.3 hrs Dark control Form A 99.3 L-Malate 60.degree. C., 1
w Form B 97.8 (Form B) 40.degree. C./75% RH, Similar to Form 98.5 1
w A 1.2 million lux- Form B 97.6 hrs Dark control Form B 97.5
Solubility Tests in Simulated Gastric and Intestinal Fluids
[0709] Solubility Tests in Simulated Gastric and Intestinal Fluids
was carried out using the procedures set forth in Example 1. The
solubility results (mg/mL) in bio-relevant solutions for Compound 1
L-Malate (Form A), Compound 1 L-Malate (Form B), and Compound 1
free base are shown in the following table:
TABLE-US-00107 SGF FaSSIF FeSSIF (original (original (original pH =
1.82) pH = 6.50) pH = 4.99) Solute Final Final 24 Final tested 1 h
24 h PH 1 h 24 h pH 1 h h PH Compound 3.41 2.81 2.07 0.03 0.03 6.47
0.87 0.95 5.00 1 L-Malate 5.35 4.69 3.26 0.10 0.08 6.02 1.66 0.73
4.79 (Form A) L-Malate N/A 6.53 2.63 N/A 1.12 3.98 N/A 1.25 4.01
(Form B)
Example 22: Preparation of Hydrochloride Salt of Compound 1
[0710] Hydrochloride Salts of Compound 1 may be prepared from
Compound 1 using the following exemplary methods.
Compound 1 Hydrochloride (Form A):
[0711] 200 mg of Compound 1 was dissolved in 10.0 mL of acetone at
60.degree. C. while stirring at 500 rpm and held at 60.degree. C.
for 1.5 hrs. 1.1 e.q. hydrochloric acid in acetone (1.027 mL, 0.5
mol/L) was then added into the Compound 1 solution and incubated at
60.degree. C. for 3 hrs, then cooled to 25.degree. C. and held at
25.degree. C. for 20 hrs. This suspension was centrifuged and the
precipitate collected and washed with acetone. The obtained wet
product was vacuum dried at 25.degree. C. for 42 hrs resulting in
168.15 mg of powder with a yield of 76.9%.
[0712] The resulting solid is Compound 1 Hydrochloride (Form A).
The ratio of Compound 1: hydrochloric acid in Compound 1
Hydrochloride (Form A) is 1:0.94 as determined by ion
chromatography. The XPRD is shown in FIG. 103; the DSC and TGA are
shown in FIG. 104; and the DVS is shown in FIG. 105.
Compound 1 Hydrochloride (Form B):
[0713] 500 mg of hydrochloride (Form A) was dissolved in 4.0 mL of
ethanol at 50.degree. C. The solution was filtered and a 6.25 fold
volume of heptane was then added dropwise to the solution which
produced a suspension. This suspension was kept constant stirring
at 500 rpm and held at 50.degree. C. for 24 hrs. The suspension was
then centrifuged and the precipitate collected, vacuum dried at
30.degree. C. for 24 hrs resulting in 365 mg of powder with a yield
of 73.0%.
[0714] The resulting solid is Compound 1 Hydrochloride (Form B).
The ratio of Compound 1: hydrochloric acid in Compound 1
Hydrochloride (Form B) is 1:0.96 as determined by ion
chromatography. The XPRD is shown in FIG. 106; the DSC and TGA are
shown in FIG. 107; and the DVS is shown in FIG. 108.
Compound 1 Hydrochloride (Form C):
[0715] 300 mg of hydrochloride salt (Form A) was suspended in 6.0
mL of 0.901 water activity solution at 50.degree. C. under stirring
at 700 rpm which produced a clear solution. Then 200 mg of the
hydrochloride salt was added which produced a suspension. The
suspension remained under constant stirring at 700 rpm and held at
50.degree. C. for 1 week. Then the suspension was centrifuged and
the precipitate collected, vacuum dried at 30.degree. C. for 24 hrs
resulting in 400 mg of powder with a yield of 80.0%.
[0716] The resulting solid is Compound 1 Hydrochloride (Form C).
The ratio of Compound 1: Hydrochloric acid in Compound 1
Hydrochloride (Form C) is 1:0.97 as determined by ion
chromatography. The XPRD is shown in FIG. 109; the DSC and TGA are
shown in FIG. 110; and the DVS is shown in FIG. 111.
Chemical and Physical Stability Test
[0717] Chemical and physical stability testing was carried out
using the procedures set forth in Example 1. The chemical and
physical stability test results for Compound 1 Hydrochloride (Form
A), Compound 1 Hydrochloride (Form B), Compound 1 Hydrochloride
(Form C) and Compound 1 free base are shown in the following
table:
TABLE-US-00108 Starting XRPD Final materials Conditions patterns
purity Compound 1 60.degree. C., 1 w Pattern A 99.3 40.degree.
C./75% RH, Pattern A 99.1 1 w 1.2 million lux- Pattern A 99.2 hrs
Dark control Pattern A 99.1 Hydrochloride 60.degree. C., 1 w Form A
99.5 (Form A) 40.degree. C./75% RH, Form A 99.4 1 w 1.2 million
lux- Form A 99.5 hrs Dark control Form A 99.5 Hydrochloride
60.degree. C., 1 w Form B 100.0 (Form B) 40.degree. C./75% RH,
Similar to 100.0 1 w Form C 1.2 million lux- Form B 98.2 hrs Dark
control Form B 98.59 Hydrochloride 60.degree. C., 1 w Form C 98.6
(Form C) 40.degree. C./75% RH, Form C 100.0 1 w 1.2 million lux-
Form C 100.0 hrs Dark control Form C 99.2
Solubility Tests in Simulated Gastric and Intestinal Fluids
[0718] Solubility Tests in Simulated Gastric and Intestinal Fluids
was carried out using the procedures set forth in Example 1. The
solubility results (mg/mL) in bio-relevant solutions for Compound 1
Hydrochloride (Form A), Compound 1 Hydrochloride (Form B), Compound
1 Hydrochloride (Form C) and Compound 1 free base are shown in the
following table:
TABLE-US-00109 SGF FaSSIF FeSSIF (original (original (original pH =
1.82) pH = 6.50) pH = 4.99) Solute 1 24 Final Final Final tested h
h pH 1 h 24 h pH 1 h 24 h pH Compound 3.41 2.81 2.07 0.03 0.03 6.47
0.87 0.95 5.00 1 Hydro- 6.28 6.28 2.05 0.86 0.84 4.05 1.17 0.67
4.93 chloride (Form A) Hydro- N/A 3.00 1.73 N/A 1.70 3.76 N/A 1.32
3.94 chloride (Form B) Hydro- N/A 1.58 1.69 N/A 0.95 4.03 N/A 1.12
3.99 chloride (Form C)
Example 22: Preparation of Napsylate Salt of Compound 1
[0719] A Napsylate Salt of Compound 1 may be prepared from Compound
1 using the following exemplary method.
Compound 1 Napsylate (Form A):
[0720] 500 mg of Compound 1 was dissolved in 16.0 mL of acetone at
60.degree. C. while stirring at 500 rpm and held at 60.degree. C.
for 1.5 hrs. 1.1 e.q. naphthalene-2-sulfonic acid hydrate in
acetone (2.565 mL, 0.5 mol/L) was then added into the Compound 1
solution and incubated at 60.degree. C. for 3 hrs, then cooled to
25.degree. C. and held at 25.degree. C. for overnight. This
suspension was centrifuged and the precipitate collected and washed
with acetone. The obtained wet product was vacuum dried at
25.degree. C. for 72 hrs resulting in 690.41 mg of powder with a
yield of 89.17%.
[0721] The resulting solid is Compound 1 Napsylate (Form A). The
ratio of Compound 1: naphthalene-2-sulfonic acid in Compound 1
Napsylate (Form A) is 1:1.04 as determined by ion chromatography.
The XPRD is shown in FIG. 112; the DSC and TGA are shown in FIG.
113; and the DVS is shown in FIG. 114.
[0722] Compound 1 Napsylate (Form A) was analyzed by .sup.1H-NMR in
deuterated DMSO resulting in the following chemical shifts: .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 0.51-0.80 (m, 8H) 0.82-1.77
(m, 25H) 2.33 (br d, J=1.75 Hz, 2H) 2.54-2.78 (m, 3H) 3.05 (s, 3H)
3.20-3.30 (m, 6H) 4.04 (br s, 1H) 5.15-5.36 (m, 2H) 7.49-7.73 (m,
5H) 7.83-8.01 (m, 3H) 8.14 (s, 1H) 8.94 (s, 1H).
Chemical and Physical Stability Test
[0723] Chemical and physical stability testing was carried out
using the procedures set forth in Example 1. The chemical and
physical stability test results for Compound 1 Napsylate (Form A)
and Compound 1 free base are shown in the following table:
TABLE-US-00110 Starting XRPD Final materials Conditions patterns
purity Compound 1 60.degree. C., 1 w Pattern A 98.2 40.degree.
C./75% RH, Pattern A 98.2 1 w 1.2 million lux- Pattern A 97.9 hrs
Dark control Pattern A 98.3 Napsylate (Form 60.degree. C., 1 w Form
A 99.1 A) 40.degree. C./75% RH, Form A 99.1 1 w 1.2 million lux-
Form A 99.0 hrs Dark control Form A 99.1
Solubility Tests in Simulated Gastric and Intestinal Fluids
[0724] Solubility Tests in Simulated Gastric and Intestinal Fluids
was carried out using the procedures set forth in Example 1. The
solubility results (mg/mL) in bio-relevant solutions for Compound 1
Napsylate (Form A) and Compound 1 free base are shown in the
following table:
TABLE-US-00111 SGF FaSSIF FeSSIF (original (original (original pH =
1.82) pH = 6.51) pH = 4.99) Solute tested 24 h Final pH 24 h Final
pH 24 h Final pH Compound 1 4.44 3.10 0.05 6.48 0.84 5.11 Napsylate
(Form 0.40 1.86 0.06 5.42 1.00 5.04 A)
Compound 1 Napsylate (Form B):
[0725] 50 mg Compound 1 and 1.1 e.q. counter ion of
naphthalene-2-sulfonic acid hydrate in solid form were weighed into
2 mL vials individually, and then 1 mL solvent EtOAc/ACN was added
into the vial. The vial was placed on the thermo-mixer with a stir
bar and heated to 50.degree. C. After keeping at 50.degree. C.
under constant stirring at 500 rpm for 21 hrs, the vial was then
cooled to 25.degree. C. After keeping at 25.degree. C. for 1 hr,
the solids in suspension were isolated by centrifugation and dried
in the vacuum oven at 30.degree. C. for 18 hrs.
[0726] The obtained dried solids were characterized by PLM and XRPD
(FIG. 115).
Example 23: Preparation of Oxalate Salt of Compound 1
[0727] An Oxalate Salt of Compound 1 may be prepared from Compound
1 using the following exemplary method.
Compound 1 Oxalate (Form A)
[0728] 500 mg of Compound 1 was dissolved in 16.0 mL of acetone at
60.degree. C. while stirring at 500 rpm and held at 60.degree. C.
for 1.5 hrs. 1.1 e.g. oxalic acid in acetone (2.565 mL, 0.5 mol/L)
was then added into the Compound 1 solution and incubated at
60.degree. C. for 3 hrs, then cooled to 25.degree. C. and held at
25.degree. C. for overnight. This suspension was centrifuged and
the precipitate collected and washed with acetone. The obtained wet
product was vacuum dried at 25.degree. C. for 72 hrs resulting in
595.76 mg of powder with a yield of 96.32%.
[0729] The resulting solid is Compound 1 Oxalate (Form A). The
ratio of Compound 1: oxalic acid in Compound 1 Oxalate (Form A) is
1:0.91 as determined by ion chromatography. The XPRD is shown in
FIG. 116; the DSC and TGA are shown in FIG. 117; and the DVS is
shown in FIG. 118.
Chemical and Physical Stability Test
[0730] Chemical and physical stability testing was carried out
using the procedures set forth in Example 1. The chemical and
physical stability test results for Compound 1 Oxalate (Form A) and
Compound 1 free base are shown in the following table:
TABLE-US-00112 Starting XRPD Final materials Conditions patterns
purity Compound 1 60.degree. C., 1 w Pattern A 98.2 40.degree.
C./75% RH, Pattern A 98.2 1 w 1.2 million lux- Pattern A 97.9 hrs
Dark control Pattern A 98.3 Oxalate (Form 60.degree. C., 1 w Form A
98.3 A) 40.degree. C./75% RH, Form A 98.4 1 w 1.2 million lux Form
A 98.2 hrs Dark control Form A 98.9
Solubility Tests in Simulated Gastric and Intestinal Fluids
[0731] Solubility Tests in Simulated Gastric and Intestinal Fluids
was carried out using the procedures set forth in Example 1. The
solubility results (mg/mL) in bio-relevant solutions for Compound 1
Oxalate (Form A) and Compound 1 free base are shown in the
following table:
TABLE-US-00113 SGF FaSSIF FeSSIF (original (original (original pH =
1.82) pH = 6.51) pH = 4.99) Solute tested 24 h Final pH 24 h Final
pH 24 h Final pH Compound 1 4.44 3.10 0.05 6.48 0.84 5.11 Oxalate
(Form A) 3.76 1.95 1.84 4.86 0.75 3.73
Compound 1 Oxylate (Form B)
[0732] 50 mg Compound 1 and 1.1 e.q. counter ion of oxalic acid in
solid form were weighed into 2 mL vials individually, and then 1 mL
EtOAc solvent was added into the vial. The vial was placed on the
thermo-mixer with a stir bar and heated to 50.degree. C. After
keeping at 50.degree. C. under constant stirring at 500 rpm for 21
hrs, the vial was then cooled to 25.degree. C. After keeping at
25.degree. C. for 1 hr, the solids in suspension were isolated by
centrifugation and dried in the vacuum oven at 30.degree. C. for 18
hrs.
[0733] The dried solids were characterized by PLM and XRPD (FIG.
119).
Example 24: Preparation of P-Aminosalicylate Salt of Compound 1
[0734] A P-Aminosalicylate Salt of Compound 1 may be prepared from
Compound 1 using the following exemplary method.
Compound 1 P-Aminosalicylate (Form A)
[0735] 500 mg of Compound 1 was dissolved in 16.0 mL of acetone at
60.degree. C. while stirring at 500 rpm and held at 60.degree. C.
for 1.5 hrs. 1.1 eq. 4-aminosalicylic acid in acetone (2.565 mL,
0.5 mol/L) was then added into the Compound 1 solution and
incubated at 60.degree. C. for 3 hrs, then cooled to 25.degree. C.
and held at 25.degree. C. for overnight. This suspension was
centrifuged and the precipitate collected and washed with acetone.
The obtained wet product was vacuum dried at 25.degree. C. for 72
hrs resulting in 583.32 mg of powder with a yield of 83.37%.
[0736] The resulting solid is Compound 1 P-Aminosalicylate (Form
A). The ratio of Compound 1: 4-aminosalicylic acid in Compound 1
P-Aminosalicylate (Form A) is 1:1.03 as determined by ion
chromatography. The XPRD is shown in FIG. 120; the DSC and TGA are
shown in FIG. 121; and the DVS is shown in FIG. 122.
[0737] Compound 1 P-Aminosalicylate (Form A) was analyzed by
.sup.1H-NMR in deuterated DMSO resulting in the following chemical
shifts: .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 0.51-0.80
(m, 7H) 0.83-1.74 (m, 22H) 1.97-2.15 (m, 3H) 2.34 (s, 1H) 2.68 (br
t, J=8.69 Hz, 1H) 2.99-3.09 (m, 2H) 3.25 (s, 4H) 4.83-5.10 (m, 2H)
5.88-6.11 (m, 3H) 6.76 (t, J=8.19 Hz, 1H) 6.90 (s, 1H) 7.04 (s, 1H)
7.42 (d, J=8.63 Hz, 1H) 7.57 (s, 1H)
Chemical and Physical Stability Test
[0738] Chemical and physical stability testing was carried out
using the procedures set forth in Example 1. The chemical and
physical stability test results for Compound 1 P-Aminosalicylate
(Form A) and Compound 1 free base are shown in the following
table:
TABLE-US-00114 Starting XRPD Final materials Conditions patterns
purity Compound 1 60.degree. C., 1 w Pattern A 98.2 40.degree.
C./75% RH, Pattern A 98.2 1 w 1.2 million lux- Pattern A 97.9 hrs
Dark control Pattern A 98.3 P- 60.degree. C., 1 w Form A 91.5
aminosalicylate 40.degree. C./75% RH, Form A 97.0 (Form A) 1 w 1.2
million lux- Form A 95.7 hrs Dark control Form A 95.8
Solubility Tests in Simulated Gastric and Intestinal Fluids
[0739] Solubility Tests in Simulated Gastric and Intestinal Fluids
was carried out using the procedures set forth in Example 1. The
solubility results (mg/mL) in bio-relevant solutions for Compound 1
P-Aminosalicylate (Form A) and Compound 1 free base are shown in
the following table:
TABLE-US-00115 SGF FaSSIF FeSSIF (original (original (original pH =
1.82) pH = 6.51) pH = 4.99) Solute tested 24 h Final pH 24 h Final
pH 24 h Final pH Compound 1 4.44 3.10 0.05 6.48 0.84 5.11
P-Aminosalicylate 2.86 3.73 0.20 5.12 1.77 5.06 (Form A)
Compound 1 P-Aminosalicylate (Form B)
[0740] 50 mg Compound 1 and 1.1 e.q. counter ion of
4-aminosalicylic acid in solid form were weighed into 2 mL vials
individually, and then 1 mL solvent EtOAc/ACN was added into the
vial. The vial was placed on the thermo-mixer with a stir bar and
heated to 50.degree. C. After keeping at 50.degree. C. under
constant stirring at 500 rpm for 21 hrs, the vial was then cooled
to 25.degree. C. After keeping at 25.degree. C. for 1 hr, the
solids in suspension were isolated by centrifugation and dried in
the vacuum oven at 30.degree. C. for 18 hrs.
[0741] The dried solids were characterized by PLM and XRPD (FIG.
123).
Example 25: Preparation of Maleate Salt of Compound 1
[0742] Maleate Salts of Compound 1 may be prepared from Compound 1
using the following exemplary methods.
Compound 1 Maleate (Form A):
[0743] 50 mg of compound 1 and 1.1 e.g. counter ion of maleic acid
in solid form were weighed into 2 mL vials individually, and then 1
mL acetone solvent was added into the vial. The vial was placed on
the thermo-mixer with a stir bar and heated to 50.degree. C. After
keeping at 50.degree. C. under constant stirring at 900 rpm for 18
hrs, the vial was then cooled to 25.degree. C., After keeping at
25.degree. C. for 1 hr, the solids in suspension were isolated by
centrifugation and dried in the vacuum oven at 30.degree. C.
overnight.
[0744] The obtained dried solids were characterized by PLM and XFPD
(FIG. 124).
Example 26: Attempts to Prepare Salts of Compound 1
[0745] The following acids formed non-crystalline salts under some
conditions:
TABLE-US-00116 Acid Solvent Maleic Acid Ethyl Acetate; IPA/Water
(95:5 V:V) L-Malic Acid IPA/Water (95:5 V:V) Succinic Acid Acetone;
ACN; IPA/Water (95:5 V:V) Naphthalene-2-sulfonic IPA/Water (95:5
V:V) Acid Ascorbic Acid IPA/Water (95:5 V:V) Salicylic Acid
Acetone; ACN; IPA/Water (95:5 V:V) Lactic Acid Acetone
2-Hydroxyethanesulfonic Acetone, Ethyl acetate acid D-Mandelic Acid
Acetone; ACN; IPA/Water (95:5 V:V) Cyclamic Acid IPA/Water (95:5
V:V) Dichloroacetic acid Ethyl acetate; ACN; IPA/Water (95:5
V:V)
[0746] Although multiple conditions (shown below) were attempted,
the acids in the following table did not provide isolable salts of
Compound 1.
TABLE-US-00117 Acid Solvent Hydrochloric Acid IPA/Water (95:5 V:V)
Sulfuric Acid IPA/Water (95:5 V:V) Acetic Acid Acetone; Ethyl
acetate; ACN; IPA/Water (95:5 V:V) Succinic Acid Ethyl Acetate
Pamoic Acid Acetone; Ethyl acetate; ACN; IPA/Water (95:5 V:V) Oleic
Acid Acetone; Ethyl acetate; ACN; IPA/Water (95:5 V:V) L-Lysine
Acid Acetone; Ethyl acetate; ACN; IPA/Water (95:5 V:V) L-Arginine
Acetone; Ethyl acetate; ACN; IPA/Water (95:5 V:V) L-Aspartic Acid
Acetone; Ethyl acetate; ACN; IPA/Water (95:5 V:V) Mucic Acid
Acetone; Ethyl acetate; ACN; IPA/Water (95:5 V:V) Hipuric Acid
Acetone; Ethyl acetate; ACN; IPA/Water (95:5 V:V) L-Pyroglutamic
Acetone; Ethyl acetate; ACN; IPA/Water (95:5 V:V) Acid Gluconic
Acid Acetone; Ethyl acetate; ACN; IPA/Water (95:5 V:V) Gly conic
Acid Acetone; Ethyl acetate; ACN; IPA/Water (95:5 V:V) Lactic Acid
Ethyl acetate; ACN; IPA/Water (95:5 V:V) D-Mandelic Acid Ethyl
Acetate Lactobionic Acid Acetone; Ethyl Acetate; ACN; IPA/Water
(95:5 V:V) Alginic Acid Acetone; Ethyl Acetate; ACN; IPA/Water
(95:5 V:V) Glycerophosphoric Acetone; Ethyl Acetate; ACN; IPA/Water
(95:5 V:V) Acid DL-Valine Acetone; Ethyl Acetate; ACN; IPA/Water
(95:5 V:V) DL-Leucine Acetone; Ethyl Acetate; ACN; IPA/Water (95:5
V:V) L-Isoleucine Acetone; Ethyl Acetate; ACN; IPA/Water (95:5
V:V)
[0747] Experimental conditions: For each of the twenty acids listed
in the table above, four solvents (acetone, EtOAc, ACN and
IPA/water (95/5, V/V)) were used according to following procedure
to determine whether isolable salts of Compound 1 were provided by
the particular solvent-acid combination.
[0748] Approximately 50 mg of Compound 1 and 1.1 molar equivalents
of the acid were placed in a 2 mL vial. Approximately 1 mL solvent
was added into the vial. The vials were placed on the thermomixer
with a stir bar and heated to 50.degree. C. After stirring (500
rpm) at 50.degree. C. for 21 hrs, the vials were cooled to
25.degree. C. and held at 25.degree. C. for 1 hr and vials were
monitored for the formation of solids. None of the experiments
provided solids after stirring for approximately one hour. For each
experiment, the solvent was evaporated in vacuum oven at 30.degree.
C. Under these conditions, none of the acids listed in the table
above provided an isolable salt of Compound 1.
TABLE-US-00118 Example 27. Bulk Density for salts of Compound 1.
Bulk Tapped Density Density Salt Form (g/mL) (g/mL) Citrate A 0.49
0.70 Phosphate A 0.15 0.33 Tartrate A 0.13 0.32 HBr A 0.27 0.50
Free Base A 0.25 0.45
INCORPORATION BY REFERENCE
[0749] All references, articles, publications, patents, patent
publications, and patent applications cited herein are incorporated
by reference in their entireties for all purposes. However, mention
of any reference, article, publication, patent, patent publication,
and patent application cited herein is not, and should not be taken
as acknowledgment or any form of suggestion that they constitute
valid prior art or form part of the common general knowledge in any
country in the world.
* * * * *