U.S. patent application number 16/763554 was filed with the patent office on 2020-08-27 for crystalline forms of arn-509, preparation method and use thereof.
The applicant listed for this patent is Crystal Pharmaceutical (Suzhou) Co., Ltd.. Invention is credited to Minhua Chen, Yuhao Chen, Jiale Qian, Chaohui Yang, Xiaoting Zhai, Yanfeng Zhang.
Application Number | 20200270226 16/763554 |
Document ID | / |
Family ID | 1000004841021 |
Filed Date | 2020-08-27 |
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United States Patent
Application |
20200270226 |
Kind Code |
A1 |
Chen; Minhua ; et
al. |
August 27, 2020 |
CRYSTALLINE FORMS OF ARN-509, PREPARATION METHOD AND USE
THEREOF
Abstract
The present disclosure relates to novel crystalline forms of
ARN-509 (structure shown in formula I), processes for preparation
of the novel crystalline forms, pharmaceutical composition of the
novel crystalline forms, and uses of the novel crystalline forms
for preparing drug products of androgen receptor antagonists and
for treating prostate cancer. The crystalline forms of ARN-509
provided by the present disclosure have one or more improved
properties compared with the prior art, and is of great value to
the future optimization and development of drugs. ##STR00001##
Inventors: |
Chen; Minhua; (Suzhou,
CN) ; Zhang; Yanfeng; (Suzhou, CN) ; Zhai;
Xiaoting; (Suzhou, CN) ; Qian; Jiale; (Suzhou,
CN) ; Chen; Yuhao; (Suzhou, CN) ; Yang;
Chaohui; (Suzhou, CN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Crystal Pharmaceutical (Suzhou) Co., Ltd. |
Suzhou, Jiangsu |
|
CN |
|
|
Family ID: |
1000004841021 |
Appl. No.: |
16/763554 |
Filed: |
May 16, 2019 |
PCT Filed: |
May 16, 2019 |
PCT NO: |
PCT/CN2019/087264 |
371 Date: |
May 13, 2020 |
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07B 2200/13 20130101;
C07D 401/04 20130101 |
International
Class: |
C07D 401/04 20060101
C07D401/04 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 20, 2018 |
CN |
201810639839.8 |
Jun 20, 2018 |
CN |
201810639840.0 |
Claims
1. A crystalline form CS8 of ARN-509, wherein the X-ray powder
diffraction pattern shows characteristic peaks at 2theta values of
7.9.+-.0.2.degree., 12.4.+-.0.2.degree., and 19.0.+-.0.2.degree.
using CuK.alpha. radiation.
2. The crystalline form CS8 according to claim 1, wherein the X-ray
powder diffraction pattern shows one or two or three characteristic
peaks at 2theta values of 15.4.+-.0.2.degree., 19.6.+-.0.2.degree.
and 22.5.+-.0.2.degree. using CuK.alpha. radiation.
3. The crystalline form CS8 according to claim 1, wherein the X-ray
powder diffraction pattern shows one or two or three characteristic
peaks at 2theta values of 23.2.+-.0.2.degree., 16.0.+-.0.2.degree.
and 24.0.+-.0.2.degree. using CuK.alpha. radiation.
4. A process for preparing crystalline form CS8 of ARN-509, wherein
the process comprises: (1) dissolving ARN-509 into a solvent of
alcohols, cooling to -20.degree. C. to 16.degree. C., precipitating
solid to obtain crystalline form CS8; or (2) dissolving ARN-509
into ethyl formate, cooling to -20.degree. C. to 10.degree. C., and
drying the obtained solid under vacuum at 5.degree. C. to
70.degree. C. to obtain crystalline form CS8; or (3) dissolving
ARN-509 into a solvent mixture of methyl acetate, alcohols and
alkanes, stirring at 0.degree. C. to 10.degree. C., separating by
filtration, and drying the obtained solid with forced air
convection at 20.degree. C. to 40.degree. C. to obtain crystalline
form CS8.
5. The process for preparing crystalline form CS8 according to
claim 4, wherein in method (1), said alcohol is methanol, said
cooling temperature is 10.degree. C.; in method (2), said cooling
temperature is -5.degree. C., said vacuum-drying temperature is
60.degree. C.; in method (3), said alcohol is methanol, said alkane
is cyclohexane, said stirring temperature is 5.degree. C., said
temperature for drying with forced air convection is 30.degree.
C.
6. A crystalline form CS9 of ARN-509, wherein the X-ray powder
diffraction pattern shows characteristic peaks at 2theta values of
7.7.+-.0.2.degree., 15.0.+-.0.2.degree., and 18.0.+-.0.2.degree.
using CuK.alpha. radiation.
7. The crystalline form CS9 according to claim 6, wherein the X-ray
powder diffraction pattern shows one or two or three characteristic
peaks at 2theta values of 12.3.+-.0.2.degree., 19.9.+-.0.2.degree.
and 20.7.+-.0.2.degree. using CuK.alpha. radiation.
8. The crystalline form CS9 according to claim 6, wherein the X-ray
powder diffraction pattern shows one or two or three characteristic
peaks at 2theta values of 15.5.+-.0.2.degree., 22.6.+-.0.2.degree.
and 23.0.+-.0.2.degree. using CuK.alpha. radiation.
9. A process for preparing crystalline form CS9 of ARN-509
according to claim 6, wherein the process comprises: (1) adding
ARN-509 into nitriles, the mixture of nitriles and water, the
mixture of nitriles and alcohols or the mixture of nitriles and
aromatic hydrocarbons, stirring at 5.degree. C. to 50.degree. C.,
centrifuging and drying to obtain solid; or (2) dissolving ARN-509
into a solvent mixture of methyl acetate, alcohols and alkanes,
heating the solution to 40.degree. C. to 60.degree. C., then
cooling to 0.degree. C. to 10.degree. C. to precipitate solid; or
(3) dissolving ARN-509 into a solvent mixture of acetonitrile and
alcohols, cooling to -20.degree. C. to 5.degree. C. to precipitate
solid.
10. The preparation process according to claim 9, wherein in method
(1), said nitrile is acetonitrile, said alcohol is methanol or
ethanol, said aromatic hydrocarbon is toluene, said stirring
temperature is room temperature or 50.degree. C.; in method (2),
said alcohol is methanol, said alkane is n-heptane; said heating
temperature is 50.degree. C., said cooling temperature is 5.degree.
C.; in method (3), said alcohol is isopropanol, said cooling
temperature is -20.degree. C.
11. A pharmaceutical composition, wherein said pharmaceutical
composition comprises a therapeutically effective amount of
crystalline form CS8 according to claim 1, and pharmaceutically
acceptable carriers, diluents or excipients.
12. A method of antagonizing an androgen receptor, comprising
administering to a subject in need thereof a therapeutically
effective amount of crystalline form CS8 according to claim 1.
13. A method of treating prostate cancer, comprising administering
to a subject in need thereof a therapeutically effective amount of
crystalline form CS8 according to claim 1.
14. The crystalline form CS8 according to claim 2, wherein the
X-ray powder diffraction pattern shows one or two or three
characteristic peaks at 2theta values of 23.2.+-.0.2.degree.,
16.0.+-.0.2.degree. and 24.0.+-.0.2.degree. using CuK.alpha.
radiation.
15. The crystalline form CS9 according to claim 7, wherein the
X-ray powder diffraction pattern shows one or two or three
characteristic peaks at 2theta values of 15.5.+-.0.2.degree.,
22.6.+-.0.2.degree. and 23.0.+-.0.2.degree. using CuK.alpha.
radiation.
16. A pharmaceutical composition, wherein said pharmaceutical
composition comprises a therapeutically effective amount of
crystalline form CS9 according to claim 6, and pharmaceutically
acceptable carriers, diluents or excipients.
17. A method of antagonizing an androgen receptor, comprising
administering to a subject in need thereof a therapeutically
effective amount of crystalline form CS9 according to claim 6.
18. A method for treating prostate cancer, comprising administering
to a subject in need thereof a therapeutically effective amount of
crystalline form CS9 according to claim 6.
Description
TECHNICAL FIELD
[0001] The present disclosure relates to the field of
pharmaceutical chemistry, particularly relates to novel crystalline
forms of ARN-509, processes for preparation and use thereof.
BACKGROUND
[0002] Prostate cancer is the cancer with highest incidence and
second highest mortality rate in men. Data from the American Cancer
Society show that there were approximately 180,000 new cases in the
United States in 2016, and about 3 million patients with prostate
cancer. In 1941, Huggins and Hodges first demonstrated the response
of prostate cancer to androgen removal. Therapies that inhibit
androgen activity have been widely used in the treatment of
prostate cancer.
[0003] Abiraterone and Enzalutamide are the first-generation
androgen receptor antagonists and have been approved for the
treatment of prostate cancer. In clinical trials, it is effective
in about 70% of patients. The response rate is much higher than the
drugs targeting other targets, which further proves the importance
of androgens for the treatment of prostate cancer.
[0004] ARN-509 (Apalutamide) is a second-generation androgen
receptor antagonist used for the treatment of prostate cancer in
the clinical research. It prevents androgen from binding to
androgen receptor by binding with the androgen receptor, thereby
inhibiting the androgen receptor signaling pathway and achieving
the purpose of treating prostate cancer. ARN-509 has shown positive
safety and efficacy in clinic trials, and shows good therapeutic
prospect.
[0005] The chemical name of ARN-509 is
4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspir-
o[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide, and the structure is
shown as Formula I:
##STR00002##
[0006] A crystalline form is a solid material whose constituents
are arranged in a highly ordered microscopic structure, forming a
crystal lattice that extends in all directions. Polymorphism is the
ability of a compound to exist in more than one crystalline form.
Different crystalline forms have different physicochemical
properties and can affect drug's in vivo dissolution and
absorption, which will further affect drug's clinical efficacy and
safety to some extent. Especially for poorly soluble drugs, the
above effects of the crystalline form will be greater. Therefore,
drug polymorphism is an important part of drug research and an
important part of drug quality control.
[0007] The prior art WO2013184681A disclosed crystalline form A,
form B, form C, form D, form E, form F, form G, form H, form I and
form J of ARN-509. Among them, form C is an isopropanol solvate,
form D is a methyl tert-butyl ether solvate, form E is a dimethyl
sulfoxide solvate, form G is a 2-methoxyethanol solvent, and form J
is an acetone solvate. Therefore, form C, form D, form E, form G
and form J are not suitable for pharmaceutical use. Form F will
transform to form A under ambient conditions. During the process of
preparation of form I, form E will be formed and it is difficult to
separate them. Form I will transform to form B under high humidity
conditions. Form H is easily transformed into form B under high
temperature and high humidity conditions. It can be seen that form
F, form H, and form I are not suitable for industrial production
and application. According to WO2013184681A, the preferred
crystalline form that may be suitable for pharmaceutical use are
form A and form B. The inventors of the present disclosure
discovered that the solubility, in vitro dissolution, grinding
stability, adhesion and compressibility of the prior art form A and
form B are poor, which is not conducive to the in vivo absorption
of drugs and industrial production of drug products.
[0008] In order to overcome the disadvantages of the prior art, the
inventors of the present disclosure surprisingly discovered
crystalline form CS8 and form CS9 of ARN-509, which have advantages
in physiochemical properties, formulation processability and
bioavailability. For example, crystalline form CS8 and form CS9
have advantages in at least one aspect of melting point,
solubility, hygroscopicity, purification ability, stability,
adhesiveness, compressibility, flowability, in vitro and in vivo
dissolution, and bioavailability, etc. Particularly, crystalline
form CS8 and form CS9 have higher solubility and in vitro
dissolution, better stability, uniform particle size distribution,
better adhesion and compressibility, which provides a new and
better choice for the development of ARN-509 and is of great
significance for drug development.
SUMMARY
[0009] The main objective of the present disclosure is to provide
novel crystalline forms of ARN-509, processes for preparation and
use thereof.
[0010] According to the objective of the present disclosure,
crystalline form CS8 of ARN-509 is provided (hereinafter referred
to as Form CS8).
[0011] The X-ray powder diffraction pattern of Form CS8 shows
characteristic peaks at 2theta values of 7.9.+-.0.2.degree.,
12.4.+-.0.2.degree. and 19.0.+-.0.2.degree. using CuK.alpha.
radiation.
[0012] Furthermore, the X-ray powder diffraction pattern of Form
CS8 shows one or two or three characteristic peaks at 2theta values
of 15.4.+-.0.2.degree., 19.6.+-.0.2.degree. and
22.5.+-.0.2.degree.. Preferably, the X-ray powder diffraction
pattern of Form CS8 shows characteristic peaks at 2theta values of
15.4.+-.0.2.degree., 19.6.+-.0.2.degree. and
22.5.+-.0.2.degree..
[0013] Furthermore, the X-ray powder diffraction pattern of Form
CS8 shows one or two or three characteristic peaks at 2theta values
of 23.2.+-.0.2.degree., 16.0.+-.0.2.degree. and
24.0.+-.0.2.degree.. Preferably, the X-ray powder diffraction
pattern of Form CS8 shows characteristic peaks at 2theta values of
23.2.+-.0.2.degree., 16.0.+-.0.2.degree. and
24.0.+-.0.2.degree..
[0014] The X-ray powder diffraction pattern of Form CS8 shows three
or four or five or six or seven or eight or nine characteristic
peaks at 2theta values of 7.9.+-.0.2.degree., 12.4.+-.0.2.degree.,
19.0.+-.0.2.degree., 15.4.+-.0.2.degree., 19.6.+-.0.2.degree.,
22.5.+-.0.2.degree., 23.2.+-.0.2.degree., 16.0.+-.0.2.degree. and
24.0.+-.0.2.degree. using CuK.alpha. radiation.
[0015] Without any limitation being implied, in a specific
embodiment of the present disclosure, the X-ray powder diffraction
pattern of Form CS8 is substantially as depicted in FIG. 1.
[0016] Without any limitation being implied, in some embodiments of
the present disclosure, Form CS8 is a hydrate.
[0017] According to the objective of the present disclosure, a
process for preparing Form CS8 is also provided. The process
comprises:
[0018] (1) Dissolving ARN-509 into a solvent of alcohols, cooling
to -20.degree. C.-16.degree. C., precipitating solid to obtain Form
CS8; or
[0019] (2) Dissolving ARN-509 into ethyl formate, cooling to
-20.degree. C.-10.degree. C., and drying the obtain solid under
vacuum at 5.degree. C.-70.degree. C. to obtain Form CS8; or
[0020] (3) Dissolving ARN-509 into a solvent mixture of methyl
acetate, alcohols and alkanes, stirring at 0.degree. C.-10.degree.
C., separating by filtration, and drying the obtained solid with
forced air convection at 20.degree. C.-40.degree. C. to obtain Form
CS8.
[0021] Furthermore, in method (1), said alcohol is preferably
methanol; said cooling temperature is preferably 10.degree. C.;
[0022] Furthermore, in method (2), said cooling temperature is
preferably -5.degree. C.; said vacuum-drying temperature is
preferably 60.degree. C.;
[0023] Furthermore, in method (3), said alcohol is preferably
methanol, said alkane is preferably cyclohexane, said stirring
temperature is preferably 5.degree. C., said drying with forced air
convection temperature is preferably 30.degree. C.
[0024] According to the objective of the present disclosure,
crystalline form CS9 of ARN-509 is provided (hereinafter referred
to as Form CS9).
[0025] The X-ray powder diffraction pattern of Form CS9 shows
characteristic peaks at 2theta values of 7.7.+-.0.2.degree.,
15.0.+-.0.2.degree. and 18.0.+-.0.2.degree. using CuK.alpha.
radiation.
[0026] Furthermore, the X-ray powder diffraction pattern of Form
CS9 shows one or two or three characteristic peaks at 2theta values
of 12.3.+-.0.2.degree., 19.9.+-.0.2.degree. and
20.7.+-.0.2.degree.. Preferably, the X-ray powder diffraction
pattern of Form CS9 shows characteristic peaks at 2theta values of
12.3.+-.0.2.degree., 19.9.+-.0.2.degree. and
20.7.+-.0.2.degree..
[0027] Furthermore, the X-ray powder diffraction pattern of Form
CS9 shows one or two or three characteristic peaks at 2theta values
of 15.5.+-.0.2.degree., 22.6.+-.0.2.degree. and
23.0.+-.0.2.degree.. Preferably, the X-ray powder diffraction
pattern of Form CS9 shows characteristic peaks at 2theta values of
15.5.+-.0.2.degree., 22.6.+-.0.2.degree. and
23.0.+-.0.2.degree..
[0028] The X-ray powder diffraction pattern of Form CS9 shows three
or four or five or six or seven or eight or nine characteristic
peaks at 2theta values of 7.7.+-.0.2.degree., 15.0.+-.0.2.degree.,
18.0.+-.0.2.degree., 12.3.+-.0.2.degree., 19.9.+-.0.2.degree.,
20.7.+-.0.2.degree., 15.5.+-.0.2.degree., 22.6.+-.0.2.degree. and
23.0.+-.0.2.degree. using CuK.alpha. radiation.
[0029] Without any limitation being implied, in a specific
embodiment of the present disclosure, the X-ray powder diffraction
pattern of Form CS9 is substantially as depicted in FIG. 5.
[0030] Without any limitation being implied, Form CS9 can be
obtained in different solvent systems and represents a group of
isomorphism. In some embodiments, Form CS9 is an acetonitrile
solvate. In some embodiments, Form CS9 can also be methyl acetate
solvate or co-solvate of methyl acetate and water.
[0031] Without any limitation being implied, in a specific
embodiment of the present disclosure, Form CS9 is a co-solvate of
methyl acetate and water. The parameters of the single crystal
structure are shown in the following table:
TABLE-US-00001 Crystal system Orthogonal Space group Pna2.sub.1
Unit cell dimensions a 9.1489(11) .ANG. .alpha. 90.00.degree. b
16.077(2) .ANG. .beta. 90.00.degree. c 16.817(2) .ANG. .gamma.
90.00.degree. Volume of unit cell (V) 2473.6(5) .ANG..sup.3 Number
of formula 4 units in unit cell (Z) Calculated density 1.395
g/cm.sup.3
[0032] Without any limitation being implied, in another specific
embodiment of the present disclosure, Form CS9 is an acetonitrile
solvate. The parameters of the single crystal structure are shown
in the following table:
TABLE-US-00002 Crystal system Orthogonal Space group Pna2.sub.1
Unit cell dimensions a 9.0288(15) .ANG. .alpha. 90.00.degree. b
15.295(2) .ANG. .beta. 90.00.degree. c 16.948(3) .ANG. .gamma.
90.00.degree. Volume of unit cell (V) 2340.5(6) .ANG..sup.3 Number
of formula 4 units in unit cell (Z) Calculated density 1.471
g/cm.sup.3
[0033] According to the objective of the present disclosure, a
process for preparing Form CS9 is also provided. The process
comprises:
[0034] (1) Adding ARN-509 into nitriles, the mixture of nitriles
and water, the mixture of nitriles and alcohols, or the mixture of
nitriles and aromatic hydrocarbons, stirring at 5.degree.
C.-50.degree. C., centrifuging and drying to obtain solid, or
[0035] (2) Dissolving ARN-509 into a solvent mixture of methyl
acetate, alcohols and alkanes, heating to 40.degree. C.-60.degree.
C., and then cooling to 0.degree. C.-10.degree. C. to precipitate
solid; or
[0036] (3) Dissolving ARN-509 into a solvent mixture of
acetonitrile and alcohols, cooling to -20.degree. C.-5.degree. C.
to precipitate solid.
[0037] Furthermore, in method (1), said nitrile is preferably
acetonitrile, said alcohol is preferably methanol or ethanol, said
aromatic hydrocarbon is preferably toluene;
[0038] Furthermore, in method (1), said stirring temperature is
preferably room temperature or 50.degree. C.;
[0039] Furthermore, in method (2), said alcohol is preferably
methanol, said alkane is preferably n-heptane;
[0040] Furthermore, in method (2), said heating temperature is
preferably 50.degree. C., said cooling temperature is preferably
5.degree. C.;
[0041] Furthermore, in method (3), said alcohol is preferably
isopropanol;
[0042] Furthermore, in method (3), said cooling temperature is
preferably -20.degree. C.
[0043] Form CS8 of the present disclosure has the following
advantages:
[0044] (1) Compared with the prior art, Form CS8 of the present
disclosure has higher solubility. In pH=1.0 HCl aqueous solution,
after equilibrated for 15 minutes, the solubility of Form CS8 is
3.2 times higher than that of Form A of the prior art and 19.7
times higher than that of Form B of the prior art. In pH=4.5 acetic
acid buffer solution, after equilibrated for 15 minutes, the
solubility of Form CS8 is 3.0 times higher than that of Form A and
16.1 times higher than that of Form B of the prior art. In pH=6.8
phosphate buffer solution, after equilibrated for 15 minutes, the
solubility of Form CS8 is 3.7 times higher than that of Form A of
the prior art and 19.0 times higher than that of Form B of the
prior art.
[0045] ARN-509 is a poorly water-soluble drug and belongs to BCS II
(low solubility and high permeability). Higher solubility is
beneficial to improve drug's in vivo absorption and
bioavailability, thus improving drug efficacy. In addition, drug
dose reduction without affecting efficacy is possible due to higher
solubility, thereby reducing the drug's side effects and improving
drug safety.
[0046] (2) Compared with the prior art, Form CS8 of the present
disclosure has better in vitro dissolution and dissolution rate. In
pH=4.5 acetic acid buffer solution+0.5% (W/W) sodium dodecyl
sulfate aqueous solution, the dissolution of Form CS8 drug products
is up to 81% at 60 minutes. However, the dissolution of Form A and
Form B of the prior art drug products are only 44% and 66%,
respectively.
[0047] Drug with different crystalline forms may lead to different
in vivo dissolution rate, which directly affects drug's in vivo
absorption, distribution, excretion and metabolism, and finally
leads to difference in clinical efficacy due to different
bioavailability. Dissolution and dissolution rates are important
prerequisites for drug absorption. Good in vitro dissolution is
conducive to increasing the degree of drug absorption and ensuring
better in vivo exposure, thereby improving drug's bioavailability
and efficacy. High dissolution rate is beneficial for the drug to
achieve peak concentration in plasma quickly after administration,
thus ensuring rapid drug action.
[0048] (3) Form CS8 drug substance of the present disclosure has
good stability and it also has good stability in drug products.
[0049] Form CS8 drug substance doesn't change for at least 6 months
when stored under the condition of 25.degree. C./60% RH. The
chemical purity is above 99.9% and remains substantially unchanged
during storage. Form CS8 is blended with the excipients to form
drug products, and stored under the condition of 25.degree. C./60%
RH, the Form CS8 drug products doesn't change for at least 3
months. The chemical purity remains substantially unchanged during
storage. These results show that Form CS8 drug substance of the
present disclosure is very stable and it has good stability in drug
products, which is beneficial for the storage of drug products.
[0050] Meanwhile, Form CS8 drug substance doesn't change for at
least 6 months when stored under the condition of 40.degree. C./75%
RH. The chemical purity is above 99.9% and remains substantially
unchanged during storage. Form CS8 is blended with the excipients
to form drug products, and stored under the condition of 40.degree.
C./75% RH, the Form CS8 drug products doesn't change for at least 3
months. The chemical purity remains substantially unchanged during
storage. Furthermore, Form CS8 doesn't change for at least 2 weeks
when stored under the condition of 60.degree. C./75% RH. The
results show that Form CS8 drug substance and drug products have
better stability under accelerated and stress conditions. Good
stability of drug substance and drug products under accelerated and
stress conditions is of great importance to the drug development.
Drug substance and drug products will go through high temperature
and high humidity conditions caused by seasonal and regional
climate differences, and weather factors during storage,
transportation, and manufacturing processes. Form CS8 drug
substance and drug products have good stability under these stress
conditions, which is beneficial to avoid the influence on drug
quality when not stored in condition recommended in label.
[0051] Meanwhile, compared with the prior art, Form CS8 has better
mechanical stability. The crystalline form and crystallinity of
Form CS8 doesn't change after grinding. While Form A of the prior
art transformed into amorphous after grinding and the crystallinity
of Form B of the prior art decreases after grinding. Grinding and
pulverization are often required in the drug manufacturing process.
Good physical stability of the drug substance can reduce the risk
of crystallinity decrease and crystal transformation during the
drug production process. Meanwhile, Form CS8 has good physical
stability under different pressure, which is beneficial to keep
crystalline form unchanged during tableting process.
[0052] Crystal transformation and crystallinity decrease can lead
to changes in the absorption of the drug, affect bioavailability,
and even cause toxicity and side effects. Good chemical stability
ensures that no impurities are generated during storage. Form CS8
has good physical and chemical stability, ensuring consistent and
controllable quality of the drug substance and drug products,
minimizing change in quality, bioavailability due to crystal
transformation or impurity generation.
[0053] Furthermore, Form CS8 of the present disclosure also has the
following advantages:
[0054] (1) Compared with the prior art, Form CS8 of the present
disclosure has uniform particle size distribution. Its uniform
particle size helps to ensure uniformity of content and reduce
variability of in vitro dissolution. Meanwhile, the preparation
process can be simplified, the pretreatment of the drug substance
is not required, the cost is reduced, and the risk of decrease in
crystallinity and crystal transformation caused by grinding can be
reduced.
[0055] (2) Compared with the prior art, Form CS8 of the present
disclosure shows superior adhesiveness. Adhesiveness evaluation
results indicate that adhesion quantity of Form CS8 is remarkably
lower than that of the prior art forms. Due to superior
adhesiveness of Form CS8, adhesion to roller and tooling during
dry-granulation and compression process can be reduced, which is
also beneficial to improve product appearance and weight variation.
In addition, superior adhesiveness of Form CS8 can reduce the
agglomeration of drug substance, which is beneficial to the
dispersion of drug substance and blending with other excipients,
improving the blend uniformity and content uniformity of drug
products.
[0056] (3) Compared with the prior art, Form CS8 of the present
disclosure has better compressibility. Failure in
hardness/friability test and tablet crack issue can be avoided due
to better compressibility of Form CS8, making the preparation
process more reliable, improving product appearance and product
quality. Better compressibility can increase the compression rate,
thus further increases the efficiency of process and reduces the
cost of compressibility improving excipients.
[0057] According to the objective of the present disclosure, a
pharmaceutical composition is provided; said pharmaceutical
composition comprises a therapeutically effective amount of Form
CS8, Form CS9 or combinations thereof, and pharmaceutically
acceptable carriers, diluents or excipients.
[0058] Furthermore, the use of Form CS8 and Form CS9 or
combinations thereof of the present disclosure for preparing
androgen receptor antagonist drugs.
[0059] Furthermore, the use of Form CS8 and Form CS9 or
combinations thereof of the present disclosure for preparing drugs
treating prostate cancer.
[0060] In the present disclosure, said "stirring" is accomplished
by using a conventional method in the field such as magnetic
stirring or mechanical stirring and the stirring speed is 50 to
1800 r/min, preferably the magnetic stirring speed is 300 to 900
r/min and mechanical stirring speed is 100 to 300 r/min.
[0061] Said "separation" is accomplished by using a conventional
method in the field such as centrifugation or filtration. The
operation of "centrifugation" is as follows: the sample to be
separated is placed into the centrifuge tube, and then centrifuged
at a rate of 10000 r/min until the solid all sink to the bottom of
the tube.
[0062] Said "drying" is accomplished at room temperature or a
higher temperature. The drying temperature is from room temperature
to about 60.degree. C., or to 50.degree. C., or to 40.degree. C.
The drying time can be 2 to 48 hours, or overnight. Drying is
accomplished in a fume hood, forced air convection oven or vacuum
oven.
[0063] Said "cooling" is accomplished by using conventional methods
in the field such as slow cooling and rapid cooling. Slow cooling
is usually accomplished at the speed of 0.1.degree. C./min. Rapid
cooling is usually accomplished by transferring the sample directly
from environment which is no lower than room temperature to
refrigerator for cooling.
[0064] In the present disclosure, "crystal" or "crystalline form"
refers to the solid being identified by the X-ray diffraction
pattern shown herein. Those skilled in the art are able to
understand that physicochemical properties discussed herein can be
characterized. The experimental errors depend on the instrument
conditions, the sampling processes and the purity of samples. In
particular, those skilled in the art generally know that the X-ray
diffraction pattern typically varies with the experimental
conditions. It is necessary to point out that, the relative
intensity of the diffraction peaks in the X-ray diffraction pattern
may also vary with the experimental conditions; therefore, the
order of the diffraction peak intensities cannot be regarded as the
sole or decisive factor. In fact, the relative intensity of the
diffraction peaks in the X-ray powder diffraction pattern is
related to the preferred orientation of the crystals, and the
diffraction peak intensities shown herein are illustrative and
identical diffraction peak intensities are not required. In
addition, the experimental error of the diffraction peak position
is usually 5% or less, and the error of these positions should also
be taken into account. An error of .+-.0.2.degree. is usually
allowed. In addition, due to experimental factors such as sample
thickness, the overall offset of the diffraction peak is caused,
and a certain offset is usually allowed. Thus, it will be
understood by those skilled in the art that a crystalline form of
the present disclosure is not necessarily to have the exactly same
X-ray diffraction pattern of the example shown herein. Any
crystalline forms whose X-ray diffraction patterns have the same or
similar characteristic peaks should be within the scope of the
present disclosure. Those skilled in the art can compare the
patterns shown in the present disclosure with that of an unknown
crystalline form in order to identify whether these two groups of
patterns reflect the same or different crystalline forms.
[0065] In some embodiments, Form CS8 and Form CS9 of the present
disclosure are pure and substantially free of any other crystalline
forms. In the present disclosure, the term "substantially free"
when used to describe a novel crystalline form, it means that the
content of other crystalline forms in the novel crystalline form is
less than 20% (w/w), specifically less than 10% (w/w), more
specifically less than 5% (w/w) and further more specifically less
than 1% (w/w).
[0066] The term "about", as used herein when referring to a
measurable value such as an amount of a compound or formulation of
this invention, time, temperature, and the like, is meant to
encompass variations of .+-.10%, .+-.5%, .+-.1%, .+-.0.5%, or even
.+-.0.1% of the specified value.
BRIEF DESCRIPTION OF THE DRAWINGS
[0067] FIG. 1 shows an XRPD pattern of Form CS8 according to
example 1.
[0068] FIG. 2 shows a DSC curve of Form CS8 according to example
1.
[0069] FIG. 3 shows a TGA curve of Form CS8 according to example
1.
[0070] FIG. 4 shows an XRPD pattern of Form CS8 according to
example 2.
[0071] FIG. 5 shows an XRPD pattern of Form CS8 according to
example 3.
[0072] FIG. 6 shows a TGA curve of Form CS8 according to example
3.
[0073] FIG. 7 shows an XRPD pattern of Form CS9 according to
example 4.
[0074] FIG. 8 shows a DSC curve of Form CS9 according to example
4.
[0075] FIG. 9 shows a TGA curve of Form CS9 according to example
4.
[0076] FIG. 10 shows an XRPD pattern of Form CS9 according to
example 5.
[0077] FIG. 11 shows a single crystal XRPD pattern of Form CS9
obtained in Example 9.
[0078] FIG. 12 shows a single crystal XRPD pattern of Form CS9
obtained in Example 10.
[0079] FIG. 13 shows an XRPD pattern overlay of Form CS8 of the
present disclosure before and after being stored under 25.degree.
C./60% RH (from top to bottom: initial, being stored for 6 months
in open dish, being stored for 6 months in closed dish).
[0080] FIG. 14 shows an XRPD pattern overlay of Form CS8 of the
present disclosure before and after being stored under 40.degree.
C./75% RH (from top to bottom: initial, being stored for 6 months
in open dish, being stored for 6 months in closed dish).
[0081] FIG. 15 shows an XRPD pattern overlay of Form CS8 of the
present disclosure before and after being stored under 60.degree.
C./75% RH (from top to bottom: initial, being stored for 2 weeks in
open dish, being stored for 2 weeks in closed dish).
[0082] FIG. 16 shows an XRPD pattern overlay of Form CS8 of the
present disclosure after being tableted under different pressures
(from top to bottom: 3 KN, 7 KN, 14 KN, before being tableted).
[0083] FIG. 17 shows an XRPD pattern overlay of Form CS8 of the
present disclosure before and after being ground (top: before
grinding; bottom: after grinding).
[0084] FIG. 18 shows an XRPD pattern overlay of Form A of the prior
art before and after being ground (top: before grinding; bottom:
after grinding).
[0085] FIG. 19 shows an XRPD pattern overlay of Form B of the prior
art before and after being ground (top: before grinding; bottom:
after grinding).
[0086] FIG. 20 shows the particle size distribution of Form CS8 of
the present disclosure.
[0087] FIG. 21 shows the particle size distribution of Form A of
the prior art.
[0088] FIG. 22 shows the particle size distribution of Form B of
the prior art.
[0089] FIG. 23 shows the dissolution profiles of Form CS8, Form A
of the prior art and Form B of the prior art.
[0090] FIG. 24 shows an XRPD pattern overlay of Form CS8 drug
product of the present disclosure before and after being stored
under 25.degree. C./60% RH (from top to bottom: 3 months, 1 month,
initial).
[0091] FIG. 25 shows an XRPD pattern overlay of Form CS8 drug
product of the present disclosure before and after being stored
under 40.degree. C./75% RH (from top to bottom: 3 months, 1 month,
initial).
DETAILED DESCRIPTION
[0092] The present disclosure is further illustrated by the
following examples which describe the preparation and use of the
crystalline forms of the present disclosure in detail. It is
obvious to those skilled in the art that many changes in the
materials and methods can be accomplished without departing from
the scope of the present disclosure. The abbreviations used in the
present disclosure are explained as follows:
[0093] XRPD: X-ray Powder Diffraction
[0094] DSC: Differential Scanning Calorimetry
[0095] TGA: Thermal Gravimetric Analysis
[0096] PSD: Particle Size Distribution
[0097] HPLC: High Performance Liquid Chromatography
[0098] Instruments and methods used for data collection:
[0099] X-ray powder diffraction patterns in the present disclosure
were acquired by a Bruker D2 PHASER X-ray powder diffractometer.
The parameters of the X-ray powder diffraction method of the
present disclosure are as follows:
[0100] X-ray Reflection: Cu, K.alpha.
[0101] K.alpha.1 (.ANG.): 1.54060; K.alpha.2 (.ANG.): 1.54439
[0102] K.alpha.2/K.alpha.1 intensity ratio: 0.50
[0103] Voltage: 30 (kV)
[0104] Current: 10 (mA)
[0105] Scan range: from 3.0 degree to 40.0 degree
[0106] The test conditions of Form CS8:
[0107] Temperature range: 20.degree. C.-50.degree. C.;
[0108] Relative humidity: 10%-45% RH.
[0109] There is no special requirement for the test conditions of
Form CS9.
[0110] Differential scanning calorimetry (DSC) data in the present
disclosure were acquired by a TA Q2000. The parameters of the DSC
method of the present disclosure are as follows:
[0111] Heating rate: 10.degree. C./min
[0112] Purge gas: nitrogen
[0113] Thermal gravimetric analysis (TGA) data in the present
disclosure were acquired by a TA Q500. The parameters of the TGA
method of the present disclosure are as follows:
[0114] Heating rate: 10.degree. C./min
[0115] Purge gas: nitrogen
[0116] The particle size distribution data in the present
disclosure were acquired by an S3500 laser particle size analyzer
of Microtrac. Microtrac S3500 is equipped with an SDC (Sample
Delivery Controller). The test is carried out in wet mode, and the
dispersion medium is Isopar G. The laser particle size analyzer
parameters are as follows:
TABLE-US-00003 Size distribution: Volume Run Time: 10 s Dispersion
medium: Isopar G Particle coordinates: Standard Run Number: Average
of 3 runs Fluid refractive index: 1.42 Particle Transparency: Trans
Residuals: Enabled Particle refractive index: 1.5 Flow rate: 60%*
Particle shape: Irregular Filtration: Enabled Ultrasonication
power: 30 W Ultrasonication time: 30 s *Flow rate 60% is 60% of 65
mL/s.
[0117] High Performance Liquid Chromatography (HPLC) data in the
present disclosure were collected from Agilent 1260&1200 with
Diode Array Detector (DAD).
[0118] The HPLC method parameters for purity test in the present
disclosure are as follows:
[0119] 1. Column: Waters XBridge C18 150.times.4.6 mm, 5 .mu.m
[0120] 2. Mobile Phase: A: 0.1% Trifluoroacetic acid (TFA) in
H.sub.2O [0121] B: 0.1% TFA in Acetonitrile
[0122] Gradient:
TABLE-US-00004 Time (min) % B 0.0 30 1.0 30 18.0 95 23.0 95 23.1 30
30.0 30
[0123] 3. Flow rate: 1.0 mL/min
[0124] 4. Injection Volume: 5 .mu.L
[0125] 5. Detection wavelength: 242 nm
[0126] 6. Column Temperature: 40.degree. C.
[0127] 7. Diluent: MeOH
The HPLC method parameters for solubility test in the present
disclosure are as follows:
[0128] 1. Column: Waters XBridge C18 150.times.4.6 mm, 5 .mu.m
[0129] 2. Mobile Phase: A: 0.1% TFA in H.sub.2O [0130] B: 0.1% TFA
in Acetonitrile
[0131] Gradient:
TABLE-US-00005 Tim (min) % B 0.0 50 5.0 90 6.0 90 6.1 50 10.0
50
[0132] 3. Flow rate: 1.0 mL/min
[0133] 4. Injection Volume: 5 .mu.L
[0134] 5. Detection wavelength: 242 nm
[0135] 6. Column Temperature: 40.degree. C.
[0136] 7. Diluent: MeOH
[0137] Unless otherwise specified, the following examples were
conducted at room temperature. Said "room temperature" refers to
10-30.degree. C.
[0138] According to the present disclosure, ARN-509 as a raw
material are solid (crystalline or amorphous), wax or oil form.
Preferably, ARN-509 as a raw material is solid powder.
[0139] Raw materials of ARN-509 used in the following examples were
prepared by known methods in the prior art, for example, the method
disclosed in WO2013184681A.
Example 1.about.3: Preparation of Form CS8
Example 1
[0140] About 2.0 g of ARN-509 was weighed and dissolved in 40.0 mL
of methanol. After filtration, the obtained filtrate was cooled to
10.degree. C. at a rate of 0.1.degree. C./min rate, and stirred for
about 2 hours. The obtained solid was separated by filtration.
[0141] The XRPD, TGA and DSC tests were performed on the obtained
solid, and the obtained solid was confirmed to be Form CS8.
[0142] The XRPD pattern is substantially as depicted in FIG. 1, and
the XRPD data are listed in Table 1.
[0143] The DSC curve of Form CS8 is substantially as depicted in
FIG. 2. The first endothermic peak appears around 55.degree. C. and
the second endothermic peak appears around 116.degree. C.
[0144] The TGA curve of Form CS8 is substantially as depicted in
FIG. 3. The TGA curve of Form CS8 shows about 3.9% weight loss when
heated to 150.degree. C.
TABLE-US-00006 TABLE 1 Diffraction d Intensity angle 2.theta.
spacing % 7.94 11.13 100.00 10.25 8.63 2.46 11.22 7.89 4.96 12.37
7.16 48.18 15.43 5.74 41.82 15.97 5.55 12.97 16.30 5.44 7.55 19.05
4.66 21.96 19.63 4.52 19.08 20.59 4.31 9.43 22.50 3.95 18.39 23.16
3.84 17.05 24.05 3.70 11.39 24.89 3.58 6.39 26.65 3.35 8.54 28.28
3.16 2.88 30.84 2.90 5.23 31.20 2.87 6.03 32.82 2.73 2.11
Example 2
[0145] About 1.37 g of ARN-509 was weighed and dissolved in 20.0 mL
of ethyl formate. After filtration, the obtained filtrate was
cooled to -5.degree. C., and stirred overnight. The obtained solid
was collected and drying under vacuum at 60.degree. C. for about 48
h to get crystals.
[0146] The XRPD test was performed on the obtained solid, and the
obtained solid was confirmed to be Form CS8.
[0147] The XRPD pattern is substantially as depicted in FIG. 4, and
the XRPD data are listed in Table 2.
TABLE-US-00007 TABLE 2 Diffraction d Intensity angle 2.theta.
spacing % 7.95 11.13 100.00 12.35 7.17 22.40 15.40 5.75 25.32 15.94
5.56 12.81 16.25 5.46 4.84 19.01 4.67 8.24 19.61 4.53 6.24 20.58
4.32 4.04 22.45 3.96 7.69 23.14 3.84 7.48 24.02 3.71 11.15 24.51
3.63 2.05 24.85 3.58 4.62 26.65 3.35 3.82 30.77 2.91 2.51 31.13
2.87 3.38
Example 3
[0148] About 48.8 mg of ARN-509 was weighed and dissolved in 0.8 mL
of methanol/methyl acetate/cyclohexane (1:3:12, v/v/v). The
obtained solution was stirred at 5.degree. C. for about 24 h,
separated by filtration, and drying the obtained solid with forced
air convection at 30.degree. C. to obtain solid.
[0149] The XRPD and TGA tests were performed on the obtained solid,
and the obtained solid was confirmed to be Form CS8.
[0150] The XRPD pattern is substantially as depicted in FIG. 5, and
the XRPD data are listed in Table 3.
[0151] The TGA curve of Form CS8 is substantially as depicted in
FIG. 6, which shows about 2.6% weight loss when heated to
150.degree. C.
TABLE-US-00008 TABLE 3 Diffraction d Intensity angle 2.theta.
spacing % 7.94 11.13 100.00 10.31 8.58 2.38 11.22 7.88 3.22 12.37
7.16 65.85 15.39 5.76 61.09 15.92 5.57 10.94 16.24 5.46 9.76 16.62
5.34 6.34 18.93 4.69 16.48 19.16 4.63 7.00 19.68 4.51 23.28 20.60
4.31 19.19 21.65 4.11 6.13 22.50 3.95 27.31 23.16 3.84 19.70 24.00
3.71 11.42 24.60 3.62 5.62 24.87 3.58 12.79 26.68 3.34 8.60 28.23
3.16 4.37 29.32 3.05 3.27 30.78 2.90 8.15 31.09 2.88 6.62 32.92
2.72 3.26 33.28 2.69 3.56
Example 4.about.10: Preparation of Form CS9
Example 4-8
[0152] A certain amount of ARN-509 was weighed, and dissolved in
corresponding volume of solvents as shown in Table 4. The obtained
solution was stirred at room temperature or 50.degree. C.
overnight, filtered and separated to obtain solid. The solid
obtained in examples 4-8 were labeled as samples 4-8.
[0153] The XRPD, TGA and DSC tests were performed on the obtained
solid of sample 4-8, and the obtained solid was confirmed to be
Form CS9.
[0154] The XRPD, TGA and DSC test results of sample 4 are as
follows:
[0155] The XRPD pattern is substantially as depicted in FIG. 7, and
the XRPD data are listed in Table 5.
[0156] The DSC curve is substantially as depicted in FIG. 8. The
endothermic peak appears around 123.degree. C.
[0157] The TGA curve is substantially as depicted in FIG. 9, which
shows about 5.8% weight loss when heated to 150.degree. C.
TABLE-US-00009 TABLE 4 Mass Solvents Volume Example (mg) (volume
ratio v/v) (mL) Temperature Samples 4 5000 acetonitrile/water 4.0
room 4 (2:1) temperature 5 116.6 Acetonitrile/methanol 0.7 room 5
(1:1) temperature 6 107.0 Acetonitrile/ethanol 0.7 room 6 (1:1)
temperature 7 108.0 Acetonitrile/toluene 0.7 room 7 (1:1)
temperature 8 111.3 Acetonitrile 0.7 50.degree. C. 8
TABLE-US-00010 TABLE 5 Diffraction d Intensity angle 2.theta.
spacing % 7.72 11.45 100.00 10.38 8.52 7.72 11.14 7.94 2.43 12.30
7.19 41.96 14.95 5.93 43.59 15.49 5.72 17.46 15.84 5.60 11.30 16.64
5.33 8.61 18.01 4.93 24.47 19.25 4.61 5.35 19.92 4.46 10.92 20.75
4.28 11.41 21.90 4.06 3.60 22.40 3.97 12.81 22.65 3.93 17.56 23.04
3.86 15.36 23.35 3.81 17.63 23.84 3.73 5.66 24.81 3.59 13.56 25.01
3.56 15.15 25.55 3.49 7.39 26.81 3.33 7.03 27.15 3.28 3.99 27.45
3.25 2.46 28.54 3.13 3.84 29.62 3.02 4.14 30.19 2.96 5.37 30.87
2.90 5.87 31.53 2.84 2.65 32.36 2.77 3.15 33.63 2.66 2.95 34.89
2.57 2.59 37.19 2.42 3.29
[0158] The XRPD pattern of sample 5 is substantially as depicted in
FIG. 10, and the XRPD data are listed in Table 6.
TABLE-US-00011 TABLE 6 Diffraction d Intensity angle 2.theta.
spacing % 7.72 11.46 100.00 10.42 8.49 6.39 12.33 7.18 24.55 13.96
6.34 2.20 14.97 5.92 27.11 15.50 5.72 11.82 15.83 5.60 8.42 16.68
5.32 5.46 17.98 4.93 13.68 19.25 4.61 4.21 19.97 4.45 10.87 20.77
4.28 8.18 21.92 4.06 3.45 22.39 3.97 8.82 22.66 3.92 13.29 23.05
3.86 15.94 23.27 3.82 12.22 23.93 3.72 6.69 24.94 3.57 17.29 25.51
3.49 5.31 26.83 3.32 5.61 27.52 3.24 4.55
[0159] Samples 5-8 and sample 4 have the same or similar XRPD
patterns, samples 5-8 and sample 4 are the same crystalline form
and have the same properties.
Example 9
[0160] About 35.5 mg of ARN-509 was weighed and dissolved in 0.5 mL
of methanol/methyl acetate/n-heptane (V/V/V, 1:1:2). The solution
was heated to 50.degree. C. (the heating rate is 1.degree. C./min),
and then cooled to 15.degree. C. (the cooling rate is 0.1.degree.
C./min). Crystal seed Form CS9 was added to the solution, and the
solution was cooled from 15.degree. C. to 5.degree. C. (the cooling
rate was 0.1.degree. C./min). After holding at 5.degree. C. for 13
hours, transparent crystal was obtained, the obtained solid was
Form CS9.
[0161] Form CS9 is a co-solvate of methyl acetate and water. Its
unit cell dimensions are listed in Table 7. The simulated XRPD
pattern is substantially as depicted in FIG. 11, and the XRPD data
are listed in Table 8.
TABLE-US-00012 TABLE 7 Crystal system Orthogonal Space group
Pna2.sub.1 Unit cell dimensions a 9.1489(11) .ANG. A 90.00.degree.
b 16.077(2) .ANG. B 90.00.degree. c 16.817(2) .ANG. .GAMMA.
90.00.degree. Volume of unit cell (V) 2473.6(5) .ANG..sup.3 Number
of formula units 4 in unit cell (Z) Calculated density 1.395
g/cm.sup.3
TABLE-US-00013 TABLE 8 Diffraction angle 2.theta. d spacing
Intensity % 7.60 11.62 100.00 10.51 4.62 11.56 12.30 8.41 49.19
14.66 8.04 43.83 15.24 4.26 8.63 15.32 3.46 3.61 15.58 5.11 12.83
16.74 5.29 13.29 17.35 6.04 15.85 19.36 3.87 5.90 20.10 4.90 12.36
20.85 4.58 11.18 21.92 4.46 9.73 22.10 3.90 6.10 22.34 4.40 8.80
22.79 7.19 19.43 22.94 5.81 15.41 22.97 7.95 22.21 23.87 4.20 8.01
23.92 3.45 3.54 24.17 5.78 14.12 24.75 5.68 13.56 25.11 4.41 9.28
25.72 3.73 4.83 26.42 3.59 4.25 27.06 4.11 7.71 27.48 4.02 6.29
28.82 3.72 4.83 29.00 4.05 7.58 29.56 3.98 6.17 29.80 3.29 2.94
29.91 3.48 3.84 30.05 4.02 6.34 30.93 4.57 10.53 31.32 3.59 4.28
31.46 3.37 3.18 33.41 3.63 4.47 33.90 3.87 5.40 35.29 3.41 3.30
37.15 3.57 4.22 38.54 3.68 4.72
Example 10
[0162] About 80.9 mg of ARN-509 was weighed and dissolved in 0.5 mL
of acetonitrile/isopropanol (V/V, 1:1) and cooled to -25.degree. C.
to obtain Form CS9.
[0163] Form CS9 obtained in this example is an acetonitrile
solvate. Its unit cell dimensions are listed in Table 9. The
simulated XRPD pattern is substantially as depicted in FIG. 12, and
the XRPD data are listed in Table 10.
TABLE-US-00014 TABLE 9 Crystal system Orthogonal Space group
Pna2.sub.1 Unit cell dimensions a 9.0288(15) .ANG. .alpha.
90.00.degree. b 15.295(2) .ANG. .beta. 90.00.degree. c 16.948(3)
.ANG. .gamma. 90.00.degree. Volume of unit cell (V) 2340.5(6)
.ANG..sup.3 Number of formula units 4 in unit cell (Z) Calculated
density 1.471 g/cm.sup.3
TABLE-US-00015 TABLE 10 Diffraction angle 2.theta. d spacing
Intensity % 7.78 11.35 100.00 10.43 8.47 20.40 12.52 7.07 61.14
15.17 5.84 42.32 15.45 5.73 5.99 15.60 5.68 18.78 16.05 5.52 12.78
16.72 5.30 12.00 18.16 4.88 21.39 18.45 4.81 4.96 19.41 4.57 7.10
20.34 4.36 19.05 21.16 4.20 23.91 22.30 3.98 4.95 22.59 3.93 10.92
22.86 3.89 7.88 23.05 3.86 29.49 23.46 3.79 28.10 23.49 3.78 22.79
23.90 3.72 5.88 23.99 3.71 8.96 25.18 3.53 20.82 25.23 3.53 15.65
25.27 3.52 26.97 25.91 3.44 6.77 26.92 3.31 12.61 27.41 3.25 11.03
27.84 3.20 7.97 28.88 3.09 9.03 29.88 2.99 7.76 30.24 2.95 3.97
30.62 2.92 7.91 30.80 2.90 5.01 31.08 2.88 4.74 31.20 2.86 14.22
31.30 2.86 9.16 32.43 2.76 6.74 32.64 2.74 6.58 33.55 2.67 4.17
33.68 2.66 3.67 34.24 2.62 8.39 35.18 2.55 6.77 35.76 2.51 6.51
37.55 2.39 5.03
Example 11: Kinetic Solubility of Form CS8, Form A and Form B of
the Prior Art
[0164] Different parts of the human body have different acidity (pH
1.0-8.0). The pH in stomach is 1.0-2.0, and the pH in the small
intestine is 4.0-7.0. The stomach and small intestine are the key
organs for drug dissolution and absorption, so measuring the
dynamic solubility of a drug in a medium with pH 1.0-7.0 plays an
important role in predicting the in vivo bioavailability.
[0165] ARN-509 is a poorly water-soluble drug and belongs to BCS II
(low solubility and high permeability). Higher solubility is
beneficial to improve in vivo dissolution, thus improving in vivo
drug efficacy directly.
[0166] About 20 mg of Form CS8, Form A and Form B of the prior art
were suspended into 2.0 mL of 0.1 mol/L HCl aqueous solution
(pH=1.0), 2.0 mL of acetic acid buffer solution (PH=4.5) and 2.0 mL
of phosphate buffer solution (pH=6.8) to make suspensions. After
equilibrated for 15 minutes, 30 minutes, and 1 hour, concentrations
(.mu.g/mL) of the saturated solutions were measured by HPLC. The
results are listed in Table 11.
TABLE-US-00016 TABLE 11 Form A of the prior art Form B of the prior
art Form CS8 15 min 30 1 h 15 30 min 1 h 15 30 1 h Medium .mu.g/mL
.mu.g/m .mu.g/m .mu.g/mL .mu.g/mL .mu.g/m .mu.g/m .mu.g/m .mu.g/m
HCl 7.4 6.2 8.0 1.2 1.5 1.3 23.6 25.1 18.7 aqueous Acetic 5.9 5.2
5.5 1.1 1.4 1.3 17.7 10.6 10.9 acid buffer solution phosphate 6.1
8.4 4.8 1.2 1.0 0.9 22.8 18.9 20.6
[0167] The results show that Form CS8 have higher solubility in
pH=1.0 hydrochloric acid aqueous solution, PH=4.5 acetic acid
buffer solution and pH=6.8 phosphate buffer solution.
Example 12: Stability Assessment of Form CS8
1. The Storage Stability of Form CS8 Under Long-Term and
Accelerated Conditions
[0168] Approximately 30 mg of Form CS8 was stored under 25.degree.
C./60% RH and 40.degree. C./75% RH in open or close dishes.
Crystalline form and chemical impurity were checked by XRPD and
HPLC, respectively. The results are shown in Table 12. XRPD pattern
overlay of Form CS8 of the present disclosure before and after
being stored under 25.degree. C./60% RH are depicted in FIG. 13.
XRPD pattern overlay of Form CS8 of the present disclosure before
and after being stored under 40.degree. C./75% RH are depicted in
FIG. 14.
TABLE-US-00017 TABLE 12 Initial Solid form Purity solid after
Initial after Condition Time form storage purity storage 25.degree.
C./60% RH 6 months From CS8 From CS8 99.96% 99.96% (closed)
25.degree. C./60% RH 6 months From CS8 From CS8 99.96% 99.96%
(open) 40.degree. C./75% RH 6 months From CS8 From CS8 99.96%
99.95% (closed) 40.degree. C./75% RH 6 months From CS8 From CS8
99.96% 99.95% (open)
[0169] The results show that Form CS8 kept stable for at least 6
months at 25.degree. C./60% RH and 40.degree. C./75% RH. It can be
seen that Form CS8 has good stability under both long-term and
accelerated conditions.
2. The Storage Stability of Form CS8 Under Stress Condition
[0170] Approximately 30 mg of Form CS8 was stored under 60.degree.
C./75% RH in open or close dishes. Crystalline form change of Form
CS8 was tested by XRPD. The results are shown in Table 13.
TABLE-US-00018 TABLE 13 Condition(container Initial solid Solid
form open or close) Time form after storage FIGS. 60.degree. C./75%
RH 2 weeks Form CS8 Form CS8 FIG. 15
[0171] The results show that Form CS8 kept stable for at least 2
weeks at 60.degree. C./75% RH. It can be seen that Form CS8 has
good stability under stress condition with high temperature and
humidity.
Example 13: Mechanical Stability of Form CS8
[0172] A certain amount of Form CS8 was compressed into pellets
under different pressures with suitable tableting die. Crystalline
form before and after tableting were checked by XRPD. The test
results are shown in Table 14, XRPD pattern overlay is depicted in
FIG. 16.
TABLE-US-00019 TABLE 14 Crystalline form Crystalline form before
tableting Pressure after tableting Form CS8 3 kN Form CS8 7 kN Form
CS8 14 kN Form CS8
[0173] The results show that Form CS8 has good stability under
different pressures.
[0174] Form CS8, Form A and Form B of the prior art were ground
manually for 5 minutes in a mortar, XRPD patterns were collected
before and after gridding. The XRPD pattern overlay of Form CS8,
Form A and Form B of the prior art are depicted in FIG. 17, FIG. 18
and FIG. 19. The results are listed in Table 15.
TABLE-US-00020 TABLE 15 Before grinding After grinding Form CS8
Crystalline form and crystallinity are basically unchanged Form A
of the prior art Almost change to amorphous Form B of the prior art
Crystallinity decreased
[0175] The results show that compared with Form A and Form B of the
prior art, Form CS8 shows better stability under grinding
condition.
Example 14: Particle Size Distribution of Form CS8, Form A and Form
B of the Prior Art
[0176] Approximately 20 mg of Form CS8, Form A and Form B of the
prior art were added into 10 mL of Isopar G (containing 0.2%
lecithin). The mixture was mixed thoroughly and transferred into
the SDC. The measurement was started when the sample amount
indicator is in appropriate position. The average particle diameter
calculated by volume, the diameter at which 10% mass is comprised
of smaller particles (D10), the diameter at which 50% mass is
comprised of smaller particles (D50) and the diameter at which 90%
mass is comprised of smaller particles (D90) were obtained in
particle size distribution test. The results are shown in Table 16.
The particle size distribution diagram of Form CS8, Form A and Form
B of the prior art were shown in FIG. 20, FIG. 21, FIG. 22.
TABLE-US-00021 TABLE 16 Form MV (.mu.m) D10 (.mu.m) D50 (.mu.m) D90
(.mu.m) Form CS8 104.7 48.60 100.8 164.9 Form A of the prior art
53.51 4.22 14.81 130.4 Form B of the prior art 420.3 12.1 241.7
1133
[0177] The results show that Form CS8 has uniform particle size
distribution, which is superior to that of Form A and Form B of the
prior art.
Example 15: Adhesiveness of Form CS8, Form A and Form B of the
Prior Art
[0178] Approximately 30 mg of Form CS8, Form A and Form B of the
prior art were weighed and then added into the dies of .phi.8 mm
round tooling, compressed at 10 KN and held for 30 s. The punch was
weighed and amount of material sticking to the punch was
calculated. The compression was repeated twice and the cumulative
amount, maximum amount and average amount of material sticking to
the punch during compression process were recorded. Detailed
experimental results are shown in Table 17.
TABLE-US-00022 TABLE 17 Average Maximum Form amount (mg) amount
(mg) Form A of the prior art 0.13 0.19 Form B of the prior art 0.15
0.17 Form CS8 0.08 0.11
[0179] Test results indicate that the adhesiveness of Form CS8 is
superior to Form A and Form B of the prior art.
Example 16: Compressibility of Form CS8, Form a and Form B of the
Prior Art
[0180] 80 mg of Form CS8, Form A and Form B of the prior art were
weighed and added into the dies of .phi.6 mm round tooling,
compressed at 10 KN manually, then stored at room temperature for
24 h until complete elastic recovery. Hardness (H) was tested with
an Intelligent Tablet Hardness Tester. Diameter (D) and thickness
(L) were tested with a caliper. Tensile strength of the powder was
calculated with the following formula: T=2H/.pi.DL. Under a certain
force, the greater the tensile strength, the better the
compressibility. The results are presented in Table 18.
TABLE-US-00023 TABLE 18 Thickness Diameter Hardness Tensile
strength Form (mm) (mm) (N) (MPa) Form A of the 2.10 6.08 12.3 0.64
prior art Form B of the 2.13 6.09 10.1 0.50 prior art Form CS8 2.19
6.05 14.6 0.70
[0181] The results indicate that CS8 has better compressibility
compared with Form A and Form B of the prior art.
Example 17 Preparation of Form CS8, Form a and Form B of the Prior
Art Drug Products
[0182] Form CS8, Form A and Form B of the prior art were blended
according to formulation in Table 19 and formulation process in
Table 20, then corresponding tablets were prepared.
TABLE-US-00024 TABLE 19 Number Component mg/unit % (w/w)
Intra-granular 1 API (ARN-509) 25.00 25.00 components (Form CS8,
Form A or Form B of the prior art) 2 Microcrystalline Cellulose
71.50 71.50 (PH 101) 3 Crospovidone (XL) 2.00 2.00 4 Magnesium
stearate (5712) 0.25 0.25 Extra-granular 5 Crospovidone (XL) 1.00
1.00 components 6 Magnesium stearate (5712) 0.25 0.25 Total 100.00
100.00
TABLE-US-00025 TABLE 20 Stage Process Preliminary Weighed
intra-granular excipients in Table 19 and mixing blend for 2 min in
a PE bag Sift out Pass the mixture through a 35 mesh sieve and then
put in a PE bag and mixed for 1 min; Dry granulation Tableted by a
single punch manual tablet press (type: ENERPAC; die: .phi. 20 mm
round; tablet weight: 500 mg; pressure: 5 .+-. 0.5 KN); Pulverize
The obtained tablet was pulverized and sieved through a 20 mesh
sieve; Mixed again Weighed extra-granular excipients and pulverized
particles and blend for 2 min in a PE bag; Tablet Tableted by a
single punch manual tablet press (type: ENERPAC; die: .phi. 20 mm
round; tablet weight: 500 mg; pressure: 5 .+-. 0.5 KN); Package Put
into a 35 cc HDPE bottles, 3 capsules per bottle with 1 g of
desiccant
Example 18 In Vitro Dissolution Profile of Form CS8, Form a and
Form B of the Prior Art Drug Products
[0183] In vitro dissolution test was performed on Form CS8, Form A
and Form B of the prior art drug products obtained from example 17.
Dissolution method according to Chinese Pharmacopoeia
2015<0931> was used. The conditions are as follows:
[0184] Medium: pH=4.5 acetate buffer solution+0.5% (w/w) sodium
lauryl sulfate aqueous solution
[0185] Method: Paddle
[0186] Volume: 900 mL
[0187] Speed: 75 rpm
[0188] Temperature: 37.degree. C.
[0189] In vitro dissolution results of Form CS8, Form A and Form B
of the prior art drug products are presented in Table 21 and FIG.
23, which indicate that compared with Form A and Form B of the
prior art, Form CS8 drug product possesses better dissolution.
TABLE-US-00026 TABLE 21 Cumulative drug release (%) Time(min) Form
CS8 Form A of the prior art Form B of the prior art 0 0 0 0 5 26 7
25 10 41 15 39 15 51 20 46 20 58 23 50 30 68 30 57 45 76 38 62 60
81 44 66
Example 19 Stability of Form CS8 in Drug Product
[0190] The tablets of Form CS8 were packed in HDPE bottles and
stored under 25.degree. C./60% RH and 40.degree. C./75% RH
conditions. Crystalline form and impurity of the sample were tested
to check the stability of Form CS8 drug product after being stored
for 3 months. The results indicate that Form CS8 drug product can
keep physically and chemically stable under 25.degree. C./60% RH
and 40.degree. C./75% RH for at least 3 months. The crystalline
form does not change, and the purity remains substantially
unchanged. The results are shown in Table 22. The XRPD patterns
overlay before and after being stored at 25.degree. C./60% RH and
40.degree. C./75% RH are shown in FIG. 24 and FIG. 25,
respectively.
TABLE-US-00027 TABLE 22 Solid form Purity Initial after Initial
after Condition Time form storage purity storage 25.degree. C./60%
RH 3 months Form CS8 Form CS8 99.76% 99.76% 40.degree. C./75% RH 3
months Form CS8 Form CS8 99.76% 99.76%
[0191] The results indicate that Form CS8 has good physically and
chemically stable in drug products.
[0192] The examples described above are only for illustrating the
technical concepts and features of the present disclosure, and
intended to make those skilled in the art being able to understand
the present disclosure and thereby implement it, and should not be
concluded to limit the protective scope of this disclosure. Any
equivalent variations or modifications according to the spirit of
the present disclosure should be covered by the protective scope of
the present disclosure.
* * * * *