U.S. patent application number 13/181460 was filed with the patent office on 2012-07-26 for romidepsin solid forms and uses thereof.
This patent application is currently assigned to Celgene Corporation. Invention is credited to David Engers, Eric Hagen, Jason Hanko, Valeriya Smolenskaya, Jeffrey Stults.
Application Number | 20120190817 13/181460 |
Document ID | / |
Family ID | 44514993 |
Filed Date | 2012-07-26 |
United States Patent
Application |
20120190817 |
Kind Code |
A2 |
Hanko; Jason ; et
al. |
July 26, 2012 |
ROMIDEPSIN SOLID FORMS AND USES THEREOF
Abstract
The present disclosure provides solid forms of a compound of
formula I. In some embodiments, the present disclosure provides
crystalline forms of Compound I. In some embodiments, the present
disclosure provides solvate forms of Compound I. In some
embodiments, the present disclosure provides amorphous Compound
I.
Inventors: |
Hanko; Jason; (West
Lafayette, IN) ; Engers; David; (West Lafayette,
IN) ; Hagen; Eric; (Lafayette, IN) ;
Smolenskaya; Valeriya; (West Lafayette, IN) ; Stults;
Jeffrey; (Half Moon Bay, CA) |
Assignee: |
Celgene Corporation
Summit
NJ
07901
|
Prior
Publication: |
|
Document Identifier |
Publication Date |
|
US 20120046442 A1 |
February 23, 2012 |
|
|
Family ID: |
44514993 |
Appl. No.: |
13/181460 |
Filed: |
July 12, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61/363522 |
Jul 12, 2010 |
|
|
|
Current U.S.
Class: |
530/323 |
Current CPC
Class: |
A61P 37/06 20180101;
A61K 38/07 20130101; A61P 7/00 20180101; C07K 5/101 20130101; A61P
17/00 20180101; A61K 38/00 20130101; A61P 31/04 20180101; A61P
35/02 20180101; C07K 11/02 20130101; A61P 35/00 20180101; A61P
43/00 20180101 |
Class at
Publication: |
530/323 |
International
Class: |
C07K 11/02 20060101
C07K011/02 |
Claims
1. Crystalline Form C of romidepsin.
2. Crystalline Form D of romidepsin.
3. Crystalline Form E of romidepsin.
4. Crystalline Form F of romidepsin.
5. Crystalline Form H of romidepsin.
6. Crystalline Form I of romidepsin.
7. Crystalline Form J of romidepsin.
8. Crystalline Form K of romidepsin.
9. Crystalline Form L of romidepsin.
10. Crystalline Form N of romidepsin.
11. A composition, comprising romidepsin, wherein substantially all
of the romidepsin is amorphous.
12. The composition of claim 11, wherein the composition has an
XRPD pattern substantially similar to FIG. 7(a).
13. The composition of claim 11, wherein the amorphous romidepsin
is obtained from a water/dichloromethane mixture, or an
isopropanol-trifluoroethanol/methanol mixture.
14. A composition, comprising amorphous romidepsin and
povidone.
15. The composition of claim 14, wherein the povidone is povidone
USP.
16. The composition of claim 14, wherein the povidone is povidone
EP.
17. The composition of any one of claim 14 to 16, wherein the ratio
of amorphous romidepsin to povidone is about 1:2.
18. A method of treating a hematological disorder comprising
administering to a subject the composition of claim 17.
19. The method of claim 18, wherein the hematological disorder is
peripheral T cell lymphoma (PTCL).
20. The method of claim 18, wherein the hematological disorder is
cutaneous T cell lymphoma (CTCL).
Description
[0001] This application claims priority to U.S. Provisional
Application No. 61/363,522, filed Jul. 12, 2010, which is
incorporated herewith by reference in its entirety.
FIELD
[0002] Provided herein are solid forms of romidepsin and
compositions comprising these forms. In some embodiments, provided
are polymorphic forms of romidepsin. In some embodiments, provided
are solvate forms of romidepsin. In some embodiments, provided is
amorphous romidepsin. Also provided are methods for producing such
forms and compositions.
BACKGROUND
[0003] Romidepsin is a natural product which was isolated from
Chromobacterium violaceum by Fujisawa Pharmaceuticals. See
Published Japanese Patent Application Hei 7 (1995)-64872; and U.S.
Pat. No. 4,977,138, issued Dec. 11, 1990, each of which is
incorporated herein by reference. Various preparations and
purifications of romidepsin are described in PCT Publication WO
02/20817, which is incorporated herein by reference.
[0004] It is a bicyclic peptide consisting of four amino acid
residues (D-valine, D-cysteine, dehydrobutyrine, and L-valine) and
a novel acid (3-hydroxy-7-mercapto-4-heptenoic acid). Romidepsin is
a depsipeptide which contains both amide and ester bonds. In
addition to the production of C. violaceum using fermentation,
romidepsin can also be prepared by synthetic or semi-synthetic
means. The total synthesis of romidepsin reported by Kahn et al.
(J. Am. Chem. Soc. 118:7237-7238, 1996) involves 14 steps and
yields romidepsin in 18% overall yield. The structure of romidepsin
is shown below and referred to hereinafter as "Compound I":
##STR1##
[0005] Compound I has been shown to have anti-microbial,
immunosuppressive, and anti-tumor activities. Compound I is
approved in the U.S. for treatment of cutaneous T-cell lymphoma
(CTCL) and peripheral T-cell lymphoma (PTCL), and is currently
being tested, for example, for use in treating patients with other
hematological malignancies (e.g., multiple myeloma, etc.) and solid
tumors (e.g., prostate cancer, pancreatic cancer, etc.). It is
thought to act by selectively inhibiting deacetylases (e.g.,
histone deacetylase, tubulin deacetylase), promising new targets
for the development of a new class of anti-cancer therapies
(Nakajima et al., Experimental Cell Res. 241:126-133, 1998). One
mode of action involves the inhibition of one or more classes of
histone deacetylases (HDAC).
SUMMARY
[0006] In one aspect, provided herein are solid forms of Compound
I.
[0007] In some embodiments, provided herein is a method of
preparation of crystalline form C of Compound I and its
characterization.
[0008] In some embodiments, provided herein is a method of
preparation of crystalline form D of Compound I and its
characterization.
[0009] In some embodiments, provided herein is a method of
preparation of crystalline form E of Compound I and its
characterization.
[0010] In some embodiments, provided herein is a method of
preparation of crystalline form I of Compound I and its
characterization.
[0011] In some embodiments, provided herein is a method of
preparation of crystalline form J of Compound I and its
characterization.
[0012] In some embodiments, provided herein is a method of
preparation of crystalline form K of Compound I and its
characterization.
[0013] In some embodiments, provided herein is a method of
preparation of crystalline form L of Compound I and its
characterization.
[0014] In some embodiments, provided herein is a method of
preparation of crystalline form N of Compound I and its
characterization.
[0015] In some embodiments, provided herein is a method of
preparation of amorphous Compound I and its characterization.
[0016] In some embodiments, Compound I, and solid forms thereof,
are used for the preparation of pharmaceutical compositions. In
some embodiments, provided are compositions and formulations (e.g.,
pharmaceutical compositions and formulations) comprising solid
forms of Compound I.
[0017] In another aspect, provided herein are methods to treat
proliferative diseases, immune-mediated diseases, infectious
diseases, certain circulatory diseases, and certain
neurodegenerative diseases using Compound I, its solid forms and
compositions comprising same. In some embodiments, provided herein
are methods to treat cancer. In some embodiments, cancers include,
but are not limited to, carcinomas, sarcomas, leukemias, lymphomas
and the like. In certain embodiments, cancer is a hematological
malignancy. In certain embodiments, cancer is a solid tumor.
[0018] In another aspect, provided herein are methods of
electrolyte supplementation for patients receiving Compound I
therapy.
DESCRIPTION OF THE DRAWINGS
[0019] FIG. 1(a) depicts a representative solution .sup.1HNMR
spectrum obtained for Compound I.
[0020] FIG. 1(b) depicts a molecular structure for Compound I.
[0021] FIG. 1(c) depicts an XRPD for Compound I Form C collected at
room temperature.
[0022] FIG. 1(d) tabulates observed peaks (part i); and prominent
peaks (part ii) present in the XRPD of FIG. 1(c).
[0023] FIG. 1(e) depicts a DSC thermogram obtained for Compound I
Form C.
[0024] FIG. 1(f) depicts a TGA thermogram obtained for Compound I
Form C.
[0025] FIG. 1(g) depicts an FT-IR spectrum obtained for Compound I
Form C.
[0026] FIG. 1(h) tabulates peak positions of bands present in the
FT-IR spectrum of FIG. 1(g).
[0027] FIG. 1(i) depicts a calculated XRPD for Compound I Form C
collected at subambient temperature.
[0028] FIG. 1(j) depicts theoretical observed peaks (part i); and
representative peaks (part ii) present in the XRPD of FIG.
1(i).
[0029] FIG. 1(k) depicts an ORTEP drawing of Compound I, Form C,
water molecules not shown.
[0030] FIG. 1(l) depicts a packing diagram of Compound I, Form C
viewed down the crystallographic a axis.
[0031] FIG. 1(m) depicts a packing diagram of Compound I, Form C
viewed down the crystallographic b axis.
[0032] FIG. 1(n) depicts a packing diagram of Compound I, Form C
viewed down the crystallographic c axis.
[0033] FIG. 1(o) tabulates positional parameters and estimated
standard deviations for Compound I, Form C.
[0034] FIG. 1(p) tabulates bond distances (Angstroms) for Compound
I, Form C.
[0035] FIG. 1(q) tabulates bond angles (degrees) for Compound I,
Form C.
[0036] FIG. 2(a) depicts an XRPD for Compound I Form D collected at
room temperature.
[0037] FIG. 2(b) tabulates observed peaks (part i); and prominent
peaks (part ii) present in the XRPD of FIG. 2(a).
[0038] FIG. 2(c) depicts a DSC thermogram obtained for Compound I
Form D.
[0039] FIG. 2(d) depicts a TGA thermogram obtained for Compound I
Form D.
[0040] FIG. 2(e) depicts an FT-IR spectrum obtained for Compound I
Form D.
[0041] FIG. 2(f) tabulates peak positions of bands present in the
FT-IR spectrum of FIG. 2(e).
[0042] FIG. 3(a) depicts an XRPD for Compound I Form E collected at
room temperature.
[0043] FIG. 3(b) tabulates observed peaks (part i); and prominent
peaks (part ii) present in the XRPD of FIG. 3(a).
[0044] FIG. 3(c) depicts a DSC thermogram obtained for Compound I
Form E.
[0045] FIG. 3(d) depicts a TGA thermogram obtained for Compound I
Form E.
[0046] FIG. 3(e) depicts an FT-IR spectrum obtained for Compound I
Form E.
[0047] FIG. 3(f) tabulates peak positions of bands present in the
FT-IR spectrum of FIG. 3(e).
[0048] FIG. 3(g) depicts an FT-Raman spectrum for Compound I Form
E.
[0049] FIG. 3(h) depicts a calculated XRPD for Compound I Form E
collected at subambient temperature.
[0050] FIG. 3(i) depicts theoretical observed peaks (part i); and
representative peaks (part ii) present in the XRPD of FIG.
3(h).
[0051] FIG. 3(j) depicts an ORTEP drawing of Compound I, Form
E.
[0052] FIG. 3(k) depicts a packing diagram of Compound I, Form E
viewed down the crystallographic a axis.
[0053] FIG. 3(l) depicts a packing diagram of Compound I, Form E
viewed down the crystallographic b axis.
[0054] FIG. 3(m) depicts a packing diagram of Compound I, Form E
viewed down the crystallographic c axis.
[0055] FIG. 3(n) tabulates positional parameters and estimated
standard deviations for Compound I, Form E.
[0056] FIG. 3(o) tabulates bond distances (Angstroms) for Compound
I, Form E.
[0057] FIG. 3(p) tabulates bond angles (degrees) for Compound I,
Form E.
[0058] FIG. 4(a) depicts an XRPD for Compound I Form H collected at
room temperature.
[0059] FIG. 4(b) tabulates observed peaks (part i); and prominent
peaks (part ii) present in the XRPD of FIG. 4(a).
[0060] FIG. 4(c) depicts a DSC thermogram obtained for Compound I
Form H.
[0061] FIG. 4(d)) depicts a TGA thermogram obtained for Compound I
Form H.
[0062] FIG. 4(e) depicts an FT-IR spectrum obtained for Compound I
Form H.
[0063] FIG. 4(f) tabulates peak positions of bands present in the
FT-IR spectrum of FIG. 4(e).
[0064] FIG. 5(a) depicts an XRPD for Compound I Form I collected at
room temperature.
[0065] FIG. 5(b) tabulates observed peaks present in the XRPD of
FIG. 5(a).
[0066] FIG. 5(c) depicts a DSC thermogram obtained for Compound I
Form I.
[0067] FIG. 5(d) depicts a TGA thermogram obtained for Compound I
Form I.
[0068] FIG. 5(e) depicts an FT-IR spectrum obtained for Compound I
Form I.
[0069] FIG. 5(f) tabulates peak positions of bands present in the
FT-IR spectrum of FIG. 5(e).
[0070] FIG. 5(g) depicts a calculated XRPD for Compound I Form I
collected at subambient temperature.
[0071] FIG. 5(h) depicts theoretical observed peaks (part i); and
representative peaks (part ii) present in the XRPD of FIG.
5(g).
[0072] FIG. 5(i) depicts an ORTEP drawing of Compound I, Form I,
chloroform not shown.
[0073] FIG. 5(j) depicts a packing diagram of Compound I, Form I
viewed down the crystallographic a axis.
[0074] FIG. 5(k) depicts a packing diagram of Compound I, Form I
viewed down the crystallographic b axis.
[0075] FIG. 5(l) depicts a packing diagram of Compound I, Form I
viewed down the crystallographic c axis.
[0076] FIG. 5(m) tabulates positional parameters and estimated
standard deviations for Compound I, Form I.
[0077] FIG. 5(n) tabulates bond distances (Angstroms) for Compound
I, Form I.
[0078] FIG. 5(o) tabulates bond angles (degrees) for Compound I,
Form I.
[0079] FIG. 5(p) depicts an XRPD for Compound I Form I.
[0080] FIG. 5(q) tabulates observed peaks present in the XRPD of
FIG. 5(p).
[0081] FIG. 5(r) tabulates prominent peaks present in the XRPD of
FIG. 5(p).
[0082] FIG. 5(s) depicts an FT-IR spectrum obtained for Compound I
Form I.
[0083] FIG. 5(t) tabulates peak positions of bands present in the
FT-IR spectrum of FIG. 5(s).
[0084] FIG. 5(u) depicts Panalytical X-Pert Pro MPD PW3040 data for
Compound I Form I.
[0085] FIG. 5(v) depicts a DSC thermogram obtained for Compound I
Form I.
[0086] FIG. 5(w) depicts a DSC thermogram obtained for Compound I
Form I.
[0087] FIG. 5(x) depicts a TGA thermogram obtained for Compound I
Form I.
[0088] FIG. 5(y) depicts an FT-IR spectrum obtained for Compound I
Form I.
[0089] FIG. 6(a) depicts an X-ray diffraction pattern overlay of
Compound I Form D and the calculated X-ray diffraction pattern of
Compound I Form J.
[0090] FIG. 6(b) depicts an ORTEP drawing of the single crystal
structure of Compound I Form J.
[0091] FIG. 6(c) depicts a calculated XRPD for Compound I Form J
collected at subambient temperature.
[0092] FIG. 6(d) depicts theoretical observed peaks (part i); and
prominent peaks (part ii) present in the XRPD of FIG. 6(c).
[0093] FIG. 6(e) depicts a packing diagram of Compound I, Form J
viewed down the crystallographic a axis.
[0094] FIG. 6(f) depicts a packing diagram of Compound I, Form J
viewed down the crystallographic b axis.
[0095] FIG. 6(g) depicts a packing diagram of Compound I, Form J
viewed down the crystallographic c axis.
[0096] FIG. 6(h) tabulates positional parameters and estimated
standard deviations for Compound I, Form J.
[0097] FIG. 6(i) tabulates bond distances (Angstroms) for Compound
I, Form J.
[0098] FIG. 6(j) tabulates bond angles (degrees) for Compound I,
Form J.
[0099] FIG. 6(k) depicts an XRPD for Compound I Form J.
[0100] FIG. 6(l) tabulates observed peaks present in the XRPD of
FIG. 6(k).
[0101] FIG. 6(m) tabulates prominent peaks present in the XRPD of
FIG. 6(k).
[0102] FIG. 6(n) depicts an FT-IR spectrum obtained for Compound I
Form J.
[0103] FIG. 6(o) tabulates peak positions of bands present in the
FT-IR spectrum of FIG. 6(n).
[0104] FIG. 6(p) depicts Panalytical X-Pert Pro MPD PW3040 data for
Compound I Form J.
[0105] FIG. 6(q) depicts a DSC thermogram obtained for Compound I
Form J.
[0106] FIG. 6(r) depicts a TGA thermogram obtained for Compound I
Form J.
[0107] FIG. 6(s) depicts an FT-IR spectrum obtained for Compound I
Form J.
[0108] FIG. 7(a) depicts an XRPD for amorphous Compound I collected
at room temperature.
[0109] FIG. 7(b) depicts a modulated DSC thermogram obtained for
amorphous Compound I.
[0110] FIG. 7(c) depicts a TGA thermogram obtained for amorphous
Compound I.
[0111] FIG. 7(d) depicts an FT-IR spectrum obtained for amorphous
Compound I.
[0112] FIG. 7(e) tabulates peak positions of bands present in the
FT-IR spectrum of FIG. 7(d).
[0113] FIG. 7(f) depicts an FT-Raman spectrum for amorphous
Compound I.
[0114] FIG. 8(a) depicts an XRPD for Compound I, Form K collected
at room temperature.
[0115] FIG. 8(b) tabulates observed peaks (part i); and prominent
peaks (part ii); present in the XRPD of FIG. 8(a).
[0116] FIG. 8(c) depicts an XRPD for Compound I, Form K.
[0117] FIG. 8(d) tabulates observed peaks present in the XRPD of
FIG. 8(c).
[0118] FIG. 8(e) tabulates prominent peaks present in the XRPD of
FIG. 8(c).
[0119] FIG. 8(f) depicts an FT-IR spectrum obtained for Compound I
Form K.
[0120] FIG. 8(g) tabulates peak positions of bands present in the
FT-IR spectrum of FIG. 8(f).
[0121] FIG. 8(h) depicts Panalytical X-Pert Pro MPD PW3040 data for
Compound I Form K.
[0122] FIG. 8(i) depicts a DSC thermogram obtained for Compound I
Form K.
[0123] FIG. 8(j) depicts a DSC thermogram obtained for Compound I
Form K.
[0124] FIG. 8(k) depicts a TGA thermogram obtained for Compound I
Form K.
[0125] FIG. 8(l) depicts data for Compound I Form K.
[0126] FIG. 9(a) depicts an XRPD for Compound I Form F.
[0127] FIG. 9(b) tabulates observed peaks present in the XRPD of
FIG. 9(a).
[0128] FIG. 9(c) tabulates prominent peaks present in the XRPD of
FIG. 9(a).
[0129] FIG. 9(d) depicts an XRPD for Compound I Form F.
[0130] FIG. 9(e) tabulates observed peaks present in the XRPD of
FIG. 9(d).
[0131] FIG. 9(o) tabulates prominent peaks present in the XRPD of
FIG. 9(d).
[0132] FIG. 9(g) depicts an FT-IR spectrum obtained for Compound I
Form F.
[0133] FIG. 9(h)) tabulates peak positions of bands present in the
FT-IR spectrum of FIG. 9(g).
[0134] FIG. 9(i) depicts Panalytical X-Pert Pro MPD PW3040 data for
Compound I Form F.
[0135] FIG. 9(j) depicts a DSC thermogram obtained for Compound I
Form F.
[0136] FIG. 9(k) depicts a TGA thermogram obtained for Compound I
Form F.
[0137] FIG. 9(l) depicts an FT-IR spectrum obtained for Compound I
Form F.
[0138] FIG. 10(a) depicts an XRPD for Compound I Form L.
[0139] FIG. 10(b) tabulates observed peaks present in the XRPD of
FIG. 10(a).
[0140] FIG. 10(c) tabulates prominent peaks present in the XRPD of
FIG. 10(a).
[0141] FIG. 10(d) depicts an FT-IR spectrum obtained for Compound I
Form L.
[0142] FIG. 10(e)) tabulates peak positions of bands present in the
FT-IR spectrum of FIG. 10(d).
[0143] FIG. 10(f) depicts Panalytical X-Pert Pro MPD PW3040 data
for Compound I Form L.
[0144] FIG. 10(g) depicts a DSC thermogram obtained for Compound I
Form L.
[0145] FIG. 10(h) depicts a TGA thermogram obtained for Compound I
Form L.
[0146] FIG. 10(i) depicts data for Compound I Form L.
[0147] FIG. 11(a) depicts an XRPD for Compound I Form N.
[0148] FIG. 11(b) depicts a DSC thermogram obtained for Compound I
Form N.
[0149] FIG. 11(c) depicts a TGA thermogram obtained for Compound I
Form N.
[0150] FIG. 12 tabulates a single crystal structure summary for
solid forms of Compound I.
DEFINITIONS
[0151] The terms "treat", "treating" or "treatment", as used
herein, refer to a method of alleviating or abrogating a disease
and/or its attendant symptoms. The terms "prevent", "preventing" or
"prevention", as used herein, refer to a method of barring a
subject from acquiring a disease.
[0152] The term "therapeutically effective amount" refers to that
amount of the compound being administered sufficient to prevent
development of or alleviate to some extent one or more of the
symptoms of the condition or disorder being treated.
[0153] The term "subject" is defined herein to include animals such
as mammals, including, but not limited to, primates (e.g., humans),
cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice and the
like. In preferred embodiments, the subject is a human.
[0154] The term "pharmaceutically acceptable salts" is meant to
include salts of active compounds which are prepared with
relatively nontoxic acids. Acid addition salts can be obtained by
contacting the neutral form of such compounds with a sufficient
amount of the desired acid, either neat or in a suitable inert
solvent. Examples of pharmaceutically acceptable acid addition
salts include those derived from inorganic acids like hydrochloric,
hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric,
monohydrogenphosphoric, dihydrogenphosphoric, sulfuric,
monohydrogensulfuric, hydriodic, or phosphorous acids and the like,
as well as the salts derived from relatively nontoxic organic acids
like acetic, propionic, isobutyric, maleic, malonic, benzoic,
succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic,
p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like.
Also included are salts of amino acids such as arginate and the
like, and salts of organic acids like glucuronic or galactunoric
acids and the like (see, for example, Berge, et al. (1977) J.
Pharm. Sci. 66:1-19).
[0155] A pharmaceutically acceptable salt form of a compound can be
prepared in situ during the final isolation and purification of the
compound, or separately by reacting the free base functionality
with a suitable organic or inorganic acid. Examples of typical
pharmaceutically acceptable, nontoxic acid addition salts are salts
of an amino group formed with inorganic acids such as hydrochloric
acid, hydrobromic acid, phosphoric acid, sulfuric acid, and
perchloric acid, or with organic acids such as acetic acid, oxalic
acid, maleic acid, tartaric acid, citric acid, succinic acid, or
malonic acid or by using other methods used in the art such as ion
exchange. Other pharmaceutically acceptable salts can include
adipate, alginate, ascorbate, aspartate, benzenesulfonate,
benzoate, bisulfate, borate, butyrate, camphorate,
camphorsulfonate, citrate, cyclopentanepropionate, digluconate,
dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate,
glycerophosphate, gluconate, hernisulfate, heptanoate, hexanoate,
hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate,
laurate, lauryl sulfate, malate, maleate, malonate,
methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate,
oleate, oxalate, palmitate, pamoate, pectinate, persulfate,
3-phenylpropionate, phosphate, picrate, pivalate, propionate,
stearate, succinate, sulfate, tartrate, thiocyanate,
p-toluenesulfonate, undecanoate, valerate salts, and the like.
Representative alkali or alkaline earth metal salts include sodium,
lithium, potassium, calcium, magnesium, and the like. Further
pharmaceutically acceptable salts can include, when appropriate,
nontoxic ammonium, quaternary ammonium, and amine cations formed
using counterions such as halide, hydroxide, carboxylate, sulfate,
phosphate, nitrate, loweralkyl sulfonate, and aryl sulfonate.
[0156] The neutral forms of the compounds may be regenerated by
contacting the salt with a base or acid and isolating the parent
compound in the conventional manner. The parent form of the
compound differs from the various salt forms in certain physical
properties, such as solubility in polar solvents, but otherwise the
salts are equivalent to the parent form of the compound for the
purposes of the present invention.
[0157] The terms, "polymorphs" and "polymorphic forms" and related
terms refer to one of a variety of different crystal structures
that can be adopted by a particular compound. In some embodiments,
polymorphs occur when a particular chemical compound can
crystallize in more than one structural arrangement. Different
polymorphs may have different physical properties such as, for
example, melting temperatures, heats of fusion, solubilities,
dissolution rates and/or vibrational spectra as a result of the
arrangement or conformation of the molecules in the crystal
lattice. The differences in physical properties exhibited by
polymorphs affect pharmaceutical parameters such as storage
stability, compressibility and density (important in formulation
and product manufacturing), and dissolution rates (an important
factor in determining bioavailability). Differences in stability
can result from changes in chemical reactivity (e.g., differential
oxidation, such that a dosage form discolors more rapidly when
comprised of one polymorph than when comprised of another
polymorph) or mechanical changes (e.g., tablets crumble on storage
as a kinetically favored polymorph converts to thermodynamically
more stable polymorph) or both (e.g., tablets of one polymorph are
more susceptible to breakdown at high humidity). As a result of
solubility/dissolution differences, in the extreme case, some
polymorphic transitions may result in lack of potency or, at the
other extreme, toxicity. In addition, the physical properties of
the crystal may be important in processing, for example, one
polymorph might be more likely to form solvates or might be
difficult to filter and wash free of impurities (i.e., particle
shape and size distribution might be different between one
polymorph relative to the other).
[0158] Polymorphs of a molecule can be obtained by a number of
methods, as known in the art. Such methods include, but are not
limited to, melt recrystallization, melt cooling, solvent
recrystallization, desolvation, rapid evaporation, rapid cooling,
slow cooling, vapor diffusion and sublimation. Polymorphism can be
detected using thermal analysis, e.g., differential scanning
calorimetry (DSC) and thermogravimetry (TGA).
[0159] Techniques for characterizing polymorphs include, but are
not limited to, differential scanning calorimetry (DSC), X-ray
powder diffractometry (XRPD), single crystal X-ray diffractometry,
vibrational spectroscopy, e.g, IR and Raman spectroscopy, solution
calorimetry, solid state NMR, hot stage optical microscopy,
scanning electron microscopy (SEM), electron crystallography and
quantitative analysis, particle size analysis (PSA), surface area
analysis, solubility studies and dissolution studies.
[0160] The term, "solvate", as used herein, refers to a crystal
form of a substance which contains solvent. The term "hydrate"
refers to a solvate wherein the solvent is water.
[0161] The term, "desolvated solvate", as used herein, refers to a
crystal form of a substance which can only be made by removing the
solvent from a solvate.
[0162] The term "prodrug", as used herein, refers to structurally
modified forms of the compound that readily undergo chemical
changes under physiological conditions to provide the compound.
Additionally, prodrugs can be converted to the compound by chemical
or biochemical methods in an ex vivo environment. Prodrugs are
often useful because, in some situations, they may be easier to
administer than the compound, or parent drug. They may, for
instance, be bioavailable by oral administration whereas the parent
drug is not. The prodrug may also have improved solubility in
pharmaceutical compositions over the parent drug. A wide variety of
prodrug derivatives are known in the art, such as those that rely
on hydrolytic cleavage or oxidative activation of the prodrug. An
example, without limitation, of a prodrug would be a compound which
is administered as an ester (the "prodrug"), but then is
metabolically hydrolyzed to the carboxylic acid, the active
entity.
[0163] As used herein, the term "about", when used in reference to
any degree 2-theta value recited herein, refers to the stated value
.+-.0.1 degree 2-theta.
[0164] The term "anhydrous", as used herein, refers to a form of a
compound that is substantially free of water. One of skill in the
art will appreciate that an anhydrous solid can contain various
amounts of residual water wherein that water is not incorporated in
the crystalline lattice. Such incorporation of residual water can
depend upon a compound's hygroscopicity and storage conditions.
[0165] The term "hydrate", as used herein, refers to a crystal form
adopted by a particular compound in which either a stoichiometric
or non-stoichiometric amount of water is incorporated into the
crystal lattice.
[0166] The term "carrier", as used herein, refers to any chemical
(e.g., solvents, diluents, or other liquid vehicles, dispersion or
suspension aids, surface active agents, isotonic agents, thickening
or emulsifying agents, preservatives, solid binders, lubricants,
and the like, as suited to the particular dosage form desired,
Remington's Pharmaceutical Sciences, Fifteenth Edition, E. W.
Martin (Mack Publishing Co., Easton, Pa., 1975)) consistent with
the stability of Compound I. In certain embodiments, the term
"carrier" refers to a pharmaceutically acceptable carrier. An
exemplary carrier herein is water.
[0167] The term "characterized by", as used herein, means that a
crystalline form is associated with a particular data set (e.g.,
one or more XRPD peaks, melting point, DSC, TGA, DSC-TGA, and/or
other characterization methods known to one of skill in the art, or
combinations thereof). In some embodiments, a solid form is
"characterized by" a set of data when that set of data
distinguishes the form from other known forms of the relevant
compound and/or detects the presence of a particular form in a
composition containing other entities (e.g., other forms of the
compound and/or components that are not the compound). The present
disclosure contains representative data obtained from a variety of
different solid forms; comparison of provided data allows one of
skill in the art to determine data sets that "characterize" any of
the solid forms described herein.
[0168] The term "electrolyte supplementation", as used herein,
refers to administration to a subject of a composition comprising
one or more electrolytes in order to increase serum electrolyte
levels in the subject. For purposes of the present disclosure, when
electrolyte supplementation is administered "prior to, during, or
after" therapy, it may be administered prior to initiation of
combination inhibitor therapy (i.e., prior to administration of any
dose) or prior to, concurrently with, or after any particular dose
or doses.
[0169] The term "formulation", as used herein, refers to a
composition that includes at least one active compound (e.g., at
least a provided form of Compound I) in combination with one or
more excipients or other pharmaceutical additives for
administration to a patient. In general, particular excipients
and/or other pharmaceutical additives are selected in accordance
with knowledge in the art to achieve a desired stability, release,
distribution and/or activity of active compound(s).
[0170] The phrase "in combination", as used herein, refers to
administration of two or more agents to a subject. It will be
appreciated that two or more agents are considered to be
administered "in combination" whenever a subject is simultaneously
exposed to both (or more) of the agents. Each of the two or more
agents may be administered according to a different schedule; it is
not required that individual doses of different agents be
administered at the same time, or in the same composition. Rather,
so long as both (or more) agents remain in the subject's body, they
are considered to be administered "in combination".
[0171] The term "isostructural" or "isostructure", as used herein,
refers to two or more solid forms of a compound containing
essentially the same three-dimensional arrangement of geometrically
similar structural units. In some embodiments, "isostructural"
forms show with similar or identical unit cell dimensions, the same
space group, and similar or identical atomic coordinates for common
atoms. In some embodiments, "isostructural" forms have the same
structure, but not the same cell dimensions nor the same chemical
composition, and have comparable variability in their atomic
coordinates to that of the cell dimensions and chemical
composition. In some embodiments, the present disclosure describes
a set of isostructural forms of Compound I including, for example,
taken from forms of Compound I described infra. In some
embodiments, the present disclosure describes a set of
isostructural forms including, for example, Form J and/or Form D.
In some embodiments, the present disclosure describes a set of
isostructural forms including, for example, Form E and/or Form H.
In some embodiments, the present disclosure describes a set of
isostructural forms including, for example, Form C and/or the
methanol solvate reported in Shigematsu et al., The Journal of
Antibiotics, Vol. 47, No. 3, "FR901228, A Novel Antitumor Bicyclic
Depsipeptide Produced by Chromobacterium violaceum No. 968, pp.
311-314 (March 1994).
[0172] The term "lyophilize", as used herein, refers to the process
of isolating a solid substance from solution and/or removal of
solvent. In some embodiments, this may be achieved by various
techniques known to one of skill in the art, including, for
example, evaporation (e.g., under vacuum, for example by rotary
evaporation), freeze drying, and/or freezing the solution and
vaporizing frozen solvent away under vacuum conditions, etc.
[0173] The term "parenteral" as used herein includes subcutaneous,
intravenous, intramuscular, intra-articular, intra-synovial,
intrasternal, intrathecal, intrahepatic, intralesional and
intracranial injection or infusion techniques.
[0174] The term "substantially all", as used herein, when used to
describe X-ray powder diffraction ("XRPD") peaks of a compound
typically means that the XRPD of that compound includes at least
about 80% of the peaks when compared to a reference. For example,
when an XRPD is said to include "substantially all" of the peaks in
a reference list, or all of the peaks in a reference XRPD, it means
that the XRPD includes at least 80% of the peaks in the specified
reference. In other embodiments, the phrase "substantially all"
means that the XRPD of that compound includes at least about 85,
90, 95, 97, 98, or 99% of the peaks when compared to a
reference.
[0175] The term "substantially free of", as used herein, means
containing no more than an insignificant amount. In some
embodiments, a composition or preparation is "substantially free
of" a recited element if it contains less than 5%, 4%, 3%, 2%, or
1%, by weight of the element. In some embodiments, the composition
or preparation contains less than 0.9%, 0.8%, 0.7%, 0.6%, 0.5%,
0.4%, 0.3%, 0.2%, 0.1% or less of the recited element. In some
embodiments, the composition or preparation contains an
undetectable amount of the recited element.
[0176] The term "substantially similar," as used herein, refers to
data sets (e.g., spectra/thermograms) that share similarities with
each other and/or that differentiate them from one or more
reference data sets. In certain embodiments, data sets are
considered to be "substantially similar" to one another when their
similarities to each other and differences from one or more
reference data sets are sufficient to permit a conclusion that the
two compared data sets are taken of the same form of a compound,
whereas the reference data set is/are taken of a different form of
the compound. In some embodiments, two "substantially similar" data
sets are the same (i.e., are identical within experimental error).
In some embodiments, presence in a data set of one or more data
points characteristic of a particular form of a compound, but
absence of some or all data points that are characteristic of a
different form (e.g., data points that are usually present in
reference data set) defines data sets as substantially similar to
each other.
[0177] The expression "unit dose", as used herein, refers to a
physically discrete unit of a formulation appropriate for a subject
to be treated (e.g., for a single dose); each unit containing a
predetermined quantity of an active agent selected to produce a
desired therapeutic effect (it being understood that multiple doses
may be required to achieve a desired or optimum effect), optionally
together with a pharmaceutically acceptable carrier, which may be
provided in a predetermined amount. The unit dose may be, for
example, a volume of liquid (e.g., an acceptable carrier)
containing a predetermined quantity of one or more therapeutic
agents, a predetermined amount of one or more therapeutic agents in
solid form, a sustained release formulation or drug delivery device
containing a predetermined amount of one or more therapeutic
agents, etc. It will be appreciated that a unit dose may contain a
variety of components in addition to the therapeutic agent(s). For
example, acceptable carriers (e.g., pharmaceutically acceptable
carriers), diluents, stabilizers, buffers, preservatives, etc., may
be included as described infra. It will be understood, however,
that the total daily usage of a formulation of the present
disclosure will be decided by the attending physician within the
scope of sound medical judgment. The specific effective dose level
for any particular subject or organism may depend upon a variety of
factors including the disorder being treated and the severity of
the disorder; activity of specific active compound employed;
specific composition employed; age, body weight, general health,
sex and diet of the subject; time of administration, and rate of
excretion of the specific active compound employed; duration of the
treatment; drugs and/or additional therapies used in combination or
coincidental with specific compound(s) employed, and like factors
well known in the medical arts.
DETAILED DESCRIPTION
[0178] It has been found that Compound I can exist in a variety of
solid forms. Such solid forms include neat crystal forms. Such
solid forms also include solvated forms and amorphous forms. The
present disclosure provides certain such solid forms of Compound I.
In certain embodiments, the present disclosure provides
compositions comprising Compound I in a form described herein. In
some embodiments of provided compositions, Compound I is present as
a mixture of one or more solid forms; in some embodiments of
provided compositions, Compound I is present in only a single
form.
[0179] In certain embodiments of the present disclosure, Compound I
is provided as a crystalline solid. In certain embodiments,
Compound I is provided as a crystalline solid substantially free of
amorphous Compound I. In certain embodiments, Compound I is
provided as an amorphous form. In certain embodiments, Compound I
is provided as a solvated form.
[0180] In some embodiments, all of Compound I that is present in a
particular composition is present in a particular form; in some
such embodiments, the composition is substantially free of any
other form of Compound I. In some embodiments, a composition
comprises a Compound I, present in a combination of different
forms.
[0181] In some embodiments, the present disclosure provides a
lyophilate of Compound I containing one or more solid forms
described herein. In some embodiments, a lyophilate comprises
amorphous Compound I. In some embodiments, a lyophilate comprises
one or more crystalline forms. In some embodiments, a lyophilate is
substantially free of one or more crystalline forms. In some
embodiments, a lyophilate is substantially free of any crystalline
form.
[0182] In some embodiments, the present disclosure provides one or
more solid forms as described herein, in combination with one or
more other components. In some such embodiments, other components
are selected from the group consisting of, for example, buffers,
carriers, crystallization inhibitors, diluents, excipients, pH
adjustors, solvents, or other pharmaceutical additives for
administration to a patient.
[0183] In certain embodiments, where Compound I is in amorphous
form (e.g., in certain lyophilates), such compositions comprise one
or more crystallization inhibitors.
[0184] To characterize individual crystal forms of a particular
compound, and/or to detect the presence of a particular form in a
complex composition techniques known to those of skill in the art,
such as that X-ray diffraction patterns, differential scanning
calorimeter thermograms, thermal gravimetic analyzer thermograms,
melting point information, polarized light microscopy, hotstage
microscopy photomicrographs, dynamic vapor sorption/desorption
information, water content, IR spectra, NMR spectra, and
hygroscopicity profiles, to name a few, are used. Those of skill in
the art will further appreciate that precise identity of all peaks,
for example, in an X-ray diffraction pattern, is not required to
reveal a match of crystal form. Rather, presence or absence of
particular characteristic peaks, and/or patterns of peaks and
intensities, are typically both necessary and sufficient to
characterize and/or identify a particular form.
[0185] Solid Forms
[0186] The present disclosure provides solid forms of Compound I.
In certain embodiments, the present disclosure provides Compound I
in a crystalline form. In some embodiments, crystalline forms are
substantially free of solvent. In some embodiments, crystalline
forms are a solvate. In some embodiments, the present disclosure
provides Compound I in an amorphous form. A summary table of the
romidepsin solid forms (Table 1 is provided below.
[0187] In one embodiment, solid forms of Compound I provided herein
possess improved properties. These properties include, but are not
limited to, bioavailability, hydroscopicity, stability (including,
without limitation, light and heat stability), solubility,
compressability, flowability, electrostatic properties, bulk
density, and rate of dissolution. TABLE-US-00001 TABLE 1 Romidepsin
Solid Forms Form A Solid Form (Desired Form) Form B Form C Form D
Form E Form H Crystallization Acetone/water Acetone/hexanes
Acetone/water (1/3) Acetone/hexanes Tert-butyl Chloroform solvent
system (85/15).sup.1 (85/15) or acetone (1/4) or acetone
alcohol/water (60/40) Crystallization Room temperature Room
temperature Cold (-5.degree. C.) Cold (-20.degree. C.) Room
temperature rotary evaporation at temperature 60.degree. C. Thermal
analysis 254.4.degree. C. (endo).sup.4 258.3.degree. C.
(endo).sup.4 83.6.degree. C. (endo) 91.4.degree. C. (exo)
158.1.degree. C. (endo) 96.3.degree. C. (endo) (DSC).sup.3
126.8.degree. C. (endo) 260.6.degree. C. (endo) 255.2.degree. C.
(endo) 256.6.degree. C. (endo) 171.9.degree. C. (exo) 257.8.degree.
C. (endo) Slurry Remains A A + B .fwdarw. A (2 hrs) A + C .fwdarw.
A (2 hrs) A + D .fwdarw. A, trace C A + E .fwdarw. A, trace E --
interconversion (2.5 hrs) (2.5 hrs) .sup.1Crystallization occurs
with addition of water to a final 15/85 acetone/water ratio.
.sup.2Crystallization occurs with seeding after addition of water
to a final 1/3 acetone/water ratio. .sup.3Samples analyzed in a
crimped aluminum pan at 10.degree. C./min, unless noted otherwise
.sup.4Sample analyzed in a crimped aluminum pan at 10.degree.
C./min with manual pinhole. Solid Form Form F Form I Form J Form K
Form L Form N Crystallization Chloroform Chloroform slurry Methyl
ethyl ketone Nitromethane Dissolved solids in Nitromethane solvent
system or vapor stress acetone and diffused with methanol
Crystallization Room temperature Room temperature Room temperature
Room temperature Room temperature Room temperature temperature or
cold (-20.degree. C.) Thermal analysis 83.6.degree. C. (minor endo)
73.8.degree. C. (endo) 130.3.degree. C. (endo) 68.8.degree. C.
(endo) 168.2.degree. C. (endo) 150.0.degree. C. (event) (DSC).sup.1
97.3.degree. C. (endo) 100.2.degree. C. (endo) 260.0.degree. C.
(endo).sup.2 81.3.degree. C. (endo) 259.2.degree. C. (endo)
259.1.degree. C. (endo) 256.4.degree. C. (endo) 257.8.degree. C.
(endo) 145.9.degree. C. (endo) 257.2.degree. C. (endo) Slurry -- --
-- -- -- -- interconversion .sup.1Samples analyzed in a crimped
aluminum pan at 10.degree. C./min, unless noted otherwise.
.sup.2Sample analyzed in a hermetically-sealed aluminum pan at
10.degree. C./min.
[0188] Crystalline Form A and Crystalline Form B
[0189] Compound I is known to exist in different crystalline forms,
known as Form A and Form B. These forms are described in PCT
Publication No. WO02/020817, filed Aug. 22, 2001, which is
incorporated herein by reference.
[0190] Crystalline Form C
[0191] In some embodiments, the present disclosure provides Form C
of Compound I, and compositions comprising Form C. In some
embodiments, a composition comprising Compound I, contains at least
some of Compound I in a crystalline form, which crystalline form
comprises Form C.
[0192] In one embodiment, Compound I Form C is obtained from an
acetone/water mixture.
[0193] In one embodiment, Compound I Form C is analyzed by one or
more of optical microscropy, X-ray powder diffraction, differential
scanning calorimetry, modulated differential scanning calorimetry,
thermogravimetric analysis, infrared spectroscopy, nuclear magnetic
resonance spectroscopy, and raman spectroscopy.
[0194] In some embodiments, crystalline Form C of Compound I is
characterized by the presence of one or more, two or more, three or
more, four or more, five or more, or six or more peaks from its
XRPD pattern, which peaks, when taken alone or together with other
characteristic data, distinguish Form C from other forms, as
described infra. In one embodiment, Compound I Form C shows an
X-ray diffraction having peaks substantially similar to those in
FIG. 1(c). For example, Form C is characterized by a peak in the
XRPD at about 11.45 2.theta.. Other characteristic peaks include
8.28, 12.19, and 21.13 2.theta..
[0195] As described herein, crystalline Form C of Compound I is
characterized, for example, by some or all, of the exemplary data
provided in FIGS. 1(c) through 1(q), infra (and discussed in
Example 2). In one embodiment, a DSC thermogram obtained for
Compound I Form C exhibits broad endothermic events at
.about.140.degree. C. (min); an endotherm at .about.257.degree. C.
(min); and a minor exothermic event at approximately 177.degree. C.
(max). In one embodiment, a TGA thermogram obtained for Compound I
Form C exhibits a weight loss of .about.5.3%.
[0196] In some embodiments, Form C is isostructural with the
methanol solvate reported in Shigematsu et al., The Journal of
Antibiotics, Vol. 47(3) "FR901228, A Novel Antitumor Bicyclic
Depsipeptide Produced by Chromobacterium violaceum No. 968, pp.
311-314 (March 1994).
[0197] Crystalline Form D
[0198] In some embodiments, the present disclosure provides a
crystalline form obtained from acetone. In some embodiments, the
acetone is cold. In some embodiments, the acetone has a temperature
of -15.degree. C. or lower (e.g., -25.degree. C., -35.degree. C.,
-50.degree. C., -70.degree. C. or lower). In some embodiments, such
a crystalline form is a solvate. In some embodiments, an acetone
solvate is referred to as Form D of Compound I. In some
embodiments, Form D may be isostructural with Form J described
infra.
[0199] In one embodiment, Compound I Form D is analyzed by one or
more of optical microscopy, X-ray powder diffraction, differential
scanning calorimetry, modulated differential scanning calorimetry,
thermogravimetric analysis, infrared spectroscopy, nuclear magnetic
resonance spectroscopy, and raman spectroscopy.
[0200] In some embodiments, the present disclosure provides Form D
of Compound I, and compositions comprising Form D. In some
embodiments, a composition comprising Compound I contains at least
some of Compound I in a crystalline form, which crystalline form
comprises Form D. In some embodiments, a composition comprising
Compound I contains at least some of Compound I in a solvated
crystalline form, which crystalline form comprises Form D. In
certain embodiments, the solvated form is an acetone solvate.
[0201] In some embodiments, crystalline Form D of Compound I is
characterized by the presence of one or more, two or more, three or
more, four or more, five or more, or six or more peaks from its
XRPD pattern, which peaks, when taken alone or together with other
characteristic data, distinguish Form D from other forms, as
described infra. In one embodiment, Compound I Form D shows an
X-ray diffraction having peaks substantially similar to those in
FIG. 2(a). For example, Form D is characterized by a peak in the
XRPD at about 7.54 2.theta.. Other characteristic peaks include
11.86 and 16.66 2.theta..
[0202] As described herein, Compound I Form D is characterized by
some or all of the exemplary data provided in 2(a) through 2(f),
infra (and discussed in Example 3). In one embodiment, a DSC
thermogram obtained for Compound I Form D exhibits a small
endothermic event at .about.91.degree. C. (min); and an endotherm
at .about.261.degree. C. (min); followed by apparent decomposition.
In one embodiment, a TGA thermogram obtained for Compound I Form D
exhibits a weight loss of .about.10.9%.
[0203] Crystalline Form E
[0204] In some embodiments, the present disclosure provides a
crystalline form obtained from t-butanol. In some embodiments, the
present disclosure provides a crystalline form obtained from a
mixture of t-butanol and water. In some embodiments, such a
crystalline form is a solvate. In some embodiments, a t-butanol
solvate is referred to as Form E of Compound I. In some
embodiments, Form E may be isostructural with Form H described
infra.
[0205] In some embodiments, the present disclosure provides Form E
of Compound I, and compositions comprising Form E. In some
embodiments, a composition comprising Compound I, contains at least
some of Compound I in a crystalline form, which crystalline form
comprises Form E. In some embodiments, a composition comprising
Compound I, contains at least some of Compound I in a solvated
crystalline form, which crystalline form comprises Form E. In
certain embodiments, the solvated form is a t-butanol solvate.
[0206] In one embodiment, Compound I Form E is analyzed by one or
more of optical microscopy, X-ray powder diffraction, differential
scanning calorimetry, modulated differential scanning calorimetry,
thermogravimetric analysis, infrared spectroscopy, nuclear magnetic
resonance spectroscopy, and raman spectroscopy.
[0207] In some embodiments, crystalline Form E of Compound I is
characterized by the presence of one or more, two or more, three or
more, four or more, five or more, or six or more peaks from its
XRPD pattern, which peaks, when taken alone or together with other
characteristic data, distinguish Form E from other forms, as
described infra. In one embodiment, Compound I Form E shows an
X-ray diffraction having peaks substantially similar to those in
FIG. 3(a). For example, Form E is characterized by a peak in the
XRPD at about 10.3 2.theta.. Other characteristic peaks include
9.0, 11.7, and 20.04 2.theta..
[0208] As described herein, Compound I Form E is characterized by
some or all of the exemplary data provided in FIGS. 3(a) through
3(p), infra (and discussed in Example 4). In one embodiment, a DSC
thermogram obtained for Compound I Form E exhibits an endothermic
event at .about.158.degree. C. (min); an endotherm at
.about.255.degree. C. (min); followed by apparent decomposition. In
one embodiment, a TGA thermogram obtained for Compound I Form E
exhibits a weight loss of .about.10.9%.
[0209] Crystalline Form F
[0210] In some embodiments, the present disclosure provides a
crystalline form obtained from chloroform.
[0211] In some embodiments, the present disclosure provides Form F
of Compound I, and compositions comprising Form F. In some
embodiments, a composition comprising Compound I, contains at least
some of Compound I in a crystalline form, which crystalline form
comprises Form F. In some embodiments, such a crystalline form is a
solvate.
[0212] In some embodiments, Compound I Form F is analyzed by one or
more of optical microscopy, X-ray powder diffraction, differential
scanning calorimetry, modulated differential scanning calorimetry,
thermogravimetric analysis, infrared spectroscopy, nuclear magnetic
resonance spectroscopy, and raman spectroscopy.
[0213] In some embodiments, crystalline Form F of Compound I is
characterized by the presence of one or more, two or more, three or
more, four or more, five or more, or six or more peaks from its
XRPD pattern, which peaks, when taken alone or together with other
characteristic data, distinguish Form F from other forms, as
described infra. In one embodiment, Compound I Form F shows an
X-ray diffraction having peaks substantially similar to those in
FIG. 9(a) or 9(d). For example, Form F is characterized by a peak
in the XRPD at about 20.28 2.theta.. Other characteristic peaks
include 10.17, 17.8, 19.34, 20.04, and 22.63 2.theta..
[0214] As described herein, Compound I Form F is characterized by
some or all of the exemplary data provided in 9(a) through (9l),
infra (and discussed in Example 5). In one embodiment, a DSC
thermogram obtained for Compound I Form F exhibits a broad
endothermic event at .about.97.degree. C. (min); and an endotherm
at .about.256.degree. C. (min). In one embodiment, a TGA thermogram
obtained for Compound I Form F exhibits a weight loss of
.about.17%. In one embodiment, provided is the Panalytical X-Pert
Pro MPD PW3040 data for Compound I Form F obtained under the
following conditions: X-ray Tube: Cu(1.54059 A.degree.), Voltage:
45 kV; Amperage 40 mA; Scan range: 1.00-39.98 .degree.2.theta.;
step size: 0.017 .degree.2.theta.; collection time: 721 sec.; scan
speed: 3.2.degree./min; slit: DS: 1/2.degree.; SS: null; revolution
time: 1.0 sec., mode: transmission. In one embodiment, provided is
the data for Compound I Form F obtained under the following
conditions: detector: DTGS KBr; number of scans: 512; resolution: 2
cm.sup.-1.
[0215] Crystalline Form H
[0216] In some embodiments, the present disclosure provides a
crystalline form obtained from chloroform. In some embodiments,
such a crystalline form is a solvate. In some embodiments, a
chloroform solvate is referred to as Form H of Compound I. In some
embodiments, Form H may be isostructural with Form E described
infra.
[0217] In some embodiments, the present disclosure provides Form H
of Compound I, and compositions comprising Form H. In some
embodiments, a composition comprising Compound I, contains at least
some of Compound I in a crystalline form, which crystalline form
comprises Form H. In some embodiments, a composition comprising
Compound I, contains at least some of Compound I in a solvated
crystalline form, which crystalline form comprises Form H. In some
embodiments, the solvated form is a chloroform solvate.
[0218] In some embodiment, Compound I Form H is analyzed by one or
more of optical microscopy, X-ray powder diffraction, differential
scanning calorimetry, modulated differential scanning calorimetry,
thermogravimetric analysis, infrared spectroscopy, nuclear magnetic
resonance spectroscopy, and raman spectroscopy.
[0219] In some embodiments, crystalline Form H of Compound I is
characterized by the presence of one or more, two or more, three or
more, four or more, five or more, or six or more peaks from its
XRPD pattern, which peaks, when taken alone or together with other
characteristic data, distinguish Form H from other forms, as
described infra. In one embodiment, Compound I Form H shows an
X-ray diffraction having peaks substantially similar to those in
FIG. 4(a). For example, Form H is characterized by a peak in the
XRPD at about 10.67 2.theta.. Other characteristic peaks include
8.94, 9.69, 10.51, 13.13, and 19.43 2.theta..
[0220] As described herein, Compound I Form H is characterized by
some or all of the exemplary data provided in 4(a) through 4(f),
infra (and discussed in Example 6). In one embodiment, a DSC
thermogram obtained for Compound I Form H exhibits an endothermic
event at .about.96.degree. C. (min); and an endotherm at
.about.257.degree. C. (min). In one embodiment, a TGA thermogram
obtained for Compound I Form H exhibits a weight loss of
.about.10.1%.
[0221] Crystalline Form I
[0222] In some embodiments, the present disclosure provides a
crystalline form obtained from chloroform. In some embodiments,
such a crystalline form is a solvate. In some embodiments, a
chloroform solvate is referred to as Form I of Compound 1.
[0223] In some embodiments, the present disclosure provides Form I
of Compound I, and compositions comprising Form I. In some
embodiments, a composition comprising Compound I, contains at least
some of Compound I in a crystalline form, which crystalline form
comprises Form I. In some embodiments, a composition comprising
Compound I, contains at least some of Compound I in a solvated
crystalline form, which crystalline form comprises Form I. In some
embodiments, the solvated form is a chloroform solvate.
[0224] In some embodiments, Compound I Form I is analyzed by one or
more of optical microscopy, X-ray powder diffraction, differential
scanning calorimetry, modulated differential scanning calorimetry,
thermogravimetric analysis, infrared spectroscopy, nuclear magnetic
resonance spectroscopy, and raman spectroscopy.
[0225] In some embodiments, crystalline Form I of Compound I is
characterized by the presence of one or more, two or more, three or
more, four or more, five or more, or six or more peaks from its
XRPD pattern, which peaks, when taken alone or together with other
characteristic data, distinguish Form I from other forms, as
described infra. In one embodiment, Compound I Form I shows an
X-ray diffraction having peaks substantially similar to those in
FIG. 5(a) or 5(p). For example, Form I is characterized by a peak
in the XRPD at about 20.96 2.theta.. Other characteristic peaks
include 10.63, 17.97, 18.74, 19.12, and 23.18 2.theta..
[0226] As described herein, crystalline Form I of Compound I is
characterized by some or all of the exemplary data provided in 5(a)
through 5(y), infra (and discussed in Example 7). In one
embodiment, a DSC thermogram obtained for Compound I Form I
exhibits a broad endothermic event at .about.74.degree. C. (min);
an endothermic event at .about.100.degree. C. (min); and an
endotherm at .about.256.4.degree. C. (min) (10.degree. C./min, C).
In another embodiment, a DSC thermogram obtained for Compound I
Form I exhibits a broad endothermic event at .about.88.degree. C.
(min); an endothermic event at .about.113.degree. C. (min); and an
endotherm at .about.256.degree. C. (min) (10.degree. C./min, C). In
one embodiment, a TGA thermogram obtained for Compound I Form I
exhibits a weight loss of .about.33%. In another embodiment, a TGA
thermogram obtained for Compound I Form I exhibits a weight loss of
.about.27%. In one embodiment, provided is the Panalytical X-Pert
Pro MPD PW3040 data for Compound I Form I obtained under the
following conditions: X-ray Tube: Cu(1.54059 A.degree.), Voltage:
45 kV; Amperage 40 mA; Scan range: 1.00-39.99 .degree.2.theta.;
step size: 0.017 .degree.2.theta.; collection time: 718 sec.; scan
speed: 3.3.degree./min; slit: DS: 1/2.degree.; SS: null; revolution
time: 1.0 sec., mode: transmission. In one embodiment, provided is
the data for Compound I Form I obtained under the following
conditions: detector: DTGS KBr; number of scans: 512; resolution: 2
cm.sup.-1.
[0227] Crystalline Form J
[0228] In some embodiments, the present disclosure provides a
crystalline form obtained from methylethylketone. In some
embodiments, such a crystalline form is a solvate. In some
embodiments, a methylethylketone solvate is referred to as Form J
of Compound I. In some embodiments, Form J may be isostructural
with Form D described infra.
[0229] In some embodiments, the present disclosure provides Form J
of Compound I, and compositions comprising Form J of Compound I. In
some embodiments, a composition comprising Compound I, contains at
least some of Compound I in a crystalline form, which crystalline
form comprises Form J. In some embodiments, a composition
comprising Compound I, contains at least some of Compound I in a
solvated crystalline form, which crystalline form comprises Form J.
In certain embodiments, the solvated form is a methylethylketone
solvate.
[0230] In some embodiments, Compound I Form J is analyzed by one or
more of optical microscopy, X-ray powder diffraction, differential
scanning calorimetry, modulated differential scanning calorimetry,
thermogravimetric analysis, infrared spectroscopy, nuclear magnetic
resonance spectroscopy, and raman spectroscopy.
[0231] In some embodiments, crystalline Form J of Compound I is
characterized by the presence of one or more, two or more, three or
more, four or more, five or more, or six or more peaks from its
XRPD pattern, which peaks, when taken alone or together with other
characteristic data, distinguish Form J from other forms, as
described infra. In one embodiment, Compound I Form J shows an
X-ray diffraction having peaks substantially similar to those in
FIG. 6(k). For example, Form J is characterized by a peak in the
XRPD at about 15.24 2.theta.. Other characteristic peaks include
7.44, 11.80, and 16.60 2.theta..
[0232] As described herein, crystalline Compound I Form J is
characterized by some or all of the exemplary data provided in 6(a)
through 6(u), infra (and discussed in Example 8). In one
embodiment, a DSC thermogram obtained for Compound I Form J
exhibits a broad endothermic event at .about.130.degree. C. (min);
and an endotherm at .about.260.degree. C. (min). In one embodiment,
a TGA thermogram obtained for Compound I Form J exhibits a weight
loss of .about.12%. In one embodiment, provided is the Panalytical
X-Pert Pro MPD PW3040 data for Compound I Form J obtained under the
following conditions: X-ray Tube: Cu(1.54059 A.degree.), Voltage:
45 kV; Amperage 40 mA; Scan range: 1.00-39.99 .degree.2.theta.;
step size: 0.017 .degree.2.theta.; collection time: 718 sec.; scan
speed: 3.3.degree./min; slit: DS: 1/2.degree.; SS: null; revolution
time: 1.0 sec., mode: transmission. In one embodiment, provided is
the data for Compound I Form J obtained under the following
conditions: detector: DTGS KBr; number of scans: 512; resolution: 2
cm.sup.-1.
[0233] Crystalline Form K
[0234] In some embodiments, the present disclosure provides Form K
of Compound I, and compositions comprising Form K. In some
embodiments, a composition comprising Compound I contains at least
some of Compound I in a crystalline form, which crystalline form
comprises Form K. In some embodiments, a composition comprising
Compound I contains at least some of Compound I in a solvated
crystalline form, which crystalline form comprises Form K. In one
embodiment, Compound I Form K is obtained from nitromethane. In one
embodiment, Compound I Form K is a nitromethane solvate.
[0235] In some embodiments, Compound I Form K is analyzed by one or
more of optical microscopy, X-ray powder diffraction, differential
scanning calorimetry, modulated differential scanning calorimetry,
thermogravimetric analysis, infrared spectroscopy, nuclear magnetic
resonance spectroscopy, and raman spectroscopy.
[0236] In some embodiments, crystalline Form K of Compound I is
characterized by the presence of one or more, two or more, three or
more, four or more, five or more, or six or more peaks from its
XRPD pattern, which peaks, when taken alone or together with other
characteristic data, distinguish Form K from other forms, as
described infra. In one embodiment, Compound I Form K shows an
X-ray diffraction having peaks substantially similar to those in
FIG. 8(c). For example, Form K is characterized by a peak in the
XRPD at about 7.89 2.theta.. Other characteristic peaks include
11.25, 16.81, 19.40, and 20.96 2.theta..
[0237] As described herein, Compound I Form K is characterized by
some or all of the exemplary data provided in 8(a) through 8(l),
infra (and discussed in Example 10). In one embodiment, a DSC
thermogram obtained for Compound I Form K exhibits a broad
endothermic event at .about.62.degree. C. (min); another broad
endothermic event at .about.155.degree. C. (min); and an endotherm
at .about.257.degree. C. (min). In another embodiment, a DSC
thermogram obtained for Compound I Form K exhibits a broad
endothermic event at .about.69.degree. C. and 81.degree. C.;
another broad endothermic event at .about.146.degree. C. (min); and
an endotherm at .about.257.degree. C. (min). In one embodiment, a
TGA thermogram obtained for Compound I Form K exhibits a weight
loss of .about.9.5%. In one embodiment, provided is the Panalytical
X-Pert Pro MPD PW3040 data for Compound I Form K obtained under the
following conditions: X-ray Tube: Cu(1.54059 A.degree.), Voltage:
45 kV; Amperage 40 mA; Scan range: 1.00-39.99 .degree.2.theta.;
step size: 0.017 .degree.2.theta.; collection time: 717 sec.; scan
speed: 3.3.degree./min; slit: DS: 1/2.degree.; SS: null; revolution
time: 1.0 sec., mode: transmission. In one embodiment, provided is
the data for Compound I Form K obtained under the following
conditions: detector: DTGS KBr; number of scans: 512; resolution: 2
cm.sup.-1.
[0238] Crystalline Form L
[0239] In some embodiments, the present disclosure provides a
crystalline form obtained from acetone and diffused with
methanol.
[0240] In some embodiments, the present disclosure provides Form L
of Compound I, and compositions comprising Form L. In some
embodiments, a composition comprising Compound I, contains at least
some of Compound I in a crystalline form, which crystalline form
comprises Form L. In one embodiment, Compound I Form L is a
methanol solvate.
[0241] In some embodiments, Compound I Form L is analyzed by one or
more of optical microscopy, X-ray powder diffraction, differential
scanning calorimetry, modulated differential scanning calorimetry,
thermogravimetric analysis, infrared spectroscopy, nuclear magnetic
resonance spectroscopy, and raman spectroscopy.
[0242] In some embodiments, crystalline Form L of Compound I is
characterized by the presence of one or more, two or more, three or
more, four or more, five or more, or six or more peaks from its
XRPD pattern, which peaks, when taken alone or together with other
characteristic data, distinguish Form L from other forms, as
described infra. In one embodiment, Compound I Form L shows an
X-ray diffraction having peaks substantially similar to those in
FIG. 10(a). For example, Form L is characterized by a peak in the
XRPD at about 21.46 2.theta.. Other characteristic peaks include
8.26, 10.05, 11.59, and 12.31 2.theta..
[0243] As described herein, Compound I Form L is characterized by
some or all of the exemplary data provided in 10(a) through 10(i),
infra (and discussed in Example 11). In one embodiment, a DSC
thermogram obtained for Compound I Form L exhibits an endothermic
event at .about.168.degree. C. (min); and an endotherm at
.about.259.degree. C. (min). In one embodiment, a TGA thermogram
obtained for Compound I Form L exhibits a weight loss of .about.6%.
In one embodiment, provided is the Panalytical X-Pert Pro MPD
PW3040 data for Compound I Form L obtained under the following
conditions: X-ray Tube: Cu(1.54059 A.degree.), Voltage: 45 kV;
Amperage 40 mA; Scan range: 1.00-39.98 .degree.2.theta.; step size:
0.017 .degree.2.theta.; collection time: 716 sec.; scan speed:
3.2.degree./min; slit: DS: 1/2.degree.; SS: null; revolution time:
1.0 sec., mode: transmission. In one embodiment, provided is the
data for Compound I Form L obtained under the following conditions:
detector: DTGS KBr; number of scans: 512; resolution: 2 cm.sup.-1
.
[0244] Crystalline Form N
[0245] In some embodiments, the present disclosure provides a
crystalline form obtained from nitromethane.
[0246] In some embodiments, the present disclosure provides Form N
of Compound I, and compositions comprising Form N. In some
embodiments, a composition comprising Compound I, contains at least
some of Compound I in a crystalline form, which crystalline form
comprises Form N. In one embodiment, Form N of Compound I is a
nitromethane solvate.
[0247] In some embodiments, Compound I Form N is analyzed by one or
more of optical microscopy, X-ray powder diffraction, differential
scanning calorimetry, modulated differential scanning calorimetry,
thermogravimetric analysis, infrared spectroscopy, nuclear magnetic
resonance spectroscopy, and raman spectroscopy.
[0248] In some embodiments, crystalline Form N of Compound I is
characterized by the presence of one or more, two or more, three or
more, four or more, five or more, or six or more peaks from its
XRPD pattern, which peaks, when taken alone or together with other
characteristic data, distinguish Form N from other forms, as
described infra. In one embodiment, Compound I Form N shows an
X-ray diffraction having peaks substantially similar to those in
FIG. 11(a). For example, Form N is characterized by a peak in the
XRPD at about 8.92 2.theta.. Other characteristic peaks include
7.07, 9.76, 10.75, 11.22, 15.46, 20.37, and 21.31 2.theta..
[0249] As described herein, Compound I Form N is characterized by
some or all of the exemplary data provided in 11(a) through 11(c),
infra (and discussed in Example 12). In one embodiment, a DSC
thermogram obtained for Compound I Form N exhibits an endotherm at
.about.150.degree. C. (min). In one embodiment, a TGA thermogram
obtained for Compound I Form N exhibits a weight loss of .about.5%.
In one embodiment, provided is the Panalytical X-Pert Pro MPD
PW3040 data for Compound I Form N obtained under the following
conditions: X-ray Tube: Cu(1.54059 A.degree.), Voltage: 45 kV;
Amperage 40 mA; Scan range: 1.00-39.99 .degree.2.theta.; step size:
0.017 .degree.2.theta.; collection time: 717 sec.; scan speed:
3.3.degree./min; slit: DS: 1/2.degree.; SS: null; revolution time:
1.0
sec., mode: transmission.
[0250] Amorphous Form
[0251] In some embodiments, the present disclosure provides
amorphous Compound I, and compositions comprising amorphous
Compound I. In some embodiments, the present disclosure provides
compositions comprising Compound I in which substantially all of
Compound I is an amorphous form (i.e., the composition is
substantially free of crystalline compound I). In some embodiments,
the present disclosure provides compositions containing Compound I
in which at least some of the Compound I is in a form other than
amorphous (e.g., is in a crystalline form such as, for example,
Form A, Form B, Form C, Form D, Form E, Form F, Form H, Form I,
Form J, Form K, Form L, Form N, and combinations thereof).
[0252] In some embodiments, amorphous Compound I is characterized
by the absence of defined peaks above background in an XRPD
pattern. In some embodiments, amorphous Compound I is characterized
by the absence of characteristic peaks that may be present in
Compound I Form A, Form B, Form C, Form D, Form E, Form F, Form H,
Form I, Form J, Form K, Form L, Form N, and combinations thereof.
In some embodiments, amorphous Compound I is characterized by
having a powder X-ray diffraction pattern substantially similar to
FIG. 7(a). In some embodiments, amorphous Compound I is obtained
from a water/dichloromethane mixture, or an
isopropanol-trifluoroethanol/methanol mixture
[0253] As described herein, amorphous Compound I is characterized
by the exemplary data provided in 7(a) through 7(f), infra (see
Example 9). In one embodiment, a DSC thermogram obtained for
amorphous Compound I exhibits a glass transition temperature of
.about.91.degree. C. In one embodiment, a TGA thermogram obtained
for amorphous Compound I exhibits a weight loss of .about.3.5%.
Compositions Comprising Provided Forms of Compound I
[0254] The present disclosure provides compositions that comprise
and/or are prepared from solid forms of Compound I as described
herein. Any of the forms provided herein of Compound I may be
incorporated into a composition. In some embodiments, the present
disclosure provides pharmaceutical compositions that comprise
and/or are prepared from solid forms of Compound I as described
herein. In some embodiments, a pharmaceutical composition comprises
a therapeutically effective amount of Compound I and at least one
pharmaceutically acceptable carrier or excipient.
[0255] In some embodiments, compositions comprising Compound I are
provided as lyophilates. In some embodiments, the present
disclosure provides a lyophilate of Compound I comprising one or
more solid forms described herein. In some embodiments, a
lyophilate comprises amorphous Compound I. In some embodiments, a
lyophilate comprises one or more crystalline forms. In some
embodiments, a lyophilate is substantially free of one or more
crystalline forms. In some embodiments, a lyophilate is
substantially free of any crystalline form.
[0256] In some embodiments, the present disclosure provides
compositions comprising or prepared from Compound I solid forms
described herein, which compositions further comprise one or more
additional components.
[0257] In some embodiments, provided compositions comprise, in
addition to Compound I, at least one other component, such as a
carrier (e.g., pharmaceutically acceptable carrier). Except insofar
as any conventional carrier medium is incompatible with compounds
or forms described herein, such as by producing any undesirable
biological effect or otherwise interacting in a deleterious manner
with any other component(s) of compositions and/or the use thereof
is contemplated to be within the scope of this disclosure.
[0258] In some embodiments, materials which can serve as acceptable
carriers (e.g., pharmaceutically acceptable carriers) include, but
are not limited to, sugars such as lactose, glucose, and sucrose;
starches such as corn starch and potato starch; cellulose and its
derivatives such as sodium carboxymethyl cellulose, ethyl
cellulose, and cellulose acetate; powdered tragacanth; malt;
gelatin; talc; Cremophor; Solutol; excipients such as cocoa butter
and suppository waxes; oils such as peanut oil, cottonseed oil;
sunflower oil; sesame oil; olive oil; corn oil and soybean oil;
glycols such a propylene glycol; esters such as ethyl oleate and
ethyl laurate; agar; buffering agents such as magnesium hydroxide
and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic
saline; Ringer's solution; ethyl alcohol, and phosphate buffer
solutions; as well as other non-toxic compatible lubricants such as
sodium lauryl sulfate and magnesium stearate; as well as coloring
agents, releasing agents, coating agents, sweetening, flavoring and
perfuming agents, preservatives and antioxidants can also be
present in the composition, according to the judgment of the
formulator.
[0259] Compositions comprising Compound I as described herein may
be formulated orally, parenterally, by inhalation spray, topically,
rectally, nasally, buccally, vaginally or via an implanted
reservoir. In some embodiments, compositions are administered
orally or parenterally.
[0260] In some embodiments, compositions are administered
parenterally. In some embodiments, compositions are administered
intraperitoneally or intravenously.
[0261] As is known in the art, injectable formulations are often
provided as solutions or suspensions, e.g., aqueous or oleaginous
suspension. Such solutions or suspensions may be formulated
according to techniques known in the art, for example, using
suitable dispersing or wetting agents and suspending agents.
Injectable formulations are typically sterile. In some embodiments,
an injectable solution or suspension comprises a non-toxic
parenterally acceptable diluent or solvent. Exemplary vehicles and
solvents typically employed include water, Ringer's solution,
isotonic sodium chloride solution, acetone, chloroform,
dichloromethane, isopropanol, methanol, methylethylketone,
tert-butyl alcohol, trifluoroethanol and 1,3-butanediol, and
combinations thereof.
[0262] In some embodiments, sterile, fixed oils are conventionally
employed as a solvent or suspending medium. Any bland fixed oil may
be employed including synthetic mono- or di-glycerides. Fatty
acids, such as oleic acid and its glyceride derivatives are often
useful in the preparation of injectables, as are natural
pharmaceutically-acceptable oils, such as olive oil or castor oil,
including their polyoxyethylated versions. In some embodiments,
such oil solutions or suspensions contain a long-chain alcohol
diluent or dispersant, such as carboxymethyl cellulose or similar
dispersing agents that are commonly used in the formulation of
pharmaceutically acceptable dosage forms including emulsions and
suspensions. In some embodiments, commonly used surfactants, such
as Tweens, Spans and other emulsifying agents or bioavailability
enhancers which are commonly used in the manufacture of acceptable
(e.g., pharmaceutically acceptable) solid, liquid, or other dosage
forms may also be used for the purposes of formulation.
[0263] Orally acceptable dosage forms include, but are not limited
to, capsules, tablets, aqueous suspensions or solutions. In the
case of tablets for oral use, carriers commonly used include
lactose and corn starch. Lubricating agents, such as magnesium
stearate, are also typically added. For oral administration in a
capsule form, useful diluents commonly include lactose and dried
cornstarch. When aqueous suspensions are prepared for oral
delivery, the active ingredient is typically combined with
emulsifying and suspending agents, optionally much as discussed
above with respect to parenteral formulations. If desired, certain
sweetening, flavoring or coloring agents may also be added.
[0264] Administration of oral compositions can be desirably linked
to periods of food intake. For example, in some embodiments, oral
compositions are administered with food; in some embodiments, oral
compositions are administered without food, or within a particular
time frame relative to consumption of food. In some embodiments,
oral compositions are administered with little or no regard to the
timing of food intake.
[0265] Compositions for oral administration can be formulated as
solid or liquid preparation. In some embodiments, a liquid
formulation such as syrup, injection, eye drops or the like, is
prepared with a pH adjustor (e.g., hydrochloric acid), solubilizer,
isotonizing agent or the like, as well as a solubilizing aid,
stabilizer, buffering agent, suspending agent, antioxidant, etc.,
if necessary. In some embodiments, a liquid formulation is
lyophilized, and an injection is administered intravenously,
subcutaneously or intramuscularly. Suspending agents that can be
used include, but not limited to, methyl cellulose, polysorbate 80,
hydroxyethyl cellulose, gum arabic, tragacanth powder, sodium
carboxymethylcellulose, polyoxyethylene sorbitan monolaurate and
the like. Solubilizing aids that can be used include, but not
limited to, polyoxyethylene hydrogenated castor oil, polysorbate
80, nicotinamide, polyoxyethylene sorbitan monolaurate and the
like. Stabilizing agents that can be used include, but not limited
to, t sodium sulfite, sodium metasulfite, ether and the like.
Preservatives that can be used include, but not limited to, methyl
paraoxybenzoate, ethyl paraoxybenzoate, sorbic acid, phenol,
cresol, chlorocresol, and the like.
[0266] In some embodiments, provided compositions may be formulated
for rectal administration, e.g., as suppositories. Such
rectally-appropriate forms can be prepared, for example, by mixing
the agent with a suitable non-irritating excipient that is solid at
room temperature but liquid at rectal temperature and therefore
will melt in the rectum to release the drug. Such materials include
cocoa butter, beeswax and/or polyethylene glycols.
[0267] In some embodiments, provided compositions are formulated
for topical administration, for example, the treatment site
includes areas or organs readily accessible by topical application,
for example, the eye, the skin, or the lower intestinal tract.
[0268] Topical application to the lower intestinal tract can often
be effected with a rectal suppository formulation (see above) or in
a suitable enema formulation. In some embodiments, topical or
transdermal patches may be used.
[0269] In some embodiments, topical formulations are prepared in a
suitable ointment containing an active component suspended or
dissolved in one or more carriers. Carriers for topical
administration typically include, but are not limited to, mineral
oil, liquid petrolatum, white petrolatum, propylene glycol,
polyoxyethylene, polyoxypropylene compound, emulsifying wax and
water. Topical compositions can be formulated in a suitable lotion
or cream, for example, containing one or more active components
suspended or dissolved in one or more pharmaceutically acceptable
carriers. Suitable carriers may include, but are not limited to,
mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters
wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water,
and combinations thereof.
[0270] Formulations for ophthalmic delivery are often prepared as
solutions or suspensions (e.g., isotonic, pH adjusted sterile
saline). In some embodiments, one or more preservatives (e.g.,
benzylalkonium chloride) is/are also included. Ophthalmic
compositions may be formulated in an ointment such as
petrolatum.
[0271] Compositions for nasal delivery are commonly formulated as
aerosols. Such aerosol formulations may, for example, be or include
solutions or suspensions (e.g., in saline), optionally containing
one or more preservatives (e.g., benzyl alcohol), absorption
promoters (e.g., to enhance bioavailability), and/or solubilizing
or dispersing agents (e.g., fluorocarbons).
[0272] In some embodiments, compositions (e.g., pharmaceutical
compositions) as described herein may include one or more
processing agents and/or crystallization inhibitors, or
combinations thereof.
[0273] In some embodiments, provided compositions contain one or
more processing agents. In some embodiments, the processing agent
is water. In some embodiments, the processing agent is tert-butyl
alcohol. In some embodiments, the processing agent is talc. In some
embodiments, the processing agent is lactose. In some embodiments,
the processing agent is precipitated calcium carbonate. In some
embodiments, the processing agent is titanium dioxide. In some
embodiments, the processing agent is silica. In some embodiments,
the processing agent is microcrystalline cellulose.
[0274] In some embodiments, provided compositions comprise one or
more crystallization inhibitors. In some embodiments, the
crystallization inhibitor is water soluble. In certain embodiments,
the crystallization inhibitor is water insoluble.
[0275] Exemplary crystallization inhibitors include, but are not
limited to, polyvinylpyrrolidone (PVP or povidone), including homo-
and copolymers of polyvinylpyrrolidone and homopolymers or
copolymers of N-vinylpyrrolidone; crospovidone; gums; cellulose
derivatives (e.g., HPMC polymers, hydroxypropyl cellulose, ethyl
cellulose, hydroxyethylcellulose, sodium carboxymethyl cellulose,
calcium carboxymethyl cellulose, sodium carboxymethyl cellulose);
dextran; acacia; homo- and copolymers of vinyllactam, and mixtures
thereof; cyclodextrins; gelatins; hypromellose phthalate; sugars;
sugar alcohols including mannitol; polyhydric alcohols;
polyethylene glycol (PEG); polyethylene oxides; polyoxyethylene
derivatives; polyvinyl alcohol; propylene glycol derivatives and
the like, SLS, Tweens, Eudragits (methacrylic acid co-polymers);
and combinations thereof; amino acids such as prolin.
[0276] In some embodiments, the Compound I in the composition is
amorphous. In some embodiments, the crystallization inhibitor is
polyvinylpyrrolidone (PVP or povidone). In some embodiments, the
crystallization inhibitor is povidone USP/NF, Ph. Eur, or JPE. In
some embodiments, the amount of Compound I and the amount of
povidone is present in a composition in a ratio of about 1:2 (by
weight). In some embodiments, the amount of Compound I and the
amount of povidone is present in a composition in a ratio of about
1:1 (by weight). In some embodiments, the amount of Compound I and
the amount of povidone is present in a composition in a ratio of
about 2:1 (by weight). In some embodiments, the amount of Compound
I and the amount of povidone is present in a composition in a ratio
of about 3:1 (by weight). In some embodiments, the amount of
Compound I and the amount of povidone is present in a composition
in a ratio of about 4:1 (by weight).). In some embodiments, the
amount of Compound I and the amount of povidone is present in a
composition in a ratio of about 5:1 (by weight).
[0277] In certain embodiments, a crystallization inhibitor employed
by the present disclosure is a PVP polymer.
[0278] In certain embodiments, PVP polymers employed in the present
disclosure have a molecular weight of about 2,000 to about 50,000
Daltons, about 2,000 to about 30,000 Daltons, about 2,000 to about
20,000 Daltons, about 2,500 to about 15,000 Daltons, about 2,500 to
about 10,000 Daltons, or about 3,000 to about 10,000 Daltons.
[0279] In certain embodiments, PVP polymers employed in the present
disclosure have a dynamic viscosity (10% in water at 20.degree. C.)
of about 1.3 to about 700, about 1.5 to about 500, about 1.8 to
about 300, about 2.0 to about 200, about 2.2 to about 150, about
2.5 to about 100, about 2.8 to about 70, about 3.0 to about 40,
about 3.2 to about 25, or about 3.5 to about 8.5 mPas.
[0280] Any type of povidone can be used in the compositions
provides herein. In some embodiments, povidone is selected from
Plasdone.RTM. PVP polymers, which are synthetic, water-soluble
homopolymers of N-vinyl-2-pyrrolidone. Plasdone polymers useful in
the compositions provided herein include, but are not limited to,
Plasdone C-12 and Plasdone C-17.
[0281] In some embodiments, povidone possesses K values between 12
and 17. In some embodiments, povidone possesses K values between 12
and 15.
[0282] In certain embodiments, PVP polymers employed in the present
disclosure are selected from Kollidon.RTM. PVP polymers (e.g.,
Kollidon.RTM. 12 PF, Kollidon.RTM. 17 PF).
[0283] In certain embodiments, a crystallization inhibitor employed
by the present disclosure is a PEG polymer.
[0284] In certain embodiments, PEG polymers employed in the present
disclosure have has an average molecular about 5,000-20,000 Dalton,
about 5,000-15,000 Dalton, or about 5,000-10,000 Dalton.
[0285] In certain embodiments, a crystallization inhibitor employed
by the present disclosure is a surfactant. In certain embodiments,
the crystallization inhibitor is a Tween.RTM. surfactant. Exemplary
Tweens.RTM. include Tween.RTM. 20, Tween.RTM. 40, Tween.RTM.60,
Tween.RTM. 65 and Tween.RTM. 80.
[0286] In certain embodiments, a crystallization inhibitor employed
by the present disclosure is an HPMC (hydroxypropylmethyl
cellulose) polymer.
[0287] HPMC polymers vary in the chain length of their cellulosic
backbone and consequently in their viscosity as measured for
example at a 2% (w/w) in water. In certain embodiments, the HPMC
polymer has a viscosity in water (at a concentration of 2% (w/w)),
of about 100 to about 100,000 cP, about 1000 to about 15,000 cP,
for example about 4000 cP. In certain embodiments, the molecular
weight of the HPMC polymer has greater than about 10,000, but not
greater than about 1,500,000, not greater than about 1,000,000, not
greater than about 500,000, or not greater than about 150,000.
[0288] HPMC polymers also vary in the relative degree of
substitution of available hydroxyl groups on the cellulosic
backbone by methoxy and hydroxypropoxy groups. With increasing
hydroxypropoxy substitution, the resulting HPMC polymer becomes
more hydrophilic in nature. In certain embodiments, the HPMC
polymer has about 15% to about 35%, about 19% to about 32%, or
about 22% to about 30%, methoxy substitution, and having about 3%
to about 15%, about 4% to about 12%, or about 7% to about 12%,
hydroxypropoxy substitution.
[0289] Exemplary HPMC polymers include, but are not limited to,
hydroxypropylmethylcellulose (HPMC), hydroxypropylmethylcellulose
acetate phthalate (HPMC-AP), hydroxypropylmethylcellulose acetate
succinate (HPMC-AS), hydroxypropylmethylcellulose acetate
trimellitate (HPMC-AT) and hydroxypropylmethylcellulose phthalate
(HPMC-P).
[0290] Grades of hydroxypropylmethylcellulose (HPMC) include, but
are not limited to, 3FG, 4FG, 5FG, 6FG, 15FG, 50FG and K100M.
Grades of hydroxypropylmethylcellulose acetate succinate (HPMC-AS)
include HPMC-AS-LF, HPMC-AS-MF, HPMC-AS-HF, HPMC-AS-LG, HPMC-AS-MG
and HPMC-AS-HG. Grades of hydroxypropyl-methylcellulose phthalate
(HPMC-P) include 50, 55, 55S.
[0291] Other exemplary HPMC polymers are available under the brand
names Methocel.TM. of Dow Chemical Co. and Metolose.TM. of
Shin-Etsu Chemical Co. Examples of suitable HPMC polymers having
medium viscosity include Methocel.TM. E4M, and Methocel.TM. K4M,
both of which have a viscosity of about 4000 cP at 2% (w/w) water.
Examples of HPMC polymers having higher viscosity include
Methocel.TM. E10M, Methocel.TM. K15M, and Methocel.TM. K100M, which
have viscosities of about 10,000 cP, 15,000 cP, and 100,000 cP
respectively viscosities at 2% (w/w) in water.
[0292] In some embodiments, provided formulation may include one or
more crystallization inhibitors. In certain embodiments, the second
crystallization inhibitor is a PVP polymer. In certain embodiments,
the second crystallization inhibitor is a PEG polymer. In certain
embodiments, the second crystallization inhibitor is a Tween.RTM.
surfactant. In certain embodiments, the formulation or composition
comprises an amount of one or more crystallization inhibitors of at
least about 1%, 5%, 10%, 12%, 15%, 18%, 20%, 25%, 30%, 35%, 40%,
45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 99% (w/w),
based on the total weight of the formulation or composition.
[0293] In some embodiments, the composition is prepared by
lyophilization from a solution. In particular embodiments, the
composition is prepared by lyophilization from a solution of
(60:40) (v/v) t-butanol/water. In some embodiments, the solvent is
tert-butanol. In some embodiments, the solvent is a mixture of
tert-butanol and water. In some embodiments, the pH adjustor is
hydrochloric acid.
[0294] ISTODAX.RTM. Label
[0295] ISTODAX.RTM. is supplied as a kit which includes a sterile,
lyophilized powder in a single-use vial containing 10 mg of
Compound I and 20 mg of the bulking agent, povidone, USP.
Additionally, each kit includes 1 sterile vial containing 2 mL of
the Diluent composed of 80% propylene glycol, USP, and 20%
dehydrated alcohol, USP.
[0296] The K value of Povidone USP is 17. The molecular weight of
povidone USP is about 10.000 Dalton.
[0297] ISTODAX.RTM. is administered at a dose of 14 mg/m.sup.2
intravenously over a 4-hour period on days 1, 8 and 15 of a 28-day
cycle. Cycles are repeated every 28 days.
[0298] Uses
[0299] Conditions to be Treated
[0300] Provided are methods and compositions relating to treatment
of cell proliferative disorders, diseases or conditions. Cell
proliferative disorders, diseases or conditions include a variety
of conditions characterized by aberrant cell growth, preferably
abnormally increased cellular proliferation. Cell proliferative
disorders, diseases, or conditions that can be treated using the
provided compositions and methods include, but are not limited to,
cancer, immune-mediated responses and diseases (e.g., transplant
rejection, graft vs. host disease, immune reaction to gene therapy,
autoimmune diseases, pathogen-induced immune dysregulation, etc.),
certain circulatory diseases, and certain neurodegenerative
diseases.
[0301] In certain embodiments, provided are methods of treating
cancer. Cancer is a group of diseases which are characterized by
uncontrolled growth and spread of abnormal cells. Cancers include,
but are not limited to, carcinomas, sarcomas, leukemias, lymphomas
and the like. In certain embodiments, cancer is a hematological
malignancy. In certain embodiments, cancer is a solid tumor.
[0302] In certain embodiments the present disclosure relates to
treatment of hematological malignancies. Manifestations of
hematological malignancies include circulating malignant cells and
malignant masses. Hematological malignancies are types of cancers
that affect the blood, bone marrow, and/or lymph nodes.
Hematological malignancies that may be treated using romidepsin
include, but are not limited to: acute lymphoblastic leukemia
(ALL), acute myelogenous leukemia (AML), chronic myelogenous
leukemia (CML), chronic lymphocytic leukemia (CLL), hairy cell
leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, cutaneous
T-cell lymphoma (CTCL), peripheral T-cell lymphoma (PTCL), multiple
myeloma, and myelodysplastic syndromes. In certain embodiments,
romidepsin is used to treat multiple myeloma. In certain particular
embodiments, the cancer is relapsed and/or refractory multiple
myeloma. In other embodiments, romidepsin is used to treat chromic
lymphocytic leukemia (CLL). In certain particular embodiments, the
cancer is relapsed and/or refractory CLL. In other embodiments,
romidepsin is used to treat chromic myelogenous leukemia (CML). In
certain embodiments, romidepsin is used to treat acute
lymphoblastic leukemia (ALL). In certain embodiments, romidepsin is
used to treat acute myelogenous leukemia (AML). In certain
embodiments, the cancer is cutaneous T-cell lymphoma (CTCL). In
other embodiments, the cancer is peripheral T-cell lymphoma (PTCL).
In certain embodiments, the cancer is a myelodysplastic
syndrome.
[0303] In some embodiments of the present disclosure, cancers
treated include, but are not limited to, leukemias and lymphomas
such as cutaneous T-cell lymphoma (CTCL), peripheral T-cell
lymphoma, lymphomas associated with human T-cell lymphotrophic
virus (HTLV) such as adult T-cell leukemia/lymphoma (ATLL), B-cell
lymphomas, acute lymphocytic leukemia, acute nonlymphocytic
leukemias, chronic lymphocytic leukemia, chronic myelogenous
leukemia, acute myelogenous leukemia, Hodgkin's disease,
non-Hodgkin's lymphomas, multiple myeloma, myelodysplastic
syndromes.
[0304] In some such embodiments the disclosure relates to treatment
of solid tumors such as lung, breast, colon, liver, pancreas,
renal, prostate, ovarian, and/or brain. In some embodiments, the
disclosure relates to treatment of pancreatic cancer. In some
embodiments, the disclosure relates to treatment of renal cancer.
In some embodiments, the disclosure relates to treatment of
prostate cancer. In some embodiments, the disclosure relates to
treatment of sarcomas. In some embodiments, the disclosure relates
to treatment of soft tissue sarcomas.
[0305] In some embodiments, cancers that can be treated are solid
cancers that include, but are not limited to, mesothelioma, common
solid tumors of adults such as head and neck cancers (e.g., oral,
laryngeal and esophageal), genitourinary cancers (e.g., prostate,
bladder, renal, uterine, ovarian, testicular, rectal and colon),
melanoma and other skin cancers, stomach cancer, brain tumors,
liver cancer and thyroid cancer, and/or childhood solid tumors such
as brain tumors, neuroblastoma, retinoblastoma, Wilms' tumor, bone
tumors, and soft-tissue sarcomas. In some embodiments, the
disclosure relates to treatment of solid tumors.
[0306] Cancers that may be treated using the methods provided
herein, including combination therapy, include but not limited to,
colon cancer, lung cancer, bone cancer, pancreatic cancer, stomach
cancer, esophageal cancer, skin cancer, brain cancer, liver cancer,
ovarian cancer, cervical cancer, uterine cancer, testicular cancer,
prostate cancer, bladder cancer, kidney cancer, and neuroendocrine
cancer.
[0307] In certain embodiments, cancer is pancreatic cancer. In
certain embodiments, cancer is prostate cancer. In certain specific
embodiments, the prostate cancer is hormone refractory prostate
cancer.
[0308] In some particular embodiments, provided are methods to
treat leukemias. In some embodiments, leukemia is chronic
lymphocytic leukemia, chronic myelogenous leukemia, acute
lymphocytic leukemia, acute myelogenous leukemia, or adult T cell
leukemia/lymphoma.
[0309] In some embodiments, provided are methods of treating
lymphomas. In some embodiments, lymphoma is Hodgkin's or
non-Hodgkin's (e.g., T-cell lymphomas such as peripheral T-cell
lymphoma, cutaneous T-cell lymphoma, etc.) lymphoma.
[0310] In some embodiments, the disclosure relates to the treatment
of multiple myeloma and/or myelodysplastic syndromes.
[0311] In some embodiments, provided are methods of treating one or
more immune-mediated responses and diseases including, but not
being limited to, rejection following transplantation of synthetic
or organic grafting materials, cells, organs, or tissue to replace
all or part of the function of tissues, such as heart, kidney,
liver, bone marrow, skin, cornea, vessels, lung, pancreas,
intestine, limb, muscle, nerve tissue, duodenum, small-bowel,
pancreatic-islet-cell, including xeno-transplants, etc.; graft vs
host disease; autoimmune diseases, such as rheumatoid arthritis,
systemic lupus erythematosus, thyroiditis, Hashimoto's thyroiditis,
multiple sclerosis, myasthenia gravis, type I diabetes,
juvenile-onset or recent-onset diabetes mellitus, uveitis, Graves'
disease, psoriasis, atopic dermatitis, Crohn's disease, ulcerative
colitis, vasculitis, auto-antibody mediated diseases, aplastic
anemia, Evan's syndrome, autoimmune hemolytic anemia, and the
like.
[0312] In some embodiments, provided are methods of treating of one
or more infectious diseases causing aberrant immune response and/or
activation, such as traumatic or pathogen induced immune
dysregulation, including for example, that which are caused by
hepatitis B and C infections, HIV, Staphylococcus aureus infection,
viral encephalitis, sepsis, parasitic diseases wherein damage is
induced by an inflammatory response (e.g., leprosy).
[0313] In some embodiments, provided are methods of treatment of
graft vs host disease, rheumatoid arthritis, systemic lupus
erythematosus, psoriasis, atopic dermatitis, Crohn's disease,
ulcerative colitis, or multiple sclerosis.
[0314] In some embodiments, provided are methods of treatment of an
immune response associated with a gene therapy treatment, such as
the introduction of foreign genes into autologous cells and
expression of the encoded product. In some embodiments, provided
are methods of treating of circulatory diseases, such as
arteriosclerosis, atherosclerosis, vasculitis, polyarteritis nodosa
or myocarditis.
[0315] In some embodiments, provided are methods of treatment of
any of a variety of neurodegenerative diseases, a non-exhaustive
list of which includes:
[0316] I. Disorders characterized by progressive dementia in the
absence of other prominent neurologic signs, such as Alzheimer's
disease; Senile dementia of the Alzheimer type; and Pick's disease
(lobar atrophy);
[0317] II. Syndromes combining progressive dementia with other
prominent neurologic abnormalities such as: A) syndromes appearing
mainly in adults (e.g., Huntington's disease, Multiple system
atrophy combining dementia with ataxia and/or manifestations of
Parkinson's disease, Progressive supranuclear palsy
(Steel-Richardson-Olszewski), diffuse Lewy body disease, and
corticodentatonigral degeneration); and B) syndromes appearing
mainly in children or young adults (e.g., Hallervorden-Spatz
disease and progressive familial myoclonic epilepsy);
[0318] III. Syndromes of gradually developing abnormalities of
posture and movement such as paralysis agitans (Parkinson's
disease), striatonigral degeneration, progressive supranuclear
palsy, torsion dystonia (torsion spasm; dystonia musculorum
deformans), spasmodic torticollis and other dyskinesis, familial
tremor, and Gilles de la Tourette syndrome;
[0319] IV. Syndromes of progressive ataxia such as cerebellar
degenerations (e.g., cerebellar cortical degeneration and
olivopontocerebellar atrophy (OPCA)); and spinocerebellar
degeneration (Friedreich's ataxia and related disorders);
[0320] V. Syndromes of central autonomic nervous system failure
(Shy-Drager syndrome);
[0321] VI. Syndromes of muscular weakness and wasting without
sensory changes (motomeuron disease such as amyotrophic lateral
sclerosis, spinal muscular atrophy (e.g., infantile spinal muscular
atrophy (Werdnig-Hoffman), juvenile spinal muscular atrophy
(Wohlfart-Kugelberg-Welander) and other forms of familial spinal
muscular atrophy), primary lateral sclerosis, and hereditary
spastic paraplegia;
[0322] VII. Syndromes combining muscular weakness and wasting with
sensory changes (progressive neural muscular atrophy; chronic
familial polyneuropathies) such as peroneal muscular atrophy
(Charcot-Marie-Tooth), hypertrophic interstitial polyneuropathy
(Dejerine-Sottas), and miscellaneous forms of chronic progressive
neuropathy;
[0323] VIII. Syndromes of progressive visual loss such as
pigmentary degeneration of the retina (retinitis pigmentosa), and
hereditary optic atrophy (Leber's disease).
[0324] In some embodiments, the neurodegenerative disease is
Alzheimer's disease, Parkinson's disease, and/or Huntington's
disease.
[0325] In some embodiments, the diseases or conditions are
associated with chromatin remodeling.
[0326] Dosing
[0327] In some embodiments, Compound I and/or compositions
containing Compound I is/are administered according to a standard
dosing regimen. In some embodiments, Compound I and/or compositions
containing Compound I is/are administered according to an
accelerated dosing regimen.
[0328] Standard Dosing for Compound I
[0329] In some embodiments, unit doses of Compound I are within the
range of about 0.5 mg/m.sup.2 to about 28 mg/m.sup.2 body surface
area. In some embodiments, the range of about 6 to about 18
mg/m.sup.2 is used. In some embodiments, the range is about 10
mg/m.sup.2 to about 17 mg/m.sup.2. In some embodiments, particular
unit doses are 10 mg/m.sup.2, 12 mg/m.sup.2, 13 mg/m.sup.2, 14
mg/m.sup.2, and 15 mg/m.sup.2.
[0330] In some embodiments, Compound I is administered
intravenously. In some embodiments, intravenous dosing regimens
include daily dosing for 2 weeks, twice weekly dosing for 4 weeks,
thrice weekly dosing for 4 weeks, and various other intermittent
schedules (e.g., on days 1, 3, and 5; on days 4 and 10; on days 1,
8 and 15; on days 1 and 15; on days 5 and 12; or on days 5, 12, and
19 of 21 or 28 day cycles).
[0331] In some embodiments, Compound I is administered in
individual unit doses over 4 hours on days 1, 8, and 15, with
courses repeating every 28 days. Often, several courses (e.g., at
least 4, at least 6, or more) are administered. Indeed, instances
have been reported of as many as 72 courses being administered. In
some embodiments, individual unit doses are administered by 4 hour
infusion.
[0332] Accelerated Dosing for Compound I
[0333] Accelerated dosing regimens for Compound I may be utilized,
in which one or more individual unit doses is administered
intravenously over a period of time that is less than or equal to
about one hour. In some embodiments, one or more individual doses
are administered intravenously over a period of time that is less
than about 50 minutes, 40 minutes, 30 minutes, 20 minutes, or less.
Any regimen that includes at least one unit dose administered over
a period of time that is less than about one hour (60 minutes) may
be considered an accelerated dosing regimen in accordance with the
present disclosure.
[0334] In some embodiments, all unit doses within a regimen are
administered intravenously over a time period that is less than or
equal to about one hour. In some embodiments, only some of the unit
doses within a regimen are administered over a time period that is
less than or equal to about one hour. In some embodiments, one or
more unit doses within a regimen are administered by a route other
than intravenous administration (e.g., oral, subcutaneous, nasal,
topical, etc).
[0335] Accelerated dosing regimens of Compound I can be
administered without a significant increase in toxicity or adverse
events, particularly in serious adverse events, as compared with a
comparable regimen (e.g., an otherwise identical regimen) in which
individual unit doses are administered intravenously over a 4-hour
period. Accelerated dosing regimens can be administered without a
significant increase in toxicity or adverse events, particularly in
serious adverse events, as compared with a standard regimen of
Compound I administered by 4-hour intravenous infusion of a dose of
about 6-14 mg/m.sup.2 on days 1, 8, and 15 of a 28 day cycle.
[0336] In some embodiments, Compound I is administered in an
accelerated dosing regimen that is identical to a standard dosing
regimen (see above) except that one or more unit doses is
administered over a time period that is less than about 1 hour
(e.g., rather than over a time period of about 4 hours).
[0337] In some embodiments, unit doses of Compound I are within the
range of about 0.5 mg/m.sup.2 to about 28 mg/m.sup.2. In certain
embodiments, unit doses are in the range of about 1 mg/m.sup.2 to
about 25 mg/m.sup.2. In certain embodiments, unit doses are in the
range of about 0.5 mg/m.sup.2 to about 15 mg/m.sup.2. In certain
embodiments, unit doses are the range of about 1 mg/m.sup.2 to
about 15 mg/m.sup.2. In certain embodiments, unit doses are in the
range of about 1 mg/m.sup.2 to about 8 mg/m.sup.2. In certain
embodiments, unit doses are in the range of about 0.5 mg/m.sup.2 to
about 5 mg/m.sup.2. In certain embodiments, the unit doses are in
the range of about 2 mg/m.sup.2 to about 10 mg/m.sup.2. In some
embodiments, unit doses are in the range of about 10 mg/m.sup.2 to
about 20 mg/m.sup.2. In certain embodiments, unit doses are in the
range of about 5 mg/m.sup.2 to about 10 mg/m.sup.2. In some
embodiments, unit doses are in the range of about 10 mg/m.sup.2 to
about 15 mg/m.sup.2. In some embodiments, unit doses are in the
range of about 6 to about 19 mg/m.sup.2. In some embodiments, unit
doses are approximately 8 mg/m.sup.2. In still other embodiments,
the unit doses are approximately 9 mg/m.sup.2. In still other
embodiments, unit doses are approximately 10 mg/m.sup.2. In still
other embodiments, unit doses are approximately 11 mg/m.sup.2. In
still other embodiments, unit doses are approximately 12
mg/m.sup.2. In still other embodiments, unit doses are
approximately 13 mg/m.sup.2. In still other embodiments, unit doses
are approximately 14 mg/m.sup.2. In still other embodiments, unit
doses are approximately 15 mg/m.sup.2. In still other embodiments,
unit doses are approximately 30 mg/m.sup.2.
[0338] In certain embodiments, different individual unit doses
within a Compound I therapy regimen are different. In some
embodiments, increasing doses of Compound I are administered over
the course of a cycle. In certain embodiments, a dose of
approximately 8 mg/m.sup.2 is administered, followed by a dose of
approximately 10 mg/m.sup.2, followed by a dose of approximately 12
mg/m.sup.2 may be administered over a cycle.
[0339] An amount of Compound I administered in individual unit
doses varies depending on the form of Compound I being
administered. The dosages given herein are dose equivalents with
respect to the active ingredient, Compound I.
[0340] In certain embodiments, individual unit doses of Compound I
are administered on one day followed by several days on which
Compound I is not administered. In certain embodiments, Compound I
is administered twice a week. In certain embodiments, Compound I is
administered once a week. In other embodiments, Compound I is
administered every other week.
[0341] In some embodiments, Compound I is administered daily (for
example for 2 weeks), twice weekly (for example for 4 weeks),
thrice weekly (for example for 4 weeks), or on any of a variety of
other intermittent schedules (e.g., on days 1, 3, and 5; on days 4
and 10; on days 1 and 15; on days 5 and 12; or on days 5, 12, and
19 of 21 or 28 day cycles).
[0342] In certain embodiments, Compound I is administered on days
1, 8, and 15 of a 28 day cycle. In certain particular embodiments,
an 8 mg/m.sup.2 dose of Compound I is administered on day 1, a 10
mg/m.sup.2 dose of Compound I is administered on day 8, and a 12
mg/m.sup.2 dose of Compound I is administered on day 15. In certain
embodiments, Compound I is administered on days 1 and 15 of a 28
day cycle with day 8 being skipped. A 28 day dosing cycle may be
repeated. In certain embodiments, a 28 day cycle is repeated 2-10,
2-7, 2-5, or 3-10 times. In certain embodiments, the treatment
includes 5 cycles. In certain embodiments, the treatment includes 6
cycles. In certain embodiments, the treatment includes 7 cycles. In
certain embodiments, the treatment includes 8 cycles. In certain
embodiments, 10 cycles are administered. In certain embodiments,
greater than 10 cycles are administered.
[0343] In certain embodiments, one or more unit doses within a
Compound I dosing regimen may be administered via a route other
than intravenous administration. In some embodiments, one or more
doses may be administered orally. In certain embodiments, Compound
I is dosed orally in the range of 10 mg/m.sup.2 to 300 mg/m.sup.2.
In certain embodiments, Compound I is dosed orally in the range of
25 mg/m.sup.2 to 100 mg/m.sup.2. In certain embodiments, Compound I
is dosed orally in the range of 100 mg/m.sup.2 to 200 mg/m.sup.2.
In certain embodiments, Compound I is dosed orally in the range of
200 mg/m.sup.2 to 300 mg/m.sup.2. In certain embodiments, Compound
I is dosed orally at greater than 300 mg/m.sup.2. In certain
embodiments, Compound I is dosed orally in the range of 50
mg/m.sup.2 to 150 mg/m.sup.2. In other embodiments, the oral dosage
ranges from 25 mg/m.sup.2 to 75 mg/m.sup.2.
[0344] In certain embodiments, Compound I is administered orally on
a daily basis. In some embodiments, Compound I is administered
orally every other day. In still other embodiments, Compound I is
administered orally every third, fourth, fifth, or sixth day. In
certain embodiments, Compound I is administered orally every week.
In certain embodiments, Compound I is administered orally every
other week.
[0345] In some embodiments, one or more unit doses of Compound I is
administered topically.
[0346] As will be appreciated by one of skill in the art, the
dosage, timing and/or routes of administration of particular unit
doses of Compound I may vary depending on the patient and condition
being treated. In certain embodiments, the cycles are continued as
long as the patient is responding. Therapy may be terminated once
there is disease progression, a cure or remission is achieved, or
side effects become intolerable. Adverse side effects may also call
for lowering the dosage of Compound I administered, or for
adjusting the schedule by which doses are administered.
[0347] Toxicity and Adverse Events with Compound I
[0348] Compound I has been administered to patients in a variety of
different clinical contexts and studies. Observed toxicities
include fatigue, nausea, vomiting, and myelosuppression
(thrombocytopenia and/or neutropenia, e.g., Grade 3). Non-specific
S-T segment changes on ECG and prolongation of QTc intervals occur
in many patients. Observed toxicities were mild to moderate.
Observed changes in ECGs did not correlate with elevated serial
serum troponin levels and multiple gated acquisition (MUGA) scans,
both of which were consistently normal.
[0349] In early development, 6 deaths occurred (out of more than
450 patients) during clinical investigations of Compound I. In all
but one of the deaths, significant cardiovascular risk factors were
either present at the time of entry into the Compound I study or
appeared during the course of the study. The sixth patient had a
history of sarcoidosis and was simultaneously administered another
drug that also is known to cause QTc prolongation.
[0350] Hematologic Events
[0351] Administration of Compound I may cause neutropenia and/or
thrombocytopenia It is generally recommended that further treatment
be withheld from patients with Grade 3 or Grade 4 neutropenia or
thrombocytopenia, until their specific cytopenia returns to Grade 1
(i.e., ANC recovered to >1.9.times.10.sup.9/L and platelet count
recovered to .gtoreq.75.times.10.sup.9/L) or below, at which point
therapy can be continued at full dose. If Grade 4 neutropenia or
thrombocytopenia lasting more than 5 days or associated with
bleeding, then it is generally recommended that treatment be
withheld until specific cytopenia returns to Grade 1 or below, at
which point therapy can continue, preferably at a reduced dose
(e.g., 10 mg/m.sup.2). If Grade 4 febrile (.gtoreq.38.5.degree. C.)
neutropenia or thrombocytopenia that requires platelet transfusion
is observed, it is generally recommended that treatment be withheld
until the specific cytopenia returns to Grade 1 or below, at which
point therapy can continue, preferably at a reduced dose (e.g., 10
mg/m.sup.2).
[0352] Hematologic events are typically observed at a rate of about
21-52% with standard Compound I dosing regimens (National Cancer
Institute IND 57,810 Annual Report, 2007). For example, the NCI
2007 Annual Report provides the following rates for the following
blood and bone marrow abnormalities: platelets (52%),
hemoglobin/anemia (41%), abnormal white blood cell count (39%),
abnormal ANC/AGC (37%), and lymphopenia (21%) (National Cancer
Institute IND 57,810 Annual Report, 2007).
[0353] Cardiac Events
[0354] Cardiac events observed with Compound I administration can
include any or all of the following: [0355] Prolongation of QTc to
.gtoreq.500 msec or an increase of .gtoreq.60 msec from
pretreatment baseline for the current treatment cycle; [0356]
Ventricular arrhythmia (i.e., ventricular tachycardia or
ventricular fibrillation [.gtoreq.3 beats in a row)` [0357] Sinus
tachycardia (pulse >140/min after recumbency); [0358] New
occurrence of atrial dysrhythmias (SVT, atrial fibrillation, or
atrial flutter), ST and T-wave changes indicative of repolarization
abnormalities or ischemia (e.g., ST depression of .gtoreq.2 mm
[measured from isoelectric line to ST segment] and/or T-wave
inversion of .gtoreq.4 mm [measured from isoelectric line to peak
of T-wave] as long as the main QRS vector is positive).
[0359] The literature reports that the median change in QTc from
baseline is 16.5 milliseconds (see, Piekarz et al., Clin Cancer Res
12:3762, 2006). Table 2 presents common recommendations for dose
modification when cardiac events are observed. TABLE-US-00002 TABLE
2 Recommendation for dose modification during cardiac events
Parameters/Symptoms Change Action Dosing/Continuation Sinus
tachycardia Pulse >140/min after Hold further dosing, If
resolved, restart recumbancy consult local treatment, preferably at
a Atrial dysrhythmia (SVT, New occurrence cardiologist, and treat
reduced dose (e.g., 10 atrial fibrillation, or atrial appropriately
mg/m.sup.2) flutter) Prolongation of QTcf To .gtoreq.500 msec If
not resolved, compared to pre-treatment OR discontinue therapy
baseline in a treatment Increase by .gtoreq.60 msec cycle
Ventricular tachycardia .gtoreq.3 beats in a row Ventricular
fibrillation New occurrence Hold further dosing and Hold further
dosing until treat appropriately. The medical monitor and medical
monitor should cardiologist evaluation is be notified and local
complete cardiologist should be consulted A subsequent episode of
any of the above, despite dose reduction Discontinue Compound I
administration T-wave morphology Inversion of .gtoreq.4 mm.sup.a
Hold further dosing, If resolved, restart ST-segment Depression of
.gtoreq.2 mm.sup.b consult local treatment, preferably at a
cardiologist, and treat reduced dose (e.g., 10 appropriately
mg/m.sup.2) In some patients, ST segment and T-wave morphology
changes may recur despite a dose reduction. In such cases, further
treatment should be withheld until the ECG changes resolve. If the
patient experiences no concomitant clinical events, treatment may
be resumed, preferably at the reduced dose level. If not resolved,
discontinue therapy. .sup.aMeasured from isoelectric line to peak
of T-wave .sup.bMeasured from isoelectric line to ST segment
[0360] Cardiac events are typically observed at a rate of about 24%
with standard Compound I dosing regimens (National Cancer Institute
IND 57,810 Annual Report, 2007)
[0361] Gastrointestinal Events
[0362] Gastrointestinal events are typically observed at a rate of
about 15-64% with standard Compound I dosing regimens (National
Cancer Institute IND 57,810 Annual Report, 2007). For example, the
NCI 2007 Annual Report provides the following rates for the
following gastrointestinal events: nausea (64%), anorexia (39%),
vomiting (39%), constipation (19%), dysguesia (18%), and diarrhea
(15%) (National Cancer Institute IND 57,810 Annual Report,
2007).
[0363] Compound I can be administered via accelerated dosing
regimens without a clinically significant increase in relevant
toxicities (e.g., in the rate and/or severity of one or more of
dose limiting toxicities, serious adverse events, and/or adverse
events). In some embodiments, provided are accelerated dosing
regimens for Compound I in which the rate of observed toxicities
(e.g., fatigue, hematological toxicities, cardiac toxicities,
gastrointestinal toxicities, constitutional toxicities, or a
combination thereof) is not materially worse than that observed for
administration of a comparable dosing regimen that differs only in
that unit doses of Compound I are administered intravenously over a
time period of about 4 hours. In some embodiments, provided are
accelerated dosing regimens for Compound I in which the rate of
observed toxicities is not materially worse than that observed for
administration of a standard Compound I therapy regimen.
[0364] In some embodiments, provided are accelerated dosing
regimens for Compound I in which the subject receiving Compound I
does not suffer one or more particular adverse events, or serious
adverse events, within a designated time period. In some
embodiments, the designated time period is during administration of
the accelerated dose. In some embodiments, the designated time
period is within about 2 to about 6 hours after the end of infusion
of the accelerated dose. In some embodiments, the designated time
period is within about 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24,
26, 28, 30, 32, 34, 36, 38, 40 42, 44, 46, 48 or more hours after
the end of infusion of the accelerated dose.
[0365] Any side effect, toxicity, or adverse event may be absent
from the designated time period. In some embodiments, the subject's
QTc remains below about 500 msec during the designated time period;
in some embodiments, the subject does not suffer a ventricular
arrhythmia during the designated time period; in some embodiments,
the subject does not suffer sinus tachycardia during the designated
time period; in some embodiments, the subject does not suffer an
atrial dysrhythmia during the designated time period; in some
embodiments the subject does not suffer ST or T-wave changes
indicative of repolarization during the designated time period.
[0366] Combination Therapy
[0367] In some embodiments, Compound I is administered in
combination with one or more other pharmaceutical agents. In some
embodiments, Compound I is administered in combination with one or
more other chemotherapeutic agents and/or in combination with one
or more other pharmaceutical agents (e.g., pain relievers,
anti-inflammatories, antibiotics, steroidal agents, anti-folates,
kinase inhibitors, methyl transferase inhibitors, antibodies,
etc.).
[0368] In certain embodiments, Compound I is administered in
combination with one or more cytotoxic agents. Exemplary cytotoxic
agents include, but are not limited to, gemcitabine, decitabine,
and flavopiridol. In certain embodiments, Compound I is
administered in combination with one or more taxanes and/or one or
more proteasome inhibitors. Exemplary proteasome inhibitors
include, but are not limited to, bortezomib (VELCADE.RTM.), peptide
boronates, salinosporamide A (NPI-0052), lactacystin, epoxomicin
(Ac(Me)-Ile-Ile-Thr-Leu-EX), MG-132 (Z-Leu-Leu-Leu-al), PR-171,
PS-519, eponemycin, aclacinomycin A, CEP-1612, CVT-63417, PS-341
(pyrazylcarbonyl-Phe-Leu-boronate), PSI
(Z-Ile-Glu(OtBu)-Ala-Leu-al), MG-262 (Z-Leu-Leu-Leu-bor), PS-273
(MNLB), omuralide (clasto-lactacystin-.beta.-lactone), NLVS
(Nip-Leu-Leu-Leu-vinyl sulfone), YLVS (Tyr-Leu-Leu-Leu-vs),
dihydroeponemycin, DFLB (dansyl-Phe-Leu-boronate), ALLN
(Ac-Leu-Leu-Nle-al), 3,4-dichloroisocoumarin,
4-(2-aminoethyl)-benzenesulfonyl fluoride, TMC-95A, gliotoxin, EGCG
((-)-epigallocatechin-3-gallate), YU101 (Ac-hFLFL-ex), and
combinations thereof.
[0369] In certain embodiments, Compound I is administered in
combination with one or more anti-folates. In some such
embodiments, Compound I is administered in combination with one or
more of: folinic acid (leucovorin), methotrexate, pralatrexate,
premextred, triazinate, or combinations thereof.
[0370] In certain embodiments, Compound I is administered in
combination with one or more kinase inhibitors (e.g., tyrosine
kinase inhibitors). In some embodiments, Compound I is administered
in combination with one or more antibodies that act as a kinase
inhibitor. In some embodiments, Compound I is administered in
combination with one or more of ABT-869, AC220, AZD7762, BIBW 2992,
BMS-690154, CDKIAT7519, CYC116, ISIS3521, GSK690693, GSK-461364,
MK-0457, MLN8054, MLN8237, MP470, ON 01910.Na, OSI-930, PHA-739358,
R935788, SNS-314, TLN-232, XL147, XL228, XL281, XL418, or
XL765.
[0371] In certain embodiments, Compound I is administered in
combination with one or more methyl transferase inhibitors.
[0372] In certain embodiments, Compound I is administered in
combination with one or more therapeutic antibodies. In some
embodiments, Compound I is administered in combination with one or
more of: bevacizumab, cetuximab, dasatinib, erlotinib, geftinib,
imatinib, lapatinib, nilotinib, panitumumab, pegaptanib,
ranibizumab, sorafenib, sunitinib, trastuzumab, or any antibody
that binds to an antigen bound by one of these moieties.
[0373] In some embodiments, Compound I is administered in
combination with an anti-inflammatory agent, pain reliever,
anti-nausea medication, or anti-pyretic. Anti-inflammatory agents
useful in the methods provided herein include, but are not limited
to, aspirin, ibuprofen, and acetaminophen, etc.
[0374] In certain embodiments, Compound I is administered in
combination with a steroidal agent. In certain embodiments,
Compound I is administered in combination with a steroidal agent
selected from the group consisting of alclometasone diproprionate,
amcinonide, beclomethasone diproprionate, betamethasone,
betamethasone benzoate, betamethasone diproprionate, betamethasone
sodium phosphate, betamethasone sodium phosphate and acetate,
betamethasone valerate, clobetasol proprionate, clocortolone
pivalate, cortisol (hydrocortisone), cortisol (hydrocortisone)
acetate, cortisol (hydrocortisone) butyrate, cortisol
(hydrocortisone) cypionate, cortisol (hydrocortisone) sodium
phosphate, cortisol (hydrocortisone) sodium succinate, cortisol
(hydrocortisone) valerate, cortisone acetate, desonide,
desoximetasone, dexamethasone, dexamethasone acetate, dexamethasone
sodium phosphate, diflorasone diacetate, fludrocortisone acetate,
flunisolide, fluocinolone acetonide, fluocinonide, fluorometholone,
flurandrenolide, halcinonide, medrysone, methylprednisolone,
methylprednisolone acetate, methylprednisolone sodium succinate,
mometasone furoate, paramethasone acetate, prednisolone,
prednisolone acetate, prednisolone sodium phosphate, prednisolone
tebutate, prednisone, triamcinolone, triamcinolone acetonide,
triamcinolone diacetate, triamcinolone hexacetonide, or
combinations thereof. In some embodiments, Compound I is
administered in combination with dexamethasone.
[0375] In certain embodiments, Compound I is administered in
combination with an agent to treat gastrointestinal disturbances
such as nausea, vomiting, and diarrhea. Such agents may include
anti-emetics, anti-diarrheals, fluid replacement, electrolyte
replacement, etc.
[0376] In certain embodiments, Compound I is administered in
combination with electrolyte replacement or supplementation such as
potassium, magnesium, and calcium. In certain embodiments, Compound
I is administered in combination with electrolyte replacement or
supplementation such as potassium, magnesium.
[0377] In certain embodiments, Compound I is administered in
combination with an anti-arrhythmic agent.
[0378] In certain embodiments, Compound I is administered in
combination with an agent that increases the production of
platelets.
[0379] In certain embodiments, Compound I is administered in
combination with an agent to boost the production of blood cells.
In certain embodiments, the agent is erythropoietin.
[0380] In some embodiments, Compound I is administered in
combination with an agent to prevent hyperglycemia.
[0381] In certain embodiments, Compound I is administered with
another HDAC or DAC inhibitor.
[0382] Electrolyte Supplementation
[0383] In some embodiments, electrolyte supplementation is
administered to subjects receiving Compound I therapy. Individuals
with low electrolyte levels (e.g., low potassium and/or magnesium
levels) are susceptible to development of unwanted side effects if
administered Compound I therapy (see, for example, published
application No. US 2008/0124403, which is incorporated herein by
reference).
[0384] Such patients may be particularly susceptible to development
of cardiac repolarization effects, including QTc prolongation
(though potentially with no significant cardiac function changes),
and/or cardiac dysrhythmias. Particular abnormalities that may be
observed include an increase in QTc interval and/or abnormalities
of the ST segment (e.g., ST segment depression) and/or the T-wave
(e.g., T-wave flattening) on ECG.
[0385] An individual with a potassium serum concentration below
about 3.5 mmol/L (3.5 mEq/L) and/or a serum magnesium concentration
below about 0.8 mml/L (1.95 mEq/L) suffers an increased risk of
developing cardiac repolarization effects and/or dysrhythmias.
[0386] Serum concentrations of potassium are generally considered
to be "normal" when they are within the range of about 3.5-5.5
mEq/L or about 3.5-5.0 mEq/L. It is often desirable to ensure that
an individuals' serum potassium concentration is within these
ranges prior to (and/or during) administration of Compound I
therapy.
[0387] Serum concentrations of magnesium are generally considered
to be "normal" when they are within the range of about 1.5-2.5
mEq/L or about 1.5-2.2 mEq/L or about 1.25-2.5 mEq/L or about
1.25-2.2 mEq/L. It is often desirable to ensure that an
individual's serum magnesium concentration is within these ranges
prior to (and/or during) administration of Compound I therapy.
[0388] In some embodiments, an individual's serum potassium and/or
magnesium concentration(s) is/are at the high end of the normal
range prior to (and/or during) administration of Compound I
therapy. In some embodiments, an individual's serum potassium
concentration is at least about 3.8 mEq/L, 3.9 mEq/L, 4.0 mEq/L, or
more prior to and/or during administration of Compound I therapy.
In some embodiments, care is taken not to increase serum potassium
concentration above about 5.0 mEq/L, 5.2 mEq/L, or 5.5 mEq/L. In
some embodiments, an individual's serum magnesium concentration is
at least about 1.9 mEq/L or more prior to and/or during
administration of Compound I therapy. In some embodiments, care is
taken not to increase magnesium concentration above about 2.5
mEq/L.
[0389] In some embodiments of the present disclosure, an
individual's serum potassium concentration is at least about 3.5
mEq/L (in some embodiments at least about 3.8 mEq/L, 3.9 mEq/L, 4.0
mEq/L, or above) and the individual's serum magnesium concentration
is at least about 1.85 mEq/L (in some embodiments at least about
1.25 mEq/L, 1.35 mEq/L, 1.45 mEq/L, 1.55 mEq/L, 1.65 mEq/L, 1.75
mEq/L, 1.85 mEq/L, 1.95 mEq/L, or above) prior to and/or during
administration of Compound I therapy.
[0390] In some embodiments, electrolyte levels (e.g., potassium
and/or magnesium levels, optionally calcium levels) are assessed
more than once during the course of Compound I therapy; in some
embodiments, different assessments are separated by a regular
interval (e.g., 0.5 days or less, 1 day, 2 days, 3 days, 4 days, 5
days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13
days, 14 days, 1 month, 2 months, 3 months, 4 months, 5 months, 6
months, etc.). In some embodiments, electrolyte levels are assessed
prior to each administration of Compound I.
[0391] An individual's serum potassium and/or magnesium and/or
other electrolyte concentration(s) may be assessed by any available
means. For example, samples may be collected from venous or
arterial blood and processed for plasma or serum analysis. In some
embodiments, venous sampling is utilized. Any available assay may
be utilized for assessment. In some embodiments, potassium is
measured by flame photometry, direct potentiometry (see, for
example, Koch et al., Clin. Chem. 29:1090, 1983), enzymatic methods
(e.g., by using tryptophanase; see, for example, Kimura et al.,
Clin. Chem. 38:44, 1992), calorimetric methods (e.g., using
tetraphenyl borate), etc. In some embodiments, magnesium is
measured by complexometric titration, flame emission photometry,
atomic absorption spectophotometry, other spectrophotometric
techniques including enzymatic techniques and dye binding methods
(e.g., Magnon dye binding and bichromatic absorbance; see, for
example, Barbour et al., Clin. Chem. 34:2103, 1988; elimination of
interference by bilirubin; see, for example, Rehak et al., Clin.
Chem 35:1031, 1989; etc.). In many embodiments, assays are
performed in an automated clinical chemistry analyzer (e.g., the
Abbott ARCHITECT.RTM., etc.).
[0392] Where both potassium and magnesium levels are assessed, they
may be assessed separately or together. Assessment of potassium
and/or magnesium levels may be performed prior to, at the same time
as, and/or after initiation of Compound I therapy.
[0393] In some embodiments, if an individual is determined to have
serum potassium and/or magnesium concentration(s) that is/are below
normal, or below the high end of normal as described herein,
potassium and/or magnesium supplementation is administered prior
to, at the same time as, or after initiation of Compound I therapy.
In some embodiments, Compound I therapy is suspended or delayed
until serum potassium and/or magnesium levels are increased. In
some embodiments, Compound I therapy is suspended or delayed until
serum potassium and/or magnesium levels are increased to within the
normal range, or to within the upper end of the normal range. In
some embodiments, Compound I therapy is suspended or delayed until
serum potassium concentration is above about 3.5 mEq/L; or is above
about 3.8 mEq/L. In some embodiments, Compound I therapy is
suspended or delayed until serum magnesium concentration is above
about 1.25 mEq/L; or is above about 1.8 mEq/L; or is above about
1.9 mEq/L. In some embodiments, Compound I therapy is suspended or
delayed until both serum potassium and serum magnesium
concentrations are increased as described.
[0394] In some embodiments, electrolyte supplementation may be
administered prior to, concurrently with, and/or subsequent to
initiation of Compound I therapy, and may include potassium and/or
magnesium supplementation. In some embodiments, electrolyte
supplementation may include supplementation of one or more
electrolytes selected from the group consisting of sodium,
potassium, chloride, calcium, magnesium, bicarbonate, phosphate,
sulfate, and combinations thereof.
[0395] A variety of different potassium supplemental forms is
available (see, for example, the web page at the following
world-wide-web address: pdrhealth.com). For example, potassium
supplements in the form of potassium chloride, potassium citrate,
potassium gluconate, potassium bicarbonate, potassium aspartate
and/or potassium orotate can readily be obtained.
[0396] One of potassium supplemental forms is high-potassium (up to
800 milligrams per serving), low-sodium vegetable juices. Some soft
drinks are rich in potassium. Some soft drinks contain potassium
gluconate which has a less bitter taste than some other potassium
supplements. Salt substitutes are high in potassium.
[0397] Certain foods high in potassium such as raisins, figs,
apricots, sardines, veal, bananas, avocado, and broccoli may be
used as potassium supplements. Foods high in potassium may provide
potassium that is easily bioavailable and/or may reduce
gastrointestinal side effects associated with the administration of
potassium salts. The potassium supplement may also be provided as
part of a multivitamin.
[0398] Potassium is typically supplemented orally or intravenously,
though other modes of delivery are within the scope of the present
disclosure.
[0399] Certain commercially available forms of potassium
supplements include, for example, potassium acetate (e.g., 2 mEq/mL
or 4 mEq/mL for injection); potassium acetate (e.g., 75 mg, 95 mg,
99 mg, and 180 mg tablets and/or 2 mEq/mL, 10 mEq/50 mL, 20 mEq/50
mL, 10 mEq/100 mL, 20 mEq/100 mL, 30 mEq/100 mL, 40 mEq/100 mL for
injection and/or 20 mEq/15 mL, 40 mEq/15 mL liquid and/or 20 mEq or
25 mEq powder for reconstitution, and/or 9 mEq, 10 mEq, or 20 mEq
extended release tablets), and potassium gluconate (e.g., 486 mg,
500 mg, 550 mg, 595 mg, 610 mg, and 620 mg tablets).
[0400] A variety of different magnesium supplemental forms are also
available. For example, supplements in the form of magnesium
chloride, magnesium gluconate, magnesium lactate, magnesium oxide
and/or magnesium sulfate can readily be obtained.
[0401] Certain foods high in magnesium such as artichoke, banana,
figs, almonds, cashews, pine nuts, brazil nuts, beans, spinach, and
tomatoes may be used as magnesium supplements. The magnesium
supplement may also be provided as part of a multivitamin.
[0402] Certain commercially available forms of magnesium
supplements include magnesium chloride (e.g., 200 mg/ml for
injection, 535 mg extended release tablets), magnesium gluconate
(3.25 mg/mL, 1000 mg/5 mL liquid; 500 mg tablet); magnesium lactate
(84 mg extended release tablet); magnesium oxide (e.g., 140 mg, 600
mg capsules, powder, and/or 200 mg, 250 mg, 400 mg, 420 mg, and 500
mg tablets), magnesium sulfate (e.g., 40 mg/mL, 80 mg/mL, 125
mg/mL, 500 mg/mL, for injection).
[0403] In some embodiments, electrolyte supplementation is
administered in an amount sufficient to reduce or delay onset of
one or more cardiac toxicities associated with Compound I therapy.
In some embodiments, the electrolyte administration may also reduce
one or more of nausea, vomiting, fatigue (lethargy, malaise,
asthenia), increased creatine phospho kinase (CPK), hyperuricemia,
hypocalcemia, hyperglycemia, fever, gastritis, diarrhea, abdominal
pain, dehydration, weight loss, hypophosphatemia, hyponatremia,
hypokalemia, hypomagnesemia, syncope, hypoxia, pleural effusion,
hypotension, myocardial ischemia, increased cardiac troponin I,
confusion, and/or myelosuppression, and combinations thereof.
[0404] In some embodiments, cardiac toxicities are selected from
the group consisting of heart-rate corrected QT (QTc) interval
prolongation, supraventricular arrhythmias (supraventricular
tachycardia (SVT)/atrial fibrillation/flutter), and combinations
thereof. In some embodiments, QTc prolongation and/or other
electrophysiological changes are reduced to normal values or ranges
after electrolyte supplementation.
[0405] Unless otherwise defined, all technical and scientific terms
used herein are accorded the meaning commonly known to one of skill
in the art. All publications, patents, published patent
applications, and other references mentioned herein are hereby
incorporated by reference in their entirety. The embodiments of the
disclosure should not be deemed to be mutually exclusive and can be
combined.
EXAMPLES
[0406] General Procedures for Characterization of Solid Forms
[0407] Provided herein is an assortment of characterizing
information to describe provided forms of Compound I. It should be
understood, however, that not all such information is required for
one skilled in the art to determine that such particular form is
present in a given composition, but that the determination of a
particular form can be achieved using any portion of the
characterizing information that one skilled in the art would
recognize as sufficient for establishing the presence of a
particular form, e.g., even a single distinguishing peak can be
sufficient for one skilled in the art to appreciate that such
particular form is present. United States Pharmacopeia provides
additional guidance with respect to characterization of crystalline
forms (see, X-Ray Diffraction, <941>. United States
Pharmacopeia, 31st ed. Rockville, Md.: United States Pharmacopeial
Convention; 2008:372-374), which is incorporated herein by
reference.
[0408] Materials
[0409] Solvents were either HPLC grade or ACS grade, unless stated
otherwise. Samples were prepared from Compound I Form A solids or
from samples generated from these solids. Form designation for the
materials was based on X-ray powder diffraction (XRPD). Care was
taken to protect samples from light, unless stated otherwise. Prior
to characterization, solids were stored as follows: Form A and Form
B (may have contained Form A solids as well) under ambient
conditions, Form E and Form H over desiccant in a freezer, Form C
in contact with mother liquor in a refrigerator, Form D in contact
with mother liquor in a freezer, and Form I in contact with mother
liquor under ambient conditions or in a freezer. Due to apparent
instability of Form D, all characterization data except solution
proton nuclear magnetic resonance spectroscopy (.sup.1H-NMR) were
collected for Form D on the same day. Although the .sup.1H-NMR
analysis was not run until a few days later, the solution for the
analysis was prepared on the same day as the rest of the
characterization.
[0410] Instrumental Techniques
[0411] Optical Microscopy
[0412] Optical microscopy was performed using a Leica MZ12.5
stereomicroscope. Samples were viewed in situ or on a glass slide
(sometimes covered in Paratone-N oil) with crossed polarizers and a
first order red compensator. Various objectives were used, ranging
from 0.8-10.times..
[0413] X-Ray Powder Diffraction (XRPD) (Inel)
[0414] XRPD patterns were collected using an Inel XRG-3000
diffractometer equipped with a curved position sensitive detector
with a 2.theta. range of 120.degree.. An incident beam of Cu
K.alpha. radiation (40 kV, 30 mA) was used to collect data in real
time at a resolution of 0.03.degree. 2.theta.. Prior to the
analysis, a silicon standard (NIST SRM 640c) was analyzed to verify
the Si 111 peak position. Samples were prepared for analysis by
packing them into thin-walled glass capillaries. Each capillary was
mounted onto a goniometer head and rotated during data acquisition.
The monochromator slit was set at 5 mm by 160 .mu.m.
[0415] PANalytical Transmission
[0416] XRPD patterns were collected using a PANalytical X'Pert Pro
diffractometer. An incident beam of Cu K.alpha. radiation was
produced using an Optix long, fine-focus source. An elliptically
graded multilayer mirror was used to focus the Cu K.alpha. X-rays
of the source through the specimen and onto the detector. Data were
collected and analyzed using X'Pert Pro Data Collector software
(v.2.2b). Prior to the analysis, a silicon specimen (NIST SRM 640c)
was analyzed to verify the Si 111 peak position. The specimen was
sandwiched between 3 .mu.m thick films, analyzed in transmission
geometry, and rotated to optimize orientation statistics. A
beam-stop was used (sometimes with helium gas) to minimize the
background generated by air scattering. Soller slits were used for
the incident and diffracted beams to minimize axial divergence.
Diffraction patterns were collected using a scanning
position-sensitive detector (X'Celerator) located 240 mm from the
specimen.
[0417] PANalytical Reflection
[0418] XRPD patterns were collected using a PANalytical X'Pert Pro
diffractometer. An incident beam of Cu K.alpha. radiation was
produced using a ceramic tube with a long, fine-focus source and a
nickel filter. The diffractometer was configured using the
symmetric Bragg-Brentano geometry with a reflection stage and a
manually operated spinner. Data were collected and analyzed using
X'Pert Pro Data Collector software (v. 2.2b). Prior to the
analysis, a silicon specimen (NIST SRM 640c) was analyzed to verify
the Si 111 peak position. The specimen was prepared as a thin,
circular layer centered on a silicon zero-background substrate.
Anti-scatter slits were used to minimize the background generated
by air scattering. Soller slits were used for the incident and
diffracted beams to minimize axial divergence. Diffraction patterns
were collected using a scanning position-sensitive detector
(X'Celerator) located 240 mm from the specimen.
[0419] Peak Identification Process (XRPD)
[0420] Peaks within the range of up to about 30.degree. 2.theta.
were selected. Different rounding algorithms were used to round
each peak to the nearest 0.01.degree. 2.theta., depending upon the
instrument used to collect the data and/or the inherent peak
resolution. The location of the peaks along the x-axis (.degree.
2.theta.) in both the figures and the tables were automatically
determined using proprietary software.sup.1 and rounded to two
significant figures after the decimal point based upon the above
criteria. Peak position variabilities are given to within
.+-.0.1.degree. 2.theta. based upon recommendations outlined in the
USP discussion of variability in x-ray powder diffraction.sup.2.
For d-space listings, the wavelength used to calculate d-spacings
was 1.541874 .ANG., a weighted average of the Cu--K.sub..alpha.1
and Cu--K.sub..alpha.2 wavelengths. Variability associated with
d-spacing estimates was calculated from the USP recommendation, at
each d-spacing, and provided in the respective data tables. .sup.1
PatternMatch.TM. 3.0.4. .sup.2 United States Pharmacopeia, USP 32,
NF 27, Vol. 1, pg. 392, May 1, 2009 <941> X-Ray
Diffraction.
[0421] For samples with only one XRPD pattern and no other means to
evaluate whether the sample provides a good approximation of the
powder average, peak tables contain data identified only as
"Prominent Peaks". These peaks are a subset of the entire observed
peak list. Prominent peaks are selected from observed peaks by
identifying preferably non-overlapping, low-angle peaks, with
strong intensity.
[0422] If multiple diffraction patterns are available, then
assessments of particle statistics (PS) and/or preferred
orientation (PO) are possible. Reproducibility among XRPD patterns
from multiple samples analyzed on a single diffractometer indicates
that the particle statistics are adequate. Consistency of relative
intensity among XRPD patterns from multiple diffractometers
indicates good orientation statistics. Alternatively, the observed
XRPD pattern may be compared with a calculated XRPD pattern based
upon a single crystal structure, if available. Two-dimensional
scattering patterns using area detectors can also be used to
evaluate PS/PO. If the effects of both PS and PO are determined to
be negligible, then the XRPD pattern is representative of the
powder average intensity for the sample and prominent peaks may be
identified as "Representative Peaks".
[0423] "Characteristic peaks" are a subset of Representative Peaks
and are used to differentiate one crystalline polymorph from
another crystalline polymorph. Characteristic peaks are determined
by evaluating which representative peaks, if any, are present in
one crystalline polymorph of a compound against all other known
crystalline polymorphs of that compound to within +0.1.degree.
2.theta.. Not all crystalline polymorphs of a compound necessarily
have at least one characteristic peak.
[0424] Differential Scanning Calorimetry (DSC)
[0425] DSC was performed using a TA Instruments Q2000 differential
scanning calorimeter. Temperature calibration was performed using
NIST traceable indium metal. The sample was placed into an aluminum
DSC pan, and the weight was accurately recorded. The pan was
covered with a lid, and the lid was crimped. A weighed, crimped
aluminum pan was placed on the reference side of the cell. The
sample cell was equilibrated at the initial temperature and heated
under a nitrogen purge. Reported temperatures are at the transition
maxima, unless stated otherwise.
[0426] Modulated Differential Scanning Calorimetry (MDSC)
[0427] MDSC data were obtained on a TA Instruments Q2000
differential scanning calorimeter equipped with a refrigerated
cooling system (RCS). Temperature calibration was performed using
NIST traceable indium metal. The sample was placed into an aluminum
DSC pan, and the weight was accurately recorded. The pan was
covered with a lid perforated with a laser pinhole, and the lid was
crimped or crimped then hermetically-sealed pan. A weighed, crimped
aluminum pan was placed on the reference side of the cell. Data
were obtained using a modulation amplitude of .+-.0.50.degree. C.
and a 60 second period with an underlying heating rate of
2.00.degree. C./minute from -50.00 to 200.00.degree. C. The
reported glass transition temperatures are obtained from the
inflection point of the step change in the reversing heat flow
versus temperature curve.
[0428] Thermogravimetric Analysis (TGA)
[0429] TG analysis was performed using a TA Instruments 2050
thermogravimetric analyzer. Temperature calibration was performed
using nickel and Alumel.TM.. The sample was placed in an aluminum
pan and inserted into the TG furnace. In one embodiment, the pan
was left open. The sample cell was equilibrated at the initial
temperature and the furnace was heated under nitrogen. In another
embodiment, the instrument was operated under a flow of helium at
10 and 90 cc/min for the purge and balance, respectively, and the
furnace was heated under helium at a rate of 20.degree. C./minute
to a final temperature of 250.degree. C.
[0430] Infrared Spectroscopy (FT-JR)
[0431] In one embodiment, FT-IR spectra for solid forms described
herein were acquired on Magna-IR 860.RTM. Fourier transform
infrared (FT-IR) spectrophotometer (Thermo Nicolet) equipped with
an Ever-Glo mid/far IR source, an extended range potassium bromide
(KBr) beamsplitter, and a deuterated triglycine sulfate (DTGS)
detector. Some amorphous solid form FT-IR spectra were acquired
using Nexus 670.RTM., equipped in the same way as described for
Magna-IR 860.RTM. above. Wavelength verification for Magna-IR
860.RTM. and Nexus 670.RTM. were performed using NIST SRM 1921b
(polystyrene). An attenuated total reflectance (ATR) accessory
(Thunderdome.TM., Thermo Spectra-Tech), with a germanium (Ge)
crystal was used for data acquisition. A background data set was
acquired with a clean Ge crystal. A Log 1/R (R=reflectance)
spectrum was obtained by taking a ratio of these two data sets
against each other.
[0432] In another embodiment, FT-IR spectra were acquired on a
Nexus 670.RTM. Fourier transform infrared spectrophotometer (Thermo
Nicolet) equipped with an Ever-Glo mid/far IR source, a potassium
bromide (KBr) beamsplitter, and a deuterated triglycine sulfate
(DTGS) detector. Wavelength verification was performed using NIST
SRM 1921b (polystyrene). An attenuated total reflectance (ATR)
accessory (Thunderdome.TM., Thermo Spectra-Tech), with a germanium
(Ge) crystal was used for data acquisition. Each spectrum
represents 512 co-added scans collected at a spectral resolution of
2 cm.sup.-1. A background data set was acquired with a clean Ge
crystal. A Log 1/R(R=reflectance) spectrum was obtained by taking a
ratio of these two data sets against each other.
[0433] Peak positions were determined using standard spectral
software. Peak position variabilities are given to within .+-.2
cm.sup.-1, based on the observed sharpness of the peaks picked and
acquisition of data using a 1 cm.sup.-1 data point spacing (2
cm.sup.-1 resolution). The accuracy and precision associated with
any particular measurement reported herein has not been
determined.
[0434] Nuclear Magnetic Resonance (NMR)
[0435] Solution proton nuclear magnetic resonance spectra
(.sup.1H-NMR) were acquired with a Varian .sub.UNITYINOVA-400
spectrometer. Samples were prepared as solutions in deuterated
dimethylsulfoxide (DMSO-d.sub.6).
[0436] Raman Spectroscopy
[0437] Raman spectra were acquired on a FT-Raman 960 spectrometer
(Thermo Nicolet) equipped with a germanium (Ge) detector.
Wavelength verification was performed using sulfur and cyclohexane.
Each sample was prepared for analysis by placing the sample into a
13 mm diameter gold-coated cup and leveling the material. Each
spectrum represents 512 co-added scans collected at a spectral
resolution of 2 cm.sup.-1.
Example 1
General Preparation of Compound I
[0438] Various preparations and purifications of Compound I were
described in U.S. Pat. No. 4,977,138, issued Dec. 11, 1990 and
International PCT Application WO02/20817, filed Aug. 22, 2001, each
of which is incorporated herein by reference in their
entireties.
[0439] In some embodiments, producing, purifying and/or storing
Compound I at an apparent pH less than approximately 6.5 and/or at
an apparent pH of about less than approximately 6.0 has been found
to prevent the formation of dimerized, oligomerized or polymerized
Compound I, as described in US Patent Application Publication No.
US 20090186382, filed Dec. 28, 2007, which is incorporated herein
by reference. In one embodiment, one or more of the purification
steps are performed at an apparent pH less than 6.5. In another
embodiment, one or more of the purification steps are performed at
an apparent pH less than 6.0. In certain embodiments, one or more
purification steps are performed at an apparent pH ranging from 4.0
to 6.0. In certain embodiments, all of the purification steps are
carried out at an apparent pH ranging from approximately 4.0 to
approximately 6.0. In order to prevent the formation of undesired
contaminants, the apparent pH of a solution containing Compound I
is not allowed to reach an apparent pH above approximately 7.0, or
more preferably above approximately 6.0. The apparent pH of all
purification processes is preferably monitored and subsequently
adjusted, if need be, to an apparent pH below approximately 6.0. In
certain embodiments, it is maintained within the apparent pH range
of approximately 4.0 to approximately 6.0. The control of apparent
pH in purification steps towards the end of the process or steps
using aqueous solutions have been found to be particularly useful
in diminishing or eliminating the formation of undesired
contaminants. Any acid or buffer may be used to control pH. In
certain embodiments, an organic acid such as acetic acid or formic
acid is used to control pH in one of more of the purification
steps. In certain embodiments, an inorganic acid such as phosphoric
acid or hydrochloric acid is used.
[0440] Any procedure for purifying Compound I, whether from
fermentation, semi-synthesis, or total synthesis, can be modified
based on the present disclosure to prevent the formation of
undesired side products by monitoring apparent pH and reducing the
apparent pH, if necessary.
[0441] Exemplary data for Compound I in the form of .sup.1H-NMR in
depicted in FIG. 1(a) and a molecular structure of Compound I is
depicted in FIG. 1(b). The .sup.1H-NMR depicted in FIG. 1(a)
displays chemical shifts and integration consistent with Compound
I, has residual acetone present (at approximately 2.08 ppm) and the
water peak (occurring at 3.33 ppm) has been truncated.
Example 2
Preparation and Characterization of Form C and/or Compositions
Containing Form C
[0442] Compound I Form C was prepared via serial seeding of
saturated solutions of romidepsin Form A with solids containing
Compound I Form C, with the resulting X-ray powder diffraction
(XRPD) pattern of each generated material exhibiting more
reflections present in the Compound I Form C pattern than the last.
The series included three experiments: (a) First Seeding Procedure;
(b) Second Seeding Procedure; and (c) Final Preparation of Compound
I Form C. An XRPD pattern collected for final product Compound I
Form C does not appear to exhibit reflections from Compound I Form
A. The experiments were conducted as follows:
(a) First Seeding Procedure-Preparation of Portion 1 and Portion 2
Samples
[0443] Compound I Form A (103 mg, 0.2 mmol) and acetone (5 mL) were
charged to a glass vial and vortexed for approximately 1 minute,
generating a clear solution. The vial was immersed in a -5.degree.
C. bath, as measured by a NIST-traceable thermometer. The sample
was left in the bath unstirred for approximately 26 hours,
producing a slight precipitate. The precipitate was removed via
filtration through a 0.2 .mu.m nylon filter disc to a clean glass
vial, resulting in a clear solution.
[0444] While the solution was still cold, cold water (15 mL) was
added, without agitation. The solution remained clear and cold,
with no visible precipitate, and the sample was returned to the
-5.degree. C. bath. The sample was left in the bath unstirred for
approximately 5 days. After the first night, the vial was gently
shaken before returning to the bath, resulting in no apparent
change in the sample. After the 5 days, solids were observed on the
bottom of the vial.
[0445] The supernatant was decanted off and the solids were gently
crushed, producing slurry. A portion of the slurry ("portion 1")
was centrifuged in small aliquots at ambient temperature in a 1.0
mm glass capillary, for analysis by X-ray powder diffraction.
Centrifugation was done in increments of several seconds to
approximately 10 minutes, with total centrifugation more than 20
minutes. X-ray powder diffraction analysis showed evidence of
reflections present in Compound I Form A and Compound I Form C,
suggesting the recovered solids were a mixture of phases.
[0446] A second portion ("portion 2") was left open in a vial at
ambient temperature to partially dry the solids while a capillary
was being prepared. Both capillary and bulk samples were stored in
a refrigerator before and after the analysis. The capillary sample
was analyzed shortly after preparation and the bulk sample was used
as seed on the day of its isolation.
(b) Second Seeding Procedure
[0447] Compound I Form A (1.03 g, 1.9 mmol) and acetone (37 mL)
were charged to a glass vial and vortexed briefly, generating a
clear solution. The vial was immersed in a -5.degree. C. bath, as
measured by a NIST-traceable thermometer. The sample was left in
the bath unstirred for approximately 1.5 hours, producing a
relatively small amount of precipitate. The precipitate was removed
via cold filtration through a 0.2 .mu.m nylon filter disc to a
clean glass round bottom flask.
[0448] The flask contained solids from "portion 2" (the amount
approximately that of a spatula tip) as seed, to encourage
formation of Compound I Form C. No precipitate was apparent but the
seed solids remained. Additional solids from "portion 2" (the
amount approximately that of a spatula tip) were added. No
precipitate was apparent but the seed solids remained.
[0449] Cold water (111 mL) was poured in all at once. After a few
minutes, there appeared to be a slight precipitate. The flask was
immersed in the -5.degree. C. bath overnight. Only a slight
precipitate was observed. The sample was briefly shaken and
returned to the bath for approximately 2 hours, resulting in
substantial precipitate. Solids were gently scraped down from the
flask walls.
[0450] Targeting solids on the flask bottom, "portion 3" was
centrifuged in small aliquots at ambient temperature in a 1.0 mm
glass capillary, for analysis by X-ray powder diffraction.
Centrifugation was done in increments of several seconds. X-ray
powder diffraction analysis showed the recovered solids to consist
mainly of Compound I Form C, and indications of presence of
Compound I Form A.
[0451] The sample was stored in a refrigerator before and after the
analysis but was not analyzed until the next day. Analysis occurred
shortly after removal from the refrigerator ("portion 4"). "Portion
4" was left sealed at ambient temperature while the capillary was
being prepared, returned to the -5.degree. C. bath for
approximately 3 days and then stored in a refrigerator briefly
before being used as seed.
(c) Final Preparation of Form C
[0452] Compound I, Form A (1.09 g, 2.0 mmol) and acetone (39 mL)
were charged to a glass vial, vortexed and briefly bath sonicated,
generating a clear solution. The vial was immersed in a -5.degree.
C. bath, as measured by a NIST-traceable thermometer. The sample
was left in the bath unstirred for approximately 2.5 hours,
producing a relatively small amount of precipitate. The solid
precipitate was removed via cold filtration through a 0.2 .mu.m
nylon filter disc to a clean glass round bottom flask, resulting in
a clear solution.
[0453] The flask was seeded with slurry from "portion 4"
(approximately 1 mL), to encourage formation of Compound I Form C.
No precipitate was apparent but the seed solids remained.
[0454] Cold water (400 mL) was poured in all at once. There
appeared to be a very slight precipitate and the seed solids
persisted. Additional slurry from "portion 4" (approximately 1 mL)
was added, with the same result, even after briefly swirling the
flask. The flask was immersed in the -5.degree. C. bath for
approximately 3 days, freezing the solvent.
[0455] After leaving the flask in the refrigerator overnight, the
solvent melted but solids remained. The flask was swirled and the
sample was centrifuged in 50 mL aliquots at ambient temperature in
two plastic centrifuge tubes simultaneously. Centrifugation was
done in increments of approximately 5 to 10 minutes, minimizing
warming of the sample and ensuring clear supernatant was generated.
The resulting supernatants were decanted off to a clean HDPE
bottle. The final flask aliquot included rinsing once with liquid
from the bottle (several mL) to recover additional solids from the
flask walls. These solids did not appear to be new precipitate but
collected on the walls when pouring sample from the flask into the
tubes. Little residual sample was present in the flask and this
residual was not recovered. After the flask sample was exhausted,
the centrifuged samples were recovered to one tube, rinsing the
other tube twice with liquid from the bottle (approximately 15 mL
per rinse). The final supernatant was left with the solids. The
tubes, flask and bottle were stored in a refrigerator when not
being manipulated. This included overnight storage since the
centrifugation was completed over two days and solids were not
isolated until the day after centrifugation.
[0456] Targeting the solids on the tube bottom, a portion of final
product Compound I Form C was centrifuged in small aliquots at
ambient temperature in a 1.0 mm glass capillary, for immediate
analysis by X-ray powder diffraction. Centrifugation was done in
increments of several seconds.
[0457] Exemplary data for Compound I Form C in the form of X-ray
diffraction patterns (XRPD), differential scanning calorimeter
thermograms (DSC), thermogravimetric analysis thermograms (TGA),
infrared spectrums (FT-IR), and single crystal structure data
(e.g., ORTEP drawings, packing diagrams, positional parameters,
bond distances and bond angles) are depicted in FIGS. 1(c) through
1(q), supra. A summary of exemplary data presented in FIGS. 1(c)
through 1(q) is as follows.
[0458] Form C is a crystalline non-stoichiometric hydrate of
Compound I, as determined from single crystal data (see FIGS. 1(i)
through 1(q)). The crystal structure contains one fully occupied
water molecule and a second water site with a refined occupancy of
approximately 73%. The characterization of Compound I, Form C is
summarized in Table 3. TABLE-US-00003 TABLE 3 Characterization of
Compound I Form C Analysis Result Figure References XRPD Form C
1(c), 1(d), 1(i), 1(j) DSC 96.6.degree. C. (broad endo, min) 1(e)
139.6.degree. C. (broad endo, min) 177.2.degree. C. (broad exo,
max) 257.1.degree. C. (endo, min) followed by decomp. TGA 5.3 wt %
loss to 103.degree. C. 1(f) FT-IR reference spectrum 1(g), 1(h)
Single Crystal Form C 1(i)-1(q) X-ray (non-stoichiometric hydrate,
.about.1.7 (non-GMP) waters)
[0459] A comparison of the XRPD pattern final product for Compound
I Form C (see FIGS. 1(c) and 1(d)); and the calculated pattern
collected at subambient temperature (see FIGS. 1(i) and 1(j)) from
the structure of Compound I, Form C, suggests that the XRPD
patterns represent a single phase and that none of the observed
reflections are attributed to Compound I Form A. The single crystal
data were collected at cryogenic temperature, so minor, uneven
shifting of 2.theta. peak positions due to temperature effects was
observed.
[0460] The differential scanning calorimetry (DSC) thermogram for
Compound I, Form C (see FIG. 1(e)) exhibits broad endothermic
events at approximately 97.degree. C. and 140.degree. C. (min),
ascribed to loss of solvent, based on the 5.3% weight loss observed
in the thermogravimetric analysis (TGA) thermogram (see FIG. 1(f)).
This weight loss corresponds to approximately 1.7 moles of water,
which is similar to the result obtained from the single crystal
data. However, the loss may include acetone, since the sample was
crystallized from an acetone/water mixture. The DSC thermogram also
exhibits an endotherm at approximately 257.degree. C. (min) (see
FIG. 1(e)). This endotherm is believed to correspond to the melt of
Compound I Form A and apparent desolvation of solids. A minor
exothermic event was observed at approximately 177.degree. C. (see
FIG. 1(e)). Based on the apparent melting temperature, this appears
to represent recrystallization to Compound I Form A. The final
weight loss from TGA suggests that decomposition is concurrent with
the apparent melt observed by DSC, as it was for Compound I Form A.
Solids were air-dried in a laboratory fume hood at ambient
temperature for approximately 2.5 hours to remove residual solvent
before the analyses, in order to obtain representative thermal data
for Compound I, Form C.
[0461] One skilled in the art will be able to readily ascertain
from the data presented that Form C may be isostructural with the
methanol solvate reported in Shigematsu et al., The Journal of
Antibiotics, Vol. 47, No. 3, "FR901228, A Novel Antitumor Bicyclic
Depsipeptide Produced by Chromobacterium violaceum No. 968, pp.
311-314 (March 1994).
Example 3
Preparation and Characterization of Form D and/or Compositions
Containing Compound I Form D
[0462] Compound I Form A (1.20 g, 2.2 mmol) and acetone (38 mL)
were charged to a glass Erlenmeyer flask, shaken, swirled, and bath
sonicated for a few minutes, dissolving most of the solids.
Undissolved solids were removed via filtration through a 0.2 .mu.m
nylon filter disc to a clean glass Erlenmeyer flask, resulting in a
clear solution. Hexanes (152 mL) was added, which precipitated
solids immediately, without agitation. The flask was left in a
freezer overnight, allowing the solids to settle to the bottom of
the flask. The clear supernatant was decanted off and aliquots of
solid were removed for immediate X-ray powder diffraction analysis.
The analysis showed that the solids consisted of Compound I Form D.
Solids were recovered from the analysis sample for thermal and
spectroscopic analyses. Unused material was stored in the
freezer.
[0463] Exemplary data for Compound I Form D in the form of an XRPD,
a DSC, a TGA and an FT-IR are depicted in FIGS. 2(a) through 2(f),
supra. A summary of exemplary data presented in FIGS. 2(a) through
2(f) is as follows. As described in Example 8, one skilled in the
art will be able to readily ascertain from the data presented
herein that Compound I Form D may be isostructural with MEK solvate
(Compound I Form J).
[0464] Form D is an unstable crystalline acetone solvate of
Compound I that converts to Form A under ambient conditions. A
crystal prepared from cold acetone solution was indexed. The
indexing solution was determined to be an orthorhombic unit cell
with the following cell parameters and calculated volume: a=9.093,
b=15.581, c=23.141 .ANG., V=3278.57(9) .ANG..sup.3. The formula
weight was determined to be 598.81 g/mol. The cell parameters are
similar to the cell obtained from the Compound I Form J crystal
structure. The similarity between the two unit cells and XRPD
patterns of Compound I Form D and Compound I Form J suggest the two
samples are related crystal forms. Since Compound I Form J was
determined to be a mono methyl ethyl ketone solvate of Compound I,
it is likely that Form D is also a mono solvate of Compound I.
Characterization of Compound I Form D is summarized in Table 4.
TABLE-US-00004 TABLE 4 Characterization of Compound I Form D
Analysis Result Figure References XRPD Form D 2(a), 2(b) DSC
91.4.degree. C. (exo, max) 2(c) 260.6.degree. C. (endo, max)
followed by decomp TGA 10.9 wt % loss to 63.degree. C. 2(d) FT-IR
reference spectrum 2(e), 2(f)
[0465] An experimental Compound I Form D pattern is provided in
FIG. 2(a) with an accompanying line list in FIG. 2(b). The pattern
is consistent with a pattern for Compound I Form D and similar to a
pattern for Compound I Form J as observed in the XRPD overlay
presented in FIG. 6(a). This high resolution pattern of FIG. 2(a)
was collected after storage of the material in a freezer and
displayed presence of Compound I Form D and Compound I Form A,
suggesting a mixture of phases, so the pattern generated from the
material after storage in the freezer was used to generate a
corresponding peak list for Compound I Form D (see FIG. 2(b)).
[0466] An FT-IR spectrum of Compound I Form D and accompanying peak
list is provided as FIG. 2(e) and FIG. 2(f). To avoid the potential
for form conversion from solvent loss, the solids for the FT-IR
data were collected immediately upon removal from the freezer.
[0467] The TGA thermogram for Compound I Form D (see FIG. 2(d))
exhibits a weight loss of approximately 10.9% and the DSC
thermogram (see FIG. 2(c)) exhibits a small exothermic event at
approximately 91.degree. C. These events appear to be mainly
related to desolvation and recrystallization to Compound I Form A,
respectively, based on the instability of Compound I Form D and
tendency for conversion to Compound I Form A. The weight loss
observed by TGA corresponds to slightly more than a mole of
acetone. To avoid the potential for Form conversion from solvent
loss, the solids were analyzed immediately upon removal from the
freezer. Since no weight loss was observed prior to the start of
the analysis, the weight loss observed is attributed to solvent
loss from the crystal lattice, also suggesting Compound I Form D is
an acetone solvate. The DSC thermogram also exhibits an endotherm
at approximately 261.degree. C. (min). The endotherm is believed to
correspond to a melt of Compound I Form A and apparent desolvation
of the solids. Final weight loss from TGA suggests that
decomposition is concurrent with apparent melt observed by DSC, as
it was for Compound I Form A.
Example 4
Preparation and Characterization of Form E and/or Compositions
Containing Form E
[0468] Compound I Form A (2.75 g, 5.1 mmol) and solution containing
a mixture of t-butanol and water [60:40 (v/v)] (31 mL) were charged
to a 50 mL Erlenmeyer flask. Solids remained. The sample was
stirred overnight at ambient temperature and the resulting solids
were collected by vacuum filtration. The recovered solids were
transferred to weigh paper and dried under ambient conditions for
approximately 2 hours. The dried solids were transferred to a glass
vial and stored under ambient conditions. X-ray powder diffraction
analysis showed the solids to consist of Compound I Form E. Solid
recovery was 2.79 g (89%).
[0469] Exemplary data for Compound I Form E in the form of an XRPD,
a DSC, a TGA an FT-IR, a Raman spectrum and single crystal
structure data (e.g., ORTEP drawings, packing diagrams, positional
parameters, bond distances and bond angles) are depicted in FIGS.
3(a) through 3(p), supra. A summary of exemplary data presented in
FIGS. 3(a) through 3(p) is as follows. One skilled in the art will
be able to readily ascertain from the data presented herein that
Compound I, Form E may be isostructural with Compound I, Form H
(see Example 6).
[0470] Compound I Form E is a crystalline mono-tert-butanol solvate
of Compound I, as determined from single crystal data (see FIGS.
3(h) through 3(p)). The characterization of Compound I Form E is
summarized in Table 5. TABLE-US-00005 TABLE 5 Characterization of
Compound I Form E Analysis Result Figure References XRPD Form E
3(a), 3(b), 3(h), 3(i) DSC 158.1.degree. C. (broad endo, min) 3(c)
255.3.degree. C. (endo, min) followed by apparent decomp. TGA 10.9
wt % loss to 200.degree. C. 3(d) Single Crystal X-ray Form E
3(h)-3(p) (non-GMP) (mono tert-butanol solvate) FT-IR reference
spectrum 3(e), 3(f) Raman reference spectrum 3(g)
[0471] A comparison of the experimental (see FIGS. 3(a) and 3(b))
and calculated (see FIGS. 3(h) and 3(i)) XRPD patterns and
accompanying peak lists of Compound I Form E are provided. The
single crystal data were collected at cryogenic temperature, so
minor uneven shifting of 2.theta. peak positions due to temperature
effects was observed. FT-IR with an accompanying peak list (see
FIGS. 3(e) and 3(f)) and FT-Raman spectra (see FIG. 3(g)) of
Compound I Form E are provided.
[0472] The DSC thermogram for Compound I Form E (see FIG. 3(c))
exhibits an endothermic event at approximately 158.degree. C.
(min), ascribed to desolvation, based on the TGA thermogram (see
FIG. 3(d)), and indicated by hot stage microscopy as partial loss
of birefringence at approximately 157.degree. C. Hot stage
microscopy showed the specimen to melt at approximately 243.degree.
C., as indicated by an endotherm in the DSC at approximately
255.degree. C. (min). Based on the melting temperature, it is
believed that the sample desolvated to Compound I Form A prior to
melt. The final weight loss from TGA suggests that decomposition is
concurrent with the melt observed by hot stage microscopy, as it
was for Compound I Form A.
Example 5
Preparation and Characterization of Form F and/or Compositions
Containing Form F
[0473] In one embodiment, compound I Form A (105.9 mg, 0.2 mmol)
and chloroform (4 mL) were charged to a glass vial and bath
conicated for approximately 1 minute, generating a clear solution,
with a few undissolved particles. Additional Compound I Form A
(281.7 mg, 0.5 mmol) was added. The resulting slurry was agitated
on a rotating wheel under ambient conditions for .about.12 hours.
The sample was removed from the wheel and the remaining solids
floated to the top of the solution. The solution was drawn off with
a pipet and a portion was filtered through a 0.2 .mu.m nylon filter
disc to a clean glass vial. The vial was left open to evaporate in
an ambient laboratory fume hood. The recovered solids were analyzed
by X-ray powder diffraction (XRPD) and consist of Compound I Form
F.
[0474] In another embodiment, Compound I Form A (740 mg, 1.4 mmol)
and chloroform (30 mL) were charged to a glass vial and bath
sonicated for a few minutes, producing a clear solution. Compound I
Form A (750 mg, 1.4 mmol) was added to ensure excess solids for
slurry. The resulting sample was agitated for approximately 4 days
on a rotating wheel. Remaining solids floated to the top upon
standing, generating a clear solution at the bottom of the vial.
Approximately 1/4 of the solution was drawn off to a clean glass
vial and solids were precipitated via slow evaporation of the
solvent (vial covered with perforated aluminum foil) in a
laboratory fume hood. After approximately 2 days, no solvent was
apparent. The solids consisting of Compound I Form F were left in a
sealed vial at ambient temperature for approximately 1 day, and
then stored in a freezer.
[0475] Exemplary data for Compound I Form F in the form of an XRPD
and an FT-IR are depicted in FIGS. 9(a) through 9(l), supra.
[0476] Compound I Form F is a crystalline chloroform solvate of
Compound I. The characterization of Compound I Form F is summarized
in Table 6. TABLE-US-00006 TABLE 6 Characterization of Compound I
Form F Analysis Result Figure References XRPD Form F 9(a)-9(f),
9(h), 9(i) DSC 83.6.degree. C. (minor endo) 9(j) 97.3.degree. C.
(endo) 256.4.degree. C. (endo) FT-IR reference spectrum 9(g), 9(h)
TGA Form F 9(k)
Example 6
Preparation and Characterization of Form H and/or Compositions
Containing Form H
[0477] Compound I Form A (500 mg, 0.9 mmol) and chloroform (5 mL)
were charged to a glass vial and bath sonicated for approximately
20 minutes, and generated a clear solution. Gentle shaking produced
solid precipitate. The resulting mixture was agitated on a rotating
wheel overnight at ambient temperature. Solids were floating on top
of the liquid, so the liquid was drawn off with a pipette.
Approximately 1/3 of the solids were dried via rotary evaporation
over approximately 15 minutes, utilizing a water bath. The
temperature range of the bath during evaporation was 57 to
64.degree. C., as measured by a NIST-traceable thermometer. The
recovered solids were stored under ambient conditions until
analyzed by XRPD. The analysis showed the solids to consist of
Compound I Form H. After XRPD analysis, the sample was stored in a
freezer with desiccant. Solid recovery was 178 mg.
[0478] Exemplary data for Compound I Form H in the form of an XRPD,
a DSC, a TGA, and an FT-IR are depicted in FIGS. 4(a) through 4(f),
supra. A summary of exemplary data presented in FIGS. 4(a) through
4(f) is as follows. One skilled in the art will be able to readily
ascertain from the data presented herein that Compound I, Form H
may be isostructural with Compound I, Form E (see Example 4).
[0479] Compound I Form H is a crystalline chloroform solvate of
Compound I. Characterization of Compound I Form H is summarized in
Table 7. TABLE-US-00007 TABLE 7 Characterization of Compound I Form
H Figure Analysis Result References XRPD Form H 4(a), 4(b) DSC
96.3.degree. C. (broad endo, min) 4(c) 256.7.degree. C. (endo, min)
followed by apparent decomp TGA 10.1 wt % loss to 150.degree. C.
4(d) FT-IR reference spectrum 4(e), 4(f)
[0480] A high resolution XRPD pattern of Compound I Form H and an
accompanying line list is provided in FIGS. 4(a) and 4(b). An FT-IR
spectrum of Compound I Form H and an accompanying line list is
provided in FIGS. 4(e) and 4(f).
[0481] Examination of Compound I Form H XRPD pattern displays
reflections from both Compound I Form H and Compound I Form A
patterns, suggesting the specimen examined was a mixture. The XRPD
pattern generated using Compound I Form H appears to be consistent
with the Form H portion of the pattern.
[0482] The DSC thermogram for Compound I Form H (see FIG. 4(c))
exhibits an endothermic event at approximately 96.degree. C. (min).
This event appears to be mainly related to desolvation, based on
the weight loss of approximately 10.1% observed in the TGA
thermogram for Compound I Form H (see FIG. 4(d)). This corresponds
to more than 0.5 moles of chloroform. To avoid the potential for
Form conversion from solvent loss, the solids were analyzed
immediately upon removal from the freezer. Since no weight loss was
observed prior to the start of the analysis, the weight loss
observed is attributed to solvent loss from the crystal lattice,
suggesting Compound I Form H is a solvate. The DSC thermogram (see
FIG. 4(c)) also exhibits an endotherm at approximately 256.degree.
C. (min). The endotherm is believed to correspond to the melt of
Compound I Form A and apparent desolvation of solids. Final weight
loss from TGA (see FIG. 4(d)) suggests that decomposition is
concurrent with the apparent melt observed by DSC, as it was for
Compound I Form A.
Example 7
Preparation and Characterization of Form I and/or Compositions
Containing Form I
[0483] In one embodiment, compound I Form A (500 mg, 0.9 mmol) and
chloroform (5 mL) were charged to a glass vial and bath sonicated
for approximately 20 minutes, and generated a clear solution.
Gentle shaking produced solid precipitate. The resulting mixture
was agitated on a rotating wheel at ambient temperature for less
than an hour and a portion of the solids was recovered for X-ray
powder diffraction (XRPD) via filtration with a 0.22 .mu.m nylon
filter in a Swinnex Millipore filter body. The filter cake was not
washed and the solids appeared dry upon recovery. The solids were
gently crushed prior to XRPD analysis. The analysis showed presence
of Compound I Form I and Compound I Form H, suggesting the
recovered solids were a mixture of phases.
[0484] The remaining sample was returned to the wheel to slurry
overnight. The solids were floating on top of the liquid, so the
liquid was drawn off with a pipette. The remaining solids were
stored in a sealed vial over desiccant in a freezer. An attempt to
collect a high resolution XRPD data indicated the solids converted
to Compound I Form H prior to analysis.
[0485] In another embodiment, compound I Form A, (517 mg, 1.0 mmol)
and chloroform (5 mL) were charged to a glass vial and bath
sonicated for approximately 20 minutes, generating a clear
solution, with a trace of solid. The resulting mixture was agitated
on a rotating wheel for approximately 1 month at ambient
temperature. The solids were stored in the mother liquor in a
refrigerator. A portion of the solids ("portion 1") was recovered
for X-ray powder diffraction (XRPD) via filtration with a 0.22
.mu.m nylon filter in a Swinnex Millipore filter body. The filter
cake was not washed and the solids appeared dry upon recovery. The
solids were gently crushed prior to XRPD analysis. The analysis
showed that the solids consisted of Compound I Form I. Another
portion ("portion 2") of the solids was recovered for solution
proton nuclear magnetic resonance spectroscopy (.sup.1H-NMR) by
pipetting to a clean glass vial and decanting off the liquid. The
XRPD and .sup.1H-NMR samples were stored at ambient temperature in
sealed vials prior to analysis.
[0486] In yet, another embodiment, Compound I Form A (.about.180
mg, 0.3 mmol) was charged to a glass vial. The vial was left
uncapped in a glass jar containing chloroform (.about.10 mL), for
vapor stress of the solids. The solids were stressed for
approximately 7 days before transfer to a freezer, where they
remained under chloroform vapor.
[0487] Exemplary data for Compound I Form I in the form of XRPDs, a
DSC, a TGA, an FT-IR, and single crystal structure data (e.g.,
ORTEP drawings, packing diagrams, positional parameters, bond
distances and bond angles) are depicted in FIGS. 5(a) through 5(y),
supra. A summary of exemplary data presented in FIGS. 5(a) through
5(y) is as follows.
[0488] Compound I Form I is a crystalline chloroform solvate of
Compound I that converts to Form H under ambient conditions. The
structure was solved for a crystal prepared from chloroform slurry.
Based on Compound I Form I XRPD pattern from a sub sample of the
bulk solids, it is believed the crystal was of Compound I Form I.
The single crystal data (see FIGS. 5(g) through 5(o)) indicate
chloroform solvate, the structure consisting of layers of Compound
I molecules separated by residual electron density believed to be
free chloroform and pockets containing refined chloroform
molecules.
[0489] The experimental data for Compound I Form I is provided in
FIGS. 5(a) to 5(y). Characterization of Compound I Form I is
summarized in Table 8. TABLE-US-00008 TABLE 8 Characterization of
Compound I Form I Figure Analysis Result References XRPD Form I
5(a), 5(b), 5(p)-5(r) DSC 73.8.degree. C. (broad endo, min) 5(c)
100.2.degree. C. (endo, min) 257.8.degree. C. (endo, min) followed
by decomp TGA 33.0 wt % loss 19 to 5(d), 5(x) 102.degree. C. FT-IR
reference spectrum 5(e), 5(f), 5(s), 5(t) Single Crystal Form I
5(g)-5(o) X-ray (chloroform solvate) (non-GMP)
[0490] The initial precipitate and the isolated solids from slurry
in chloroform both exhibited an XRPD pattern consistent with
Compound I Form I. The high resolution XRPD pattern collected on a
sample of bulk solids appears to be Compound I Form H. Because
Compound I Form H was prepared by drying solids exhibiting XRPD
pattern for Compound I Form I, it is possible that the sample
converted to Compound I Form I during data collection. In contrast,
the initial XRPD data for Compound I Form I solids were collected
on solids in a glass capillary, thus retarding the drying of the
solids.
[0491] The DSC thermogram for Compound I Form I (see FIG. 5(c))
exhibits a broad endothermic event at approximately 74.degree. C.
and an endothermic event at approximately 100.degree. C. (min).
These events appear to be mainly related to desolvation, based on
the weight loss of approximately 33% from 19 to 102.degree. C.
observed in the TGA thermogram (see FIG. 5(d)). This corresponds to
more than 2 moles of chloroform. The TGA thermogram also exhibits
weight loss prior to 19.degree. C., which is likely due to residual
chloroform; however, there appears to be a clear transition into
the main weight loss. The DSC thermogram (see FIG. 5(c)) also
exhibits an endotherm at approximately 258.degree. C. (min). The
endotherm is believed to correspond to the melt of Compound I Form
A and the apparent desolvation of the solids. The final weight loss
from TGA suggests that decomposition is concurrent with the
apparent melt observed by DSC, as it was for Compound I Form A. In
an attempt to avoid the potential for form conversion from solvent
loss, the solids were analyzed immediately upon removal from the
freezer.
[0492] An FT-IR spectrum of Compound I Form I (see FIGS. 5(e) and
5(s)) is provided. To avoid potential for Form conversion from
solvent loss, solids were analyzed immediately upon removal from
the freezer.
Example 8
Preparation and Characterization of Form J and/or Compositions
Containing Form J
[0493] In one embodiment, Compound I (56.4 mg) Form J was dissolved
in methyl ethyl ketone (4.5 mL). The solution was filtered through
a 0.2-.mu.m nylon filter. The sample was placed in a vial capped
with perforated aluminum foil (single pinhole) in a laboratory fume
hood and allowed to evaporate to dryness under ambient conditions.
The sample was stored under ambient conditions until indexed by
single crystal X-ray. Crystallization may be performed using
methods known to one of skill in the art.
[0494] In another embodiment, Compound I Form A (Sandoz lot
49800203, 1.03 g, 1.9 mmol) and methyl ethyl ketone (80 mL) were
charged to an Erlenmeyer flask, briefly swirled and bath sonicated
for a few minutes, producing a clear solution. Approximately half
of the solution was filtered through a 0.2 .mu.m nylon filter to a
clean glass vial. The vial was capped and placed into a freezer, in
order to precipitate solids from the solution. After approximately
5 days, the sample was removed from the freezer and the
precipitated solids were isolated by decanting off the clear
supernatant. The solids were stored wet with solvent in a
freezer.
[0495] Exemplary data for Compound I Form J in the form of single
crystal structure data (e.g., ORTEP drawings, packing diagrams,
positional parameters, bond distances and bond angles) are depicted
in FIGS. 6(a) through 6(j), supra. A summary of exemplary data
presented in FIGS. 6(a) through 6(j) is as follows.
[0496] The single crystal structure of Compound I Form J confirmed
the molecular structure and the contents of the unit cell. The
sample crystallized in the chiral orthorhombic space group
P2.sub.12.sub.12.sub.1 and was determined to be a methyl ethyl
ketone (MEK) solvate of Compound I. The structure of Compound I
Form J (MEK solvate) consists of layers of Compound I molecules
hydrogen bonded to neighboring Compound I molecule running
perpendicular to the crystallographic c axis. The reflections in
the experimental pattern of the acetone solvate (Compound I Form D)
are represented in the calculated XRPD pattern of the MEK solvate
(Compound I Form J), suggesting that the two forms may be
isostructural (see Example 3).
[0497] Compound I Form J is a crystalline methyl ethyl ketone
solvate of Compound I. The experimental data for Compound I Form J
is provided in FIGS. 6(a) to 6(s). The characterization of Compound
I Form J is summarized in Table 9. TABLE-US-00009 TABLE 9
Characterization of Compound I Form J Analysis Result Figure
References XRPD Form J 6(a) 6(m) DSC 130.3.degree. C. (endo) 6(q)
260.0.degree. C. (endo) FT-IR reference spectrum 6(n), 6(o) TGA
Form J 6(r)
Example 9
Preparation and Characterization of Amorphous Compound I and/or
Compositions Containing Amorphous Compound I
[0498] Preparation from 9:1 Dioxane/Water
[0499] Compound I (1.0652 g) was dissolved in 9:1 dioxane/water (10
mL). The solution was filtered through a 0.2-.mu.m nylon filter,
and frozen in a 300 mL round-bottom flask immersed in a bath of dry
ice and isopropanol. The flask containing the frozen sample was
attached to a lyophilizer and dried for approximately 4 days. After
drying, the solids were isolated and stored in the freezer over
desiccant until used.
[0500] Preparation by a Rotary Evaporator
[0501] Compound I (133.4 mg) was dissolved in dichloromethane (1.5
mL). The solution was filtered through a 0.2-.mu.m nylon filter.
The sample vial was placed on the rotary evaporator and immersed in
a water bath at ambient temperature. The solvent was rapidly
evaporated to dryness under vacuum. The solids were then stored in
the freezer over desiccant until used.
[0502] Preparation by Fast Evaporation
[0503] Compound I (24.7 mg) was dissolved in a binary solvent
mixture of water (1.5 mL) and dichloromethane (0.5 mL). The
solution was filtered through a 0.2-.mu.m nylon filter. The sample
was placed uncapped in a laboratory fume hood and allowed to
evaporate to dryness under ambient conditions. The solids were
stored under ambient conditions until used.
[0504] Exemplary data for amorphous Compound I in the form of
XRPD's, modulated DSC thermogram, TGA, FT-IR, FT-Raman spectroscopy
and .sup.1HNMR are depicted in FIGS. 7(a) through 7(f), supra. A
summary of exemplary data (e.g., a summary of XRPD results in Table
10) are presented for amorphous Compound I below.
[0505] A high resolution XRPD pattern of amorphous Compound I is
provided in FIG. 7(a). The modulated DSC thermogram for amorphous
Compound I (see FIG. 7(b)) exhibits a glass transition temperature
at approximately 91.degree. C. Weight loss of approximately 3.5%
was observed in the TGA thermogram (see FIG. 7(c)). An FT-IR
spectrum of amorphous Compound I (see FIGS. 7(d) and 7(e)) and an
FT-Raman spectrum (see FIG. 7(f)) are also provided. TABLE-US-00010
TABLE 10 Preparation of X-ray Amorphous Compound I and/or
Compositions Containing Amorphous Compound I Conditions
Description.sup.a XRPD Result rotary evaporation in dichloromethane
white solids, chunk, no B x-ray amorphous + (concentration: 268
mg/mL) Form A rotary evaporation in dichloromethane white solids,
chunk, no B x-ray amorphous (concentration: 89 mg/mL) fast
evaporation (FE) in dichloromethane white solids, irregular, B/E
not analyzed (concentration: 102 mg/mL) freeze drying in
dioxane/water (9:1), 2 white solids, chunk, no B x-ray amorphous
days freeze drying in dioxane/water (9:1), 2 white solids, chunk,
partial B x-ray amorphous + days, .about.2 g scale-up Form A + Form
K + peaks freeze drying in dioxane/water (9:1), 2 white solids,
chunk, no B x-ray amorphous + days, .about.2 g scale-up Form K +
peaks freeze drying in dioxane/water (9:1), 4 white solids, chunk,
no B x-ray amorphous days, .about.1 g scale-up freeze drying in
dioxane/water (9:1), 4 white solids, chunk, no B x-ray amorphous
days, .about.1 g scale-up .sup.aB = birefringence, E =
extinction.
Example 10
Preparation and Characterization of Compound I, Form K
[0506] In one embodiment, Compound I Form A (410 mg, 0.8 mmol) and
nitromethane (20 mL) were charged to a glass vial and bath
sonicated for several minutes, producing a clear solution. The
solution was filtered through a 0.2 .mu.m nylon filter to a clean
glass vial and allowed to evaporate slowly (vial covered with
perforated aluminum foil) in a laboratory fume hood. After
approximately 12 days, the sample was split into approximately four
equal portions to speed up the evaporation. The sample was
continued as a slow evaporation for an additional 7 days. Two of
the four vials were uncapped (fast evaporation) and allowed to
evaporate overnight. The next day, a small amount of solvent was
visible in only one of the samples. After the majority of the
solvent was removed by decantation, the precipitated solids from
the other three samples were pooled into the original sample. The
recombined solids were stored in a sealed vial in a freezer.
[0507] Slow Evaporation (SE)
[0508] In another embodiment, solutions were prepared in various
solvents at ambient temperature and passed through a 0.2-.mu.m
nylon filter into a glass vial. The filtered solution was allowed
to evaporate at ambient in a vial covered with aluminum foil
perforated with one or more pinholes. Any solids formed were
isolated and analyzed. From nitromethane by slow evaporation,
solids obtained display an XRPD pattern for Compound I, Form K
(FIG. 8(a).
[0509] Vapor Diffusion
[0510] In yet another embodiment, solutions were prepared with
various solvents at ambient temperature and passed through a
0.2-.mu.m nylon filter into a glass vial. This filled vial was
placed in a glass vial containing an antisolvent and capped. In
general, the anti-solvent is miscible with and, typically, more
volatile than the solvent. The experiment was left undisturbed at
ambient temperature. Any solids formed were isolated and
analyzed.
[0511] Two scale-up lyophilization attempts (approx. 2-g scale
using dioxane/water 9:1 v/v) were performed. The first attempt
generated a disordered crystalline material with evidence of peaks
also found in Form A and Form K as determined by visual comparison
of XRPD. The second attempt generated a disordered crystalline
material with evidence of peaks also found in Form K by visual
comparison.
[0512] Compound I Form K is a crystalline nitromethane solvate of
Compound I. The experimental data for Compound I Form K is provided
in FIGS. 8(a) to 8(l). The characterization of Compound I Form K is
summarized in Table 11. TABLE-US-00011 TABLE 11 Characterization of
Compound I Form K Analysis Result Figure References XRPD Form K
8(a)-8(e), DSC 155.3.degree. C. (endo) 8(i) 257.3.degree. C. (endo)
FT-IR reference spectrum 8(f), 8(g) TGA Form K 8(k)
Example 11
Preparation and Characterization of Compound I, Form L
[0513] Compound I, Form A (910 mg, 1.7 mmol) and acetone (48 mL)
were charged to a glass beaker and stirred for several minutes,
producing a clear solution. The solution was filtered through a 0.2
.mu.m nylon filter to a clean glass beaker and the beaker was left
uncovered in a glass jar containing methanol (.about.50 mL), in
order to precipitate solids from the solution via vapor diffusion.
After approximately 12 days, the precipitated solids were isolated
by decanting off the clear supernatant. The solids were transferred
to a clean glass vial and stored under methanol vapor in a
freezer.
[0514] Compound I Form L is a crystalline methanole solvate of
Compound I. The experimental data for Compound I Form L is provided
in FIGS. 10(a) to 10(i). The characterization of Compound I Form L
is summarized in Table 12. TABLE-US-00012 TABLE 12 Characterization
of Compound I Form L Analysis Result Figure References XRPD Form L
10(a)-10(c) DSC 168.2.degree. C. (endo) 10(g) 259.2.degree. C.
(endo) FT-IR reference spectrum 10(d), 10(e) TGA Form L 10(h)
Example 12
Preparation and Characterization of Compound I, Form N
[0515] In one embodiment, Compound I, Form N was vacuum dried at
ambient temperature for approximately 5 hours, at approximately 50
mTorr, losing approximately 12.4% of the initial weight. The
resulting solids were characterized by proton NMR spectroscopy. The
spectrum showed that the solids contained approximately 1/3 mole
nitromethane. Subsequently, the dried sample was characterized by
DSC. The observed results are subject to the conditions used at the
time of analysis. The DSC data collected in a crimped pan, exhibits
a minor endothermic event at approximately 150.degree. C., which
may be related to volatiles loss on heating, and an intense
endotherm at approximately 256.degree. C. (onset). The remaining
solids (43 mg) were dried for approximately 22 hours in a vacuum
oven at approximately 42.degree. C., at approximately 20 mTorr. The
weight loss was not determined but the dried solids were
characterized by XRPD. The resulting pattern contains XRPD peaks of
Form N but exhibits additional unknown peaks, suggesting conversion
had occurred. Therefore, subsequent solvent removal experiments
were carried out at ambient temperature.
[0516] Form A (1.6 g, estimated) was slurried in nitromethane (9
mL) for approximately 5 days. Solids were recovered via vacuum
filtration and washed with nitromethane (2.times.1 mL). The solids
were left on the filter under vacuum for several minutes.
Approximately 1.3 g of solid were recovered. The solids exhibited a
mixture of rectangular plates and prisms by polarized light
microscopy. The resulting high-resolution XRPD pattern was
consistent with Form N.
[0517] Two ambient-temperature vacuum drying experiments were
carried out in an attempt to remove the nitromethane from Form N.
In one embodiment, 94.0 mg of solid were dried for approximately
16.5 hours, at approximately 20 mTorr, losing approximately 0.7% of
the initial weight. In another embodiment, 308.3 mg of solid were
dried for approximately 5 days, at approximately 5 mTorr, gaining
approximately 0.7% of the initial weight (approximately 0.1% gain
from 3 to 5 days). There appeared to be no change in the solids by
polarized light microscopy and both samples exhibited Form N by
high-resolution XRPD analysis. In one embodiment, the patterns
exhibit a weak unknown peak at approximately 9.1 .degree.2.theta.,
which is more pronounced for the 5-day sample than the 16.5-hour
sample. Both samples contained approximately 1/3 mole of
nitromethane by proton NMR spectroscopy.
[0518] In one embodiment, the sample was characterized by DSC and
TGA in an open pan configuration to ensure that solvent could
freely leave during analysis. The observed results are subject to
the conditions used at the time of analysis. The resulting DSC
thermogram exhibits a broad endothermic event at approximately
161.degree. C., with a shoulder at approximately 148.degree. C.
This event appears to be concurrent with the weight loss of
approximately 4.9% from 130-160.degree. C. observed in the TGA
thermogram, which correlates to approximately 1/2 mole of
nitromethane, assuming the weight loss is attributed only to
solvent loss. The thermogram exhibits an endotherm at approximately
256-259.degree. C. (onset). The final weight loss from TGA suggests
that decomposition is concurrent with this endotherm.
[0519] In one embodiment, in order to remove the nitromethane from
Form N sample, 152.4 mg of solid were slurried in acetonitrile (1
mL) for approximately 1 hour. Solids were recovered via vacuum
filtration, washing with acetonitrile (4.times.1 mL). The solids
were left on the filter under vacuum for several minutes to dry the
solids. 97.7 mg of solid were recovered. In another embodiment,
309.5 mg of solid were slurried in water (4 mL) for approximately
24.5 hours. Solids were recovered via vacuum filtration, washing
with water (2.times.1 mL). The solids were left on the filter under
vacuum for approximately 1.5 hours to dry the solids. 270.4 mg of
solid were recovered. There was no change in the solids by
polarized light microscopy; however, by XRPD analysis, pattern T
resulted from acetonitrile and a mixture of Forms C and A resulted
from water. The high-resolution XRPD pattern for the solids from
water slurry exhibited additional peaks present in the Form N XRPD
pattern, suggesting incomplete conversion.
[0520] In addition, the proton NMR data for Form N suggests the
material contains approximately 1/3 mole of nitromethane. The space
group of the Form N solution (P2.sub.12.sub.12) can only exhibit
less than one molecule of solvent in the asymmetric unit if the
solvent position is partially occupied, i.e. some of the asymmetric
units contain solvent molecules and others do not.
[0521] The experimental data for Compound I Form N is provided in
FIGS. 11(a) to 11(c). The characterization of Compound I Form N is
summarized in Table 13. TABLE-US-00013 TABLE 13 Characterization of
Compound I Form N Analysis Result Figure References XRPD Form N
11(a) DSC 150.0.degree. C. (event) 11(b) 259.2.degree. C. (endo)
TGA Form N 11(c)
[0522] Characterization of solids from Compound I Form N
preparation is summarized in Table 14. TABLE-US-00014 TABLE 14
Characterization of Solids from Romidepsin Form N
Preparation/Solvent Removal Attempts Starting Material (XRPD
Result) Conditions Analysis Result (Form N + 10.3 mg, DSC (sample
preparation peaks).sup.a heated to 180.degree. C. (crimped)
analysis) by DSC XRPD Form A + 2 weak peaks of Form N (Form N) 71.5
mg, Weight 12.4% wt loss on drying RT vac dry Change 5 hours DSC
150.degree. C. (broad endo, min) at 50 mTorr.sup.b (crimped)
256.degree. C. (endo, onset) with concurrent decomp (Form N) 43 mg
XRPD unknown + Form N 42.degree. C. vac dry 22 hours at 20
mTorr.sup.b (Form A) 1.5 g, 9 mL Initial 0.9 g nitromethane,
Recovery slurry 4 days, Weight 0.4% wt loss on drying vac filter
with Change acetone wash, PLM platy/bladed particles (B/E) RT vac
dry HR XRPD Form B + peaks.sup.c 6 hours at 50 mTorr.sup.b 1.6 g
(estimated) Initial 1.3 g 9 mL Recovery nitromethane, PLM
rectangular plates/prisms slurry 5 days, (B/E) vac filter with HR
XRPD Form N nitromethane wash (Form N) 94.0 mg, Weight 0.7% wt loss
on drying RT vac dry Change 16.5 hours PLM rectangular
plates/prisms at 20 mTorr.sup.b (B/E) HR XRPD Form N + weak peak at
9.1 .degree. 2.theta. .sup.1H-NMR consistent with structure 1/3
mole nitromethane (Form N) 308.3 mg, Weight 0.7% wt gain on
drying.sup.e RT vac dry Change 5 days PLM rectangular plates/prisms
at 5 mTorr.sup.d (B/E) HR XRPD Form N + weak peak at 9.1 .degree.
2.theta. DSC (open) 161.degree. C. (broad endo, min) with shoulder
at 148.degree. C. 259.degree. C. (endo, onset) with concurrent
decomp TGA 4.9% wt loss 130-160.degree. C. (equates to .about.0.5
mole nitromethane) .sup.1H-NMR consistent with structure 1/3 mole
nitromethane 152.4 mg, Initial 97.7 mg 1 mL Recovery acetonitrile,
PLM rectangular plates/prisms brief vortex, (B/E).sup.f slurry 1
hour, XRPD pattern T vac filter with acetonitrile wash/dry several
minutes 309.5 mg, Initial 270.4 mg 4 mL water, Recovery brief
vortex, PLM rectangular plates/prisms slurry 24.5 (B/E).sup.f
hours, HR XRPD Forms C + A + peaks.sup.g vac filter with water
wash/ dry 1.5 hours .sup.aForm N; additional weak peaks are present
in the XRPD pattern at approximately 8.37, 11.37, 13.10, 16.23, and
21.86 .degree. 2.theta.. .sup.bVacuum pressure from in-line gauge
for vacuum system. .sup.cAdditional peaks in the XRPD pattern
present in XRPD pattern of Form A. .sup.dSample stored in covered
container at RT for 1 day prior to drying. Sample dried in
stand-alone oven; vacuum pressure for oven measured by McLeod
gauge. .sup.e0.1% wt gain since check at 3 days. .sup.fParticles
appeared unchanged by solvent. .sup.gAdditional peaks in the XRPD
pattern present in XRPD pattern of Form N.
Example 13
Solubility Studies
[0523] The ambient temperature solubility data for the Compound I
Form A are summarized in Table 15. The solids exhibited apparent
solubilities of well over 100 mg/ml for dimethylformamide (DMF),
dichloromethane (DCM) and 2,2,2-trifluoroethanol (TFE). The
material exhibited moderate solubility (e.g., >10 mg/ml) in the
majority of solvent and solvent combinations tested. The only
exception was isopropanol (IPA) at 4.6 mg/mL. Some solubility data
was obtained on multiple samples as presented in Table 15 below.
TABLE-US-00015 TABLE 15 Solubility data for Compound I, Form A
Results Results Solvents.sup.a [mg/ml] Solvents.sup.b [mg/ml]
Acetone 22.4, 28.2 (1:0.2) 16.3 Ethanol:TFE (0.5:0.1) 38 (1.5:0.8)
Ethyl 8.9 Acetone:DCM Acetate:Acetone (1:0.2) Acetonitrile 17.9
(1.5:1) 8.0.sup.d (ACN):TFE Heptane:DCM 2-Butanone (MEK) 12.5
Isopropanol (IPA) 4.6 (1:0.1)2- 20.6 (1:1)2- 11.5.sup.d
Butanone:TFE Propanol:Acetone Chloroform 26.5 (4.5:3) Isopropyl 6.8
Ether:Ethanol Dichloromethane 135.3, (1.5:1) 8.7.sup.d (DCM) 280
Methanol:TFE Dimethylformamide 248.5 Nitromethane 23.6 (DMF)
(1:0.5) 13.3 2,2,2- 158.9 Dioxane:Acetone trifluoroethanol (TFE)
Ethanol (EtOH) 23.5 (0.1:0.1) 97 TFE:DCM (1:1) Ethanol/IPA 28.sup.c
(1:0.1) 21.4 Toluene:TFE (1:3) Ethanol/IPA 10.sup.c (1.5:0.5) 12.4
Water:DCM .sup.aRatio of solvents based on volume, in milliliters.
.sup.bSolubility assessment performed at ambient temperature,
unless otherwise noted. Reported values are less than or equal to
the actual solubility of Compound I in each test solution based on
visual observation and therefore are approximate. .sup.cExperiment
performed on hot plate set to 70.degree. C. .sup.dExperiment
performed on hot plate set to 60.degree. C.
Example 14
Polymorph Screen
[0524] A series of solvent-based experiments were set up utilizing
slurry, evaporation, crash precipitation, and vapor diffusion
techniques. The samples were prepared with Compound I Form A and
the experimental results are summarized in Tables 16 and 17.
[0525] In one embodiment, experiments using solvents from the
crystallization processes for Forms A and B resulted in
characterization of selected solids recovered from these
experiments that displayed unique XRPD patterns designated as Forms
A to E, H, and J, and are described below. Several unique XRPD
patterns were also obtained from other experimental conditions,
including an x-ray amorphous solid. No further characterization of
these solids was performed. A summary of exemplary XRPD results for
crystallization experiments are presented in Table 16.
TABLE-US-00016 TABLE 16 Summary of XRPD Results for Crystallization
Experiments Solvent Conditions Habit/Description XRPD Result
Dichloromethane fast evaporation clear film Form A (w/disorder)
(DCM) Acetone fast evaporation white flakes Form B + peaks (Form A)
(1.5:1) fast evaporation opaque film x-ray amorph MeOH:TFE (1:0.2)
fast evaporation film on vial walls x-ray amorph EtOH:TFE (1:1)
fast evaporation opaque film Form A IPA:Acetone (w/disorder)
(1.5:0.8) fast evaporation blades/needles on Form A (w/disorder)
EtOAc:Acetone vial walls (1.5:1) fast evaporation small needles on
vial wall Form A Heptane:DCM (w/disorder) (1.5:0.5) fast
evaporation white solids, x-ray amorphous Water:DCM agglomerates
(1:0.1) fast evaporation flakes B + A MEK:TFE (1:0.2) fast
evaporation -- -- ACN:TFE (1:0.1) fast evaporation Agglomerate
solids Form A Toluene:TFE 2,2,2- fast evaporation clear film
similar to Form E Trifluoroethanol (TFE) (1:0.5) fast evaporation
long needles, asperites Form A Dioxane:Acetone (0.5:0.1) fast
evaporation Agglomerate plates Form B + peaks (Form Acetone:DCM A)
(0.1:0.1) fast evaporation clear film x-ray amorph TFE:DCM Methyl
ethyl ketone slow evaporation -- Form J similar to Form (MEK) D
Dimethylformamide slow evaporation no solids -- (DMF) (4.5:3) slow
evaporation thin film with B/E similar to Form A + Isopropyl peaks
ether:EtOH Chloroform Slurry, vac dried, 60.degree. C. Dried solids
Form H (1:3) Acetone/water -5.degree. C., 1 day seeded with Dried
solids Form C + peaks (Form Form C + peaks (Form A) A) (1:3)
Acetone/water -5.degree. C., 41 days seeded with Dried solids Form
C Form C + peaks (Form A)
[0526] A summary of exemplary XRPD results for vapor diffusion
experiments are presented in Table 17. TABLE-US-00017 TABLE 17
Summary of XRPD Results for Vapor Diffusion Experiments Habit/ XRPD
Solvent.sup.a Conditions Description.sup.b Result Dichloromethane
Heptane Agglomerate flakes Form A Water white solids precipitate,
-- undefined habit Methanol no solids -- Acetone Heptane
Agglomerate blades Form B (w/ with B/E disorder) Water white
solids, Form A undefined habit with B/E (3.5:1) Heptane no solids
-- Isopropyl alcohol: Water white solids precipitate, --
Trifluoroethanol undefined habit Methanol Agglomerated needles/
x-ray blades with B/E amorphous + peaks Ethanol Heptane white
solids precipitate, -- Water undefined habit -- Methanol --
Trifluoroethanol Heptane no solids -- Water white solids
precipitate, -- Methanol undefined habit -- .sup.aSolvent ratios in
parenthesis on volume basis, unless otherwise noted .sup.bB:
birefringence, E: extinction (E) under cross polars
Example 15
Composition/Formulation
[0527] This example illustrates various components present in a
representative formulation containing Compound I according to the
present disclosure, which was formulated as a bulk solution batch
using the following steps: (a) preparing a Compound I solid form;
(b) preparing a compounding solution comprising tert-butyl alcohol
and water; (c) combining Compound I solid form and the compounding
solution to form a mixture; (d) adding povidone to the mixture; (e)
adjusting the pH of the mixture by adding hydrochloric acid
solution, resulting in a formulated solution; (f) performing
sterile filtration of the formulated solution; and (g) lyophilizing
the formulated solution under aseptic conditions, to yield a final
composition comprising Compound I. The steps are detailed in Table
18 below. TABLE-US-00018 TABLE 18 Various components of the bulk
solution Quantity per Ref to Quality Component Function 51 L Batch
Standard Compound I Active 204 g Internal pharmaceutical ingredient
Povidone Excipient 408 g USP 0.1N hydrochloric pH adjustment 510 mL
NF/EP acid Nitrogen Processing agent N/A NF/EP and inert atmosphere
for vial Headspace Water for Injection* Processing agent 22.3 kg
USP/EP Tert-butyl alcohol* Processing agent 26.1 kg ACS *Removed
during lyophilization
Example 16
Preparation of Lyophilate
[0528] Preparation of Compounding Solution
[0529] Following preparation and sterilization of components
(stoppers and vials) of equipment needed, all processing equipment
was inspected to assure it was free from residual rinse water.
Vessel 1, a 20 gallon, jacketed, stainless steel vessel, was purged
with nitrogen NF/EP. The required amount of tert-butyl alcohol was
added to Vessel 1. The temperature of the tert-butyl alcohol and
compounding vessel were adjusted to 28 to 32.degree. C. in advance
to maintain this raw material as a free-flowing liquid. Following
the addition of tert-butyl alcohol and initiation of mixing, the
required amount of water for injection (WFI) was added and the
solution was mixed to completeness for 10.+-.2 minutes, to result
in a final compounding solution of 56 L. A portion (25%) of the
compounding solution was transferred to a second, smaller,
jacketed, stainless steel vessel (Vessel 2) for use in subsequent
compounding steps. Both vessels were temperature controlled at 28
to 32.degree. C., and Vessel 1 was maintained with a nitrogen NF/EP
overlay.
[0530] Preparation of Formulated Bulk Solution
[0531] Compound I solid form drug substance was weighed in an
isolator and then transferred directly to the compounding solution
tank (Vessel 1) by way of a single-use, disposable isolator
transfer bag, to form a drug substance solution. The transfer bag
was rinsed 3 times with a portion of the compounding solution from
Vessel 2 and each rinse was added to the compounding solution
tank.
[0532] The drug substance solution was mixed for 30.+-.5 minutes at
28 to 32.degree. C. Following dissolution of amorphous Compound I,
the specified amount of povidone, USP, was added to the compounding
vessel. The weighing container was rinsed once with a portion of
the compounding solution and the rinse was transferred to the
compounding tank that was mixed for 20.+-.5 minutes at 28 to
32.degree. C. to dissolve the povidone.
[0533] The pH of the bulk solution was adjusted with a
predetermined amount of 0.1 N HCl solution and was mixed for
10.+-.2 minutes at 28 to 32.degree. C. to form a formulated bulk
solution. The formulated bulk solution was sampled and the apparent
pH was verified to be between 3.6 and 4.0. The QS volume of
compounding solution required to achieve the calculated target
weight was transferred from Vessel 2 to Vessel 1. The formulated
bulk solution was mixed for 10.+-.2 minutes at 28 to 32.degree. C.
and then sampled for quality control (QC) testing, including
appearance, assay, density, pH, and bioburden. The compounding tank
was sealed, and the temperature was maintained at 28 to 32.degree.
C. until sterile filtration.
[0534] Sterile Filtration of Formulated Bulk Solution
[0535] The compounding tank containing the formulated bulk solution
was moved from the Class 100,000 compounding suite to an anteroom
adjacent to the Class 10,000 filling suite. The formulated bulk
solution was transferred via a 3/8'' stainless-steel braided
Teflon.RTM. hose passed through a port in the wall of the sterile
filling suite to the filling suite by over pressurization with
sterile nitrogen, NF/EP. The formulated bulk solution was first
clarified through a Millipore Opticap.RTM. filter (0.22 .mu.m
Durapore.RTM. membrane) and then was sterilized by filtration
through a filter assembly located within the aseptic core
containing 2 Millipore Millipak.RTM. 0.22 .mu.m Durapore.RTM.
filters in series, into a sterile receiving vessel. The integrity
of the product sterilizing filters was tested for pressure and flow
pre- and post-filtration using Isopropyl Water (IPA)/Water
(60%/40%) as the wetting solution. The minimum pressure hold value
was 10 psi prior to filtration, and the maximum flow is 1.3 mL/min
at 12 psi after filtration. The sterile-filtered formulated bulk
solution was sampled for QC testing, including appearance, assay,
density, and pH.
[0536] Aseptic Filling of Vials for Drug Product
[0537] Aseptic filling and stoppering of the sterile vials occurred
under Class 100 conditions using an automated TL filling line.
Process controls included defined weight checks of vials to verify
accurate fill volume throughout the filling operation.
[0538] Immediately following filling of each vial, a sterile
lyophilization stopper was partially seated in the vial and each
tray of filled vials was moved to the loading area for the
lyophilizer within the Class 100 aseptic area. Trays were
immediately loaded onto precooled shelves in the lyophilizer.
[0539] Lyophilization
[0540] Vials containing compositions were lyophilized under aseptic
conditions using a preprogrammed lyophilization cycle. A summary of
the lyophilization cycle process and controls is provided in Table
19. TABLE-US-00019 TABLE 19 Lyophilization Process and Controls
Lyophilizer Program Segments Process Set Points Controls Limits
1-4: Chamber loading and Load vials into chamber Shelf temperature:
0 .+-. 3.degree. C. freezing Ramp shelf temperature down to Shelf
temperature: -40.degree. C. -45 .+-. 3.degree. C. Product
thermocouples: .ltoreq.-40.degree. C. 5: Hold Hold at temperature
for 2 .+-. 0.5 hours Product thermocouples: .ltoreq.-40.degree. C.
6: Evacuate chamber Evacuate chamber vacuum to 100-200 Chamber
pressure: 100-200 .mu.m .mu.m 7-8: Ramp temperature Ramp shelf
temperature up to -20 .+-. Shelf temperature: .gtoreq.-23.degree.
C. and hold 3.degree. C. over 3 hours (.about.8.degree. C./hour)
Product thermocouples: .gtoreq.-23.degree. C. Hold for 2 .+-. 0.5
hours 9: Ramp temperature; Ramp shelf temperature up to 0 .+-.
Shelf temperature: 0 .+-. 3.degree. C. nitrogen sweep 3.degree. C.
over 2 .+-. 0.5 hours (.about.10.degree. C./hour) Product
thermocouples: .gtoreq.-3.degree. C. Nitrogen sweep at 135 .mu.m
Chamber pressure: 100-200 .mu.m 10: Ramp temperature Ramp shelf
temperature up to 33 .+-. Shelf temperature: 33 .+-. 3.degree. C.
and hold 3.degree. C. over 6 hours (.about.6.degree. C./hour)
Product thermocouples: .gtoreq.27.degree. C. Hold at temperature
for 2 hours Chamber pressure: 100-200 .mu.m 11: Terminal
drying.sup.1 Pull chamber pressure to .ltoreq.100 .mu.m Shelf
temperature: 33 .+-. 3.degree. C. Hold for 16 .+-. 1 hours Product
thermocouples: .gtoreq.27.degree. C. Chamber pressure: <100
.mu.m 12: End cycle; stopper; Increase chamber pressure to 14 to 15
Shelf temperature: 5 .+-. 3.degree. C. hold for unloading.sup.2
psia with Nitrogen NF/EP Product thermocouples: 5.degree. C. Ramp
shelf temperature down to Chamber pressure: 15 psia 5 .+-.
3.degree. C. Seat stoppers 13: Product unloading Ramp shelf
temperature up to Product thermocouples: .gtoreq.15.degree. C. 20
.+-. 3.degree. C. Chamber pressure: 14 psia Open chamber and unload
.sup.1Total terminal drying time, including initial 2 hour hold, is
18 .+-. 1 hours .sup.2The shelf is cooled to 5 .+-. 3.degree. C.
only if it is necessary to hold the product for an extended time
prior to unloading.
[0541] In one embodiment, an additional step after the secondary
drying following step 11 (Table 19) includes drying the vials at
the temperature of 50.degree. C. up to 24 hours at the pressure of
50 .mu.m Hg. In another embodiment, an additional step includes
drying the vials at the temperature of 50.degree. C. up to 48 hours
at the pressure of 50 .mu.m Hg.
[0542] In another embodiment, an additional step after the
secondary drying following step 11 (Table 19) includes drying the
vials at the temperature of 60.degree. C. up to 3 hours at the
pressure of 100 .mu.m Hg. In yet another embodiment, an additional
step includes drying the vials at the temperature of 60.degree. C.
up to 6 hours at the pressure of 100 .mu.m Hg. In another
embodiment, an additional step includes drying the vials at the
temperature of 60.degree. C. up to 12 hours at the pressure of 100
.mu.m Hg. In another embodiment, an additional step includes drying
the vials at the temperature of 60.degree. C. up to 24 hours at the
pressure of 100 .mu.m Hg. In another embodiment, an additional step
includes drying the vials at the temperature of 60.degree. C. up to
48 hours at the pressure of 100 .mu.m Hg.
[0543] In another embodiment, an additional step after the
secondary drying following step 11 (Table 19) includes drying the
vials at the temperature of 70.degree. C. up to 24 hours at the
pressure of 25 mm Hg. In another embodiment, an additional step
includes drying the vials at the temperature of 70.degree. C. up to
48 hours at the pressure of 25 mm Hg.
[0544] Following completion of the cycle (Segment 12), the vials
were backfilled with sterile nitrogen, NF/EP, at atmospheric
pressure and the stoppers were completely seated prior to opening
the lyophilizer chamber. The trays were unloaded and transferred to
the sealing area.
[0545] Vials containing compositions were sealed immediately
following unloading from the lyophilization chamber. Each seal was
imprinted with the Composition lot number using a video jet printer
incorporated into the automated sealing line. Seal inspection is
performed every 15 minutes during the sealing operation.
[0546] Following sealing operations, Compound I composition vials
were inspected, labeled and packaged and appropriate process
validation and/or Evaluation was subsequently performed.
EQUIVALENTS
[0547] Those skilled in the art will recognize, or be able to
ascertain using no more than routine experimentation, many
equivalents to the specific embodiments of the disclosure,
described herein. The scope of the present disclosure is not
intended to be limited to the above Description, but rather is as
set forth in the appended claims.
[0548] In the claims articles such as "a," "an," and "the" may mean
one or more than one unless indicated to the contrary or otherwise
evident from the context. Claims or descriptions that include "or"
between one or more members of a group are considered satisfied if
one, more than one, or all of the group members are present in,
employed in, or otherwise relevant to a given product or process
unless indicated to the contrary or otherwise evident from the
context. The disclosure includes embodiments in which exactly one
member of the group is present in, employed in, or otherwise
relevant to a given product or process. The disclosure includes
embodiments in which more than one, or all of the group members are
present in, employed in, or otherwise relevant to a given product
or process. Furthermore, it is to be understood that the disclosure
encompasses all variations, combinations, and permutations in which
one or more limitations, elements, clauses, descriptive terms,
etc., from one or more of the listed claims is introduced into
another claim. For example, any claim that is dependent on another
claim can be modified to include one or more limitations found in
any other claim that is dependent on the same base claim.
[0549] Where elements are presented as lists, e.g., in Markush
group format, it is to be understood that each subgroup of the
elements is also disclosed, and any element(s) can be removed from
the group. It should it be understood that, in general, where the
disclosure, or aspects of the disclosure, is/are referred to as
comprising particular elements, features, etc., certain embodiments
of the disclosure or aspects of the disclosure consist, or consist
essentially of, such elements, features, etc. For purposes of
simplicity those embodiments have not been specifically set forth
in haec verba herein. It is noted that the term "comprising" is
intended to be open and permits the inclusion of additional
elements or steps.
[0550] Where ranges are given, endpoints are included. Furthermore,
it is to be understood that unless otherwise indicated or otherwise
evident from the context and understanding of one of skill in the
art, values that are expressed as ranges can assume any specific
value or subrange within the stated ranges in different embodiments
of the disclosure, to the tenth of the unit of the lower limit of
the range, unless the context clearly dictates otherwise.
[0551] In addition, it is to be understood that any particular
embodiment of the present disclosure that falls within the prior
art may be explicitly excluded from any one or more of the claims.
Since such embodiments are deemed to be known to one of skill in
the art, they may be excluded even if the exclusion is not set
forth explicitly herein. Any particular embodiment of the
compositions of the disclosure (e.g., any targeting moiety, any
disease, disorder, and/or condition, any linking agent, any method
of administration, any therapeutic application, etc.) can be
excluded from any one or more claims, for any reason, whether or
not related to the existence of prior art.
[0552] Publications discussed above and throughout the text are
provided solely for their disclosure prior to the filing date of
the present application. Nothing herein is to be construed as an
admission that the inventors are not entitled to antedate such
disclosure by virtue of prior disclosure.
* * * * *