U.S. patent application number 15/464455 was filed with the patent office on 2017-07-06 for atrasentan mandelate salts.
The applicant listed for this patent is AbbVie Inc.. Invention is credited to Yuchuan Gong, Geoff G. Zhang.
Application Number | 20170190692 15/464455 |
Document ID | / |
Family ID | 52472936 |
Filed Date | 2017-07-06 |
United States Patent
Application |
20170190692 |
Kind Code |
A1 |
Gong; Yuchuan ; et
al. |
July 6, 2017 |
ATRASENTAN MANDELATE SALTS
Abstract
The present disclosure relates to: (a) mandelate salts of
atrasentan, (b) pharmaceutical compositions comprising an
atrasentan mandelate salt, and, optionally, one or more additional
therapeutic agents; (b) methods of using an atrasentan mandelate
salt to treat nephropathy, chronic kidney disease, and/or other
conditions; (c) kits comprising a first pharmaceutical composition
comprising an atrasentan mandelate salt, and, optionally, a second
pharmaceutical composition comprising one or more additional
therapeutic agents; (d) methods for the preparation of an
atrasentan mandelate salt; and (e) atrasentan mandelate salts
prepared by such method.
Inventors: |
Gong; Yuchuan; (Waukegan,
IL) ; Zhang; Geoff G.; (Vernon Hills, IL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
AbbVie Inc. |
North Chicago |
IL |
US |
|
|
Family ID: |
52472936 |
Appl. No.: |
15/464455 |
Filed: |
March 21, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14594742 |
Jan 12, 2015 |
9637476 |
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15464455 |
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14133297 |
Dec 18, 2013 |
8962675 |
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14594742 |
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61877101 |
Sep 12, 2013 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 405/04 20130101;
A61P 7/12 20180101; C07C 59/54 20130101; C07B 2200/07 20130101;
C07B 2200/13 20130101; C07C 59/50 20130101; A61P 13/12
20180101 |
International
Class: |
C07D 405/04 20060101
C07D405/04; C07C 59/50 20060101 C07C059/50 |
Claims
1. A crystalline atrasentan S-mandelate solvated salt.
2-3. (canceled)
4. An amorphous atrasentan S-mandelate salt.
5. The salt of claim 1, wherein the molar ratio of atrasentan to
S-mandelate is about 1:1.
6-7. (canceled)
8. The salt of claim 1, wherein the solvated salt is selected from
the group consisting of an acetonitrile solvate, an ethanol
solvate, and a pyridine solvate.
9-13. (canceled)
14. An atrasentan R-mandelate salt.
15. The salt of claim 14, wherein the salt is a crystalline
R-mandelate salt.
16. The salt of claim 14, wherein the salt is an amorphous
R-mandelate salt.
17. The salt of claim 15, wherein the molar ratio of atrasentan to
R-mandelate is about 1:1.
18. The salt of claim 17, wherein the salt is an anhydrous
salt.
19. The salt of claim 18, wherein the salt is a crystalline
R-mandelate salt having an X-ray powder diffraction pattern
comprising peaks at 5.7.+-.0.2, 11.8.+-.0.2, and 20.9.+-.0.2
degrees two theta when measured at about 25.degree. C. with
monochromatic K.alpha.1 radiation.
20. A pharmaceutical composition comprising an atrasentan mandelate
salt and a pharmaceutically-acceptable carrier.
21. The composition of claim 20, wherein the composition comprises
from about 0.25 mg to about 1.25 mg of the salt on an atrasentan
parent equivalent weight basis.
22. The composition of claim 20, wherein the salt is a crystalline
S-mandelate solvated salt.
23. The composition of claim 22, wherein the molar ratio of
atrasentan to S-mandelate is about 1:1.
24. The composition of claim 20, wherein the salt is an R-mandelate
salt.
25. A method of treating chronic kidney disease, comprising
administering a therapeutically effective amount of an atrasentan
mandelate salt to a human subject susceptible to or suffering from
chronic kidney disease.
26. The method of claim 25, wherein the amount of the salt
administered is from about 0.25 mg daily to about 1.25 mg daily on
an atrasentan parent equivalent weight basis.
27. A method of treating nephropathy, comprising administering a
therapeutically effective amount of an atrasentan mandelate salt to
a human subject susceptible to or suffering from nephropathy.
28. The method of claim 27, wherein the amount of the salt
administered is from about 0.25 mg daily to about 1.25 mg daily on
an atrasentan parent equivalent weight basis.
29. The method of claim 27, wherein the method reduces the
urinary-albumin-to-creatinine ratio in the subject.
30. The method of claim 27, wherein the method reduces the rate of
increase in serum creatinine concentration in the subject.
31. The composition of claim 15, wherein the salt is a hydrate.
32. The composition of claim 15, wherein the salt is a solvated
salt.
33. The composition of claim 32, wherein the solvated salt is
selected from the group consisting of an acetonitrile solvate, an
ethanol solvate, and a pyridine solvate.
Description
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application claims priority to U.S. Provisional
Application Ser. No. 61/877,101 filed on Sep. 12, 2013. The entire
text of that provisional application is incorporated by reference
into this application.
FIELD OF THE INVENTION
[0002] The present disclosure relates to: (a) mandelate salts of
atrasentan, (b) pharmaceutical compositions comprising an
atrasentan mandelate salt, and, optionally, one or more additional
therapeutic agents; (b) methods of using an atrasentan mandelate
salt to treat nephropathy, chronic kidney disease, and/or other
conditions; (c) kits comprising a first pharmaceutical composition
comprising an atrasentan mandelate salt, and, optionally, a second
pharmaceutical composition comprising one or more additional
therapeutic agents; (d) methods for the preparation of an
atrasentan mandelate salt; and (e) atrasentan mandelate salts
prepared by such methods.
BACKGROUND OF THE INVENTION
[0003] Atrasentan is a potent and selective antagonist for the
endothelin A (ET.sub.A) receptor. It previously was evaluated in
clinical trials for the treatment of prostate cancer and is now
being evaluated in clinical trials for the treatment of chronic
kidney disease associated with Type II diabetes.
[0004] The compound atrasentan was first reported in U.S. Pat. No.
5,767,144. Subsequently, several published international
applications reported atrasentan monohydrochloride salts.
WO2006/034085 reports amorphous atrasentan monohydrochloride.
WO2006/034094 reports crystalline Form I of atrasentan
monohydrochloride. WO2006/034084 reports crystalline Form II of
atrasentan monohydrochloride. WO2006/034234 reports crystalline
Form III of atrasentan monohydrochloride.
[0005] The preparation of atrasentan monohydrochloride and
corresponding pharmaceutical formulations containing atrasentan
monohydrochloride presents a number of manufacturing challenges
that are discussed in greater detail below. There is a present need
for pharmaceutically acceptable, alternative salts of atrasentan
that reduce or eliminate the manufacturing challenges encountered
with respect to the monohydrochloride salt.
SUMMARY OF THE INVENTION
[0006] The present disclosure relates to atrasentan mandelate
salts. In one aspect, the salt is an atrasentan S-mandelate salt.
In another aspect, the salt is an atrasentan R-mandelate salt.
[0007] In one aspect, the present disclosure relates to
pharmaceutical compositions comprising an atrasentan mandelate salt
and a pharmaceutically acceptable carrier.
[0008] In another aspect, the present disclosure relates to
pharmaceutical compositions comprising an atrasentan mandelate
salt, and further comprising one or more additional therapeutic
agents.
[0009] In another aspect, the present disclosure relates to methods
of treating nephropathy in a human subject suffering from or
susceptible to nephropathy comprising administering to the subject
a therapeutically effective amount of an atrasentan mandelate
salt.
[0010] In another aspect, the present disclosure relates to methods
of treating chronic kidney disease in a human subject suffering
from or susceptible to chronic kidney disease comprising
administering to the subject a therapeutically effective amount of
an atrasentan mandelate salt.
[0011] In another aspect, the present disclosure relates to methods
of reducing the urinary-albumin-to-creatinine ratio in a human
subject suffering from or susceptible to chronic kidney disease
comprising administering to the subject a therapeutically effective
amount of an atrasentan mandelate salt.
[0012] In another aspect, the present disclosure relates to methods
of reducing the rate of increase in serum creatinine concentration
in a human subject suffering from or susceptible to chronic kidney
disease, comprising administering to the subject a therapeutically
effective amount of an atrasentan mandelate salt.
[0013] In another aspect, the present disclosure relates to methods
of treatment comprising administering a therapeutically effective
amount of an atrasentan mandelate salt, in combination with one or
more additional therapeutic agents (e.g., an inhibitor of one or
more elements of the renin-angiotensin-aldosterone system).
[0014] In another aspect, the present disclosure relates to kits
comprising one or more pharmaceutical compositions comprising an
atrasentan mandelate salt. The kit optionally can comprise one or
more additional therapeutic agents and/or instructions, for
example, instructions for using the kit.
[0015] In another aspect, the present disclosure relates to methods
for the preparation of an atrasentan mandelate salt, wherein the
method comprises the steps of (a) contacting atrasentan with a
solvent comprising mandelic acid to form the atrasentan mandelate
salt, and (b) isolating the atrasentan mandelate salt.
[0016] In another aspect, the present disclosure relates to
atrasentan mandelate salts prepared in accordance with the method
comprising the steps of (a) contacting atrasentan with a solvent
comprising mandelic acid to form the atrasentan mandelate salt, and
(b) isolating the atrasentan mandelate salt.
BRIEF DESCRIPTION OF THE DRAWINGS
[0017] FIG. 1-A is a microscopic image of atrasentan hemi-sulfate
salt (1:1 stoichiometry), monohydrate.
[0018] FIG. 1-B is a microscopic image of for atrasentan
S-mandelate salt (1:1 stoichiometry), anhydrate.
[0019] FIG. 1-C is a microscopic image of atrasentan
monohydrochloride salt, crystalline Form II.
[0020] FIG. 2-A is an X-ray powder diffraction pattern for
atrasentan hemi-sulfate salt (1:1 stoichiometry), monohydrate.
[0021] FIG. 2-B is an X-ray powder diffraction pattern for
atrasentan S-mandelate salt (1:1 stoichiometry), anhydrate.
[0022] FIG. 2-C is an X-ray powder diffraction pattern for
atrasentan S-mandelate salt (1:1 stoichiometry) crystallized from
acetonitrile.
[0023] FIG. 2-D is an X-ray powder diffraction pattern for
atrasentan S-mandelate salt (1:1 stoichiometry) crystallized from
ethanol.
[0024] FIG. 2-E is an X-ray powder diffraction pattern for
atrasentan S-mandelate salt (1:1 stoichiometry) crystallized from
pyridine.
[0025] FIG. 2-F is an X-ray powder diffraction pattern for
atrasentan S-mandelate salt (2:1 stoichiometry), hydrate.
[0026] FIG. 2-G is an X-ray powder diffraction pattern for
atrasentan R-mandelate salt (1:1 stoichiometry), anhydrate.
[0027] FIG. 2-H is an X-ray powder diffraction pattern for
atrasentan n-butylamine salt (1:1 stoichiometry), anhydrate.
[0028] FIG. 2-I is an X-ray powder diffraction pattern for
atrasentan parent, anhydrate.
[0029] FIG. 2-J is an X-ray powder diffraction pattern for
atrasentan parent, quarter-hydrate.
[0030] FIG. 2-K is an X-ray powder diffraction pattern for
atrasentan parent, hemi-hydrate.
[0031] FIG. 2-L is an X-ray powder diffraction pattern for
atrasentan monohydrochloride salt, crystalline Form I.
[0032] FIG. 2-M is an X-ray powder diffraction pattern for
atrasentan monohydrochloride salt, crystalline Form II.
[0033] FIG. 2-N is an X-ray powder diffraction pattern for
atrasentan monohydrochloride salt, crystalline Form III.
[0034] FIG. 3 is a bar chart illustrating the oxidative stability
of atrasentan S-mandelate (1:1 stoichiometry), anhydrate;
atrasentan monohydrochloride, crystalline Form II; and atrasentan
parent, hemihydrate.
[0035] FIG. 4 is a graph illustrating the intrinsic dissolution
rate as a function of pH for atrasentan S-mandelate (1:1
stoichiometry), anhydrate, and atrasentan parent, hemihydrate.
[0036] FIG. 5 is a graph illustrating the intrinsic dissolution
rate as a function of chloride ion concentration for atrasentan
S-mandelate (1:1 stoichiometry), anhydrate, and atrasentan
monohydrochloride, crystalline Form II.
[0037] FIG. 6-A is a moisture sorption isotherm for atrasentan
hemi-sulfate salt (1:1 stoichiometry), monohydrate.
[0038] FIG. 6-B is a moisture sorption isotherm for atrasentan
S-mandelate salt (1:1 stoichiometry), anhydrate.
[0039] FIG. 7-A is a differential scanning calorimetry curve for
atrasentan hemi-sulfate salt (1:1 stoichiometry), monohydrate.
[0040] FIG. 7-B is a differential scanning calorimetry curve for
atrasentan S-mandelate salt (1:1 stoichiometry), anhydrate.
DETAILED DESCRIPTION OF THE INVENTION
[0041] This written description uses examples to disclose the
invention, including the best mode, and also to enable any person
skilled in the art to practice the invention, including making and
using any of the disclosed salts, substances, or compositions, and
performing any of the disclosed methods or processes. The
patentable scope of the invention is defined by the claims, and may
include other examples that occur to those skilled in the art. Such
other examples are intended to be within the scope of the claims if
they have elements that do not differ from the literal language of
the claims, or if they include equivalent elements with
insubstantial differences from the literal language of the
claims.
I. DEFINITIONS
[0042] Section headings as used in this section and the entire
disclosure are not intended to be limiting.
[0043] Where a numeric range is recited, each intervening number
within the range is explicitly contemplated with the same degree of
precision. For example, for the range 6 to 9, the numbers 7 and 8
are contemplated in addition to 6 and 9, and for the range 6.0 to
7.0, the numbers 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9
and 7.0 are explicitly contemplated. In the same manner, all
recited ratios also include all sub-ratios falling within the
broader ratio.
[0044] The singular forms "a," "an" and "the" include plural
referents unless the context clearly dictates otherwise.
[0045] The term "about" generally refers to a range of numbers that
one of skill in the art would consider equivalent to the recited
value (i.e., having the same function or result). In many
instances, the term "about" may include numbers that are rounded to
the nearest significant figure.
[0046] The term "amorphous" as applied to an atrasentan mandelate
salt refers to a solid state wherein the atrasentan mandelate salt
molecules are present in a disordered arrangement and do not form a
distinguishable crystal lattice or unit cell. When subjected to
X-ray powder diffraction, an amorphous atrasentan mandelate salt
does not produce any characteristic crystalline peaks.
[0047] The term "atrasentan" refers to the compound
(2R,3R,4S)-4-(1,3-benzodioxol-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4--
methoxyphenyl)pyrrolidine-3-carboxylic acid which has the structure
shown below:
##STR00001##
The term "atrasentan parent" as used throughout this disclosure is
intended to encompass the parent form (i.e., non-salt form) of the
compound shown, including any zwitterionic form of the compound.
Unless otherwise stated, any reference to an amount of atrasentan
mandelate salt in this disclosure is based on the atrasentan parent
equivalent weight. For example, 0.75 mg of atrasentan refers to
0.75 mg of atrasentan parent or an equivalent amount of an
atrasentan mandelate salt. Methods for making atrasentan are
described, for example, in U.S. Pat. Nos. 5,731,434; 5,622,971;
5,767,144; 6,162,927; 6,380,241; 6,462,194; 6,946,481; 7,208,517;
and 7,365,093. The contents of these patents are incorporated by
reference in this application.
[0048] Unless the context requires otherwise, the terms "comprise,"
"comprises," and "comprising" are used on the basis and clear
understanding that they are to be interpreted inclusively, rather
than exclusively, and that Applicant intends each of those words to
be so interpreted in construing this patent, including the claims
below.
[0049] The term "crystalline" as applied to an atrasentan mandelate
salt refers to a solid state form wherein the atrasentan mandelate
salt molecules are arranged to form a distinguishable crystal
lattice (i) comprising distinguishable unit cells, and (ii)
yielding diffraction peaks when subjected to X-ray radiation.
[0050] The term "crystalline purity" means the crystalline purity
of an atrasentan mandelate salt with regard to a particular
crystalline form of the atrasentan mandelate salt as determined by
the powder X-ray diffraction analytical methods described in this
application.
[0051] The term "crystallization" as used throughout this
application can refer to crystallization and/or recrystallization
depending upon the applicable circumstances relating to the
preparation of the atrasentan mandelate salt.
[0052] The term "mandelic acid" refers to the compound
2-hydroxy-2-phenylacetic acid which has the structure shown
below:
##STR00002##
The stereoisomers of mandelic acid are characterized as "R" or "S"
depending on the configuration of substituents around the chiral
carbon atom. The terms "R" and "S" are configurations as defined in
IUPAC 1974 Recommendations for Section E, Fundamental
Stereochemistry, Pure Appl. Chem., 1976, 45: 13-30.
[0053] The term "pharmaceutically acceptable" (such as in the
recitation of a "pharmaceutically acceptable salt" or a
"pharmaceutically acceptable diluent") refers to a material that is
compatible with administration to a subject, e.g., the material
does not cause an undesirable biological effect. Examples of
pharmaceutically acceptable salts are described in "Handbook of
Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and
Wermuth (Wiley-VCH, Weinheim, Germany, 2002). Examples of
pharmaceutically acceptable excipients are described in the
"Handbook of Pharmaceutical Excipients," Rowe et al., Ed.
(Pharmaceutical Press, 7th Ed., 2012).
[0054] The term "subject" refers to an animal. In one aspect, the
animal is a mammal, including a human or non-human, preferably a
human subject.
[0055] The terms "treating" and "treatment" refer to ameliorating,
suppressing, eradicating, reducing the severity of, decreasing the
frequency of incidence of, preventing, reducing the risk of, or
delaying the onset of the condition.
[0056] The abbreviation "PXRD" means powder X-ray diffraction.
[0057] The abbreviation "UACR" refers to
urinary-albumin-to-creatinine ratio.
[0058] The abbreviation "v/v" refers to volume/volume.
II. ATRASENTAN MANDELATE SALTS
[0059] The present disclosure relates to atrasentan mandelate
salts. As with all pharmaceutical compounds and compositions, the
chemical and physical properties of atrasentan are important in its
commercial development. These properties include, but are not
limited to: (1) packing properties such as molar volume, bulk
density and hygroscopicity, (2) thermodynamic properties such as
melting temperature, vapor pressure and solubility, (3) kinetic
properties such as dissolution rate and stability (including
stability at ambient conditions, especially to moisture and under
storage conditions), (4) surface properties such as surface area,
wettability, interfacial tension and shape, (5) mechanical
properties such as hardness, tensile strength, compatibility,
handling, flow and blend; and (6) filtration properties. These
properties can affect, for example, the processing and storage of
atrasentan and pharmaceutical compositions comprising atrasentan.
Salts, particularly crystalline salts, of atrasentan that improve
upon one or more of these properties relative to other salts and/or
solid state forms of atrasentan are desirable.
[0060] The atrasentan dosage forms prepared and administered in
clinical trials to date have contained crystalline Form II
atrasentan monohydrochloride (reported in WO2006/034084). Form II
is the most thermodynamically stable of the three crystalline forms
of atrasentan monohydrochloride salts that have been identified
(i.e., Form I, Form II, and Form III). Although atrasentan clinical
trials have proceeded with crystalline Form II of atrasentan
monohydrochloride, efforts have continued to identify alternative
atrasentan salts that provide further advantages relative to the
monohydrochloride salt.
[0061] For example, one property of the crystalline Form I, Form
II, and Form III atrasentan monohydrochloride salts that could be
beneficially improved is crystal morphology. All of the known
atrasentan monohydrochloride salts have a needle morphology that
can create challenges during the preparation and formulation of
such salts. For example, the needle morphology results in a
relatively low bulk powder density that makes powder handling more
difficult during the preparation of the atrasentan dosage form. The
needle morphology also increases the difficulty of filtration,
requiring a longer time in solid-liquid separation. These problems
reduce the efficiency of the atrasentan purification (since the
mother liquor will be enriched in impurities), increase energy
consumption (due to removal of excess residual organic solvent in
compliance with International Conference on Harmonization
guidelines), and potentially lead to sintering or caking of the
solid that may require an additional milling step.
[0062] Another property of the monohydrochloride salt that could be
beneficially improved is corrosivity. The preparation of the
crystalline Form I, Form II, and Form III atrasentan
monohydrochloride salts requires the use and handling of corrosive
hydrochloric acid and typically is carried out in a glass-lined
reactor rather than a standard stainless steel reactor. In
addition, during the preparation of the atrasentan
monohydrochloride dosage form, the monohydrochloride salt can cause
corrosion of the tooling (such as the punch and die of the tablet
press) over time. Further, the monohydrochloride salt potentially
can decompose to yield hydrogen chloride gas over time and/or at
higher temperatures.
[0063] Prior efforts to prepare suitable crystalline forms of
atrasentan (including crystalline atrasentan parent, crystalline
atrasentan salts other than hydrochloride salts, co-crystals, and
crystalline ionic or molecular adducts) have been unsuccessful.
Applicant, however, has now succeeded in preparing and isolating
crystalline atrasentan mandelate salts and has discovered that such
salts have several advantages over the monohydrochloride salt. The
mandelate salts exhibit improved crystal morphology and either have
a reduced aspect ratio (the ratio of the height of a particle to
the cross-sectional dimension of a particle) and are less
needle-like or have a plate or prismatic shape. This crystal
morphology results in a higher bulk powder density and improved
powder handling properties for the mandelate salt. For example, a
120 mg tablet containing 0.75 mg of atrasentan will have a drug
loading of 0.67% for the hydrochloride salt (i.e., 0.8025 mg of the
hydrochloride salt per tablet) compared to a drug loading of 0.88%
for the mandelate salt (i.e., 1.05 mg of the mandelate salt per
tablet). As the drug loading increases, the likelihood of achieving
acceptable content uniformity also increases. In addition, the
improvement in crystal morphology also facilitates solid-liquid
separation during filtration.
[0064] The mandelate salts also represent an improvement over the
hydrochloride salts with respect to corrosivity. There is no need
to handle corrosive hydrochloric acid during the preparation of the
mandelate salt. Further, the previously-discussed concerns
regarding corrosion of tooling and longer-term chemical stability
associated with the monohydrochloride salt are materially reduced
for the mandelate salt.
[0065] Accordingly, in one embodiment the disclosure relates to an
atrasentan mandelate salt. In one aspect, the salt is an atrasentan
S-mandelate salt. In another aspect, the salt is an atrasentan
R-mandelate salt. The atrasentan mandelate salt can be in the form
of an anhydrate, a hydrate, or a solvate.
[0066] In another embodiment, the salt is a crystalline atrasentan
S-mandelate salt. In another aspect, the atrasentan S-mandelate
salt is an amorphous salt. In another aspect, the atrasentan
S-mandelate salt is an anhydrous salt. In another aspect, the
atrasentan S-mandelate salt is a solvated salt. In another aspect,
the atrasentan S-mandelate salt is a solvated salt selected from
the group consisting of an acetonitrile solvate, an ethanol
solvate, and a pyridine solvate. In another aspect, the atrasentan
S-mandelate salt is a hydrated salt.
[0067] In another embodiment, the salt is a crystalline atrasentan
R-mandelate salt. In another aspect, the atrasentan R-mandelate
salt is an amorphous salt. In another aspect, the atrasentan
R-mandelate salt is an anhydrous salt. In another aspect, the
atrasentan R-mandelate salt is a solvated salt. In another aspect,
the atrasentan R-mandelate salt is a hydrated salt.
[0068] (a) S-Mandelate Salt (1:1 Stoichiometry)
[0069] In one embodiment, the salt is a crystalline atrasentan
S-mandelate salt wherein the molar ratio of atrasentan to
S-mandelate is about 1:1. In one aspect, the atrasentan S-mandelate
salt is an anhydrous salt. In another aspect, the atrasentan
S-mandelate salt is a solvated salt. In another aspect, the
atrasentan S-mandelate salt is a solvated salt selected from the
group consisting of an acetonitrile solvate, an ethanol solvate,
and a pyridine solvate. In another aspect, the atrasentan
S-mandelate salt is a hydrated salt.
[0070] In another embodiment, the salt is a crystalline S-mandelate
salt having an X-ray powder diffraction pattern comprising peaks at
5.5.+-.0.2, 9.7.+-.0.2, and 19.4.+-.0.2 degrees two theta when
measured at about 25.degree. C. with monochromatic K.alpha.1
radiation. In one aspect, the salt is a crystalline S-mandelate
salt having an X-ray powder diffraction pattern comprising peaks at
5.5.+-.0.2, 9.7.+-.0.2, 12.1.+-.0.2, and 19.4.+-.0.2 degrees two
theta when measured at about 25.degree. C. with monochromatic
K.alpha.1 radiation. In another aspect, the salt is a crystalline
S-mandelate salt having an X-ray powder diffraction pattern
comprising peaks at 5.5.+-.0.2, 9.7.+-.0.2, 12.1.+-.0.2,
18.0.+-.0.2, 18.4.+-.0.2, and 19.4.+-.0.2 degrees two theta when
measured at about 25.degree. C. with monochromatic K.alpha.1
radiation. In another aspect, the experimental error associated
with the X-ray powder diffraction peak values recited in the
various embodiments above is .+-.0.1 degrees two theta. In another
aspect, the salt is an anhydrous salt. In another aspect, the molar
ratio of atrasentan to S-mandelate is about 1:1.
[0071] In another embodiment, the salt is a crystalline S-mandelate
salt having an orthorhombic lattice type. In one aspect, the salt
has a P212121 space group. In another aspect, the salt has unit
cell a, b and c values of about 9.954 .ANG., about 11.049 .ANG.,
and about 30.861 .ANG., respectively. In another aspect, the salt
has unit cell .alpha., .beta. and .gamma. values of about
90.degree., about 90.degree., and about 90.degree., respectively.
In another aspect, the salt has at least three or more of the
following properties: (a) an orthorhombic lattice type, (b) a
P212121 space group, (c) unit cell a, b and c values of about 9.954
.ANG., about 11.049 .ANG., and about 30.861 .ANG., respectively,
and/or (d) unit cell .alpha., .beta. and .gamma. values of about
90.degree., about 90.degree., and about 90.degree., respectively.
In another aspect, the salt has: (a) an orthorhombic lattice type,
(b) a P212121 space group, (c) unit cell a, b and c values of about
9.954 .ANG., about 11.049 .ANG., and about 30.861 .ANG.,
respectively, and (d) unit cell .alpha., .beta. and .gamma. values
of about 90.degree., about 90.degree., and about 90.degree.,
respectively. In another aspect, the salt is an anhydrous salt. In
another aspect, the molar ratio of atrasentan to S-mandelate is
about 1:1.
[0072] (b) S-Mandelate Salt (2:1 Stoichiometry)
[0073] In one embodiment, the salt is a crystalline atrasentan
S-mandelate salt wherein the molar ratio of atrasentan to
S-mandelate is about 2:1. In one aspect, the atrasentan S-mandelate
salt is an anhydrous salt. In another aspect, the atrasentan
S-mandelate salt is a solvated salt. In another aspect, the
atrasentan S-mandelate salt is a hydrated salt.
[0074] In another embodiment, the salt is a crystalline S-mandelate
salt having an X-ray powder diffraction pattern comprising peaks at
4.5.+-.0.2, 8.6.+-.0.2, and 18.1.+-.0.2 degrees two theta when
measured at about 25.degree. C. with monochromatic K.alpha.1
radiation. In one aspect, the salt is a crystalline S-mandelate
salt having an X-ray powder diffraction pattern comprising peaks at
4.5.+-.0.2, 8.6.+-.0.2, 18.1.+-.0.2, and 18.7.+-.0.2 degrees two
theta when measured at about 25.degree. C. with monochromatic
K.alpha.1 radiation. In another aspect, the salt is a crystalline
S-mandelate salt having an X-ray powder diffraction pattern
comprising peaks at 4.5.+-.0.2, 8.6.+-.0.2, 9.1.+-.0.2,
18.1.+-.0.2, and 18.7.+-.0.2 degrees two theta when measured at
about 25.degree. C. with monochromatic K.alpha.1 radiation. In
another aspect, the experimental error associated with the X-ray
powder diffraction peak values recited in the various embodiments
above is .+-.0.1 degrees two theta. In another aspect, the salt is
an anhydrous salt. In another aspect, the salt is a hydrated
salt.
[0075] (c) R-Mandelate Salt (1:1 Stoichiometry)
[0076] In one embodiment, the salt is a crystalline atrasentan
R-mandelate salt wherein the molar ratio of atrasentan to
R-mandelate is about 1:1. In one aspect, the atrasentan R-mandelate
salt is an anhydrous salt. In another aspect, the atrasentan
R-mandelate salt is a solvated salt. In another aspect, the
atrasentan R-mandelate salt is a hydrated salt.
[0077] In another embodiment, the salt is a crystalline R-mandelate
salt having an X-ray powder diffraction pattern comprising peaks at
5.7.+-.0.2, 11.8.+-.0.2, and 20.9.+-.0.2 degrees two theta when
measured at about 25.degree. C. with monochromatic K.alpha.1
radiation. In one aspect, the salt is a crystalline R-mandelate
salt having an X-ray powder diffraction pattern comprising peaks at
5.7.+-.0.2, 8.2.+-.0.2, 11.8.+-.0.2, and 20.9.+-.0.2 degrees two
theta when measured at about 25.degree. C. with monochromatic
K.alpha.1 radiation. In another aspect, the salt is a crystalline
R-mandelate salt having an X-ray powder diffraction pattern
comprising peaks at 5.7.+-.0.2, 8.2.+-.0.2, 8.6.+-.0.2,
11.8.+-.0.2, and 20.9.+-.0.2 degrees two theta when measured at
about 25.degree. C. with monochromatic K.alpha.1 radiation. In
another aspect, the experimental error associated with the X-ray
powder diffraction peak values recited in the various embodiments
above is .+-.0.1 degrees two theta. In another aspect, the salt is
an anhydrous salt.
III. METHODS OF TREATMENT
[0078] The present disclosure also relates to methods of treating a
condition in a subject, particularly a human subject suffering from
or susceptible to the condition, comprising administering to the
subject a therapeutically effective amount of an atrasentan
mandelate salt as described in the present disclosure.
[0079] In one embodiment, the present disclosure relates to methods
of treating nephropathy in a human subject suffering from or
susceptible to nephropathy comprising administering to the subject
a therapeutically effective amount of an atrasentan mandelate salt.
In a further aspect, the nephropathy treated is diabetic
nephropathy. In a further aspect, the subject selected for
treatment is suffering from diabetic nephropathy. In a further
aspect, the subject selected for treatment is suffering from type 2
diabetes mellitus. In a further aspect, the subject selected for
treatment is suffering from one or more of the following
conditions: (a) diabetic nephropathy; (b) type 2 diabetes; (c)
Stage 3 chronic kidney disease, Stage 4 chronic kidney disease, or
end stage renal disease; (d) a urinary-albumin-to-creatinine ratio
greater than about 30 mg/g (i.e., the subject is suffering from
microalbuminuria); (e) a urinary-albumin-to-creatinine ratio
greater than about 300 mg/g (i.e., the subject is suffering from
macroalbuminuria); and/or (f) an estimated glomerular filtration
rate from about 25 ml/min/1.73 m.sup.2 to about 59 ml/min/1.73
m.sup.2. In a further aspect, the subject is also administered a
second therapeutic agent that inhibits one or more elements of the
renin-angiotensin-aldosterone system. In a further aspect, the
second therapeutic agent that inhibits one or more elements of the
renin-angiotensin-aldosterone system is selected from the group
consisting of diuretics, angiotensin converting enzyme inhibitors,
angiotensin II receptor blockers, calcium channel blockers, renin
inhibitors, and aldosterone antagonists. In a further aspect, the
second therapeutic agent that inhibits one or more elements of the
renin-angiotensin-aldosterone system is selected from the group
consisting of angiotensin converting enzyme inhibitors and
angiotensin II receptor blockers.
[0080] In another embodiment, the present disclosure relates to
methods of treating chronic kidney disease in a human subject
suffering from or susceptible to chronic kidney disease comprising
administering to the subject a therapeutically effective amount of
an atrasentan mandelate salt. In a further aspect, the chronic
kidney disease is Stage 3 or Stage 4 chronic kidney disease. In a
further aspect, the chronic kidney disease is end stage renal
disease. In a further aspect, the treatment delays progression of
chronic kidney disease in the subject. In a further aspect, the
treatment delays progression of end stage renal disease in the
subject. In a further aspect, the subject selected for treatment is
suffering from diabetic nephropathy. In a further aspect, the
subject selected for treatment is suffering from type 2 diabetes
mellitus. In a further aspect, the subject selected for treatment
is suffering from Stage 3 or Stage 4 chronic kidney disease. In a
further aspect, the subject selected for treatment is suffering
from end stage renal disease. In a further aspect, the subject
selected for treatment is suffering from one or more of the
following conditions: (a) diabetic nephropathy; (b) type 2
diabetes; (c) Stage 3 chronic kidney disease, Stage 4 chronic
kidney disease, or end stage renal disease; (d) a
urinary-albumin-to-creatinine ratio greater than about 30 mg/g; (e)
a urinary-albumin-to-creatinine ratio greater than about 300 mg/g;
and/or (f) an estimated glomerular filtration rate from about 25
ml/min/1.73 m.sup.2 to about 59 ml/min/1.73 m.sup.2. In a further
aspect, the subject is also administered a second therapeutic agent
that inhibits one or more elements of the
renin-angiotensin-aldosterone system. In a further aspect, the
second therapeutic agent that inhibits one or more elements of the
renin-angiotensin-aldosterone system is selected from the group
consisting of diuretics, angiotensin converting enzyme inhibitors,
angiotensin II receptor blockers, calcium channel blockers, renin
inhibitors, and aldosterone antagonists. In a further aspect, the
second therapeutic agent that inhibits one or more elements of the
renin-angiotensin-aldosterone system is selected from the group
consisting of angiotensin converting enzyme inhibitors and
angiotensin II receptor blockers.
[0081] In another embodiment, the present disclosure relates to
methods of reducing the urinary-albumin-to-creatinine ratio in a
human subject suffering from or susceptible to chronic kidney
disease comprising administering to the subject a therapeutically
effective amount of an atrasentan mandelate salt.
[0082] In another embodiment, the present disclosure relates to
methods of reducing the rate of increase in serum creatinine
concentration in a human subject suffering from or susceptible to
chronic kidney disease comprising administering to the subject a
therapeutically effective amount of an atrasentan mandelate
salt.
[0083] In additional embodiments, the amount of the atrasentan
mandelate salt administered to the subject in any of the
above-described methods is from about 0.25 mg daily to about 1.25
mg daily on an atrasentan parent equivalent weight basis. In one
aspect, the amount of the atrasentan mandelate salt administered to
the subject is from about 0.40 mg daily to about 1.00 mg daily on
an atrasentan parent equivalent weight basis. In another aspect,
the amount of the atrasentan mandelate salt administered to the
subject is from about 0.40 mg daily to about 0.85 mg daily on an
atrasentan parent equivalent weight basis. In another aspect, the
amount of the atrasentan mandelate salt administered to the subject
is about 0.50 mg daily on an atrasentan parent equivalent weight
basis. In another aspect, the amount of the atrasentan mandelate
salt administered to the subject is about 0.75 mg daily on an
atrasentan parent equivalent weight basis.
[0084] In another embodiment, the present disclosure relates to the
use of an atrasentan mandelate salt for treating a condition as
described in the various embodiments of the disclosure.
[0085] In another embodiment, the present disclosure relates to the
use of an atrasentan mandelate salt in the preparation of a
medicament for treating a condition as described in the various
embodiments of the disclosure.
IV. PHARMACEUTICAL COMPOSITIONS
[0086] The present disclosure also relates to pharmaceutical
compositions comprising an atrasentan mandelate salt as described
in the present disclosure, and a pharmaceutically acceptable
carrier. Such pharmaceutical compositions can be formulated for
various routes of systemic or local delivery for example, by oral
administration, topical administration, transmucosal
administration, rectal administration, intravaginal administration,
or administration by subcutaneous, intrathecal, intravenous,
intramuscular, intraperitoneal, intranasal, intraocular or
intraventricular injection.
[0087] The pharmaceutical compositions often further comprise one
or more pharmaceutically acceptable excipients in addition to the
carrier. The term "excipient" is used in this application to
describe any ingredient other than atrasentan, or a
pharmaceutically acceptable salt thereof, or another
pharmacological agent. The choice of excipient(s) will depend to a
large extent on factors such as the particular mode of
administration, the effect of the excipient on solubility and
stability, and the nature of the dosage form. The pharmaceutical
compositions can be formulated for immediate release or modified
release. Modified release formulations include delayed-,
sustained-, pulsed-, controlled-, targeted and programmed release
formulations. Methods generally known in the art can be employed to
manufacture the pharmaceutical compositions of the present
invention, e.g., conventional granulating, mixing, dissolving,
encapsulating, lyophilizing, emulsifying, or levigating processes,
among others. The pharmaceutical compositions discussed below are
given by way of example and should not be construed as limiting the
present invention.
[0088] (d) Oral Administration
[0089] For oral, buccal, and sublingual administration, the
atrasentan mandelate salt can be formulated as a solid dosage form
such as a powder, suspension, granule, tablet, pill, capsule,
gelcap, or caplet. These solid dosage forms can be prepared, for
example, by mixing the atrasentan mandelate salt with at least one
excipient such as sucrose, lactose, cellulose sugar, mannitol,
maltitol, dextran, sorbitol, starch, agar, alginates, chitins,
chitosans, pectins, tragacanth gum, gum arabic, gelatins,
collagens, casein, albumin, synthetic or semi-synthetic polymers or
glycerides, methyl cellulose, hydroxypropylmethylcellulose, and/or
polyvinylpyrrolidone. Solid dosage forms optionally can contain
additional excipients to aid in administration, such as an inactive
diluent, a lubricant (such as magnesium stearate), a preservative
(such as a paraben acid or sorbic acid), an antioxidant (such as
ascorbic acid, tocopherol or cysteine), a disintegrating agent, a
binder, a thickener, a buffer, a sweetener, a flavoring agent, or a
perfuming agent. Dyestuffs or pigments can be added to the
pharmaceutical composition for identification. Tablets and pills
can be further treated with suitable coating materials known in the
art (e.g., enteric coating materials).
[0090] Atrasentan mandelate salts also can be formulated for oral
administration as a liquid dosage form such as an emulsion, syrup,
elixir, suspension, slurry, or solution. Such liquid dosage forms
generally contain one or more pharmaceutically acceptable
excipients in addition to the atrasentan mandelate salt, e.g., a
sterile liquid (such as water, an oil, an alcohol, or a combination
of these excipients), a surfactant, a suspending agent, or an
emulsifying agent. Examples of pharmaceutically acceptable oils
include peanut oil, sesame oil, cottonseed oil, corn oil, olive oil
and mixtures of oils. Examples of pharmaceutically acceptable
alcohols include ethanol, isopropyl alcohol, hexadecyl alcohol,
glycerol and propylene glycol. Additionally, liquid suspensions can
also contain, for example, esters of fatty acids (such as ethyl
oleate, isopropyl myristate, fatty acid glycerides and acetylated
fatty acid glycerides) and ethers (such as poly(ethyleneglycol)),
petroleum hydrocarbons including mineral oil and petrolatum.
[0091] (e) Parenteral Administration
[0092] The atrasentan mandelate salt can be formulated for
administration by injection, e.g., by subcutaneous, intrathecal,
intravenous, intramuscular, intraperitoneal, intranasal,
intraocular or intraventricular injection. Such injectable dosage
forms can be in solution phase or in the form of a suspension (such
as an aqueous suspension or oil suspension employing a suitable
dispersant or wetting agent and a suspending agent). Injectable
dosage forms generally are prepared using a solvent or diluent.
Pharmaceutically acceptable solvents or vehicles include sterilized
water, Ringer's solution, and isotonic aqueous saline solution.
Alternatively, sterile oils or fatty acids can be employed as
solvents or suspending agents. Generally, the oil or fatty acid is
non-volatile, including natural or synthetic oils, fatty acids,
mono-, di- or tri-glycerides.
[0093] Injectable dosage forms also can be prepared as a powder
suitable for reconstitution with an appropriate vehicle as
described above. Examples of these injectable dosage forms include
freeze-dried powders, rotary-dried powders, spray-dried powders,
amorphous powders, granules, precipitates, and particulates.
[0094] Injectable dosage forms optionally can contain additional
excipients including stabilizers, cyclodextrins (such as a
beta-cyclodextrin), pH modifiers, surfactants, bioavailability
modifiers, and combinations of these excipients. They can be
formulated for administration by bolus injection or continuous
infusion. A unit dosage form for injection can be in ampoules or in
multi-dose containers.
[0095] (f) Topical Administration
[0096] The atrasentan mandelate salt can be formulated for
administration topically to the skin or mucosa, i.e., dermally or
transdermally. Topical formulations include, e.g., gels, hydrogels,
lotions, solutions, creams, ointments, dusting powders, dressings,
foams, films, skin patches, wafers, implants, sponges, fibers,
bandages and microemulsions. Typical carriers used in topical
formulations include, e.g., alcohol, water, mineral oil, liquid
petrolatum, white petrolatum, glycerin, polyethylene glycol and
propylene glycol. Topical formulations may also employ liposomes
and penetration enhancers.
[0097] (g) Inhaled/Intranasal Administration
[0098] The atrasentan mandelate salt can be formulated for
inhalation or administration nasally. These pharmaceutical
formulations can be a spray or aerosol containing an appropriate
solvent and optionally other excipients including stabilizers,
antimicrobial agents, antioxidants, pH modifiers, surfactants,
bioavailability modifiers, and combinations of these. A propellant
for an aerosol formulation can include, e.g., compressed air,
nitrogen, carbon dioxide, or a hydrocarbon-based, low-boiling
solvent. The atrasentan mandelate salt can be conveniently
delivered in the form of an aerosol spray presentation from a
nebulizer or the like.
[0099] (h) Rectal/Intravaginal Administration
[0100] The atrasentan mandelate salt can be formulated for rectal
or intravaginal administration. These formulations can be in the
form of a suppository, pessary, ointment, enema, a tablet, or a
cream for release of the atrasentan mandelate salt, such as in the
intestines, sigmoid flexure and/or rectum. Rectal suppositories are
prepared by mixing an atrasentan mandelate salt of the present
invention with an acceptable vehicle (e.g., cocoa butter or
polyethylene glycol) which is present in a solid phase at normal
storing temperatures, and present in a liquid phase at those
temperatures suitable to release a drug inside the body, such as in
the rectum. Oils can also be employed in the preparation of
formulations of the soft gelatin type and suppositories. Water,
saline, aqueous dextrose and related sugar solutions, and glycerols
can be employed in the preparation of suspension formulations which
can also contain suspending agents such as pectins, carbomers,
methyl cellulose, hydroxypropyl cellulose or carboxymethyl
cellulose, as well as buffers and preservatives.
[0101] (i) Ocular and Aural Administration
[0102] The atrasentan mandelate salt can be formulated for
administration directly to the eye or ear, typically in the form of
drops of a micronized suspension or solution in isotonic,
pH-adjusted, sterile saline. Other formulations suitable for ocular
and aural administration include, e.g., ointments, biodegradable
(e.g., absorbable gel sponges, collagen) and non-biodegradable
(e.g., silicone) implants, wafers, lenses, and particulate or
vesicular systems, such as niosomes or liposomes. Ocular and aural
formulation may also incorporate additional excipients such as
preservatives (such as benzalkonium chloride) and a polymer such as
a crossed-linked polyacrylic acid, polyvinyl alcohol, or hyaluronic
acid; a cellulosic polymer (such as hydroxypropylmethylcellulose,
hydroxyethylcellulose, or methyl cellulose); or a
heteropolysaccharide polymer (such as gelan gum). These
formulations also may be delivered by iontophoresis.
[0103] (j) Other Technologies
[0104] The atrasentan mandelate salt may be combined with soluble
macromolecular entities, such as cyclodextrin and suitable
derivatives thereof or polyethylene glycol-containing polymers, in
order to improve solubility, dissolution rate, taste-masking,
bioavailability and/or stability for use in any of the
aforementioned modes of administration. Drug-cyclodextrin
complexes, for example, are found to be generally useful for most
dosage forms and administration routes. Both inclusion and
non-inclusion complexes may be used. As an alternative to direct
complexation with the drug, the cyclodextrin may be used as an
auxiliary additive, i.e. as a carrier, diluent, or solubiliser.
Alpha-, beta- and gamma-cyclodextrins are commonly used for these
purposes, examples of which may be found in International Patent
Applications Nos. WO1991/11172, WO1994/02518 and WO1998/55148.
[0105] The pharmaceutical compositions for administering the
atrasentan mandelate salt can also comprise, for example, micelles
or liposomes, or some other encapsulated form, or can be
administered in an extended release form to provide a prolonged
storage and/or delivery effect. Therefore, the pharmaceutical
compositions can be compressed into pellets or cylinders and
implanted intramuscularly or subcutaneously as depot injections or
as implants such as stents. Such implants can employ known
materials such as silicones and biodegradable polymers.
[0106] Besides those representative dosage forms described above,
pharmaceutically acceptable excipients and carriers are generally
known to those skilled in the art and are thus included in the
instant invention. Such excipients and carriers are described, for
example, in "Remington's Pharmaceutical Sciences," Mack Pub. Co.,
New Jersey (1991).
[0107] In one embodiment, the pharmaceutical composition is a solid
pharmaceutical dosage form comprising from about 0.25 mg to about
1.25 mg of the atrasentan mandelate salt on an atrasentan parent
equivalent weight basis. In one aspect, the pharmaceutical
composition comprises from about 0.40 mg to about 1.00 mg of the
atrasentan mandelate salt on an atrasentan parent equivalent weight
basis. In another aspect, the pharmaceutical composition comprises
from about 0.40 mg to about 0.85 mg of the atrasentan mandelate
salt on an atrasentan parent equivalent weight basis. In another
aspect, the pharmaceutical composition comprises from about 0.50 of
the atrasentan mandelate salt on an atrasentan parent equivalent
weight basis. In another aspect, the pharmaceutical composition
comprises from about 0.75 of the atrasentan mandelate salt on an
atrasentan parent equivalent weight basis.
[0108] In another embodiment, the pharmaceutical composition is a
tablet. In one aspect, the tablet has a weight from about 37.5 mg
to about 1500 mg. In another aspect, the tablet has a weight from
about 50 mg to about 750 mg. In another aspect, the tablet has a
weight from about 50 mg to about 250 mg. In another aspect, the
tablet has a weight from about 75 mg to about 500 mg. In another
aspect, the tablet has a weight from about 75 mg to about 150 mg.
In another aspect, the tablet has a weight from about 100 mg to
about 250 mg. In another aspect, the tablet has a weight from about
100 mg to about 230 mg.
[0109] In general, the tablet optionally can be surrounded or
coated with at least one non-rate-controlling layer. The
non-rate-controlling layer can be formed as a single layer, coating
or membrane or a plurality of single layers, coatings or membranes.
The functions of the non-rate-controlling layer can include, for
example, providing further stability for the atrasentan, serving as
a process aid and/or as a cosmetic enhancement for the formulation,
and/or acting as a masking agent to reduce any undesired odor
associated with the formulation (such as the odor commonly
associated with L-cysteine).
[0110] When the dosage form comprises a non-rate-controlling layer,
the non-rate-controlling layer can be made of one or more polymers,
as well as, other ingredients known in the art, such as, but not
limited to, plasticizers, pigments/opacifiers, waxes, etc. Examples
of polymers that can be used include, but are not limited to,
hydroxypropylmethylcellulose, hydroxypropyl cellulose,
methylcellulose, polyvinyl alcohol and polyethylene glycol.
Examples of plasticizers that can be used include, but are not
limited to, polyethylene glycol(s), glycerin, triacetin, triethyl
citrate, diethyl phthalate, L-cysteine, and mineral oils. Examples
of pigments/opacifiers that can be used include, but are not
limited to, water soluble dyes (for example, sunset yellow,
quinoline yellow, erythrosine, and tartrazine), pigments (for
example, aluminum lakes, titanium oxides, iron oxides and talc),
and natural products (for example, riboflavin, carotenoids,
chlorophyll, anthocyanins, and carmine). An example of a wax that
can be used includes, but is not limited to, a paraffin wax.
[0111] In another embodiment, the dosage form is a tablet coated
with a pharmaceutically acceptable polymer.
[0112] In another embodiment, the dosage form is a capsule.
[0113] In another embodiment, the dosage form is packaged in a
semi-permeable container. In one aspect, the semi-permeable
container is a blister pack.
[0114] In another embodiment, the dosage form is packaged in a
substantially impermeable container.
[0115] In another embodiment, the dosage form is an immediate
release dosage form. In one aspect, the dosage form is an immediate
release tablet and releases at least about 85% of the atrasentan,
or pharmaceutically acceptable salt thereof, within about 45
minutes as determined in an in vitro dissolution test conducted
using a USP Dissolution Apparatus 2 (Paddle Apparatus), a 0.01N
hydrochloric acid dissolution medium, and a paddle rotation of 50
RPM. In another aspect, the dosage form is an immediate release
tablet and releases at least about 75% of the atrasentan mandelate
salt within about 30 minutes.
V. COMBINATION THERAPY AND FIXED-DOSE COMBINATIONS
[0116] The methods of the present disclosure also contemplate
treatments comprising administering an atrasentan mandelate salt in
combination with one or more additional therapeutic agents (such as
an inhibitor of one or more elements of the
renin-angiotensin-aldosterone system as previously discussed
above). Accordingly, the atrasentan mandelate salts of the present
disclosure can be administered alone or in combination with one or
more additional therapeutic agents. When administered to a subject
in combination with one or more additional therapeutic agents, the
atrasentan mandelate salt and additional therapeutic agent(s) can
be administered as separate dosage forms or as a single dosage form
comprising the atrasentan mandelate salt and the additional
therapeutic agent(s) (i.e., a fixed-dose combination). If
administered as a separate dosage form, the additional therapeutic
agent may be administered either simultaneously with, or
sequentially with, the dosage form comprising the atrasentan
mandelate salt.
[0117] Representative additional therapeutic agents include, for
example, diuretics, antihypertensive agents, therapeutic agents for
diabetes or diabetic complications, and therapeutic agents for
hyperlipidemia.
[0118] In one embodiment, the atrasentan mandelate salt may be
co-administered with one or more diuretics such as
hydrochlorothiazide (such as MICROZIDE.TM. or ORETIC.TM.),
hydroflumethiazide (such as SALURON.TM.), bemetanide (such as
BUMEX.TM.), torsemide (such as DEMADEX.TM.), metolazone (such as
ZAROXOLYN.TM.), chlorothiazide (such as DIURIL.TM., ESIDRIX.TM. or
HYDRODIURIL.TM.), triamterene (such as DYRENIUM.TM.), ethacrynic
acid (such as EDECRIN.TM.), chlorthalidone (such as HYGROTON.TM.),
furosemide (such as LASIX.TM.), indapamide (such as LOZOL.TM.), or
amiloride (such as MIDAMOR.TM. or MODURETIC.TM.).
[0119] In another embodiment, the atrasentan mandelate salt may be
co-administered with one or more angiotensin converting enzyme
(ACE) inhibitors such as quinapril (such as ACCUPRIL.TM.),
perindopril (such as ACEON.TM.), captopril (such as CAPOTEN.TM.),
enalapril (such as VASOTEC.TM.), ENALAPRILAT.TM., ramipril (such as
ALTACE.TM.), cilazapril, delapril, fosenopril (such as
MONOPRIL.TM.) zofenopril, indolapril, benazepril (such as
LOTENSIN.TM.), lisinopril (such as PRINIVIL.TM. or ZESTRIL.TM.),
spirapril, trandolapril (such as MAVIK.TM.), perindep, pentopril,
moexipril (such as UNIVASC.TM.), or pivopril.
[0120] In another embodiment, the atrasentan mandelate salt may be
co-administered with one or more angiotensin II receptor blockers
such as candesartan (such as ATACAND.TM.), eprosartan (such as
TEVETEN.TM.), irbesartan (such as AVEPRO.TM.), losartan (such as
COZAAR.TM.), olmesartan, olmesartan medoxomil (such as
BENICAR.TM.), tasosartan, telmisartan (such as MICARDIS.TM.)
valsartan (such as DIOVAN.TM.), zolasartan, F1-6828K, RNH-6270,
UR-7198, Way-126227, KRH-594, TAK-536, BRA-657, or TA-606.
[0121] In another embodiment, the atrasentan mandelate salt may be
co-administered with one or more calcium channel blockers such as
nifedipine (such as ADALAT.TM., ADALAT CC.TM., or PROCARDIA.TM.),
verapamil (such as GALAN.TM., COVERA-HS.TM., ISOPTIN SR.TM., or
VERELAN.TM.), diltiazem (such as CARDIZEM.TM., CARDIZEM CD.TM.,
CARDIZEM LA.TM., CARDIZEM SR.TM., DILACOR.TM., TIAMATE.TM., or
TIAZAC.TM.), isradipine (such as DYNACIRC.TM. or DYNACIRC CR.TM.),
amlodipine (such as NORVASC.TM.), felodipine (such as PLENDIL.TM.),
nisoldipine (such as SULAR.TM.), bepridil (such as VASCOR.TM.)
vatanidipine, clevidipine, lercanidipine, or dilitiazem.
[0122] In another embodiment, the atrasentan mandelate salt may be
co-administered with one or more renin inhibitors such as aliskiren
(such as TEKTURNA.TM.).
[0123] In another embodiment, the atrasentan mandelate salt may be
co-administered with one or more aldosterone receptor antagonists
such as eplerenone (such as INSPRA.TM.) or spironolactone (such as
ALDACTONE.TM.).
[0124] In another embodiment, the atrasentan mandelate salt may be
co-administered with one or more alpha blockers such as doxazosin
(such as CARDURA.TM.), phenoxybenzamine (such as DIBENZYLINE.TM.),
terazosin (such as HYTRIN.TM.), CDR1-93/478, or CR-2991.
[0125] In another embodiment, the atrasentan mandelate salt may be
co-administered with one or more beta blockers such as timolol
(such as BLOCARDEN.TM.), carteolol (such as CARTROL.TM.),
carvedilol (such as COREG.TM.) nadolol (such as CORGARD.TM.),
propranolol (such as INNOPRAN XL.TM.), betaxolol (such as
KERLONE.TM.), penbutolol (such as LEVATOL.TM.), metoprolol (such as
LOPRESSOR.TM. or TOPROL-XL.TM.), atenolol (such as TENORMIN.TM.),
pindolol (such as VISKEN.TM.), or bisoprolol.
[0126] In another embodiment, the atrasentan mandelate salt may be
co-administered with one or more alpha-beta blockers such as
labetalol (such as NORMODYNE.TM. or TRANDATE.TM.).
[0127] In another embodiment, the atrasentan mandelate salt may be
co-administered with one or more central antiadrenergics such as
methyldopa (such as ALDOMET.TM.), clonidine (such as CATAPRES.TM.
or CATAPRES-TTS.TM.), guanfacine (such as TENEX.TM.), or guanabenz
(such as WYTENSIN.TM.).
[0128] In another embodiment, the atrasentan mandelate salt may be
co-administered with one or more glycosides/inotropic agents such
as digoxin (such as LANOXIN.TM.).
[0129] In another embodiment, the atrasentan mandelate salt may be
co-administered with one or more alpha glucosidase inhibitors, such
as miglitol (such as GLYSET.TM.) or acarbose (such as
PRECOSE.TM.).
[0130] In another embodiment, the atrasentan mandelate salt may be
co-administered with one or more biguanides, such as rosiglitazone
(such as AVANDAMET.TM.) or metformin (such as GLUCOPHAGE.TM. or
GLUCOPHAGE XR.TM.).
[0131] In another embodiment, the atrasentan mandelate salt may be
co-administered with one or more insulins, such as HUMALOG.TM.,
HUMALOG 50/50.TM., HUMALOG 75/25.TM., HUMULIN 50/50.TM., HUMALIN
75/25.TM., HUMALIN L.TM., HUMALIN N.TM., HUMALIN R.TM., HUMALIN R
U-500.TM., HUMALIN U.TM., ILETIN II LENTE.TM., ILETIN II NPH.TM.,
ILETIN II REGULAR.TM., LANTUS.TM., NOVOLIN 70/30.TM., NOVILIN
N.TM., NOVILIN R.TM., NOVOLOG.TM., or VELOSULIN BR.TM., and
EXUBERA.TM..
[0132] In another embodiment, the atrasentan mandelate salt may be
co-administered with one or more meglitnides, such as repaglinide
(such as PRANDIN.TM.) or nateglinide (such as STARLIX.TM.).
[0133] In another embodiment, the atrasentan mandelate salt may be
co-administered with one or more sulfonylureas, such as glimepiride
(such as AMARYL.TM.), glyburide (such as DIABETA.TM., GLYNASE
PRESTAB.TM. or MICRONASE.TM.), or glipizide (such as GLUCOTROL.TM.,
or GLUCOTROL XL.TM.).
[0134] In another embodiment, the atrasentan mandelate salt may be
co-administered with one or more thiazolidinediones, such as
pioglitazone (such as ACTOS.TM.) or rosiglitazone (such as
AVANDIA.TM.).
[0135] In another embodiment, the atrasentan mandelate salt may be
co-administered with niacin or one or more nicotinic acid
derivatives, such as NIACOR.TM., NIASPAN.TM., NICOLAR.TM., or
SLO-NIACIN.TM..
[0136] In another embodiment, the atrasentan mandelate salt may be
co-administered with one or more fibric acid derivatives, such as
clofibrate (such as ATROMID-S.TM.), gemfibrozil (such as
LOPID.TM.), or fenofibrate (such as TRICOR.TM.).
[0137] In another embodiment, the atrasentan mandelate salt may be
co-administered with one or more bile acid sequestrants, such as
colestipol (such as COLESTID.TM.), cholestyramine (such as
LOCHOLEST.TM., PREVALITE.TM., QUESTRAN.TM., or QUESTRAN LIGHT.TM.),
or colesevelam (such as WELCHOL.TM.).
[0138] In another embodiment, the atrasentan mandelate salt may be
co-administered with one or more cholesterol absorption inhibitors,
such as ezetimibe (such as ZETIA.TM.).
[0139] In another embodiment, the atrasentan mandelate salt may be
co-administered with one or more 3-hydroxy-3-methylglutaryl
coenzyme A (HMG-CoA) reductase inhibitors (statins) such as
fluvastatin (such as LESCOL.TM.) atorvastatin (such as
LIPITOR.TM.), lovastatin (such as ALTOCOR.TM. or MEVACOR.TM.),
pravastatin (such as PRAVACHOL.TM.), rosuvastatin (such as
CRESTOR.TM.), or simvastatin (such as ZOCOR.TM.).
[0140] In another embodiment, the present disclosure relates to the
use of a pharmaceutical composition comprising an atrasentan
mandelate salt for treating a condition as described in the various
embodiments of the disclosure.
[0141] In another embodiment, the present disclosure relates to the
use of a first pharmaceutical composition in combination with a
second pharmaceutical composition for treating a condition as
described in the various embodiments of the disclosure, wherein the
first pharmaceutical composition comprises an atrasentan mandelate
salt, and the second pharmaceutical composition comprises a second
therapeutic agent.
[0142] In another embodiment, the present disclosure relates to the
use of a pharmaceutical composition comprising an atrasentan
mandelate salt for treating a condition as described in the various
embodiments of the disclosure, wherein the pharmaceutical
composition further comprises one or more additional therapeutic
agents.
[0143] In another embodiment, the present disclosure relates to a
pharmaceutical composition comprising an atrasentan mandelate salt,
and further comprising a second therapeutic agent. In one aspect,
the second therapeutic agent inhibits one or more elements of the
renin-angiotensin-aldosterone system. In a further aspect, the
second therapeutic agent is selected from the group consisting of
diuretics, angiotensin converting enzyme inhibitors, angiotensin II
receptor blockers, calcium channel blockers, renin inhibitors, and
aldosterone antagonists. In a further aspect, the second
therapeutic agent is selected from the group consisting of
angiotensin converting enzyme inhibitors and angiotensin II
receptor blockers. In a further aspect, the second therapeutic
agent is an angiotensin converting enzyme inhibitor. In a further
aspect, the second therapeutic agent is an angiotensin II receptor
blocker.
VI. KITS
[0144] The present disclosure also relates to kits comprising one
or more solid pharmaceutical dosage forms (such as tablets or
capsules) comprising an atrasentan mandelate salt. The kit
optionally can comprise one or more additional therapeutic agents
and/or instructions, for example, instructions for using the
kit.
[0145] In one embodiment, the kit comprises a semi-permeable
container containing one or more solid pharmaceutical dosage forms
comprising an atrasentan mandelate salt. In one aspect, the
semi-permeable container is a blister pack.
[0146] In another embodiment, the kit comprises a substantially
impermeable container containing one or more solid pharmaceutical
dosage forms comprising an atrasentan mandelate salt.
[0147] In another embodiment, the kit comprises a first dosage form
and a second dosage form, wherein the first dosage form is a solid
pharmaceutical dosage form comprising an atrasentan mandelate salt,
and the second dosage form comprises a second therapeutic agent. In
a further aspect, the second therapeutic agent is selected from the
group consisting of diuretics, angiotensin converting enzyme
inhibitors, angiotensin II receptor blockers, calcium channel
blockers, renin inhibitors, and aldosterone antagonists. In a
further aspect, the second therapeutic agent is selected from the
group consisting of angiotensin converting enzyme inhibitors and
angiotensin II receptor blockers. In a further aspect, the second
therapeutic agent is an angiotensin converting enzyme inhibitor. In
a further aspect, the second therapeutic agent is an angiotensin II
receptor blocker. In a further aspect, the kit comprises a
semi-permeable container containing the first dosage form and the
second dosage form. In a further aspect, the kit comprises a
blister pack containing the first dosage form and the second dosage
form. In a further aspect, the kit comprises an impermeable
container containing the first dosage form and the second dosage
form.
VII. METHODS OF PREPARATION
[0148] The present disclosure also relates to methods for preparing
an atrasentan mandelate salt, wherein the method comprises the
steps of (a) contacting atrasentan with a solvent comprising
mandelic acid to form a mixture comprising an atrasentan mandelate
salt, and (b) isolating the atrasentan mandelate salt from the
mixture. In one embodiment, the molar ratio of mandelic acid to
atrasentan in the contacting step is greater than about 1:1. In
another embodiment, the isolated salt is a crystalline salt such as
an anhydrous crystalline salt. In another embodiment, the molar
ratio of mandelic acid to atrasentan in the contacting step is
greater than about 1:1, and the isolated salt is a crystalline salt
such as an anhydrous crystalline salt. In one embodiment, the
mandelic acid is S-mandelic acid. In another embodiment, the
mandelic acid is R-mandelic acid. In another embodiment, the
contacting step optionally comprises heating the mixture to
substantially dissolve any solids present. In another embodiment,
the contacting step optionally comprises stirring or agitating the
mixture. In another embodiment, the isolation step optionally
comprises cooling the mixture. In another embodiment, the isolation
step optionally comprises filtering the mixture.
[0149] The solvent selected can be a single solvent or a mixture of
two or more different solvents. In one embodiment, the solvent
comprises water. In another embodiment the solvent comprises
methanol. In another embodiment, the solvent comprises water and
methanol. In another embodiment, the solvent is a 1:1 volume to
volume mixture of water and methanol. In another embodiment, the
solvent comprises at least one member selected from the group
consisting of acetonitrile, ethanol, and pyridine.
[0150] Crystallization/precipitation of the salt can be facilitated
as needed by methods such as cooling, seeding, partial removal of
the solvent from the atrasentan/solvent solution, addition of an
anti-solvent to the atrasentan/solvent solution, or combinations of
such methods. In one embodiment, the atrasentan/solvent solution is
seeded with the desired crystalline atrasentan mandelate salt, such
as an anhydrous crystalline atrasentan S-mandelate salt having a
molar ratio of atrasentan to S-mandelate of about 1:1.
[0151] The mandelate salt can be isolated using conventional
isolation methods such as filtration, filtration under vacuum or
pressure, decantation, centrifugation, manual separation, or a
combination of those methods.
[0152] The isolated mandelate salt can be further dried in, for
example, a vacuum tray dryer, Rotocon vacuum dryer, vacuum paddle
dryer, or pilot plant Rota vapor, to further lower residual
solvents. Drying can be carried out under reduced pressure until
the residual solvent content is reduced to the desired amount (such
as an amount that is within the limits of applicable International
Conference on Harmonization guidelines.
[0153] Where the desired salt is an atrasentan S-mandelate salt
having a molar ratio of atrasentan to S-mandelate of about 1:1, the
method may employ a molar excess of mandelic acid in the contacting
step, particularly where the use of a lower amount of mandelic acid
results in a mixture of atrasentan S-mandelate salts (e.g., a
mixture of one salt having a molar ratio of atrasentan to
S-mandelate of about 1:1 and a second salt having a molar ratio of
atrasentan to S-mandelate of about 2:1). Accordingly, in one
embodiment, the molar ratio of mandelic acid to atrasentan in the
contacting step is at least about 2:1. In another embodiment, the
molar ratio of mandelic acid to atrasentan in the contacting step
is at least about 3:1. In another embodiment, the molar ratio of
mandelic acid to atrasentan in the contacting step is at least
about 4:1.
[0154] In one embodiment, the isolated salt comprises at least
about 95 weight percent of atrasentan S-mandelate salt having a
molar ratio of atrasentan to S-mandelate of about 1:1. In another
aspect, the weight percent is at least about 96 weight percent. In
another aspect, the weight percent is at least about 97 weight
percent. In another aspect, the weight percent is at least about 98
weight percent. In another aspect, the weight percent is at least
about 99 weight percent. In another aspect, the isolated salt is
substantially atrasentan S-mandelate salt having a molar ratio of
atrasentan to S-mandelate of about 1:1.
[0155] In another embodiment, the isolated salt comprises at least
about 95 weight percent of crystalline atrasentan S-mandelate salt
and has a crystalline purity of at least about 90 percent with
respect to crystalline atrasentan S-mandelate salt having a molar
ratio of atrasentan to S-mandelate of about 1:1. In another aspect,
the weight percent is at least about 96 weight percent and the
crystalline purity is at least 93 percent. In another aspect, the
weight percent is at least about 97 weight percent and the
crystalline purity is at least 95 percent. In another aspect, the
weight percent is at least about 98 weight percent and the
crystalline purity is at least 97 percent. In another aspect, the
weight percent is at least about 99 weight percent and the
crystalline purity is at least 99 percent. In another aspect, the
isolated salt is substantially anhydrous crystalline atrasentan
S-mandelate salt having a molar ratio of atrasentan to S-mandelate
of about 1:1.
VIII. PRODUCT-BY-PROCESS
[0156] The present disclosure also relates to atrasentan mandelate
salts prepared in accordance with any of the methods described in
the disclosure.
IX. EXAMPLES
Example 1: Atrasentan Salts
[0157] Several studies were conducted to identify new atrasentan
salts (particularly new crystalline atrasentan salts) and are
described below.
[0158] A. Experiment A
[0159] Solutions of several different organic or inorganic acids in
a methanol solvent were prepared for use in the study. These
solutions (including their concentrations) are reported in Table
1-A below.
TABLE-US-00001 TABLE 1-A SALT FORMING CONC. VOLUME AGENT SOLVENT
(M) (.mu.L) PRECIPITATION H.sub.2SO.sub.4 Methanol 1 100 Yes
(amorphous) H.sub.3PO.sub.4 Methanol 1 100 No Citric acid Methanol
0.5 200 No L-Tartaric acid Methanol 0.5 200 No Malonic acid
Methanol 0.5 200 No Succinic acid Methanol 0.5 200 No Glycolic acid
Methanol 0.5 200 No L-Malic acid Methanol 0.5 200 No S-Mandelic
Methanol 0.5 200 Yes acid (gel-like semi-solid)
[0160] Each acid/methanol solution prepared was added with stirring
to a vial containing 25 mg of atrasentan parent dissolved
completely in 100 .mu.L of methanol. Each addition was carried out
at room temperature and the volume of acid/methanol solution added
to the vial is reported in Table 1-A.
[0161] A solid precipitate resulted from the
H.sub.2SO.sub.4/methanol addition. The precipitate was isolated and
determined to be an amorphous solid.
[0162] A gel-like semi-solid precipitate resulted from the
S-mandelic acid/methanol addition. The solution containing the
precipitate was stirred for at least one week, but the precipitate
remained a gel-like semi-solid.
[0163] No precipitation was observed for any of the other
acid/solvent additions. For each addition where no precipitation
was observed, the vial was covered with parafilm having two
pin-holes and the solution was allowed to slowly evaporate. An
amorphous film was observed in each vial after the solution was
completely dried.
[0164] No crystalline atrasentan salts were successfully prepared
and isolated.
[0165] B. Experiment B
[0166] Aqueous solutions of several different organic or inorganic
acids (including a methanol/water solution for one acid) were
prepared for use in the study. These solutions (including their
concentrations) are reported in Table 1-B below.
TABLE-US-00002 TABLE 1-B SALT FORMING CONC. VOLUME AGENT SOLVENT
(M) (.mu.L) PRECIPITATION H.sub.2SO.sub.4 Water 1 400 Yes
(crystalline) H.sub.3PO.sub.4 Water 1 300 Yes (gel-like semi-solid)
Citric acid Water 1 200 Yes (gel-like semi-solid) L-Tartaric acid
Water 1 200 Yes (gel-like semi-solid) Malonic acid Water 1 200 Yes
(gel-like semi-solid) Succinic acid Methanol/ 1 200 Yes Water
(gel-like semi-solid) (1:1, v/v) Glycolic acid H.sub.2O 1 200 Yes
(gel-like semi-solid) L-Malic acid H.sub.2O 1 200 Yes (gel-like
semi-solid) S-Mandelic H.sub.2O 0.5 200 Yes acid (gel-like
semi-solid) R-Mandelic H.sub.2O 0.5 200 Yes acid (gel-like
semi-solid)
[0167] Each aqueous solution prepared was added with stirring to a
vial containing 25 mg of atrasentan parent dissolved completely in
100 .mu.L of 2-propanol/water (80/20, v/v). Each addition was
carried out at room temperature and the volume of the aqueous
solution added to the vial is reported in Table 1-B.
[0168] A solid precipitate resulted from the H.sub.2SO.sub.4/water
addition. The precipitate was isolated as a crystalline solid and
determined to be a monohydrate of the atrasentan hemi-sulfate salt
(1:1 molar ratio of atrasentan to sulfate).
[0169] A gel-like semi-solid precipitate resulted from all of the
other aqueous solution additions. Each solution was then heated to
70.degree. C. to re-dissolve the semi-solid precipitate. In several
cases, up to 25 .mu.L of additional 2-propanol/water (80/20, v/v)
was added to the vial as needed to completely re-dissolve the
semi-solid precipitate. After the semi-solid precipitate was
re-dissolved, each solution was cooled slowly to room temperature.
A gel-like semi-solid was observed at the bottom of each vial
within 10 hours.
[0170] Except for the monohydrate of the hemi-sulfate salt, no
other crystalline atrasentan salts were successfully prepared and
isolated.
[0171] C. Experiment C
[0172] Aqueous solutions of several different organic or inorganic
acids (or a methanol/water solution for one acid) and an aqueous
solution of nicotinamide were prepared for use in the study. These
solutions (including their concentrations) are reported in Table
1-C below.
TABLE-US-00003 TABLE 1-C REMAINED SALT FORMING CONC. VOLUME AS
AGENT SOLVENT (M) (.mu.L) PARENT? H.sub.3PO.sub.4 Water 1 1000 Yes
Citric acid Water 1 1000 Yes L-Tartaric acid Water 1 1000 Yes
Malonic acid Water 1 1000 Yes Succinic acid Methanol/Water 1 1000
Yes (1:1, v/v) Glycolic acid Water 1 1000 Yes L-Malic acid Water 1
1000 Yes S-Mandelic acid Water 0.5 1000 Yes R-Mandelic acid Water
0.5 1000 Yes Nicotinamide Water 1 1000 Yes
[0173] About 52 mg of atrasentan parent was suspended in 1 mL of
each aqueous solution prepared and the resulting suspensions were
stirred for three to seven days. The solids isolated from each
suspension were analyzed and determined to be the atrasentan parent
solid.
[0174] No crystalline atrasentan salts or co-crystals were
successfully prepared and isolated.
[0175] D. Experiment D
[0176] Aqueous solutions of several different organic or inorganic
acids (or a methanol/water solution for one acid) were prepared for
use in the study. These solutions (including their concentrations)
are reported in Table 1-D below.
TABLE-US-00004 TABLE 1-D SALT FORMING CONC. VOL. AGENT SOLVENT (M)
(.mu.L) OBSERVATIONS H.sub.3PO.sub.4 Water 1 400 Good suspension
Citric acid Water 1 300 Agglomerated Glycolic acid Water 1 200 Good
suspension L-Lactic acid Water 1 200 Good suspension L-Malic acid
Water 1 200 Good suspension Malonic acid Water 1 200 Gelled up
Succinic acid Methanol/ 0.5 200 Good suspension Water (1:1, v/v)
L-Tartaric acid Water 1 200 Good suspension S-Mandelic acid Water
0.5 200 Gelled up R-Mandelic acid Water 0.5 200 Gelled up
[0177] Each aqueous solution prepared was added with stirring to a
4 mL vial containing 50 mg of atrasentan parent in solid form. The
additions were carried out at room temperature and the volume of
the aqueous solution added to the vial is reported in Table 1-D.
The atrasentan only partially dissolved in each aqueous solution.
The resulting suspensions were stirred for more than a week. The
solids isolated from each suspension were analyzed and determined
to be the atrasentan parent.
[0178] No crystalline atrasentan salts were successfully prepared
and isolated.
[0179] E. Experiment E
[0180] Atrasentan parent was added to an aqueous sodium hydroxide
solution. The solution turned pink immediately upon the addition of
the atrasentan and no sodium salt of atrasentan was isolated.
Because atrasentan generally degrades under basic conditions, it is
believed that the atrasentan degraded in the presence of the sodium
hydroxide and was not converted into a sodium salt.
Example 2: Atrasentan S-Mandelate Salt
[0181] Several additional studies were conducted to prepare and
isolate atrasentan S-mandelate (particularly crystalline atrasentan
S-mandelate) and are described below.
[0182] A. Experiment A
[0183] About 25 mg of atrasentan parent was suspended in 0.2 mL of
an aqueous solution of S-mandelic acid (0.5 M) at room temperature.
The suspended solid quickly converted to a gel-like semi-solid when
the solution was stirred. After three days of stirring at room
temperature, a sample of the suspended semi-solid was inspected
under microscope and a few birefringent particles were
observed.
[0184] B. Experiment B
[0185] About 22 mg of atrasentan parent was suspended in 0.25 mL of
methanol/water (50/50, v/v) at room temperature. S-Mandelic acid
(13.8 mg) was added to the suspension. The suspended solids
partially dissolved in the S-mandelic acid and were converted
quickly to a gel-like semi-solid. The solution was heated to
40.degree. C. and the semi-solid was re-dissolved. The solution was
then slowly cooled to room temperature and produced a solid
precipitate. The precipitate was isolated, analyzed by PXRD, and
determined to be a mixture of an anhydrate of atrasentan
S-mandelate (1:1 stoichiometry) and a hemi-hydrate of atrasentan
parent.
[0186] C. Experiment C
[0187] About 100 mg of atrasentan parent was suspended in 1 mL of
methanol/water (1:1, v/v) at room temperature. S-Mandelic acid (41
mg) was added to the suspension. The majority of the suspended
solids dissolved, but a gel-like semi-solid was observed at the
bottom of the vial. The suspension was heated to 50.degree. C., but
the semi-solid remained undissolved. When the suspension was
stirred for 10 minutes at 50.degree. C., additional precipitation
was observed. When the suspension was stirred overnight, the
semi-solid partially converted to crystalline particles. A sample
of the crystalline particles was analyzed by PXRD and determined to
be a mixture of an anhydrate of atrasentan S-mandelate (1:1
stoichiometry) and an anhydrate of atrasentan S-mandelate (2:1
stoichiometry). Additional S-mandelic acid (about 15 mg) was added
to the suspension with stirring to further convert the semi-solid
to crystalline particles. The resulting crystalline particles were
isolated, analyzed by PXRD, and determined to be an anhydrate of
atrasentan S-mandelate (1:1 stoichiometry). Increasing the amount
of S-mandelic acid present in the suspension resulted in the
conversion of the atrasentan S-mandelate (2:1 stoichiometry) to
atrasentan S-mandelate (1:1 stoichiometry).
[0188] D. Experiment D
[0189] About 500 mg of atrasentan parent was dissolved in 2.5 mL
methanol at room temperature. S-Mandelic acid (315 mg) was added to
the solution. Water was gradually added to the solution in
increments of 0.1 mL (to reduce solubility and facilitate
precipitation). After a total of 1.5 mL of water had been added to
the solution, precipitation of fine particles was observed. An
additional amount of S-mandelic acid (about 150 mg) was added to
the suspension after 10 minutes followed by an additional amount of
water (1 mL). The suspension was then stirred for three hours. The
solids present in the suspension were isolated, analyzed by PXRD,
and determined to be an anhydrate of atrasentan S-mandelate (1:1
stoichiometry).
[0190] E. Experiment E
[0191] About 22 mg of atrasentan parent was suspended in 0.25 mL of
a methanol/water (1/1, v/v) mixture in a 1 mL scintillation vial at
room temperature with stirring. After 9.8 mg of S-mandelic acid had
been added to the suspension, the atrasentan was completely
dissolved and a semi-solid agglomerate appeared at the bottom of
the vial shortly afterwards. The mixture was stirred continuously
overnight and the semi-solid agglomerate turned into a white solid
that was suspended in the solution. The solid was isolated by
filtration and analyzed by PXRD. The PXRD data indicated the solid
was a combination of at least two different crystalline forms.
Example 3: Crystallization of Atrasentan S-Mandelate Salt from
Additional Solvents
[0192] A. Crystallization from Acetonitrile
[0193] An excess amount of S-mandelic acid was suspended in
acetonitrile (1 mL) to prepare a saturated S-mandelic
acid/acetonitrile solution. After saturation was achieved, the
excess S-mandelic acid was removed from the solution by filtration.
An excess amount of atrasentan S-mandelate salt (1:1 stoichiometry)
was suspended in the S-mandelic acid/acetonitrile solution at room
temperature for three days with stirring. The resulting solid was
isolated by filtration and analyzed by PXRD about 10 minutes after
isolation (see Example 8).
[0194] B. Crystallization from Ethanol
[0195] An excess amount of S-mandelic acid was suspended in ethanol
(1 mL) to prepare a saturated S-mandelic acid/acetonitrile
solution. After saturation was achieved, the excess S-mandelic acid
was removed from the solution by filtration. An excess amount of
atrasentan S-mandelate salt (1:1 stoichiometry) was suspended in
the S-mandelic acid/ethanol solution at room temperature for three
days with stirring. The resulting solid was isolated by filtration
and analyzed by PXRD about 10 minutes after isolation (see Example
8).
[0196] C. Crystallization from Pyridine
[0197] An excess amount of S-mandelic acid was suspended in
pyridine (1 mL) to prepare a saturated S-mandelic acid/pyridine
solution. After saturation was achieved, the excess S-mandelic acid
was removed from the solution by filtration. An excess amount of
atrasentan S-mandelate salt (1:1 stoichiometry) was suspended in
the S-mandelic acid/ethanol solution at room temperature for three
days with stirring. The resulting solid was isolated by filtration
and analyzed by PXRD about 10 minutes after isolation (see Example
8).
Example 4: Atrasentan S-Mandelate Salt (2:1 Stoichiometry)
[0198] 100.6 mg of atrasentan parent was suspended in 1 mL of a
methanol/water (1/1, v/v) mixture in a 4 mL scintillation vial at
50.degree. C. with stirring. A semi-solid agglomerate appeared at
the bottom of the vial after 31 mg of S-mandelic acid had been
added to the suspension. The mixture was stirred continuously for
15 minutes and then the semi-solid agglomerate turned into a white
solid that was suspended in the solution. The solid was isolated by
filtration and analyzed by PXRD (see Example 8). The solid was
found to be a hydrate of atrasentan S-mandelate salt (2:1
stoichiometry).
Example 5: Atrasentan R-Mandelate Salt (1:1 Stoichiometry)
[0199] About 100 mg of atrasentan parent was added to about 1 mL of
an R-mandelic acid/water solution (0.5 M) at room temperature. A
gel-like precipitate was observed in the resulting suspension. The
suspension was sonicated for 15 minutes and heated to 50.degree. C.
with stirring. As the suspension was stirred and the temperature
maintained at 50.degree. C., the gel-like precipitate converted to
a white solid. The white solid was isolated, dried, analyzed by
PXRD (see Example 8), and determined to be an anhydrate of
atrasentan R-mandelate (1:1 stoichiometry).
Example 6: Atrasentan n-Butylamine Salt (1:1 Stoichiometry)
[0200] Atrasentan monohydrochloride (11.42 mg) was added to a 2 mL
glass vial containing a mixture of n-butylamine (100 .mu.L) and
isopropanyl acetate (400 .mu.L) and dissolved by vortexing. A
crystalline solid of was collected after the solvent was removed by
evaporation under ambient conditions. The crystalline solid was
analyzed by PXRD (see Example 8) and determined to be an anhydrate
of atrasentan n-butylamine (1:1 stoichiometry).
[0201] Although the atrasentan n-butylamine salt was successfully
isolated, n-butylamine is generally toxic and an n-butylamine salt
is not a pharmaceutically acceptable salt.
Example 7: Crystal Morphology
[0202] The crystal morphology of several different atrasentan salts
was assessed by microscopy and the results reported in Table 7-A
below.
TABLE-US-00005 TABLE 7-A ATRASENTAN ANALYTICAL CRYSTAL SALT
CHARACTERIZATION MORPHOLOGY Parent Anhydrate Needle Parent
Quarter-hydrate Needle Parent Hemi-hydrate Prism Hemi-Sulfate
Monohydrate Needle (1:1 Stoichiometry) (Example 1, Experiment 2)
S-Mandelate Anhydrate Prism (1:1 Stoichiometry) (Example 2,
Experiment 4) S-Mandelate Crystallized From Acetonitrile Prism (1:1
Stoichiometry) (Example 3) S-Mandelate Crystallized From Ethanol
Not Determined (1:1 Stoichiometry) (Example 3) S-Mandelate
Crystallized From Pyridine Not Determined (1:1 Stoichiometry)
(Example 3) S-Mandelate Hydrate Prism (2:1 Stoichiometry) (Example
4) R-Mandelate Anhydrate Prism (1:1 Stoichiometry) (Example 5)
n-Butylamine Anhydrate Bar (1:1 Stoichiometry) (Example 6)
Hydrochloride Crystalline Form I Needle (1:1 Stoichiometry)
(Reported in WO2006/034094) Hydrochloride Crystalline Form II
Needle (1:1 Stoichiometry) (Reported in WO2006/034084)
Hydrochloride Crystalline Form III Needle (1:1 Stoichiometry)
(Reported in WO2006/034234)
[0203] Microscopic images of (a) atrasentan hemi-sulfate (1:1
stoichiometry), monohydrate, (b) atrasentan S-mandelate salt (1:1
stoichiometry), anhydrate, and (c) atrasentan monohydrochloride
salt, crystalline Form II are attached as FIG. 1-A, FIG. 1-B, and
FIG. 1-C, respectively.
Example 8: PXRD Analysis of Crystalline Atrasentan Salts
[0204] Several of the atrasentan crystalline forms listed in Table
7-A were analyzed by X-ray powder diffraction ("PXRD").
Specifically, the PXRD studies were performed on a G3000
diffractometer (Inel Corp., Artenay, France) equipped with a curved
position sensitive detector and parallel beam optics. The
diffractometer was operated with a copper anode tube (1.5 kW fine
focus) at 40 kV and 30 mA. An incident beam germanium monochromator
provided monochromatic K.alpha.1 radiation. The diffractometer was
calibrated using the attenuated direct beam at one-degree
intervals. Calibration was checked using a silicon powder line
position reference standard (NIST 640c). The sample was loaded onto
an aluminum sample holder and leveled with a glass slide. The
instrument was computer controlled using the Symphonix software
(Inel Corp., Artenay, France) and the data was analyzed using the
Jade software (version 6.5, Materials Data, Inc., Livermore,
Calif.). All studies were conducted at room temperature (i.e.,
about 25.degree. C.).
[0205] Tables 8-A through 8-N set out the significant parameters of
the main peaks in terms of 20 values and intensities for the
crystalline forms analyzed. It is known in the art that an X-ray
powder diffraction pattern may be obtained which has one or more
measurement errors depending on measurement conditions (such as
equipment, sample preparation or machine used). In particular, it
is generally known that intensities in an X-ray powder diffraction
pattern may fluctuate depending on measurement conditions and
sample preparation. For example, persons skilled in the art of
X-ray powder diffraction will realize that the relative intensities
of peaks may vary according to the orientation of the sample under
testing and on the type and setting of the instrument used. The
skilled person also will realize that the position of reflections
can be affected by the precise height at which the sample sits in
the diffractometer and the zero calibration of the diffractometer.
The surface planarity of the sample also may have an effect on the
results. A person skilled in the art will appreciate that the
diffraction pattern data presented below is not to be construed as
absolute and any crystalline form that provides a power diffraction
pattern substantially identical to those disclosed below fall
within the scope of the present disclosure (for further information
see Jenkins, R & Snyder, R. L. `Introduction to X-Ray Powder
Diffractometry` John Wiley & Sons, 1996).
TABLE-US-00006 TABLE 8-A PXRD Peak Listing Hemi-Sulfate Salt (1:1
Stoichiometry), Monohydrate PEAK POSITION (.degree.2.THETA.)
RELATIVE INTENSITY 5.5 100.0 7.3 7.1 8.3 31.8 11.0 2.1 11.8 1.8
13.1 3.7 16.0 4.4 16.5 11.0 16.8 13.7 17.1 7.4 19.0 7.2 19.3 9.1
19.8 7.1 22.1 9.1 23.8 13.8 25.8 9.1
[0206] The PXRD pattern corresponding to the data reported in Table
8-A is graphically shown in FIG. 2-A.
TABLE-US-00007 TABLE 8-B PXRD Peak Listing S-Mandelate Salt (1:1
Stoichiometry), Anhydrate PEAK POSITION (.degree.2.THETA.) RELATIVE
INTENSITY 5.5 100.0 8.4 7.3 9.1 10.9 9.7 62.9 10.3 12.8 11.2 2.5
11.8 4.8 12.1 51.5 13.7 12.0 14.2 11.3 16.1 26.2 16.3 23.7 17.7
14.1 18.0 37.5 18.4 37.0 19.4 94.6 20.0 26.5 20.6 10.7 20.8 33.1
21.2 23.2 22.3 20.1 23.0 37.7 23.9 20.8 24.2 17.3
[0207] The PXRD pattern corresponding to the data reported in Table
8-B is graphically shown in FIG. 2-B.
TABLE-US-00008 TABLE 8-C PXRD Peak Listing S-Mandelate Salt (1:1
Stoichiometry)-Crystallized From Acetonitrile PEAK POSITION
(.degree.2.THETA.) RELATIVE INTENSITY 6.0 100.0 7.7 0.6 9.0 1.8 9.2
0.6 10.0 6.6 12.1 1.8 12.5 1.8 13.9 8.6 14.4 8.7 15.7 3.5 16.1 2.5
16.4 2.4 17.5 9.1 18.3 4.9 20.2 2.0 21.0 5.5 23.8 7.6
[0208] The PXRD pattern corresponding to the data reported in Table
8-C is graphically shown in FIG. 2-C.
TABLE-US-00009 TABLE 8-D PXRD Peak Listing S-Mandelate Salt (1:1
Stoichiometry)-Crystallized From Ethanol PEAK POSITION
(.degree.2.THETA.) RELATIVE INTENSITY 6.0 100.0 6.7 10.2 8.4 30.3
9.6 2.2 12.1 35.8 13.0 10.3 13.6 15.4 15.6 9.4 16.9 5.4 18.5 8.9
19.4 6.4 20.3 6.2 20.5 6.2 21.1 13.1 21.6 7.6 22.1 8.9 22.8 5.6
[0209] The PXRD pattern corresponding to the data reported in Table
8-D is graphically shown in FIG. 2-D.
TABLE-US-00010 TABLE 8-E PXRD Peak Listing S-Mandelate Salt (1:1
Stoichiometry)-Crystallized From Pyridine PEAK POSITION
(.degree.2.THETA.) RELATIVE INTENSITY 6.7 17.2 11.6 22.4 13.0 9.6
13.4 8.7 15.0 4.6 16.9 2.0 17.4 17.9 18.5 1.5 19.1 3.2 20.2 100.0
21.6 3.9 22.4 14.4 22.6 19.3 23.4 12.0
[0210] The PXRD pattern corresponding to the data reported in Table
8-E is graphically shown in FIG. 2-E.
TABLE-US-00011 TABLE 8-F PXRD Peak Listing S-Mandelate Salt (2:1
Stoichiometry), Hydrate PEAK POSITION (.degree.2.THETA.) RELATIVE
INTENSITY 4.5 100.0 6.7 5.9 8.2 7.3 8.6 84.8 9.1 27.5 9.5 19.5 10.7
19.4 11.7 13.2 12.3 17.6 13.4 14.9 14.1 19.9 17.2 15.0 17.4 15.1
18.1 95.1 18.5 19.4 18.7 73.5 19.2 16.1 19.6 12.2 20.3 13.4 20.7
17.9 21.6 24.5 22.0 15.1 24.0 15.3 24.2 12.3
[0211] The PXRD pattern corresponding to the data reported in Table
8-F is graphically shown in FIG. 2-F.
TABLE-US-00012 TABLE 8-G PXRD Peak Listing R-Mandelate Salt (1:1
Stoichiometry), Anhydrate PEAK POSITION (.degree.2.THETA.) RELATIVE
INTENSITY 5.7 100.0 8.2 32.7 8.6 25.3 10.1 16.7 11.5 15.3 11.8 49.0
16.2 42.7 16.4 12.1 16.8 18.5 18.4 28.1 18.7 47.1 19.3 36.5 20.2
16.3 20.9 62.4 21.8 10.0 23.4 26.4 24.7 18.7 25.3 20.7
[0212] The PXRD pattern corresponding to the data reported in Table
8-G is graphically shown in FIG. 2-G.
TABLE-US-00013 TABLE 8-H PXRD Peak Listing n-Butylamine Salt (1:1
Stoichiometry), Anhydrate PEAK POSITION (.degree.2.THETA.) RELATIVE
INTENSITY 5.4 2.9 7.6 100.0 7.8 83.9 8.5 4.0 8.7 4.9 10.9 40.1 13.8
14.5 14.3 88.2 14.8 68.8 15.2 23.9 17.6 40.3 17.9 23.2 18.3 97.4
18.5 25.4 19.5 20.6 20.0 65.8 20.9 35.9 21.3 33.0 22.0 37.0 22.3
38.7 22.7 43.4 23.7 21.4 23.9 25.5 24.3 23.7 24.8 50.7
[0213] The PXRD pattern corresponding to the data reported in Table
8-H is graphically shown in FIG. 2-H.
TABLE-US-00014 TABLE 8-I PXRD Peak Listing Parent, Anhydrate PEAK
POSITION (.degree.2.THETA.) RELATIVE INTENSITY 1.305 6.7 1.634 5.5
7.168 25.5 8.759 16.0 11.314 100.0 12.142 7.4 14.327 20.2 15.002
19.2 15.638 11.5 16.457 8.4 17.388 86.8 19.625 5.4 19.986 11.6
20.151 28.6 20.469 7.8 20.929 41.7 21.575 51.5 22.750 15.3 23.161
14.4 23.773 14.9 24.816 9.1 26.382 17.8
[0214] The PXRD pattern corresponding to the data reported in Table
8-I is graphically shown in FIG. 2-I.
TABLE-US-00015 TABLE 8-J PXRD Peak Listing Parent, Quarter-Hydrate
PEAK POSITION (.degree.2.THETA.) RELATIVE INTENSITY 3.7 100.0 7.5
7.1 8.4 32.1 9.9 22.0 10.2 4.0 11.2 2.5 12.0 6.1 13.4 4.2 14.1 5.2
16.4 9.5 16.7 6.6 18.0 23.3 18.5 30.0 19.5 9.5 22.2 16.6 22.6 35.7
24.8 13.2 25.8 15.6
[0215] The PXRD pattern corresponding to the data reported in Table
8-J is graphically shown in FIG. 2-J.
TABLE-US-00016 TABLE 8-K PXRD Peak Listing Parent, Hemi-Hydrate
PEAK POSITION (.degree.2.THETA.) RELATIVE INTENSITY 3.6 100.0 8.6
8.5 8.9 8.8 9.1 6.6 9.3 2.9 10.0 8.0 10.7 4.6 10.9 6.0 12.2 9.2
13.1 6.8 14.9 3.8 15.2 4.5 15.5 3.1 16.0 16.4 17.3 3.0 17.7 8.4
18.0 9.0 18.3 9.4 19.6 12.8 20.2 6.3 21.3 30.0 21.9 23.2
[0216] The PXRD pattern corresponding to the data reported in Table
8-K is graphically shown in FIG. 2-K.
TABLE-US-00017 TABLE 8-L PXRD Peak Listing Monohydrochloride Salt,
Crystalline Form I PEAK POSITION (.degree.2.THETA.) RELATIVE
INTENSITY 8.3 100.0 9.7 97.9 10.1 58.9 10.9 27.5 11.8 7.0 12.1 8.3
13.1 75.6 13.5 25.9 14.8 20.2 15.7 46.7 16.1 22.0 16.7 42.4 17.2
46.6 17.5 22.8 19.5 47.7 20.2 11.0 20.7 26.8 21.8 11.4 22.6 33.5
23.2 29.2 24.2 27.6
[0217] The PXRD pattern corresponding to the data reported in Table
8-L is graphically shown in FIG. 2-L.
TABLE-US-00018 TABLE 8-M PXRD Peak Listing Monohydrochloride Salt,
Crystalline Form II PEAK POSITION (.degree.2.THETA.) RELATIVE
INTENSITY 8.3 100.0 9.7 97.9 10.1 58.9 10.9 27.5 13.1 75.6 13.5
25.9 14.8 20.2 15.7 46.7 16.1 22.0 16.7 42.4 17.2 46.6 17.5 22.8
19.5 47.7 20.2 11.0 20.7 26.8 21.8 11.4 22.6 33.5 23.2 29.2 24.2
27.6
[0218] The PXRD pattern corresponding to the data reported in Table
8-M is graphically shown in FIG. 2-M.
TABLE-US-00019 TABLE 8-N PXRD Peak Listing Monohydrochloride Salt,
Crystalline Form III PEAK POSITION (.degree.2.THETA.) RELATIVE
INTENSITY 6.7 79.6 8.5 27.4 10.0 3.6 11.2 6.9 12.9 4.4 15.7 25.1
16.1 4.7 17.1 12.9 19.3 10.0 20.1 6.0 20.7 23.3 22.0 80.2
[0219] The PXRD pattern corresponding to the data reported in Table
8-N is graphically shown in FIG. 2-N.
Example 9: Unit Cell Parameters
[0220] Unit cell parameters were determined and are reported below
in Tables 9-A, 9-B, and 9-C for the hemi-sulfate salt (1:1
stoichiometry), monohydrate; the n-butylamine salt (1:1
stoichiometry), anhydrate; and the S-mandelate salt (1:1
stoichiometry), anhydrate, respectively.
[0221] Single crystal X-ray diffraction data were collected using a
Bruker Apex II diffractometer (Bruker AXS, Madison, Wis.) equipped
with an Apex II CCD area detector. The diffractometer was operated
with a molybdenum anode tube (2.0 kW fine focus) at 50 kV and 40
mA. An incident beam silicon monochrometer provided Mo-K.alpha.1
monochromatic radiation. The data were collected under a stream of
cold nitrogen gas at 100 K using a Kryoflex low temperature device
(Bruker AXS, Madison, Wis.). The beam diameter for data collection
was 5 mm and the detector distance was 6 cm. The alignment of the
goniometer was checked using a spherical
2-Dimethylsufuranylidene-1,3-indanedione (YLID) crystal. The
instrument was computer controlled using the BIS and Apex 2
software programs (Bruker AXS, Madison, Wis.). The data were
analyzed using Apex 2 software (Version 2011.2-0, Bruker AXS,
Madison, Wis.).
TABLE-US-00020 TABLE 9-A Unit Cell Parameters Hemi-Sulfate Salt
(1:1 Stoichiometry), Monohydrate Lattice Type Monoclinic Space
Group C2 a (.ANG.) 32.47 b (.ANG.) 5.628 c (.ANG.) 15.891 .alpha.
(.degree.) 90 .beta. (.degree.) 97.449 .gamma. (.degree.) 90 Volume
(.ANG..sup.3) 2879.43 Z 4
TABLE-US-00021 TABLE 9-B Unit Cell Parameters n-Butylamine Salt
(1:1 Stoichiometry), Anhydrate Lattice Type Orthorhombic Space
Group P2.sub.12.sub.12.sub.1 a (.ANG.) 6.437 b (.ANG.) 22.601 c
(.ANG.) 23.324 .alpha. (.degree.) 90 .beta. (.degree.) 90 .gamma.
(.degree.) 90 Volume (.ANG..sup.3) 3393.24 Z 4
TABLE-US-00022 TABLE 9-C Unit Cell Parameters S-Mandelate Salt (1:1
Stoichiometry), Anhydrate Lattice Type Orthorhombic Space Group P
212121 a (.ANG.) 9.954 (2) b (.ANG.) 11.049 (2) c (.ANG.) 30.861
(6) .alpha. (.degree.) 90.00 .beta. (.degree.) 90.00 .gamma.
(.degree.) 90.00 Volume (.ANG..sup.3) 3394 (1) Z 4
[0222] Unless otherwise indicated, in each Example below: (a) the
atrasentan parent tested was the hemi-hydrate, (b) the atrasentan
hydrochloride salt tested was the crystalline form II of the
monohydrochloride salt, and (c) the atrasentan mandelate salt
tested was the anhydrate of the S-mandelate salt (1:1
stoichiometry).
Example 10: Bulk Density
[0223] A study is conducted to evaluate the bulk density, tap
density, and flow properties of atrasentan parent, atrasentan
mandelate salt, and atrasentan hydrochloride salt.
[0224] A. General Methods
[0225] Bulk and tap density are measured following United States
Pharmacopeia and National Formulary guidelines (USP <616>).
Approximately 60 mL of each sample is added into a 100 mL graduated
cylinder. The powder is carefully leveled without compacting, and
the volume is read directly from the cylinder and used to calculate
the bulk density according to the relationship: mass/volume. The
cylinder containing the powder sample is then mechanically tapped
using a VanKel Tap Density Tester (Model 50-1200, Varian, Inc.,
Palo Alto, Calif.) until there is no change in volume. The volume
of the sample is then read and used in the calculation of tap
density.
[0226] Flow properties of each sample are characterized using a
Schulze ring shear tester RST-XS (Dietmar Schulze
Schuttgutmesstechnik, Wolfenbuttel, Germany). A standard annular
cell of a cross-sectional area of 24 cm.sup.2 and a volume of 30
cm.sup.3 is used to measure the yield loci. All experiments are
performed at 23.+-.2.degree. C. and 33.+-.2% relative humidity to
minimize the effects of temperature and moisture on flow
properties. During each measurement, the powder is first
pre-sheared under a pre-consolidation stress until a steady-state
is reached. The pre-sheared powder is then subjected to shear under
a normal stress. Thus one shear point of the yield locus, a plot of
shear stress at failure as a function of the normal stress, is
obtained. To measure another shear point of the yield locus, the
sample is then pre-sheared again under the same pre-consolidation
stress and sheared to failure under a subsequently increased normal
stress. A complete yield locus is then plotted through all measured
shear points.
[0227] In this study, the procedure is conducted in triplicates
with applying pre-consolidation stresses of 1 kPa and four normal
stress levels equally spaced between 20 to 60% of the
pre-consolidation stress. From each yield locus, major principle
stress (.sigma..sub.l) and unconfined yield strength (f.sub.c) are
derived by drawing two critical Mohr stress circles with the
software RST-CONTROL 95 (Dietmar Schulze Schuttgutmesstechnik,
Wolfenbuttel, Germany). The major principle stress (.sigma..sub.l)
results from the Mohr stress circle which is tangential to the
yield locus and intersects at the point of normal and shear
stresses at steady state flow. The unconfined yield strength (t)
results from the Mohr stress circle which is tangential to the
yield locus and runs through the origin. Flow function coefficient
(FFC=.sigma..sub.l/f.sub.c) is used to characterize the flow of a
powder.
[0228] B. Bulk Density and Tap Density Measurement
[0229] Bulk density and tap density were measured for samples of
the following materials: (i) unmilled atrasentan hydrochloride salt
having the morphology and particle size distribution listed below
in Table 10; and (ii) unmilled atrasentan mandelate salt having the
morphology and particle size distribution listed below in Table 10.
Each sample had a moisture content less than 2% by weight at 80%
relative humidity. Bulk density was measured in accordance with
Bulk Density, Method I of United States Pharmacopeia and National
Formulary Guidelines (USP <616>) except that a 100 mL
cylinder was filled with the sample for the testing. Tap density
was measured in accordance with Tapped Density, Method I of United
States Pharmacopeia and National Formulary guidelines (USP
<616>) except that a 100 mL cylinder was filled with the
sample for the testing. Results are reported below in Table 10.
TABLE-US-00023 TABLE 10 Bulk Density and Tap Density SALT
HYDROCHLORIDE MANDELATE MORPHOLOGY Needle Prismatic DESCRIPTION
Unmilled Unmilled PARTICLE SIZE D10 (.mu.m) 6.0 16 DISTRIBUTION D50
(.mu.m) 20 49 D90 (.mu.m) 86 141 BULK DENSITY (g/mL) 0.11 0.25 TAP
DENSITY (g/mL) 0.20 0.40
Example 11: Oxidative Stability
[0230] A study was conducted to evaluate the oxidative stability of
atrasentan parent, atrasentan mandelate salt, and atrasentan
hydrochloride salt.
[0231] About 1 mg of each solid was placed in a 4 mL glass vial and
about 10 mg of urea-H.sub.2O.sub.2 co-crystal was placed in another
4 mL vial. The two vials then were connected by a connector (Kontes
connector, 13-425X13-425, apt NO 747205-1313) and left in an oven
at 40.degree. C. for seven days. Blank samples were prepared by
placing about 1 mg of each compound in a 4 mL vial and then storing
the vial in a freezer at about -20.degree. C. for the same period
of time. The oven samples and freezer blanks were analyzed at the
same time by HPLC. The HPLC conditions are summarized in Table 11-A
below. The measured data are reported in Table 11-B below and the
normalized data from Table 11-B are shown in a bar chart in FIG.
3.
TABLE-US-00024 TABLE 11-A HPLC Conditions HPLC METHOD Column YMC,
150 mm .times. 4.6 mm, paced with spherical 3 .mu.m C4 particles,
120 .ANG. pore size Flow rate 1 ml/min Column temperature
17.degree. C. injection volume 20 .mu.l Detector wavelength 234 nm
GRADIENT Mobile phase A pH 2.0 Perchloric acid solution: Adjust pH
of Milli-Q water to pH 2.0 using perchloric acid Mobile phase B
Acetonitrile Time (minutes) Perchloric acid solution (%)
Acetonitrile (%) 0 70 30 5 70 30 45 45 55 75 45 55 77 70 30 90 70
30
TABLE-US-00025 TABLE 11-B Oxidative Stability Data RECOVERED
INITIAL SAMPLE RECOVERY CONCEN. WEIGHT WEIGHT RECOVERED AVERAGE
AVERAGE % PROPORTION SAMPLE (mg/mL) (mg) (mg) (%) (%) STD
(NORMALIZED) (%) Parent Blank 1 29.126 1.165 1.13 103.10 102.26
0.84 89.56 Parent Blank 2 27.867 1.115 1.09 102.26 Parent Blank 3
27.636 1.105 1.09 101.42 Parent Sample 1 22.737 0.909 0.97 93.76
91.58 2.20 91.69 Parent Sample 2 21.760 0.870 0.95 91.62 89.60
Parent Sample 3 24.577 0.983 1.1 89.37 87.39 Hydrochloride Blank 1
26.127 1.045 1.08 96.77 96.09 0.60 89.48 Hydrochloride Blank 2
30.687 1.227 1.28 95.90 Hydrochloride Blank 3 29.160 1.166 1.22
95.61 Hydrochloride Sample 1 21.029 0.841 0.96 87.62 85.98 2.49
91.18 Hydrochloride Sample 2 24.637 0.985 1.13 87.21 90.76
Hydrochloride Sample 3 22.856 0.914 1.1 83.11 86.49 Mandelate Blank
1 22.676 0.907 1.07 84.77 80.14 4.18 99.30 Mandelate Blank 2 20.545
0.822 1.04 79.02 Mandelate Blank 3 19.349 0.774 1.01 76.63
Mandelate Sample 1 22.248 0.890 1.08 82.40 79.58 3.50 102.82
Mandelate Sample 2 20.975 0.839 1.04 80.67 100.66 Mandelate Sample
3 22.856 0.914 1.1 83.11 94.41
[0232] The oxidative stability data reported in Table 11-B were
further evaluated by ANOVA analysis. The ANOVA results are reported
in Table 11-C below.
TABLE-US-00026 TABLE 11-C ANOVA Analysis STANDARD t ESTIMATE ERROR
VALUE Pr (>|t|) (Intercept) 0.99297 0.01839 54.008 2.71E-09
Hydrochloride -0.09822 0.02600 -3.777 0.00921 Salt-Mandelate Salt
Atrasentan -0.09738 0.02600 -3.745 0.00956 Parent-Mandelate
Salt
[0233] The data show that the mandelate salt had a statistically
significantly higher sample recovery proportion than the
hydrochloride salt and atrasentan parent and, therefore, had
greater oxidative stability than the atrasentan parent and
hydrochloride salt.
Example 12: Intrinsic Dissolution Rate (Function of pH)
[0234] A study was conducted to evaluate the intrinsic dissolution
rate as a function of pH for two different crystal forms having
prismatic morphology (atrasentan parent and atrasentan mandelate
salt).
[0235] About 100 mg of the sample tested was prepared by
compressing the sample in a stainless steel die under 1100 pounds
force with a dwell time of one minute to form a pellet. The die
(diameter: 0.373 inch, area: 0.704 cm.sup.2) containing the pellet
was submerged in 250 mL of a phosphate buffer dissolution test
medium having a pH of 2.0, 5.0, or 7.4. The medium was stirred by a
paddle at 50 rpm and maintained at 37.degree. C. To measure the
concentration of the sample material in the medium, a fiber optic
dip probe (.mu.Diss Profile, pION Inc) was used to monitor the UV
absorbance as a function of time. The measured data are reported in
Table 12-A below and are shown graphically in FIG. 4.
TABLE-US-00027 TABLE 12-A Intrinsic Dissolution Rate ("IDR")
MANDELATE IDR** PARENT IDR** pH (mg/min/cm.sup.2) (mg/min/cm.sup.2)
2.0 1.0 .times. 10.sup.-1 2.7 .times. 10.sup.-2 (n = 1) 6.9 .times.
10.sup.-2 5.0 2.1 .times. 10.sup.-2 5.1 .times. 10.sup.-3 1.8
.times. 10.sup.-2 5.4 .times. 10.sup.-3 7.4 1.1 .times. 10.sup.-1
3.6 .times. 10.sup.-2 (n = 1) 1.0 .times. 10.sup.-1 **Data reported
for two runs (i.e., n = 2) unless otherwise indicated.
[0236] The intrinsic dissolution data reported in Table 12-A were
further evaluated using a paired t-test analysis that provided the
following results: [0237] t=2.6645 [0238] df=3 [0239]
p-value=0.03802 (<0.05).
[0240] The S-mandelate salt exhibited a statistically greater
intrinsic dissolution rate than the corresponding atrasentan
parent.
Example 13: Intrinsic Dissolution Rate (Function of [Cl.sup.-])
[0241] A study was conducted to evaluate the intrinsic dissolution
rate as a function of chloride ion concentration ([Cl.sup.-]) for
atrasentan mandelate salt and atrasentan hydrochloride salt.
[0242] About 100 mg of the sample tested was prepared by
compressing the sample in a stainless steel die under 1100 pounds
force with a dwell time of one minute to form a pellet. The die
(diameter: 0.373 inch, area: 0.704 cm.sup.2) containing the pellet
was submerged in 250 mL of a phosphate buffer dissolution test
medium having a pH of 2.0 and a chloride ion concentration of 0 M,
0.017 M, or 0.17 M. The medium was stirred by a paddle at 50 rpm
and maintained at 37.degree. C. To measure the concentration of the
sample material in test medium, a fiber optic dip probe (.mu.Diss
Profile, pION Inc) was used to monitor the UV absorbance as a
function of time. The measured data are reported in Table 13-A
below and are shown graphically in FIG. 5.
TABLE-US-00028 TABLE 13-A Intrinsic Dissolution Rate ("IDR")
[Cl.sup.-1] HYDROCHLORIDE IDR MANDELATE IDR (M) (mg/min/cm.sup.2)
(mg/min/cm.sup.2) 0.17 4.2 .times. 10.sup.-2 (n = 1) 8.3 .times.
10.sup.-2 (n = 3)** 0.017 1.3 .times. 10.sup.-1 (n = 1) 1.0 .times.
10.sup.-1 (n = 1) 0.0 1.4 .times. 10.sup.-1 (n = 1) 1.0 .times.
10.sup.-1 (n = 1) **Measured values were 8.2 .times. 10.sup.-2, 8.6
.times. 10.sup.-2, and 8.0 .times. 10.sup.-2.
[0243] The intrinsic dissolution data reported in Table 13-A were
further evaluated using linear regression analysis. The linear
regression analysis results are reported in Table 13-B.
TABLE-US-00029 TABLE 13-B Linear Regression Analysis HYDROCHLORIDE
MANDELATE SALT MODEL: SALT MODEL: IDR = a1 + b1 .times. [CI.sup.-]
IDR = a2 + b2 .times. [CI.sup.-] a1 = 0.103458 a2 = 0.1377269 b1 =
-0.122241 b2 = -0.5608597 p-value = 0.00383 p-value = 0.00934 Slope
difference (b1 - b2) = 0.4386 (p-value <0.0001)
[0244] The S-mandelate salt exhibited a statistically smaller slope
than the hydrochloride salt in the linear regression analysis which
indicates the intrinsic dissolution rate of the mandelate salt is
less sensitive to chloride ion concentration than the intrinsic
dissolution rate of the hydrochloride salt.
Example 14: Corrosivity (Suspension at 50.degree. C.)
[0245] A study was conducted to evaluate the corrosivity of
atrasentan mandelate salt and atrasentan hydrochloride salt. The
test was conducted in accordance with the American Society for
Testing and Materials (ASTM) Practice G31-72 "Standard Practice for
Laboratory Immersion Corrosion Testing of Metals" (Reapproved 2004)
(see Annual Book of ASTM (American Society for Testing and
Materials) Standards, Vol. 03.02, 2004).
[0246] Six stainless steel 316LW (welded) coupons were hand
polished and stamped with identifying marks. They were then washed
in an ultrasonic bath with detergent for fifteen minutes, rinsed
with tap water, rinsed with acetone, and then dried. The dimensions
of each coupon were measured using a digital caliper with accuracy
of .+-.0.05 mm. The coupons were weighed with an analytical balance
to an accuracy of .+-.0.1 mg.
[0247] Three of the coupons were completely submerged in the liquid
phase of an atrasentan mandelate salt suspension (an aqueous
suspension containing 9.545% atrasentan mandelate salt by weight
and 8.8% HPMC E5 by weight). The remaining three coupons were
completely submerged in the liquid phase of an atrasentan
monohydrochloride salt suspension (an aqueous suspension containing
7.215% atrasentan monohydrochloride salt by weight and 8.8% HPMC E5
by weight). The suspensions were agitated using a magnetic stir bar
and maintained at 50.degree. C. After days 1, 5, and 15, one coupon
and 5 mL of the exposed suspension were removed from each
suspension. The appearance of the removed coupons was observed and
recorded. The coupons then were washed in an ultrasonic bath with
detergent for fifteen minutes, rinsed with tap water, rinsed with
acetone, dried, and weighed.
[0248] The corrosion rate (inches per year, "IPY") was calculated
using the following formula (see Annual Book of ASTM (American
Society for Testing and Materials) Standards, Vol. 03.02,
2004):
Corrosion Rate = 3450 .times. .DELTA. W A .times. t .times. .rho.
##EQU00001## [0249] where: [0250] .DELTA.W=weight loss (g) [0251]
A=surface area of coupon (cm.sup.2) [0252] t=duration of experiment
(hours) [0253] .rho.=density of coupon (g/cm.sup.3)
[0254] The corrosivity test conditions and results for the two
suspensions are reported in Tables 14-A and 14-B below. Table 14-C
below (reproduced from Corrosion Resistance Tables, Fourth Edition,
Revised and Expanded, edited by Philip A. Schweitzer, 1995)
provides a general guide for interpreting the corrosion test
results for metal specimens at the testing temperature.
TABLE-US-00030 TABLE 14-A Corrosion Results for Mandelate Salt
Suspension COUPON B COUPON A COUPON C Test Duration (h) 24 120 360
Length (cm) 3.716 3.771 3.771 Width (cm) 1.585 1.616 1.618
Thickness (cm) 0.292 0.306 0.303 Surface Area (cm.sup.2) 14.88
15.48 15.47 Starting Weight (g) 12.9573 14.0885 13.5392 Final
Weight (g) 12.957 14.0881 13.5387 Weight Change (g) 0.0003 0.0004
0.0005 Corrosion Rate (IPY) 3.63 .times. 10.sup.-4 9.31 .times.
10.sup.-5 3.88 .times. 10.sup.-5 Appearance Unchanged Unchanged
Unchanged
TABLE-US-00031 TABLE 14-B Corrosion Results for Hydrochloride Salt
Suspension COUPON F COUPON E COUPON D Test Duration (h) 24 120 360
Length (cm) 3.669 3.718 3.769 Width (cm) 1.59 1.596 1.597 Thickness
(cm) 0.296 0.298 0.297 Surface Area (cm.sup.2) 14.78 15.04 15.23
Starting Weight (g) 12.8682 12.9074 13.4665 Final Weight (g) 12.868
12.9073 13.4653 Weight Change (g) 0.0002 0.0001 0.0012 Corrosion
Rate (IPY) 2.44 .times. 10.sup.-4 2.40 .times. 10.sup.-5 9.47
.times. 10.sup.-5 Appearance Unchanged Unchanged Unchanged
TABLE-US-00032 TABLE 14-C Corrosion Guide CORROSION RESISTIVITY
CORROSION RATE Excellent .ltoreq.2.0 .times. 10.sup.-3 inch/year
Good .ltoreq.2.0 .times. 10.sup.-2 inch/year Satisfactory
.ltoreq.5.0 .times. 10.sup.-2 inch/year Unsatisfactory .gtoreq.5.0
.times. 10.sup.-2 inch/year
Example 15: Corrosivity (Suspension at 75.degree. C.)
[0255] A second study was conducted to evaluate the corrosivity of
atrasentan mandelate salt and atrasentan hydrochloride salt. The
test was conducted in accordance with Annual Book of ASTM (American
Society for Testing and Materials) Standards, Vol. 03.02, 2004.
[0256] Six stainless steel 316LW (welded) coupons were hand
polished and stamped with identifying marks. They were then washed
in an ultrasonic bath with detergent for fifteen minutes, rinsed
with tap water, rinsed with acetone, and then dried. The dimensions
of each coupon were measured using a digital caliper with accuracy
of .+-.0.05 mm. The coupons were weighed with an analytical balance
to an accuracy of .+-.0.1 mg.
[0257] Three of the coupons were completely submerged in the liquid
phase of an atrasentan mandelate salt suspension and the remaining
three coupons were completely submerged in the liquid phase of an
atrasentan monohydrochloride salt suspension. The compositions of
the salt suspensions are described in Tables 15-A and 15-B
below.
TABLE-US-00033 TABLE 15-A Composition of Mandelate Salt Suspension
ACTUAL WEIGHT WEIGHT SUSPENSION COMPONENT (g) PERCENT Atrasentan
Mandelate (662.8 g/mol) 5.7125 27.53 HPMC E5 (8.8% solution added)
0.3555 1.71 Lactose MH regular 6.0085 28.96 Water 8.6745 41.80
Total 20.751 100.00
TABLE-US-00034 TABLE 15-B Composition of Hydrochloride Salt
Suspension ACTUAL WEIGHT WEIGHT SUSPENSION COMPONENT (g) PERCENT
Atrasentan Monohydrochloride 4.3089 18.24 (547.1 g/mol) HPMC E5
(8.8% solution added) 0.35728 1.51 Lactose MH regular 6.043 25.58
Water 12.91272 54.66 Total 23.6219 100.00
[0258] The suspensions were placed in an oven and maintained at
75.degree. C. One coupon was removed from each suspension each
week. The appearance of the removed coupons was observed and
recorded. The coupons then were washed in an ultrasonic bath with
detergent for fifteen minutes, rinsed with tap water, rinsed with
acetone, dried, and weighed.
[0259] The corrosion rate was calculated in the same manner as
discussed in Example 14. The corrosivity test conditions and
results for the two suspensions are summarized in Tables 15-C and
15-D.
TABLE-US-00035 TABLE 15-C Corrosion Results for Mandelate Salt
Suspension TEST DETAILS Coupon Type SS316LW Density (g/cm.sup.3)
7.98 F E D COUPON DETAILS Location Length (cm) 3.768 3.71 3.715
Width (cm) 1.588 1.581 1.577 Thickness (cm) 0.312 0.29 0.294
Starting weight (g) 13.8479 12.8965 12.7577 Final weight (g)
13.8478 12.8961 12.7565 Appearance Unchanged Unchanged Unchanged
TEST RESULTS Time (hours) 169.25 337.92 570.75 Surface Area
(cm.sup.2) 15.31 14.80 14.83 Weight Change (g) -0.0001 -0.0004
-0.0012 Corrosion Rate (IPY) 1.67 .times. 10.sup.-5 3.46 .times.
10.sup.-5 6.13 .times. 10.sup.-5
TABLE-US-00036 TABLE 15-D Corrosion Results for Hydrochloride Salt
Suspension TEST DETAILS Coupon Type SS316LW Density (g/cm.sup.3)
7.98 A C B COUPON DETAILS Location Length (cm) 3.748 3.639 3.726
Width (cm) 1.599 1.586 1.579 Thickness (cm) 0.308 0.301 0.293
Starting weight (g) 13.9433 12.8431 12.8826 Final weight (g)
13.9424 12.8405 12.8776 Appearance Unchanged Unchanged Etching
Visible on Weld TEST RESULTS Time (hours) 169.25 337.92 570.75
Surface Area (cm.sup.2) 15.28 14.69 14.88 Weight Change (g) -0.0009
-0.0026 -0.0050 Corrosion Rate (IPY) 1.50 .times. 10.sup.-4 2.26
.times. 10.sup.-4 2.55 .times. 10.sup.-4
Example 16: Moisture Sorption Isotherm
[0260] A study was conducted to evaluate the moisture sorption
isotherms of atrasentan hemi-sulfate salt (1:1 stoichiometry),
monohydrate, and atrasentan S-mandelate salt (1:1 stoichiometry),
anhydrate. A sample (about 5 mg to about 20 mg) of the powder to be
tested was loaded onto the tared pan of a DVS Advantage dynamic
gravimetric water sorption analyzer (Surface Measurement Systems
Ltd, Alperton, United Kingdom). The moisture sorption isotherm for
each sample was collected at 10% relative humidity intervals as the
relative humidity was adjusted in the following manner: (a) 0% to
90% to 0% to 90% to 40% for the hemi-sulfate salt, and (b) 0% to
90% to 0% for the S-mandelate salt. For each step, the dm/dt
criteria were 0.001% over 5 minutes with a minimum dm/dt time of 30
minutes and a maximum dm/dt of 120 minutes. Data was collected
isothermally at 25.degree. C. with a nitrogen flow rate of 200
cm.sup.2/minute. The sample was maintained at 30% relative humidity
and analyzed by PXRD. The moisture sorption isotherms generated for
the hemi-sulfate and S-mandelate salt samples are shown in FIG. 6-A
and FIG. 6-B, respectively. The hemi-sulfate salt exhibited partial
conversion from the hydrate form to the anhydrate form as the
relative humidity decreased below 10%.
Example 17: Differential Scanning Calorimetry
[0261] Atrasentan hemi-sulfate salt (1:1 stoichiometry),
monohydrate, and atrasentan S-mandelate salt (1:1 stoichiometry),
anhydrate, were analyzed by differential scanning calorimetry
("DSC"). A differential scanning calorimeter (Q-2000, TA
Instruments, New Castle, Del.) equipped with Universal Analysis
2000 software (Version 4.5A, TA Instruments, New Castle, Del.) was
used to determine the DSC thermal traces. The temperature axis was
calibrated with biphenyl, indium, and tin standards. The cell
constant was calibrated with indium. Unless otherwise stated, the
sample (2 to 5 mg) was encapsulated in a ventilated aluminum pan,
and heated at a rate of 10.degree. C./minute under a nitrogen gas
flow of 50 mL/minute during the study. The DSC curves generated for
the hemi-sulfate and S-mandelate salt samples are shown in FIG. 7-A
and FIG. 7-B, respectively.
[0262] All references (patent and non-patent) cited above are
incorporated by reference into this patent application. The
discussion of those references is intended merely to summarize the
assertions made by their authors. No admission is made that any
reference (or a portion of any reference) is relevant prior art (or
prior art at all). Applicants reserve the right to challenge the
accuracy and pertinence of the cited references.
* * * * *