U.S. patent application number 17/188625 was filed with the patent office on 2021-07-22 for amorphous forms of selinexor and process for their preparation.
The applicant listed for this patent is DR. REDDY'S LABORATORIES LIMITED. Invention is credited to Satarupa BHATTACHARJEE, Ramesh CHAKKA, Ramanaiah CHENNURU, Vishnu Vardhana Vema Reddy EDA, Vamsi Krishna MUDAPAKA, Srinivas ORUGANTI, Vishweshwar PEDDY, Srividya RAMAKRISHNAN.
Application Number | 20210221795 17/188625 |
Document ID | / |
Family ID | 1000005505074 |
Filed Date | 2021-07-22 |
United States Patent
Application |
20210221795 |
Kind Code |
A1 |
CHENNURU; Ramanaiah ; et
al. |
July 22, 2021 |
AMORPHOUS FORMS OF SELINEXOR AND PROCESS FOR THEIR PREPARATION
Abstract
Aspects of the present application relate to solid forms of
Selinexor, processes for their preparation and pharmaceutical
compositions thereof. Specific aspects relate to crystalline and
amorphous forms of Selinexor.
Inventors: |
CHENNURU; Ramanaiah;
(Nellore, IN) ; BHATTACHARJEE; Satarupa; (Howrah,
IN) ; ORUGANTI; Srinivas; (Hyderabad, IN) ;
EDA; Vishnu Vardhana Vema Reddy; (Hyderabad, IN) ;
CHAKKA; Ramesh; (Hyderabad, IN) ; PEDDY;
Vishweshwar; (Hyderabad, IN) ; RAMAKRISHNAN;
Srividya; (Hyderabad, IN) ; MUDAPAKA; Vamsi
Krishna; (Khammam, IN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
DR. REDDY'S LABORATORIES LIMITED |
Hyderabad |
|
IN |
|
|
Family ID: |
1000005505074 |
Appl. No.: |
17/188625 |
Filed: |
March 1, 2021 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
16068552 |
Jul 6, 2018 |
|
|
|
PCT/IB2017/050047 |
Jan 6, 2017 |
|
|
|
17188625 |
|
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 249/08 20130101;
C07B 2200/13 20130101; C07D 403/12 20130101 |
International
Class: |
C07D 403/12 20060101
C07D403/12; C07D 249/08 20060101 C07D249/08 |
Foreign Application Data
Date |
Code |
Application Number |
Jan 8, 2016 |
IN |
201641000711 |
May 3, 2016 |
IN |
201641015422 |
Nov 4, 2016 |
IN |
201641037733 |
Dec 7, 2016 |
IN |
201641041753 |
Claims
1-45. (canceled)
46-74. (canceled)
75. An amorphous form of Selinexor.
76. A process for preparing the amorphous form of Selinexor of
claim 75, comprising the steps of: a) providing a solution of
Selinexor in a solvent or a mixture thereof; b) removing the
solvent from the solution obtained in step a); c) isolating the
amorphous form of Selinexor; and d) optionally combining amorphous
form of step c) with at least one pharmaceutically acceptable
excipient.
77. An amorphous solid dispersion of Selinexor together with at
least one pharmaceutically acceptable excipient.
78. A process for preparing the amorphous solid dispersion of
Selinexor of claim 77, comprising the steps of: a) providing a
solution of Selinexor and at least one pharmaceutically acceptable
excipient in a solvent or a mixture thereof; b) removing the
solvent from the solution obtained in step a), c) isolating the
amorphous solid dispersion of Selinexor; and d) optionally
combining amorphous solid dispersion of step c) with at least one
additional pharmaceutically acceptable excipient.
79. (canceled)
80. A pharmaceutical composition comprising the amorphous form of
Selinexor of claim 75 combined with at least one pharmaceutically
acceptable excipient.
81. A pharmaceutical composition comprising the amorphous solid
dispersion of Selinexor of claim 77 combined with at least one
additional pharmaceutically acceptable excipient.
82. (canceled)
Description
INTRODUCTION
[0001] Aspects of the present application relate to solid forms of
Selinexor, processes for their preparation and pharmaceutical
compositions thereof. Specific aspects relate to crystalline and
amorphous forms of Selinexor.
[0002] The drug compound having the adopted name "Selinexor" has
chemical name:
(Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-IH-I,2,4-triazol-1-yl)-N'-
-(pyrazin-2yl) acrylohydrazide as below.
##STR00001##
[0003] Selinexor (KPT-330) is a first-in-class, oral Selective
Inhibitor of Nuclear Export/SINE.TM. compound. Selinexor functions
by binding with and inhibiting the nuclear export protein XPO1
(also called CRM1), leading to the accumulation of tumor suppressor
proteins in the cell nucleus. This reinitiates and amplifies their
tumor suppressor function and is believed to lead to the selective
induction of apoptosis in cancer cells, while largely sparing
normal cells. Over 1,200 patients have been treated with Selinexor
in company and investigator-sponsored Phase 1 and Phase 2 clinical
trials in advanced hematologic malignancies and solid tumors.
Karyopharm has initiated four later-phase clinical trials of
Selinexor, including one in older patients with acute myeloid
leukemia (SOPRA), one in patients with Richter's transformation
(SIRRT), one in patients with diffuse large B-cell lymphoma (SADAL)
and a single-arm trial of Selinexor and lose-dose dexamethasone in
patients with multiple myeloma (STORM). Patients may receive a
twice-weekly combination of Selinexor in combination with low dose
dexamethasone. Randomized 1:1, Selinexor will be dosed either at 60
mg+dexamethasone or at 100 mg+dexamethasone.
[0004] U.S. Pat. No. 8,999,996 B2 discloses Selinexor and a
pharmaceutically acceptable salt thereof, pharmaceutical
compositions and use for treating disorders associated with CRM1
activity. Further, it discloses preparative methods for the
preparation of compounds disclosed therein including Selinexor by
reacting
(Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-IH-I,2,4-triazol-1-yl)acrylic
acid in 1:1 CH.sub.2Cl.sub.2:AcOEt with 2-Hydrazinopyrazine at
-40.degree. C. followed by addition of T.sub.3P[Propylphosphonic
anhydride] (50%) and DIPEA. After 30 minutes, the reaction mixture
was concentrated and the crude oil was purified by preparative TLC
using 5% MeOH in CH.sub.2Cl.sub.2 as mobile phase (under ammonia
atmosphere) to afford 40 mg of Selinexor with purity: 95.78%.
However, it is not disclosed about the nature of the compound
obtained therein.
[0005] WO 2016025904 A1 discloses various crystalline forms of
Selinexor namely Form A, Form B, Form C, Form D, compositions and
MoU thereof for the treatment of disorder associated with CRM1
activity and their preparative processes.
[0006] Prior art process for the preparation of Selinexor suffers
from disadvantages interms of process such as the use of lengthy
procedures to practice and resulting in low yields, which may not
be viable at industrial scale. Synthetic product obtained therein
has very low purity and contains significant amounts of unreacted
starting materials and trans-isomer of Selinexor, which are further
purified by time consuming and expensive chromatographic
separations leading to loss of yield. Hence, there remains a need
for improved process for the preparation of Selinexor which is
industrially viable and reproducible. Particularly, it is desirable
to have a process avoiding purification steps still meeting desired
pharmaceutical quality.
[0007] In general, polymorphism refers to the ability of a
substance to exist as two or more crystalline phases that have
different spatial arrangements and/or conformations of molecules in
their crystal lattices. Thus, "polymorphs" refer to different
crystalline forms of the same pure substance in which the molecules
have different spatial arrangements of the molecules, atoms, and/or
ions forming the crystal. Different polymorphs may have different
physical properties such as melting point, solubility, etc. The
variation in solid forms may appreciably influence the
pharmaceutical properties, such as bioavailability, handling
properties, dissolution rate, and stability, and in turn such
properties may significantly influence the processing, shelf life,
and commercial acceptance of a polymorphic form.
[0008] For these reasons, the drug manufacturing companies put
efforts into identifying all polymorphic forms of new drug
substances e.g., crystalline, amorphous, solvates, stable
dispersions with a pharmaceutically acceptable carriers. The
existence and possible numbers of polymorphic forms for a given
compound may not be predicted, and there are no "standard"
procedures that may be used to prepare polymorphic forms of a
substance. This is well-known in the art, as reported, for example,
by A. Goho, "Tricky Business," Science News, Vol. 166(8), August
2004.
[0009] There remains a need for the identification of stable and
commercially viable solid form of Selinexor with characteristics
suitable to formulate a dosage form. Particularly, it is desirable
to have a reproducible crystalline form of Selinexor and process
for its preparation. Further, need for the identification of a
solid form with suitable physical properties, which may lead to its
selection as the final drug substance for pharmaceutical dosage
form development. Particularly, it is desirable to have an
amorphous form or a crystalline form of drug to meet the needs of
drug development and reproducible process for their
preparation.
SUMMARY
[0010] In an aspect, the present application provides an improved
process for the preparation of Selinexor, comprising the steps of:
[0011] a) N-alkylation of triazole compound of formula (II) to
obtain the N-alkylated ester of formula (IV), wherein X may be
hydrogen, Y may be a leaving group such as a halogen or a
sulphonate group (or) X and Y may together form a triple bond
between carbons atoms to which there are linked and R may be an
optionally substituted alkyl, optionally substituted aryl,
optionally substituted arylalkyl, optionally substituted heteroaryl
group;
[0011] ##STR00002## [0012] b) optionally purifying the N-alkylated
ester of formula (IV); [0013] c) hydrolysis of the N-alkylated
ester of formula (IV) of step a) or step b) to corresponding
N-alkylated acid of formula (IVa);
[0013] ##STR00003## [0014] d) purifying the N-alkylated acid of
formula (IVa) through formation of its addition salt of formula
(VI), wherein B is a base;
[0014] ##STR00004## [0015] e) converting the addition salt of
formula (VI) or N-alkylated acid of formula (IVa) to Selinexor of
formula (I), wherein Z may be hydrogen or a protecting group.
[0016] f) optionally, removing the protecting group to obtain
Selinexor.
[0017] In another aspect, the present application provides a
process for the preparation of Selinexor or a salt thereof,
comprising the steps of: [0018] a) N-alkylation of triazole
compound of formula (II) to obtain the N-alkylated ester of formula
(IV), wherein X may be hydrogen and Y may be a leaving group such
as a halogen or a sulphonate group (or) X and Y together form a
triple bond between carbons atoms to which there are linked, R may
be an optionally substituted alkyl, optionally substituted aryl,
optionally substituted arylalkyl, optionally substituted heteroaryl
group;
[0018] ##STR00005## [0019] b) optionally purifying the N-alkylated
ester of formula (IV) of step a); [0020] c) reacting the
N-alkylated ester of step a) or step b) with 2-Hydrazinopyrazine
derivative of formula V, wherein Z may be hydrogen or protecting
group to obtain Selinexor of formula I.
[0020] ##STR00006## [0021] d) Optionally, removing the protecting
group to obtain Selinexor. [0022] e) purifying the Selinexor
obtained in step c) or d).
[0023] In another aspect, the present application provides an
addition salt of N-alkylated acid of formula VI.
[0024] In another aspect, the present application provides a
process for the preparation of Selinexor comprising the step of
preparing an addition salt of N-alkylated acid of formula VI.
[0025] In another aspect, the present application provides a
pharmaceutical composition comprising Selinexor obtained according
any of the aspects of this application and at least one
pharmaceutically acceptable excipient.
[0026] In another aspect, the present application provides
crystalline Form-Alpha of Selinexor, characterized by a PXRD
pattern comprising the peaks at about 4.38, 12.45, 13.13, 15.85,
19.98 and 21.35.+-.0.2.degree. 2.theta.. In an embodiment, the
application provides crystalline form Alpha of Selinexor,
characterized by a PXRD pattern having one or more additional peaks
at about 14.51, 14.77, 20.30 and 27.32.+-.0.2.degree. 2.theta..
[0027] In another aspect, the present application provides
crystalline Form-Beta of Selinexor, characterized by a PXRD pattern
comprising the peaks at about 5.87, 11.73, 18.71, 20.53 and
24.05.+-.0.2.degree. 2.theta.. In an embodiment, the application
provides crystalline Form-Beta of Selinexor, characterized by a
PXRD pattern having one or more additional peaks at about 16.28 and
21.28.+-.0.2.degree. 2.theta..
[0028] In another aspect, the present application provides
crystalline Form-Gamma of Selinexor, characterized by a PXRD
pattern comprising the peaks at about 3.28, 11.95, 14.62, 15.74 and
20.96.+-.0.2.degree. 2.theta.. In an embodiment, the application
provides crystalline Form-Gamma of Selinexor, characterized by a
PXRD pattern having one or more additional peaks at about 16.95,
18.23, 20.01 and 22.13.+-.0.2.degree. 2.theta..
[0029] In another aspect, the present application provides
crystalline Form-Delta of Selinexor, characterized by a PXRD
pattern comprising the peaks at about 6.11, 12.16, 13.00, 20.28 and
24.43.+-.0.2.degree. 2.theta.. In an embodiment, the application
provides crystalline Form-Delta of Selinexor, characterized by a
PXRD pattern having one or more additional peaks at about 19.35,
23.39 and 23.78.+-.0.2.degree. 2.theta..
[0030] In another aspect, the present application provides
crystalline Form-Epsilon of Selinexor, characterized by a PXRD
pattern comprising the peaks at about 5.87, 11.72, 17.61, 18.68,
20.50, 22.78, 23.20, 23.53 and 23.97.+-.0.2.degree. 2.theta.. In an
embodiment, the application provides crystalline Form-Epsilon of
Selinexor, characterized by a PXRD pattern having one or more
additional peaks at about 16.26, 21.25, 25.35, 29.22 and
30.14.+-.0.2.degree. 2.theta..
[0031] In another aspect, the present application provides
crystalline Form--Zeta of Selinexor, characterized by a PXRD
pattern comprising the peaks at about 4.86, 6.99, 7.74, 10.86,
15.50 and 19.47.+-.0.2.degree. 2.theta.. In an embodiment, the
application provides crystalline Form--Zeta of Selinexor,
characterized by a PXRD pattern having one or more additional peaks
at about 14.00, 18.27, 20.73, 21.51 and 22.14.+-.0.2.degree.
2.theta..
[0032] In another aspect, the present application provides
crystalline Form-Eta of Selinexor, characterized by a PXRD pattern
comprising the peaks at about 3.54, 7.03, 9.91, 11.59, 19.84, 20.44
and 21.64.+-.0.2.degree. 2.theta.. In an embodiment, the
application provides crystalline Form-Eta of Selinexor,
characterized by a PXRD pattern having one or more additional peaks
at about 17.55, 21.09, 22.45 and 23.28.+-.0.2.degree. 2.theta..
[0033] In another aspect, the present application provides
crystalline Form-Theta of Selinexor, characterized by a PXRD
pattern comprising the peaks at about 6.96, 13.92, 20.95 and
22.82.+-.0.2.degree. 2.theta.. In an embodiment, the application
provides crystalline Form-Theta of Selinexor, characterized by a
PXRD pattern having one or more additional peaks at about 17.24,
20.03, 20.37 and 23.41.+-.0.2.degree. 2.theta..
[0034] In another aspect, the present application provides
crystalline Form--Iota of Selinexor, characterized by a PXRD
pattern comprising the peaks at about 3.69, 7.33, 11.01, 14.66,
16.19 and 18.36.+-.0.2.degree. 2.theta..
[0035] In another aspect, the present application provides
crystalline Form--Kappa of Selinexor, characterized by a PXRD
pattern comprising the peaks at about 3.22, 11.71, 12.56, 14.42 and
25.20.+-.0.2.degree. 2.theta..
[0036] In another aspect, the present application provides
crystalline Form-Lambda of Selinexor, characterized by a PXRD
pattern comprising the peaks at about 12.61, 19.00, 19.95 and
21.29.+-.0.2.degree. 2.theta.. In an embodiment, the application
provides crystalline Form-Lambda of Selinexor, characterized by a
PXRD pattern having one or more additional peaks at about 14.13,
21.29, 21.75, 23.10, 24.65 and 30.86.+-.0.2.degree. 2.theta..
[0037] In another aspect, the present application provides
crystalline Form-Mu of Selinexor, characterized by a PXRD pattern
comprising the peaks at about 9.31, 17.45, 17.85 and
22.72.+-.0.2.degree. 2.theta.. In an embodiment, the application
provides crystalline Form-Mu of Selinexor, characterized by a PXRD
pattern having one or more additional peaks at about 21.20, 25.01
and 27.59.+-.0.2.degree. 2.theta..
[0038] In another aspect, the present application provides
crystalline Form--Nu of Selinexor, characterized by a PXRD pattern
comprising the peaks at about 10.75, 17.52, 21.84, 22.16 and
22.38.+-.0.2.degree. 2.theta.. In an embodiment, the application
provides crystalline Form-Nu of Selinexor, characterized by a PXRD
pattern having one or more additional peaks at about 18.30, 24.53
and 28.91.+-.0.2.degree. 2.theta..
[0039] In another aspect, the present application provides
crystalline Form--Xi of Selinexor, characterized by a PXRD pattern
comprising the peaks at about 10.54, 11.68, 12.72 and
24.56.+-.0.2.degree. 2.theta.. In an embodiment, the application
provides crystalline Form-Xi of Selinexor, characterized by a PXRD
pattern having one or more additional peaks at about 3.70, 7.36,
18.10, 19.72 and 21.21.+-.0.2.degree. 2.theta..
[0040] In another aspect, the present application provides an
amorphous form of Selinexor.
[0041] In another aspect, the present application provides a
pharmaceutical composition comprising amorphous form of Selinexor
combined with at least one pharmaceutically acceptable
excipient.
[0042] In another aspect, the present application provides
amorphous solid dispersion of Selinexor together with at least one
pharmaceutically acceptable excipient.
[0043] In another aspect, the present application provides a
pharmaceutical composition comprising amorphous solid dispersion of
Selinexor combined with at least one additional pharmaceutically
acceptable excipient.
[0044] In another aspect, the present application provides process
for preparing a crystalline form of Selinexor, which comprises:
[0045] a) combining amorphous Selinexor with a solvent or a mixture
thereof; [0046] b) stirring the mixture of step a); [0047] c)
optionally adding an anti-solvent to the mixture of step a) or b)
[0048] d) isolating crystalline form of Selinexor.
[0049] In another aspect, the present application provides a
process for the preparation of crystalline form of Selinexor or a
solvate thereof, comprising the step of converting amorphous
Selinexor to crystalline form of Selinexor or a solvate
thereof.
[0050] In another aspect, the present application provides process
for preparing a crystalline Form-Alpha of Selinexor, which
comprises: [0051] a) combining Selinexor with acetone:water
mixture; [0052] b) stirring the mixture of step a); [0053] c)
isolating crystalline Form-Alpha of Selinexor.
[0054] In another aspect, the present application provides process
for preparing a crystalline Form-Delta of Selinexor, which
comprises: [0055] a) combining Selinexor with methanol; [0056] b)
stirring the mixture of step a); [0057] c) isolating crystalline
Form-Delta of Selinexor.
[0058] In another aspect, the present application provides process
for preparing a crystalline Form-Epsilon of Selinexor, which
comprises: [0059] a) combining Selinexor with ethanol; [0060] b)
stirring the mixture of step a); [0061] c) isolating crystalline
Form-Epsilon of Selinexor.
[0062] In another aspect, the present application provides process
for preparing a crystalline Form-Zeta of Selinexor, which
comprises: [0063] a) combining Selinexor with acetic acid and
water; [0064] b) stirring the mixture of step a); [0065] c)
isolating crystalline Form-Zeta of Selinexor.
[0066] In another aspect, the present application provides process
for preparing a crystalline Form-Eta of Selinexor, which comprises:
[0067] a) combining Selinexor with nitromethane; [0068] b) stirring
the mixture of step a); [0069] c) isolating crystalline Form-Eta of
Selinexor.
[0070] In another aspect, the present application provides process
for preparing a crystalline Form-Theta of Selinexor, which
comprises: [0071] a) providing a solution of Selinexor in formic
acid; [0072] b) contacting the solution of step a) with an
anti-solvent; [0073] c) isolating crystalline Form-Theta of
Selinexor.
[0074] In another aspect, the present application provides process
for preparing a crystalline Form-Iota of Selinexor, which comprises
the step of drying Form-Eta of Selinexor.
[0075] In another aspect, the present application provides process
for preparing a crystalline Form-Kappa of Selinexor, which
comprises: [0076] a) combining Selinexor with water; [0077] b)
stirring the mixture of step a); [0078] c) isolating crystalline
Form-Kappa of Selinexor.
[0079] In another aspect, the present application provides process
for preparing a crystalline Form-Lambda of Selinexor, which
comprises: [0080] a) combining Selinexor with glycerol; [0081] b)
stirring the mixture of step a); [0082] c) isolating crystalline
Form-Lambda of Selinexor.
[0083] In another aspect, the present application provides process
for preparing a crystalline Form-Mu of Selinexor, which comprises:
[0084] a) combining Selinexor with dimethyl formamide; [0085] b)
stirring the mixture of step a); [0086] c) isolating crystalline
Form-Mu of Selinexor.
[0087] In another aspect, the present application provides process
for preparing a crystalline Form-Nu of Selinexor, which comprises:
[0088] a) combining Selinexor with dimethylacetamide; [0089] b)
stirring the mixture of step a); [0090] c) isolating crystalline
Form-Nu of Selinexor.
[0091] In another aspect, the present application provides process
for preparing a crystalline Form-Xi of Selinexor, which comprises
the step of drying Form-kappa of Selinexor.
[0092] In another aspect, the present application provides process
for preparing a crystalline Form-Kappa of Selinexor, which
comprises: [0093] a) providing a solution of Selinexor in methanol
or a mixture thereof; [0094] b) contacting the solution of step a)
with water; [0095] c) isolating crystalline Form-Kappa of
Selinexor.
[0096] In another aspect, the present application provides a
process for the preparation of an amorphous form of Selinexor,
comprising the steps of: [0097] a) providing a solution of
Selinexor in a solvent or a mixture thereof; [0098] b) removing the
solvent from the solution obtained in step a); and [0099] c)
isolating the amorphous form of Selinexor. [0100] d) optionally
combining amorphous form of step c) with at least one
pharmaceutically acceptable excipient.
[0101] In another aspect, the present application provides a
process for the preparation of an amorphous solid dispersion of
Selinexor, comprising the steps of: [0102] a) providing a solution
of Selinexor and at least one pharmaceutically acceptable excipient
in a solvent or a mixture thereof; [0103] b) removing the solvent
from the solution obtained in step a), and [0104] c) isolating the
amorphous solid dispersion of Selinexor. [0105] d) optionally
combining amorphous solid dispersion of step c) with at least one
additional pharmaceutically acceptable excipient.
[0106] In another aspect, the present application provides a
pharmaceutical composition comprising the any of the solid forms of
Selinexor described in the specification and at least one
pharmaceutically acceptable excipient. In embodiments, the present
application provides a pharmaceutical composition comprising
amorphous form, its solid dispersion or crystalline forms of
Selinexor and at least one pharmaceutically acceptable
excipient.
[0107] In another aspect, the present application provides
pharmaceutical composition comprising Selinexor and at least one
pharmaceutically acceptable excipient, wherein Selinexor may be
selected from group comprising of crystalline Form-Alpha,
Form-Beta, Form-Gamma, Form-Delta, Form-Epsilon, Form-Zeta,
Form-Eta, Form-Theta, Form-Iota, Form-Kappa, Form-Lambda, Form-Mu,
Form-Nu and Form-Xi of Selinexor or mixtures thereof.
BRIEF DESCRIPTION OF THE DRAWING
[0108] FIG. 1 is an illustrative X-ray powder diffraction pattern
of crystalline Form-Alpha of Selinexor prepared by the method of
Example No 4.
[0109] FIG. 2 is an illustrative X-ray powder diffraction pattern
of crystalline Form-Alpha of Selinexor prepared by the method of
Example No 5.
[0110] FIG. 3 is an illustrative X-ray powder diffraction pattern
of crystalline Form-Beta of Selinexor prepared by the method of
Example No 6.
[0111] FIG. 4 is an illustrative X-ray powder diffraction pattern
of crystalline Form-Gamma of Selinexor prepared by the method of
Example No 7.
[0112] According to National Institute of Standards and Technology
(NIST), for silica powder, one of the PXRD peak position is at
28.44.degree. (2.theta.). Silica powder was spiked to all the
crystalline forms (Forms-Alpha, Beta and Gamma) of Selinexor in
order to obtain accurate PXRD peak positions. In FIGS. 1 to 4, peak
at 28.44.degree. (2.theta.) corresponds to silica powder.
[0113] FIG. 5 is an illustrative X-ray powder diffraction pattern
of crystalline Form-Delta of Selinexor prepared by the method of
Example No 8.
[0114] FIG. 6 is an illustrative X-ray powder diffraction pattern
of crystalline Form-Epsilon of Selinexor prepared by the method of
Example No 9.
[0115] FIG. 7 is an illustrative X-ray powder diffraction pattern
of crystalline Form-Zeta of Selinexor prepared by the method of
Example No 10.
[0116] FIG. 8 is an illustrative X-ray powder diffraction pattern
of crystalline Form-Eta of Selinexor prepared by the method of
Example No 11.
[0117] FIG. 9 is an illustrative X-ray powder diffraction pattern
of crystalline Form-Theta of Selinexor prepared by the method of
Example No 12.
[0118] FIG. 10 is an illustrative X-ray powder diffraction pattern
of crystalline Form-Iota of Selinexor prepared by the method of
Example No 13.
[0119] FIG. 11 is an illustrative X-ray powder diffraction pattern
of crystalline Form-Kappa of Selinexor prepared by the method of
Example No 14.
[0120] FIG. 12 is an illustrative X-ray powder diffraction pattern
of crystalline Form-Lambda of Selinexor prepared by the method of
Example No 15.
[0121] FIG. 13 is an illustrative X-ray powder diffraction pattern
of crystalline Form-Mu of Selinexor prepared by the method of
Example No 16.
[0122] FIG. 14 is an illustrative X-ray powder diffraction pattern
of crystalline Form-Nu of Selinexor prepared by the method of
Example No 17.
[0123] FIG. 15 is an illustrative X-ray powder diffraction pattern
of crystalline Form-Xi of Selinexor prepared by the method of
Example No 18.
[0124] FIG. 16 is an illustrative X-ray powder diffraction pattern
of amorphous form of Selinexor prepared by the method of Example No
19.
[0125] FIG. 17 is an illustrative X-ray powder diffraction pattern
of amorphous solid dispersion of Selinexor with povidone K-30
prepared by the method of Example No 21.
[0126] FIG. 18 is an illustrative X-ray powder diffraction pattern
of amorphous solid dispersion of Selinexor with HPMC phthalate
prepared by the method of Example No 22.
[0127] FIG. 19 is an illustrative X-ray powder diffraction pattern
of amorphous solid dispersion of Selinexor with povidone K-30 and
Syloid-244 FP NF prepared by the method of Example No 21.
[0128] FIG. 20 is an illustrative X-ray powder diffraction pattern
of amorphous solid dispersion of Selinexor with HPMC phthalate and
Syloid-244 FP NF prepared by the method of Example No 22.
[0129] FIG. 21 is an illustrative X-ray powder diffraction pattern
of amorphous form Selinexor with Syloid-244 FP NF prepared by the
method of Example No 23.
[0130] FIG. 22 is an illustrative X-ray powder diffraction pattern
of crystalline Form-Kappa of Selinexor prepared by the alternate
method of Example No 14.
DETAILED DESCRIPTION
[0131] In an aspect, the present application provides an improved
process for the preparation of Selinexor, comprising the steps of:
[0132] a) N-alkylation of triazole compound of formula (II) to
obtain the N-alkylated ester of formula (IV), wherein X may be
hydrogen, Y may be a leaving group such as a halogen or a
sulphonate group (or) X and Y may together form a triple bond
between carbons atoms to which there are linked and R may be an
optionally substituted alkyl, optionally substituted aryl,
optionally substituted arylalkyl, optionally substituted heteroaryl
group;
[0132] ##STR00007## [0133] b) optionally purifying the N-alkylated
ester of formula (IV); [0134] c) hydrolysis of the N-alkylated
ester of formula (IV) of step a) or step b) to corresponding
N-alkylated acid of formula (IVa);
[0134] ##STR00008## [0135] d) purifying the N-alkylated acid of
formula (IVa) through formation of its addition salt of formula
(VI), wherein B is a base;
[0135] ##STR00009## [0136] e) converting the addition salt of
formula (IV) or N-alkylated acid of formula (IVa) to Selinexor of
formula (I), wherein Z may be hydrogen or a protecting group.
[0137] f) optionally, removing the protecting group to obtain
Selinexor. The individual steps of the process are described herein
below.
[0138] Starting materials, triazole compound of formula (II) and
ester compound of formula (III) are either commercially available
or may be prepared by the procedures known in art or the procedures
described and exemplified in present application.
[0139] The starting materials can be purified by techniques known
in art like column chromatography, fractional distillation,
acid-base treatment, slurring or re-crystallization, before
using.
[0140] In an embodiment, step a) may be carried out by N-alkylation
of triazole compound of formula (II) with an ester compound of
formula (III) to obtain the N-alkylated ester of formula (IV),
wherein X may be hydrogen, Y may be a leaving group such as a
halogen or a sulphonate group (or) X and Y may together form a
triple bond between carbons atoms to which there are linked and R
may be an optionally substituted alkyl, optionally substituted
aryl, optionally substituted arylalkyl, optionally substituted
heteroaryl group.
##STR00010##
[0141] In an embodiment, N-alkylation of triazole compound of
formula (II) may be carried out in the presence of a base. Base may
be selected from the group consisting of
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU),
1,5-diazabicyclo[4.3.0]non-5-ene (DBN),
1,4-diazabicyclo(2.2.2)octane (DABCO), N,N-dicyclohexylmethylamine,
2,6-di-tert-butyl-4-methylpyridine, quinuclidine,
1,2,2,6,6-pentamethylpiperidine (PMP),
7-methyl-1,5,7-triazabicyclo(4.4.0)dec-5-ene (MTBD),
triphenylphosphine, tri-tert-butylphosphine,
tricyclohexylphosphine, triethylamine, diisopropyl amine or the
like.
[0142] In an embodiment, N-alkylation of triazole compound of
formula (II) may be carried out in the presence of a suitable
solvent. Suitable solvent may include, but not limited to ether
solvent such as tetrahydrofuran, dioxane; ketone solvent such as
acetone, methyl ethyl ketone, methyl isobutyl ketone; ester solvent
such as ethyl acetate, isopropyl acetate; alcohol solvent such as
methanol, ethanol, isopropyl alcohol, butanol; nitrile solvent such
as acetonitrile; halogenated hydrocarbons such as dichloromethane;
water and the like.
[0143] In an embodiment, N-alkylation of triazole compound of
formula (II) may be carried out at suitable temperature at about
-30.degree. C. to reflux temperature of the solvent used. In
preferred embodiment, N-alkylation may be carried out at about
-10.degree. C. to 50.degree. C.
[0144] In an embodiment, N-alkylation of triazole compound of
formula (II) may be carried out for sufficient time to complete
alkylation of triazole compound. In preferred embodiment,
N-alkylation may be carried out for at least 30 minutes or
more.
[0145] In an embodiment, step b) of this aspect may be carried out
by optionally purifying N-alkylated ester of formula (IV) before
proceeding to next step. In an embodiment N-alkylated ester may be
purified by methods known in the art such as chromatographic
separations, fractional distillation, acid-base treatment,
recrystallization, slurry or procedures described or exemplified in
the present application.
[0146] In an embodiment, N-alkylated ester of formula (IV) may be
purified by chromatographic separations, recrystallizing or
slurrying in a solvent or mixture of solvents.
[0147] In an embodiment, N-alkylated ester of formula (IV) may be
purified by recrystallizing or slurrying in a solvent or mixture of
solvents. In embodiments, the recrystallization or slurrying of
N-alkylated ester may be repeated to attain desired quality of the
product. In an embodiment, the recrystallization or slurrying of
N-alkylated ester may be repeated to obtain substantially single
isomer i.e., cis-isomer of N-alkylated ester of formula (IV). It is
evident from the exemplification of the present application, that
the unwanted trans-isomer of the N-alkylated ester of formula (IV)
has been well controlled with this purification method.
[0148] In an embodiment, N-alkylated ester of formula (IV) may be
purified by slurrying it in a solvent or mixture of solvents at
suitable temperature and for sufficient time to obtain the product
with desired quality. In an embodiment, N-alkylated ester of
formula (IV) may be slurried in the solvent at temperature of about
-50.degree. C. to about 0.degree. C. In an embodiment, N-alkylated
ester of formula (IV) may be slurried in the solvent for at least
10 minutes or more.
[0149] Solvent may include, but not limited to hydrocarbons such as
hexane, cyclohexane, pentane, cyclopentane, toluene, xylene, or the
like.
[0150] In a preferred embodiment, N-alkylated ester of formula (IV)
may be purified by slurrying in a solvent system comprising at
least one hydrocarbon solvent such as hexane, heptane or the
like.
[0151] N-alkylated ester of formula (IV) or its addition salt
recovered by the processes of application can be subjected to
drying at suitable temperatures, such as about
30.degree.-100.degree. C. and suitable pressures, using drying
equipment known in the art, such as air dryer, vacuum dryer,
fluidized bed dryer, spin flash dryer, flash dryer, and the like.
Drying can be carried out at temperatures and times sufficient to
achieve desired quality of product.
[0152] Step c) of this aspect may be carried out by hydrolyzing the
N-alkylated ester of formula (IV) to corresponding N-alkylated acid
of formula (IVa) under suitable conditions. Hydrolysis of
N-alkylated ester may be carried out according any method known in
the art for ester hydrolysis or by following procedures described
or exemplified in the present application.
##STR00011##
[0153] In an embodiment, N-alkylated ester may be hydrolyzed under
acidic, basic or neutral conditions to obtain N-alkylated acid of
formula (IVa). In preferred embodiment, the N-alkylated ester may
be hydrolyzed using suitable acid or base.
[0154] Suitable acid may be selected from group comprising of
inorganic or organic acid such as concentrated or diluted
Hydrochloric acid, Sulphuric acid, phosphoric acid, formic acid,
acetic acid, alkyl sulphonic acids or the like.
[0155] Suitable base may be selected from group comprising of
hydroxides, carbonates, bicarbonates or alkoxides of alkali or
alkali earth metal such as Lithium, Sodium, Potassium, Cesium,
Calcium, Magnesium or the like.
[0156] Step d) of this aspect may be carried out by purification of
N-alkylated acid of formula (IVa) through the formation of its
addition salt of formula (VI)
[0157] Alternatively, N-alkylated acid may be purified by
chromatographic separations, recrystallizing or slurrying in a
solvent or mixture of solvents.
[0158] Inventors of the present application have identified, that
the purity of N-alkylated acid of formula (IVa) was surprisingly
enhanced to significant extent through acid-base treatment such as
through formation of its salt and it is evidential as per the
exemplification of the present application.
[0159] In an embodiment, N-alkylated acid of formula (IVa) may be
purified comprising the steps of [0160] I. converting the
N-alkylated acid of formula (IVa) to its addition salt of
N-alkylated acid of formula (VI), wherein B is a base. [0161] II.
neutralizing this addition salt to obtain pure N-alkylated acid of
formula IVa;
##STR00012##
[0162] In an embodiment, N-alkylated acid of formula (IVa) may be
treated with a base to obtain an addition salt thereof under
suitable conditions. Base may be a inorganic or organic base
selected from the group comprising of hydroxides, carbonates,
alkoxides, bicarbonates of alkali metals, alkaline earth metals,
non-toxic metals, ammonium for example the sodium, potassium,
lithium, calcium, magnesium, aluminum, zinc, ammonium
trimethylammonium, triethanolammonium, Pyridinium, substituted
Pyridinium salts; mono-, di- and trisubstituted amines such as,
Dicyclohexylamine (DCHA), tert-Butyl amine, diethyl amine,
dibutylamine, Morpholine, 3-diemthylamino-1-propylamine,
diisopropyl amine, N-tert-butylbenzylamine, N-benzylmethylamine,
.alpha.-Methyl benzyl amine, (s)-.alpha.-methyl benzylamine, benzyl
amine, dibenzylamine, cyclohexyl amine, tert-octylamine.
Tris(hydroxymethyl)aminomethane, 2-Amino-2-methyl-1-propanol,
2-Amino-2-methyl-1,3-propanediol,
2,2'-(Propane-1,3-diyldiimino)bis[2-(hydroxymethyl)
propane-1,3-diol],2-[Bis(2-hydroxyethyl)imino]-2-(hydroxymethyl)-1,3-prop-
anediol, 2-Aminoethanol,
(2R,3R,4R,5S)-6-Methylaminohexane-1,2,3,4,5-pentol,
2,2',2''-Nitrilotriethanol or the like.
[0163] In an embodiment, N-alkylated acid may be treated with the
base in the presence of a solvent or mixture of solvents. In an
embodiment, the mixture of N-alkylated acid of formula (IVa) and
the solvent may be either homogenous or heterogeneous. Solvent that
are disclosed in any aspect of the present application may be used
for the purification of N-alkylated acid of formula (IVa).
[0164] In an embodiment, N-alkylated acid of formula (IVa) may be
treated with the base for sufficient time and suitable temperature
to complete formation of its addition salt.
[0165] In an embodiment, base may be treated with N-alkylated acid
by adding the base for sufficient time either gradually in a single
lot or periodically in multiple lots. Base may be treated directly
or in diluted state in a solvent.
[0166] In an embodiment, base may be treated with N-alkylated acid
at suitable temperature of about 0.degree. C. to reflux temperature
of the reaction mixture. In preferred embodiment, base treatment
may be carried out at 0.degree. C. to 60.degree. C.
[0167] In an embodiment, the addition salt of N-alkylated acid of
formula (VI) may be isolated by any methods known in the art or by
following the procedures described or exemplified in the present
application. In embodiments, the addition salt of N-alkylated acid
may be isolated by cooling crystallization, anti-solvent addition
or evaporation of the solvent or combinations thereof.
[0168] In an embodiment, the addition salt of N-alkylated acid may
be neutralized before proceeding to next step (or) the addition
salt of N-alkylated acid of formula (VI) may be directly used in
the next step for the preparation of Selinexor of formula I.
[0169] In an embodiment, the addition salt of N-alkylated acid of
formula (VI) may be neutralized with an acid to obtain pure
N-alkylated acid. Acid may be selected from the group comprising of
inorganic or organic acids such as hydrochloric acid, hydrobromic
acid, sulphuric acid, phosphoric acid, Perchloric acid, formic
acid, acetic acid, alkyl or aryl sulphonic acid or the like. Acid
may be used in concentrated or in diluted state such as aqueous or
alcoholic solutions.
[0170] In an embodiment, addition salt of N-alkylated acid of
formula (VI) may be treated with the acid optionally in the
presence of a solvent or mixture of solvents. In an embodiment, the
mixture of addition salt of N-alkylated acid of formula (VI) and
the solvent may be either homogenous or heterogeneous.
[0171] In an embodiment, addition salt of N-alkylated acid of
formula (VI) may be treated with the acid for sufficient time and
suitable temperature to complete liberation of pure N-alkylated
acid of formula (IVa).
[0172] In an embodiment, acid may be treated with addition salt of
formula (VI) by adding the acid for sufficient time either
gradually in a single lot or periodically in multiple lots.
[0173] In an embodiment, acid may be treated with addition salt at
suitable temperature of about 0.degree. C. to reflux temperature of
the reaction mixture. In preferred embodiment, base treatment may
be carried out at 0.degree. C. to 60.degree. C.
[0174] In an embodiment, the N-alkylated acid of formula (IVa) may
be isolated by any methods known in the art or by following the
procedures described or exemplified in the present application. In
embodiments, N-alkylated acid may be isolated by cooling
crystallization, anti-solvent addition or evaporation of the
solvent or combinations thereof.
[0175] In an embodiment, the N-alkylated acid of formula (IVa) or
its addition salt of formula (VI) may be recovered employing any of
the techniques known to a person skilled in art. Techniques for the
recovering pure N-alkylate acid may include, but not limited to:
decantation, filtration by gravity or suction, centrifugation, and
the like, and optionally washing with a solvent.
[0176] The N-alkylate acid of formula (IVa) or its addition salt of
formula (VI) recovered by the processes of application can be
subjected to drying at suitable temperatures, such as about
30.degree.-100.degree. C. and suitable pressures, using drying
equipment known in the art, such as air dryer, vacuum dryer,
fluidized bed dryer, spin flash dryer, flash dryer, and the like.
Drying can be carried out at temperatures and times sufficient to
achieve desired quality of product.
[0177] Step e) of this aspect may be carried out by converting the
addition salt of formula (IV) or N-alkylated acid of formula (IVa)
to Selinexor of formula (I).
[0178] In an embodiment, N-alkylated acid of formula (IVa) may be
reacted with 2-Hydrazinopyrazine derivative of formula V, wherein Z
may be hydrogen or protecting group.
##STR00013##
[0179] In an embodiment, step e) of this aspect may be carried out
by reacting the addition salt thereof of formula (VI) with
2-Hydrazinopyrazine derivative of formula V optionally in the
presence of a base according any methods known in the art or
procedures described or exemplified in the present application.
[0180] In an embodiment, step e) of this aspect may be carried out
by reacting N-alkylated acid of formula (IVa) with
2-Hydrazinopyrazine derivative of formula V, wherein the
N-alkylated acid is either in isolated state or generated in situ
without its isolation. In embodiments, the N-alkylated acid of
formula (IVa) is generated in situ either by hydrolysis of
corresponding ester of formula (IV) or by neutralization of
corresponding addition salt of formula (VI). In embodiments,
hydrolysis of the ester or neutralization of addition salt may be
carried out according to the methods known in the art or procedures
described or exemplified in the present application.
[0181] In an embodiment, N-alkylated acid of formula (IVa) may be
reacted with 2-Hydrazinopyrazine derivative of formula V optionally
in the presence of a catalyst.
[0182] Catalyst that may be used for the reaction of N-alkylated
ester of formula (IV) or N-alkylated acid of formula (IVa) with
2-Hydrazinopyrazine derivative of formula V may be selected from
the group comprising of pyridine, dimethyl aminopyridine, triethyl
amine, diisopropyl ethyl amine, metal alkoxides such as
sodiummethoxide, organoaluminium reagents such as trialkyl or
triaryl aluminium, 1-hydroxy benzotriazole (HOBT),
1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) OR ITS HCl
salt, Carbonyldiimidazole (CDI), dicyclohexylcarbodiimide, Propane
Phosphonic Acid Anhydride (T.sub.3P), HOBT+EDC,
dicyclohexylcarbodiimide (DCC) or the like.
[0183] Step f) of this aspect may be carried out by optionally
removing the protecting the group to obtain Selinexor of formula
(I), wherein Z may be hydrogen. Removal of protecting group may be
carried out according to methods known in the art for deprotection
of nitrogen or according to the procedures described or exemplified
in the present application.
[0184] Selinexor obtained according to the present aspect may be
optionally purified by according to the suitable methods known in
the art which include, but not limited to chromatographic
separations, recrystallizing or slurrying in a solvent or mixture
of solvents, acid-base treatment i.e., through salt formation or
the like. Suitable acid that may be used is selected from any of
the acceptable organic or inorganic acids known in the art and
suitable for the formation of acid-addition salt or any acid
disclosed in any aspect of the instant application.
[0185] Selinexor of formula (I) or its addition salt recovered by
the processes of application can be subjected to drying at suitable
temperatures, such as about 30.degree.-100.degree. C. and suitable
pressures, using drying equipment known in the art, such as air
dryer, vacuum dryer, fluidized bed dryer, spin flash dryer, flash
dryer, and the like. Drying can be carried out at temperatures and
times sufficient to achieve desired quality of product.
[0186] In another aspect, the present application provides a
process for the preparation of Selinexor or a salt thereof,
comprising the steps of: [0187] a) N-alkylation of triazole
compound of formula (II) to obtain the N-alkylated ester of formula
(IV), wherein X may be hydrogen and Y may be a leaving group such
as a halogen or a sulphonate group (or) X and Y together form a
triple bond between carbons atoms to which there are linked, R may
be an optionally substituted alkyl, optionally substituted aryl,
optionally substituted arylalkyl, optionally substituted heteroaryl
group;
[0187] ##STR00014## [0188] b) optionally purifying the N-alkylated
ester of formula (IV) of step a); [0189] c) reacting the
N-alkylated ester of step a) or step b) with 2-Hydrazinopyrazine
derivative of formula V, wherein Z may be hydrogen or protecting
group to obtain Selinexor of formula I.
[0189] ##STR00015## [0190] d) Optionally, removing the protecting
group to obtain Selinexor. [0191] e) purifying the Selinexor
obtained in step c) or d).
[0192] Starting materials, triazole compound of formula (II) and
ester compound of formula (III) are either commercially available
or may be prepared by the procedures known in art or the procedures
described and exemplified in present application.
[0193] The starting materials can be purified by techniques known
in art like column chromatography, fractional distillation,
acid-base treatment, slurring or re-crystallization, before
using.
[0194] Process of this aspect is advantageous interms of reduced
number of steps for the preparation of Selinexor of formula (I).
The process of this aspect avoids the step of hydrolysis of
N-alkylated ester of formula (IV) and converting it directly to
Selinexor of formula (I) as against the process known in the prior
art.
[0195] Step a) of this aspect may be carried out by N-alkylation of
triazole compound of formula (II) to obtain the N-alkylated ester
of formula (IV). N-alkylation may be carried out according to any
of the procedures described in any of the previous aspect or
exemplified in the present application.
[0196] In embodiments, N-alkylated ester of formula (IV) may be
purified using methods such as recrystallization or slurrying in a
suitable solvent or mixture of solvents, chromatographic separation
or acid-base treatment i.e., through salt formation and
neutralization.
[0197] Step b) of this aspect may be carried out by optionally
purifying the N-alkylated ester of formula (IV) according to any of
the methods known in the art or procedures as described in previous
aspect or exemplified in the present application. In an embodiment,
purification of N-alkylated ester of formula (IV) may be carried
out through the formation of its addition salt according to methods
described in any aspect of the instant application.
[0198] In an alternate embodiment, the N-alkylated ester of formula
(IV) may be optionally purified by slurrying in a solvent or
mixture of solvents at suitable temperature and sufficient time.
Solvent that may be used include, but not limited to an alcohol
such as methanol, ethanol, isopropyl alcohol; an ester such as
ethyl acetate, isopropyl acetate; an ketone such as acetone, methyl
isobutyl ketone; hydrocarbons such as hexane, cyclohexane, pentane,
cyclopentane, toluene, xylene; water or the mixtures thereof.
[0199] N-alkylated ester of formula (IV) may be purified by
slurrying in a solvent or mixture of solvents for sufficient time
till the desired content of either of the Cis or trans isomer is
obtained. In an embodiment, N-alkylated ester of formula (IV) may
be purified by slurrying at suitable temperature of about
-50.degree. C. and above.
[0200] N-alkylated ester of formula (IV) or its addition salt
recovered by the processes of application can be subjected to
drying at suitable temperatures, such as about
30.degree.-100.degree. C. and suitable pressures, using drying
equipment known in the art, such as air dryer, vacuum dryer,
fluidized bed dryer, spin flash dryer, flash dryer, and the like.
Drying can be carried out at temperatures and times sufficient to
achieve desired quality of product.
[0201] Step c) of this aspect may be carried out by reacting the
N-alkylated ester of formula (IV) with 2-Hydrazinopyrazine
derivative of formula V to obtain Selinexor of formula (I), wherein
Z may be hydrogen or protecting group.
[0202] In an embodiment, N-alkylated ester of formula (IV) may be
reacted with 2-Hydrazinopyrazine derivative of formula V, to obtain
Selinexor of formula I optionally in the presence of a solvent. Any
of the solvents disclosed in any aspect of the instant application
may be used.
[0203] N-alkylated ester of formula (IV) may be reacted with
2-Hydrazinopyrazine derivative of formula V using any of the
methods or conditions known in the art or procedures described or
exemplified in this specification.
[0204] In an embodiment, N-alkylated ester of formula (IV) may be
reacted with 2-Hydrazinopyrazine derivative of formula V by heating
the reaction mixture. In an embodiment, the reaction mixture may be
heated to about 50.degree. C. to reflux temperature of the reaction
mixture.
[0205] In an embodiment, N-alkylated ester of formula (IV) may be
reacted with 2-Hydrazinopyrazine derivative of formula V for
sufficient time to complete the formation of Selinexor of formula
(I).
[0206] In an embodiment, N-alkylated ester of formula (IV) may be
reacted with 2-Hydrazinopyrazine derivative of formula V optionally
in the presence of a catalyst. Catalyst may be selected from the
group comprising of pyridine, dimethyl aminopyridine, triethyl
amine, diisopropyl ethyl amine, metal alkoxides such as
sodiummethoxide, organoaluminium reagents such as trialkyl or
triaryl aluminium, 1-hydroxy benzotriazole (HOBT),
1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) OR ITS HCl
salt, Carbonyldiimidazole (CDI), dicylohexylcarbodiimide, Propane
Phosphonic Acid Anhydride (T3P) or the like.
[0207] Step d) of this aspect may be carried out by optionally
removing the protecting the group to obtain Selinexor of formula
(I), wherein Z may be hydrogen. Removal of protecting group may be
carried out according to methods known in the art for deprotection
of nitrogen or according to the procedures described or exemplified
in the present application.
[0208] Step e) of this aspect may be carried out by purifying
Selinexor obtained in step c) of d) according to the suitable
methods known in the art which include, but not limited to
chromatographic separations, recrystallizing or slurrying in a
solvent or mixture of solvents, acid-base treatment i.e., through
salt formation or the like. Suitable acid that may be used is
selected from any of the acceptable organic or inorganic acids
known in the art and suitable for the formation of acid-addition
salt or any acid disclosed in any aspect of the instant
application.
[0209] In an embodiment, Selinexor may be purified through the
formation of its acid addition salt.
[0210] In an embodiment, formation of acid addition salt of
Selinexor may be obtained according to the methods known in the art
or procedures described or exemplified in the instant application.
In embodiments, Selinexor may be combined with a suitable acid
optionally in the presence of a solvent or mixture of solvents to
provide its acid addition salt.
[0211] The acid addition salt of Selinexor may be optionally
isolated or converted into free Selinexor in situ without its
isolation. In an embodiment, the salt of Selinexor may be combined
with a suitable base to obtain free Selinexor.
[0212] In alternate embodiment, the salt of Selinexor may be
isolated and then neutralized with a base to obtain Selinexor.
Selinexor obtained by this method may be substantially pure
Cis-isomer of Selinexor with enhanced chemical purity.
[0213] Selinexor of formula (I) or its addition salt recovered by
the processes of application can be subjected to drying at suitable
temperatures, such as about 30.degree.-100.degree. C. and suitable
pressures, using drying equipment known in the art, such as air
dryer, vacuum dryer, fluidized bed dryer, spin flash dryer, flash
dryer, and the like. Drying can be carried out at temperatures and
times sufficient to achieve desired quality of product.
[0214] In another aspect, the present application provides an
addition salt of N-alkylated acid of formula VI.
[0215] In an embodiment, a addition salt of N-alkylated acid of
formula VI may be a salt with a base selected from inorganic or
organic base comprising hydroxides, carbonates, alkoxides,
bicarbonates of alkali metals, alkaline earth metals, non-toxic
metals, ammonium for example sodium, potassium, lithium, calcium,
magnesium, aluminum, zinc, ammonium trimethylammonium,
triethanolammonium, Pyridinium, substituted Pyridinium salts;
mono-, di- and trisubstituted amines such as, Dicyclohexylamine
(DCHA), tert-Butyl amine, diethyl amine, dibutylamine, Morpholine,
3-diemthylamino-1-propylamine, diisopropyl amine,
N-tert-butylbenzylamine, N-benzylmethylamine, .alpha.-Methyl benzyl
amine, (s)-.alpha.-methyl benzylamine, benzyl amine, dibenzylamine,
cyclohexyl amine, tert-octylamine. Tris(hydroxymethyl)aminomethane,
2-Amino-2-methyl-1-propanol, 2-Amino-2-methyl-1,3-propanediol,
2,2'-(Propane-1,3-diyldiimino)bis[2-(hydroxymethyl)
propane-1,3-diol],2-[Bis(2-hydroxyethyl)imino]-2-(hydroxymethyl)-1,3-prop-
anediol, 2-Aminoethanol,
(2R,3R,4R,5S)-6-Methylaminohexane-1,2,3,4,5-pentol,
2,2',2''-Nitrilotriethanol or the like.
[0216] In another aspect, the present application provides a
process for the preparation of Selinexor comprising the step of
preparing an addition salt of N-alkylated acid of formula VI.
[0217] In an embodiment, the process of preparing Selinexor using
an addition salt of N-alkylated acid of formula VI obtained
according to procedures described or exemplified in any aspect of
the present application.
[0218] In embodiments, the addition salt of N-alkylated acid may be
neutralized to obtain corresponding free acid of formula (IVa)
before proceeding to next step (or) the addition salt of
N-alkylated acid of formula (VI) may be directly used for the
preparation of Selinexor. Neutralization of addition salt of
N-alkylated acid may be carried out according to procedures
described or exemplified in any aspect of the present application
to obtain corresponding free acid of formula (IVa).
[0219] In another aspect, the present application provides
N-alkylated acid of formula IVa or N-alkylated ester of formula IV
having a chemical purity of at least 99% by HPLC or at least 99.5%
by HPLC or at least 99.9% by HPLC.
[0220] In another aspect, the present application provides
N-alkylated acid of formula IVa or N-alkylated ester of formula IV
with corresponding trans-isomer content of not more than 0.1% by
HPLC or not more than 0.05% by HPLC.
[0221] In another aspect, the present application provides a
pharmaceutical composition comprising Selinexor obtained according
any of the aspects of this application and at least one
pharmaceutically acceptable excipient.
[0222] In another aspect, the present application provides
Selinexor or its pharmaceutical composition comprising trans-isomer
of Selinexor or
(E)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic
acid of not more than 0.1% by HPLC or not more than 0.05% by
HPLC.
[0223] In another aspect, the present application provides
crystalline form of Selinexor. In embodiments, the crystalline form
of Selinexor may be selected from the group comprising Form-Alpha,
Form-Beta, Form-Gamma, Form-Delta, Form-Epsilon, Form-Zeta,
Form-Eta, Form-Theta, Form-Iota, Form-Kappa, Form-Lambda, Form-Mu,
Form Nu and Form-Xi of Selinexor or mixtures thereof.
[0224] In another aspect, the present application provides a
crystalline Form-Alpha of Selinexor, characterized by a PXRD
pattern comprising the peaks at about 4.38, 12.45, 13.13, 15.85,
19.98 and 21.35.+-.0.2.degree. 2.theta.. In an embodiment, the
application provides crystalline form Alpha of Selinexor,
characterized by a PXRD pattern having one or more additional peaks
at about 14.51, 14.77, 20.30 and 27.32.+-.0.2.degree. 2.theta..
[0225] In an embodiment, the present application provides a
crystalline Form-Alpha of Selinexor, characterized by a PXRD
pattern having peaks located substantially as shown in FIG. 1 or
2.
[0226] In another aspect, the present application provides
crystalline Form-Beta of Selinexor, characterized by a PXRD pattern
comprising the peaks at about 5.87, 11.73, 18.71, 20.53 and
24.05.+-.0.2.degree. 2.theta.. In an embodiment, the application
provides crystalline Form-Beta of Selinexor, characterized by a
PXRD pattern having one or more additional peaks at about 16.28 and
21.28.+-.0.2.degree. 2.theta..
[0227] In an embodiment, the present application provides a
crystalline Form-Beta of Selinexor, characterized by a PXRD pattern
having peaks located substantially as shown in FIG. 3.
[0228] In another aspect, the present application provides
crystalline Form-Gamma of Selinexor, characterized by a PXRD
pattern comprising the peaks at about 3.28, 11.95, 14.62, 15.74 and
20.96.+-.0.2.degree. 2.theta.. In an embodiment, the application
provides crystalline Form-Gamma of Selinexor, characterized by a
PXRD pattern having one or more additional peaks at about 16.95,
18.23, 20.01 and 22.13.+-.0.2.degree. 2.theta..
[0229] In an embodiment, the present application provides a
crystalline Form-Gamma of Selinexor, characterized by a PXRD
pattern having peaks located substantially as shown in FIG. 4.
[0230] In an aspect, the present application provides crystalline
Form-Delta of Selinexor, characterized by a PXRD pattern comprising
the peaks at about 6.11, 12.16, 13.00, 20.28 and
24.43.+-.0.2.degree. 2.theta.. In an embodiment, the application
provides crystalline Form-Delta of Selinexor, characterized by a
PXRD pattern having one or more additional peaks at about 19.35,
23.39 and 23.78.+-.0.2.degree. 2.theta..
[0231] In an embodiment, the present application provides a
crystalline Form-Delta of Selinexor, characterized by a PXRD
pattern having peaks located substantially as shown in FIG. 5.
[0232] In another aspect, the present application provides
crystalline Form-Epsilon of Selinexor, characterized by a PXRD
pattern comprising the peaks at about 5.87, 11.72, 17.61, 18.68,
20.50, 22.78, 23.20, 23.53 and 23.97.+-.0.2.degree. 2.theta.. In an
embodiment, the application provides crystalline Form-Epsilon of
Selinexor, characterized by a PXRD pattern having one or more
additional peaks at about 16.26, 21.25, 25.35, 29.22 and
30.14.+-.0.2.degree. 2.theta..
[0233] In an embodiment, the present application provides a
crystalline Form-Epsilon of Selinexor, characterized by a PXRD
pattern having peaks located substantially as shown in FIG. 6.
[0234] In another aspect, the present application provides
crystalline Form-Zeta of Selinexor, characterized by a PXRD pattern
comprising the peaks at about 4.86, 6.99, 7.74, 10.86, 15.50 and
19.47.+-.0.2.degree. 2.theta.. In an embodiment, the application
provides crystalline Form--Zeta of Selinexor, characterized by a
PXRD pattern having one or more additional peaks at about 14.00,
18.27, 20.73, 21.51 and 22.14.+-.0.2.degree. 2.theta..
[0235] In an embodiment, the present application provides a
crystalline Form-Zeta of Selinexor, characterized by a PXRD pattern
having peaks located substantially as shown in FIG. 7.
[0236] In another aspect, the present application provides
crystalline Form-Eta of Selinexor, characterized by a PXRD pattern
comprising the peaks at about 3.54, 7.03, 9.91, 11.59, 19.84, 20.44
and 21.64.+-.0.2.degree. 2.theta.. In an embodiment, the
application provides crystalline Form-Eta of Selinexor,
characterized by a PXRD pattern having one or more additional peaks
at about 17.55, 21.09, 22.45 and 23.28.+-.0.2.degree. 2.theta..
[0237] In an embodiment, the present application provides a
crystalline Form-Eta of Selinexor, characterized by a PXRD pattern
having peaks located substantially as shown in FIG. 8.
[0238] In another aspect, the present application provides
crystalline Form--Theta of Selinexor, characterized by a PXRD
pattern comprising the peaks at about 6.96, 13.92, 20.95 and
22.82.+-.0.2.degree. 2.theta.. In an embodiment, the application
provides crystalline Form-Theta of Selinexor, characterized by a
PXRD pattern having one or more additional peaks at about 17.24,
20.03, 20.37 and 23.41.+-.0.2.degree. 2.theta..
[0239] In an embodiment, the present application provides a
crystalline Form-Theta of Selinexor, characterized by a PXRD
pattern having peaks located substantially as shown in FIG. 9.
[0240] In another aspect, the present application provides
crystalline Form--Iota of Selinexor, characterized by a PXRD
pattern comprising the peaks at about 3.69, 7.33, 11.01, 14.66,
16.19 and 18.36.+-.0.2.degree. 2.theta..
[0241] In an embodiment, the present application provides a
crystalline Form-Iota of Selinexor, characterized by a PXRD pattern
having peaks located substantially as shown in FIG. 10.
[0242] In another aspect, the present application provides
crystalline Form--Kappa of Selinexor, characterized by a PXRD
pattern comprising the peaks at about 3.22, 11.71, 12.56, 14.42 and
25.20.+-.0.2.degree. 2.theta..
[0243] In an embodiment, the present application provides a
crystalline Form-Kappa of Selinexor, characterized by a PXRD
pattern having peaks located substantially as shown in FIGS. 11
& 22.
[0244] In another aspect, the present application provides
crystalline Form-Lambda of Selinexor, characterized by a PXRD
pattern comprising the peaks at about 12.61, 19.00, 19.95 and
21.29.+-.0.2.degree. 2.theta.. In an embodiment, the application
provides crystalline Form-Lambda of Selinexor, characterized by a
PXRD pattern having one or more additional peaks at about 14.13,
21.29, 21.75, 23.10, 24.65 and 30.86.+-.0.2.degree. 20.
[0245] In an embodiment, the present application provides a
crystalline Form-Lambda of Selinexor, characterized by a PXRD
pattern having peaks located substantially as shown in FIG. 12.
[0246] In another aspect, the present application provides
crystalline Form-Mu of Selinexor, characterized by a PXRD pattern
comprising the peaks at about 9.31, 17.45, 17.85 and
22.72.+-.0.2.degree. 2.theta.. In an embodiment, the application
provides crystalline Form-Mu of Selinexor, characterized by a PXRD
pattern having one or more additional peaks at about 21.20, 25.01
and 27.59.+-.0.2.degree. 2.theta..
[0247] In an embodiment, the present application provides a
crystalline Form-Mu of Selinexor, characterized by a PXRD pattern
having peaks located substantially as shown in FIG. 13
[0248] In another aspect, the present application provides
crystalline Form--Nu of Selinexor, characterized by a PXRD pattern
comprising the peaks at about 10.75, 17.52, 21.84, 22.16 and
22.38.+-.0.2.degree. 2.theta.. In an embodiment, the application
provides crystalline Form-Nu of Selinexor, characterized by a PXRD
pattern having one or more additional peaks at about 18.30, 24.53
and 28.91.+-.0.2.degree. 2.theta..
[0249] In an embodiment, the present application provides a
crystalline Form-Nu of Selinexor, characterized by a PXRD pattern
having peaks located substantially as shown in FIG. 14.
[0250] In another aspect, the present application provides
crystalline Form--Xi of Selinexor, characterized by a PXRD pattern
comprising the peaks at about 10.54, 11.68, 12.72 and
24.56.+-.0.2.degree. 2.theta.. In an embodiment, the application
provides crystalline Form-Xi of Selinexor, characterized by a PXRD
pattern having one or more additional peaks at about 3.70, 7.36,
18.10, 19.72 and 21.21.+-.0.2.degree. 2.theta..
[0251] In an embodiment, the present application provides a
crystalline Form-Xi of Selinexor, characterized by a PXRD pattern
having peaks located substantially as shown in FIG. 15.
[0252] In another aspect, the present application provides an
amorphous form of Selinexor. In an embodiment, the present
application provides an amorphous form of Selinexor characterized
by a powder X-ray diffraction (PXRD) pattern, substantially as
illustrated by FIG. 16.
[0253] The present application provides a stable amorphous form of
Selinexor suitable for powder handling and downstream processes.
Amorphous form of Selinexor of the present application which was
surprisingly found to be highly stable under mechanical stress such
as grinding and milling and stable under hygroscopic conditions
such as higher relative humidity conditions of more than 60% RH. In
an embodiment, the present application provides a stable amorphous
form of Selinexor with less than 5% of crystallinity, preferably
with less than 1% crystallinity and more preferably devoid of
crystallinity as per X-ray diffraction analysis.
[0254] In another aspect, the present application provides a
pharmaceutical composition comprising amorphous form of Selinexor
combined with at least one pharmaceutically acceptable
excipient.
[0255] In an embodiment, pharmaceutically acceptable excipient may
be selected from the group consisting of silicon dioxide, e.g.
colloidal or fumed silicon dioxide or porous silica; copolymers,
such as polyethylene/polyvinyl alcohol copolymer,
polyethylene/polyvinyl pyrrolidinone copolymer; and cellulose,
preferably microcrystalline cellulose.
[0256] In an aspect, the present application provides amorphous
solid dispersion of Selinexor together with at least one
pharmaceutically acceptable excipient.
[0257] In an embodiment, the present application provides amorphous
solid dispersion of Selinexor together with at least one
pharmaceutically acceptable excipient characterized by a powder
X-ray diffraction (PXRD) pattern, substantially as illustrated by
FIGS. 17-20.
[0258] In an embodiment, pharmaceutically acceptable excipient of
this aspect may be selected from the group consisting of polyvinyl
pyrrolidone, povidone K-30, povidone K-60, Povidone K-90,
polyvinylpyrrolidone vinylacetate, co-povidone NF, polyvinylacetal
diethylaminoacetate (AEA.RTM.), polyvinyl acetate phthalate,
polysorbate 80, polyoxyethylene-polyoxypropylene copolymers
(Poloxamer.RTM. 188), polyoxyethylene (40) stearate, polyethyene
glycol monomethyl ether, polyethyene glycol, poloxamer 188,
pluronic F-68, methylcellulose, methacrylic acid copolymer
(Eudragit), hydroxypropylmethyl cellulose phthalate,
hydroxypropylmethyl cellulose acetate succinate,
hydroxypropylmethyl cellulose, hydroxypropyl cellulose SL,
hydroxyethyl cellulose, gelucire 44/14, ethyl cellulose,
D-alpha-tocopheryl polyethylene glycol 1000 succinate, cellulose
acetate phthalate, carboxymethylethylcellulose and the like;
cyclodextrins, gelatins, hypromellose phthalates, sugars,
polyhydric alcohols, and the like; water soluble sugar excipients,
preferably having low hygroscopicity, which include, but are not
limited to, mannitol, lactose, fructose, sorbitol, xylitol,
maltodextrin, dextrates, dextrins, lactitol and the like;
polyethylene oxides, polyoxyethylene derivatives, polyvinyl
alcohols, propylene glycol derivatives and the like; organic amines
such as alkyl amines (primary, secondary, and tertiary), aromatic
amines, alicyclic amines, cyclic amines, aralkyl amines,
hydroxylamine or its derivatives, hydrazine or its derivatives, and
guanidine or its derivatives, or any other excipient at any aspect
of present application. The use of mixtures of more than one of the
pharmaceutical excipients to provide desired release profiles or
for the enhancement of stability is within the scope of this
invention. Also, all viscosity grades, molecular weights,
commercially available products, their copolymers, and mixtures are
all within the scope of this invention without limitation.
[0259] In another aspect, the present application provides a
pharmaceutical composition comprising amorphous solid dispersion of
Selinexor combined with at least one pharmaceutically acceptable
excipient.
[0260] In an embodiment, pharmaceutically acceptable excipient may
be different from the excipient used in solid dispersion. In an
embodiment, pharmaceutically acceptable excipient selected from the
group consisting of silicon dioxide, e.g. colloidal or fumed
silicon dioxide or porous silica; copolymers, such as
polyethylene/polyvinyl alcohol copolymer, polyethylene/polyvinyl
pyrrolidinone copolymer; and cellulose, preferably microcrystalline
cellulose.
[0261] In another aspect, the present application provides process
for preparing a crystalline form of Selinexor, which comprises:
[0262] a) combining amorphous Selinexor with a solvent or a mixture
thereof; [0263] b) stirring the mixture of step a); [0264] c)
optionally adding an anti-solvent to the mixture of step a) or b)
[0265] d) isolating crystalline form of Selinexor.
[0266] In an embodiment, Selinexor that is used in step a) of this
aspect may be either the amorphous form of Selinexor or by directly
taking a synthetic reaction mixture comprising Selinexor and a
solvent or mixture of solvents.
[0267] In an embodiment, amorphous Selinexor that is used in step
a) may be purified by any methods known in the art such as column
chromatography, fractional distillation, acid-base treatment,
slurring or re-crystallization, before using.
[0268] In an embodiment of step a), solvent may include, but not
limited to water; ketones, such as acetone, methyl ethyl ketone,
methyl isobutyl ketone, and diethyl ketone; esters, such as ethyl
acetate, propyl acetate, isopropyl acetate, and butyl acetate;
alcohols, such as methanol, ethanol, ethylene glycol, 1-propanol,
2-propanol (isopropyl alcohol), 1-butanol, 2-butanol, iso-butyl
alcohol, t-butyl alcohol, 2-ethoxyethanol; nitriles, such as
acetonitrile and propionitrile; halogenated hydrocarbons, such as
dichloromethane, chloroform and carbontetrachloride; and
dimethoxyethane; aprotic non-poplar solvents such as
dimethylsulfoxide; formamide, N,N-dimethylformamide,
N,N-dimethylacetamide, N-methyl-2-pyrrolidone; any mixtures of two
or more thereof.
[0269] In an embodiment, amorphous Selinexor may be combined with
solvent at any suitable temperatures, such as at about 0.degree. C.
to about the reflux temperature of the solvent or mixture thereof.
The mixture of Selinexor in solvent may be prepared preferably at
about 0.degree. C. to 80.degree. C.
[0270] In an embodiment the mixture of amorphous Selinexor and
solvent may be either a heterogeneous or homogeneous phase.
[0271] In an embodiment, the mixture of amorphous Selinexor and
solvent may be optionally filtered to make particle free solution
when it is a homogeneous clear solution and treated with a
decolorizing agent, such as carbon, before filtration.
[0272] In an embodiment, the mixture of amorphous Selinexor and
solvent may be cooled to suitable temperature for the precipitation
of crystalline Selinexor from the mixture. In an embodiment, the
mixture of amorphous Selinexor and solvent may be cooled
drastically or gradually with either constant rate of cooling or by
step-wise cooling periodically to achieve desired nature of the
crystalline Selinexor.
[0273] In an embodiment, the mixture of amorphous Selinexor and
solvent may be stirred for sufficient time to complete formation of
crystalline Selinexor. In an embodiment, the mixture of amorphous
Selinexor and solvent may be stirred for at least 1 hour or more,
preferably for at least 24 hours or more and more preferably at
least 48 hours or more.
[0274] In an embodiment, the mixture of amorphous Selinexor and
solvent may be stirred at suitable temperature for the formation of
crystalline form of Selinexor. In an embodiment, the mixture of
amorphous Selinexor and solvent may be stirred at 0.degree. C. and
above, preferably between 0.degree. C. to reflux temperature of the
solvent used, more preferably between 0.degree. C. and 50.degree.
C.
[0275] In an embodiment, optionally an anti-solvent may be added to
the mixture of step a) or b). In an embodiment, anti-solvent may be
added for sufficient time and at suitable temperature to complete
the formation of crystalline Selinexor. Anti-solvents may include
but not limited to water; aliphatic hydrocarbons, such as hexane,
heptane, cyclohexane; aromatic hydrocarbons, such as toluene,
xylene and chlorobenzene; ethers, such as diethyl ether,
di-isopropyl ether, tetrahydrofuran, dioxane; or the like.
[0276] In an embodiment, isolation of crystalline form of Selinexor
may be carried out by any methods known in the art or procedures
described in the present application. In an embodiment, crystalline
Selinexor may be isolated by employing any of the techniques, but
not limited to: decantation, filtration by gravity or suction,
centrifugation, adding solvent to make slurry followed by
filtration, or other techniques specific to the equipment used and
the like, and optionally washing with a solvent.
[0277] In an embodiment, isolated crystalline form of Selinexor may
be dried in a suitable drying equipment such as tray dryer, vacuum
oven, rotatory cone dryer, air oven, fluidized bed dryer, spin
flash dryer, flash dryer, or the like. The drying may be carried
out at atmospheric pressure or under reduced pressures at
temperatures of less than about 100.degree. C., less than about
60.degree. C., less than about 40.degree. C., or any other suitable
temperatures. Drying can be carried out at temperatures and times
sufficient to achieve desired quality of product. Drying may be
carried out for any time period required for obtaining a desired
quality, such as from about 15 minutes to 10 hours or longer.
[0278] In embodiments, the crystalline Selinexor isolated at step
d) of this aspect may be selected from the group comprising of
Form-Alpha, Form-Beta, Form-Gamma, Form-Delta, Form-Epsilon,
Form-Zeta, Form-Eta, Form-Theta, Form-Iota, Form-Kappa,
Form-Lambda, Form-Mu, Form Nu and Form-Xi or mixtures thereof.
[0279] In another aspect, the present application provides a
process for the preparation of crystalline form of Selinexor or a
solvate thereof, comprising the step of converting amorphous
Selinexor to crystalline form of Selinexor or a solvate
thereof.
[0280] In an embodiment, crystalline form of Selinexor may be
selected from the group comprising of crystalline form A, Form B,
Form C, Form D, Form-Alpha, Form-Beta, Form-Gamma, Form-Delta,
Form-Epsilon, Form-Zeta, Form-Eta, Form-Theta, Form-Iota,
Form-Kappa, Form-Lambda, Form-Mu, Form Nu and Form-Xi or mixtures
thereof.
[0281] In an embodiment, the step of converting amorphous Selinexor
to crystalline form may be carried out by suspending or
re-crystallizing amorphous Selinexor in a suitable solvent or
mixture of solvents.
[0282] Re-crystallizing amorphous Selinexor may be carried out by
according previous aspects or any of the methods or procedures
described or exemplified in the present application. In an
embodiment, amorphous Selinexor may be suspended in a suitable
solvent or mixture of solvents under suitable conditions in which
crystalline Form is stable.
[0283] In another aspect, the present application provides process
for preparing a crystalline Form-Alpha of Selinexor, which
comprises: [0284] a) combining Selinexor with acetone:water
mixture; [0285] b) stirring the mixture of step a); [0286] c)
isolating crystalline Form-Alpha of Selinexor.
[0287] In an embodiment, Selinexor that is used in step a) may be
purified by any methods known in the art such as column
chromatography, fractional distillation, acid-base treatment,
slurring or re-crystallization, before using.
[0288] In an embodiment, Selinexor that is used in step a) of this
aspect may be either the amorphous form or any other crystalline
form of Selinexor or by directly taking a synthetic reaction
mixture comprising Selinexor and acetone:water mixture.
[0289] In an embodiment, Selinexor may be combined with mixture of
acetone and water at any suitable temperatures, such as at about
0.degree. C. to about the reflux temperature of the solvent
mixture. The mixture of Selinexor and acetone-water solvent may be
prepared preferably at about 0.degree. C. to 60.degree. C.
[0290] In an embodiment the mixture of Selinexor and acetone-water
may be either a heterogeneous or homogeneous phase.
[0291] The acetone to water ratio of the acetone-water mixture may
be between about 1:1 to 20:1, preferably between about 1:1 to
15:1
[0292] In an embodiment, the mixture of Selinexor and acetone-water
may be optionally filtered to make particle free solution when it
is a homogenous clear solution and treated with a decolorizing
agent, such as carbon, before filtration.
[0293] In an embodiment, Selinexor that may be used in step a) of
this aspect may be amorphous form of Selinexor.
[0294] In an embodiment, the mixture of Selinexor and acetone-water
at step b) may be stirred for sufficient time to complete formation
of crystalline Form-Alpha of Selinexor. In an embodiment, the
mixture of Selinexor and acetone-water may be stirred for at least
1 hour or more, preferably for at least 24 hours or more and more
preferably at least 48 hours or more.
[0295] In an embodiment, the mixture of Selinexor and acetone-water
may be stirred at suitable temperature for the formation of
crystalline Form-Alpha of Selinexor. In an embodiment, the mixture
of Selinexor and acetone-water may be stirred at 0.degree. C. and
above, preferably between 0.degree. C. to reflux temperature of the
solvent used, more preferably between 0.degree. C. and 50.degree.
C.
[0296] In an embodiment, isolation of crystalline Form-Alpha of
Selinexor may be carried out by any methods known in the art or
procedures described in the present application. In an embodiment,
crystalline Form-Alpha of Selinexor may be isolated by employing
any of the techniques, but not limited to: decantation, filtration
by gravity or suction, centrifugation, adding solvent to make
slurry followed by filtration, or other techniques specific to the
equipment used and the like, and optionally washing with a
solvent.
[0297] Drying process for crystalline Form-Alpha of Selinexor may
be carried out in the similar manner as described in the above
aspect for crystalline Selinexor.
[0298] In another aspect, the present application provides a
process for preparing a crystalline Form-Delta of Selinexor, which
comprises: [0299] a) combining Selinexor with methanol; [0300] b)
stirring the mixture of step a); [0301] c) isolating crystalline
Form-Delta of Selinexor.
[0302] In an embodiment, Selinexor may be combined with methanol at
any suitable temperatures, such as at about 0.degree. C. to about
the reflux temperature of the mixture. The mixture of Selinexor and
methanol may be prepared preferably at about 0.degree. C. to
60.degree. C.
[0303] In an embodiment the mixture of Selinexor and methanol may
be either a heterogeneous or homogeneous phase.
[0304] In an embodiment, the mixture of Selinexor and methanol may
be optionally filtered to make particle free solution, in case the
mixture forms a homogenous clear solution and may be treated with a
decolorizing agent, such as carbon, before filtration.
[0305] In an embodiment, Selinexor that may be used in step a) of
this aspect may be amorphous form of Selinexor.
[0306] In an embodiment, the mixture of Selinexor and methanol at
step b) may be stirred for sufficient time to complete formation of
crystalline Form-Delta of Selinexor. In an embodiment, the mixture
of Selinexor and methanol may be stirred for at least 5 minutes or
more.
[0307] In an embodiment, the mixture of Selinexor and methanol may
be stirred at suitable temperature for the formation of crystalline
Form-Delta of Selinexor. In an embodiment, the mixture of Selinexor
and methanol may be stirred at 0.degree. C. and above, preferably
between 0.degree. C. to reflux temperature of the reaction
mixture.
[0308] In an embodiment, isolation of crystalline Form-Delta of
Selinexor may be carried out by any methods known in the art or
procedures described in the present application. In an embodiment,
crystalline Form-Delta of Selinexor may be isolated by employing
any of the techniques, but not limited to: decantation, filtration
by gravity or suction, centrifugation, adding solvent to make
slurry followed by filtration, or other techniques specific to the
equipment used and the like, and optionally washing with a
solvent.
[0309] In an embodiment, isolated crystalline Form-Delta of
Selinexor may be dried in a suitable drying equipment such as tray
dryer, vacuum oven, rotatory cone dryer, air oven, fluidized bed
dryer, spin flash dryer, flash dryer, or the like. The drying may
be carried out at atmospheric pressure or under reduced pressures
at temperatures of less than about 100.degree. C., less than about
60.degree. C., less than about 40.degree. C., or any other suitable
temperatures. Drying can be carried out at temperatures and times
sufficient to achieve desired quality of product. Drying may be
carried out for any time period required for obtaining a desired
quality, such as from about 15 minutes to 10 hours or longer.
[0310] In another aspect, the present application provides a
process for preparing a crystalline Form-Epsilon of Selinexor,
which comprises: [0311] a) combining Selinexor with ethanol; [0312]
b) stirring the mixture of step a); [0313] c) isolating crystalline
Form-Epsilon of Selinexor.
[0314] In an embodiment, Selinexor may be combined with ethanol at
any suitable temperatures, such as at about 0.degree. C. to about
the reflux temperature of the reaction mixture. The mixture of
Selinexor and ethanol may be prepared preferably at about 0.degree.
C. to 60.degree. C.
[0315] In an embodiment the mixture of Selinexor and ethanol may be
either a heterogeneous or homogeneous phase.
[0316] In an embodiment, the mixture of Selinexor and ethanol may
be optionally filtered to make particle free solution, in case the
mixture forms a homogenous clear solution and may be treated with a
decolorizing agent, such as carbon, before filtration.
[0317] In an embodiment, Selinexor that may be used in step a) of
this aspect may be amorphous form of Selinexor.
[0318] In an embodiment, the mixture of Selinexor and ethanol at
step b) may be stirred for sufficient time to complete formation of
crystalline Form-Epsilon of Selinexor. In an embodiment, the
mixture of Selinexor and ethanol may be stirred for at least 5
minutes or more.
[0319] In an embodiment, the mixture of Selinexor and ethanol may
be stirred at suitable temperature for the formation of crystalline
Form-Epsilon of Selinexor.
[0320] In an embodiment, the mixture of Selinexor and ethanol may
be stirred at 0.degree. C. and above, preferably between 0.degree.
C. to reflux temperature of the reaction mixture.
[0321] In an embodiment, isolation of crystalline Form-Epsilon of
Selinexor may be carried out by any methods known in the art or
procedures described in the present application. In an embodiment,
crystalline Form-Epsilon of Selinexor may be isolated by employing
any of the techniques, but not limited to: decantation, filtration
by gravity or suction, centrifugation, adding solvent to make
slurry followed by filtration, or other techniques specific to the
equipment used and the like, and optionally washing with a
solvent.
[0322] Drying process for crystalline Form-Epsilon of Selinexor may
be carried out in the similar manner as described in the above
aspect for crystalline Form-Delta of Selinexor.
[0323] In another aspect, the present application provides process
for preparing a crystalline Form-Zeta of Selinexor, which
comprises: [0324] a) combining Selinexor with acetic acid and
water; [0325] b) stirring the mixture of step a); [0326] c)
isolating crystalline Form-Zeta of Selinexor.
[0327] In an embodiment, Selinexor may be combined with acetic acid
and water at any suitable temperatures, such as at about 0.degree.
C. to about the reflux temperature of reaction mixture. The mixture
of Selinexor with acetic acid and water may be prepared preferably
at about 0.degree. C. to 60.degree. C.
[0328] In an embodiment the mixture of Selinexor with acetic acid
and water may be either a heterogeneous or homogeneous phase.
[0329] In an embodiment, the mixture of Selinexor and water may be
optionally filtered to make particle free solution, in case the
mixture forms a homogenous clear solution and may be treated with a
decolorizing agent, such as carbon, before filtration.
[0330] In an embodiment, Selinexor that may be used in step a) of
this aspect may be amorphous form of Selinexor.
[0331] In an embodiment, the mixture of Selinexor with acetic acid
and water at step b) may be stirred for sufficient time to complete
formation of crystalline Form-Zeta of Selinexor. In an embodiment,
the mixture of Selinexor with acetic acid and water may be stirred
for at least 5 minutes or more.
[0332] In an embodiment, the mixture of Selinexor with acetic acid
and water may be stirred at suitable temperature for the formation
of crystalline Form-Zeta of Selinexor. In an embodiment, the
mixture of Selinexor and water may be stirred at 0.degree. C. and
above, preferably between 0.degree. C. to reflux temperature of
reaction mixture.
[0333] In an embodiment, isolation of crystalline Form-Zeta of
Selinexor may be carried out by any methods known in the art or
procedures described in the present application. In an embodiment,
crystalline Form-Zeta of Selinexor may be isolated by employing any
of the techniques, but not limited to: decantation, filtration by
gravity or suction, centrifugation, adding solvent to make slurry
followed by filtration, or other techniques specific to the
equipment used and the like, and optionally washing with a
solvent.
[0334] Drying process for crystalline Form-Zeta of Selinexor may be
carried out in the similar manner as described in the above aspect
for crystalline Form-Delta of Selinexor.
[0335] In another aspect, the present application provides process
for preparing a crystalline Form-Theta of Selinexor, which
comprises: [0336] a) providing a solution of Selinexor in formic
acid; [0337] b) contacting the solution of step a) with an
anti-solvent; [0338] c) isolating crystalline Form-Theta of
Selinexor.
[0339] In an embodiment, Selinexor may be combined with Formic acid
at any suitable temperatures, such as at about 0.degree. C. to
about the reflux temperature of the reaction mixture. The mixture
of Selinexor in solvent may be prepared preferably at about
0.degree. C. to 50.degree. C.
[0340] In an embodiment the mixture of Selinexor and Formic acid
may be either a heterogeneous or homogeneous phase.
[0341] In an embodiment, the mixture of Selinexor and Formic acid
may be optionally filtered to make particle free solution, in case
the mixture forms a homogeneous clear solution and may be treated
with a decolorizing agent, such as carbon, before filtration.
[0342] In an embodiment, the mixture of Selinexor and formic acid
may be optionally cooled to suitable temperature.
[0343] In an embodiment, the mixture of step a) may be contacted
with an anti-solvent. Anti-solvent may be added for sufficient time
and at suitable temperature for the formation of crystalline
Form-Theta of Selinexor. Anti-solvents may be selected from the
group comprising of water; ethers, such as diethyl ether,
di-isopropyl ether, tetrahydrofuran, dioxane; aliphatic
hydrocarbons, such as hexane, heptane, cyclohexane; aromatic
hydrocarbons, such as toluene, xylene and chlorobenzene; or
mixtures thereof.
[0344] In an embodiment, the mixture of Selinexor and formic acid
may be stirred for sufficient time for the formation of crystalline
Form-Theta of Selinexor, before or after contacting with
anti-solvent.
[0345] In an embodiment, isolation of crystalline Form-Theta of
Selinexor may be carried out by any methods known in the art or
procedures described in the present application. In an embodiment,
crystalline Form-Theta of Selinexor may be isolated by employing
any of the techniques, but not limited to: decantation, filtration
by gravity or suction, centrifugation, adding solvent to make
slurry followed by filtration, or other techniques specific to the
equipment used and the like, and optionally washing with a
solvent.
[0346] Drying process for crystalline Form-Theta of Selinexor may
be carried out in the similar manner as described in the above
aspect for crystalline Form-Delta of Selinexor.
[0347] In another aspect, the present application provides process
for preparing a crystalline Form-Eta of Selinexor, which comprises:
[0348] a) combining Selinexor with nitromethane; [0349] b) stirring
the mixture of step a); [0350] c) isolating crystalline Form-Eta of
Selinexor.
[0351] In an embodiment, Selinexor may be combined with
nitromethane at any suitable temperatures, such as at about
0.degree. C. to about the reflux temperature of reaction mixture.
The mixture of Selinexor and nitromethane may be prepared
preferably at about 0.degree. C. to 60.degree. C.
[0352] In an embodiment the mixture of Selinexor and nitromethane
may be either a heterogeneous or homogeneous phase.
[0353] In an embodiment, the mixture of Selinexor and nitromethane
may be optionally filtered to make particle free solution, in case
it forms a homogenous clear solution and may be treated with a
decolorizing agent, such as carbon, before filtration.
[0354] In an embodiment, the mixture of Selinexor and nitromethane
at step b) may be stirred for sufficient time to complete formation
of crystalline Form-Eta of Selinexor. In an embodiment, the mixture
of Selinexor and nitromethane may be stirred for at least 5 minutes
or more.
[0355] In an embodiment, the mixture of Selinexor and nitromethane
may be stirred at suitable temperature for the formation of
crystalline Form-Eta of Selinexor. In an embodiment, the mixture of
Selinexor and nitromethane may be stirred at 0.degree. C. and
above, preferably between 0.degree. C. to reflux temperature of
reaction mixture.
[0356] In an embodiment, isolation of crystalline Form-Eta of
Selinexor may be carried out by any methods known in the art or
procedures described in the present application. In an embodiment,
crystalline Form-Eta of Selinexor may be isolated by employing any
of the techniques, but not limited to: decantation, filtration by
gravity or suction, centrifugation, adding solvent to make slurry
followed by filtration, or other techniques specific to the
equipment used and the like, and optionally washing with a
solvent.
[0357] In another aspect, the present application provides process
for preparing a crystalline Form-Iota of Selinexor, which comprises
the step of drying Form-Eta of Selinexor.
[0358] In an embodiment, drying Form-Eta of Selinexor may be
carried out in suitable drying equipment such as a tray drier
optionally under reduced pressure or other drying conditions known
in the art such as Buchi rotavapour vacuum drying, rotatory cone
vacuum drying; fluid bed drying optionally under nitrogen
atmosphere, thin film drying; or the like.
[0359] In an embodiment, drying Form-Eta of Selinexor may be
carried out at suitable temperatures of about 25.degree. C. and
above, optionally under reduced pressure. In an embodiment, drying
may be carried out at about 50.degree. C. and above.
[0360] In an embodiment, drying Form-Eta of Selinexor may be
carried out for sufficient time to complete its conversion to
Form-Iota of Selinexor. Drying can be carried out at temperatures
and times sufficient to achieve desired quality of product. Drying
may be carried out for any time period required for obtaining a
desired quality, such as from about 15 minutes to 5 hours or
longer.
[0361] In another aspect, the present application provides process
for preparing a crystalline Form-Kappa of Selinexor, which
comprises: [0362] a) combining Selinexor with water; [0363] b)
stirring the mixture of step a); [0364] c) isolating crystalline
Form-Kappa of Selinexor.
[0365] In an embodiment, Selinexor may be combined with water at
any suitable temperatures, such as at about 0.degree. C. to about
the reflux temperature of reaction mixture. The mixture of
Selinexor and water may be prepared preferably at about 0.degree.
C. to 60.degree. C.
[0366] In an embodiment the mixture of Selinexor and water may be
either a heterogeneous or homogeneous phase.
[0367] In an embodiment, the mixture of Selinexor and water may be
optionally filtered to make particle free solution, in case it
forms a homogenous clear solution and may be treated with a
decolorizing agent, such as carbon, before filtration.
[0368] In an embodiment, Selinexor that may be used in step a) of
this aspect may be amorphous form of Selinexor.
[0369] In an embodiment, the mixture of Selinexor and water at step
b) may be stirred for sufficient time to complete formation of
crystalline Form-Kappa of Selinexor. In an embodiment, the mixture
of Selinexor and water may be stirred for at least 5 minutes or
more.
[0370] In an embodiment, the mixture of Selinexor and water may be
stirred at suitable temperature for the formation of crystalline
Form-Kappa of Selinexor. In an embodiment, the mixture of Selinexor
and water may be stirred at 0.degree. C. and above, preferably
between 0.degree. C. to reflux temperature of reaction mixture.
[0371] In an embodiment, isolation of crystalline Form-Kappa of
Selinexor may be carried out by any methods known in the art or
procedures described in the present application. In an embodiment,
crystalline Form-Kappa of Selinexor may be isolated by employing
any of the techniques, but not limited to: decantation, filtration
by gravity or suction, centrifugation, adding solvent to make
slurry followed by filtration, or other techniques specific to the
equipment used and the like, and optionally washing with a
solvent.
[0372] In another aspect, the present application provides process
for preparing a crystalline Form-Lambda of Selinexor, which
comprises: [0373] a) combining Selinexor with glycerol; [0374] b)
stirring the mixture of step a); [0375] c) isolating crystalline
Form-Lambda of Selinexor.
[0376] In an embodiment, Selinexor may be combined with glycerol at
any suitable temperatures, such as at about 0.degree. C. to about
the reflux temperature of the mixture. The mixture of Selinexor and
methanol may be prepared preferably at about 0.degree. C. to
60.degree. C.
[0377] In an embodiment the mixture of Selinexor and glycerol may
be either a heterogeneous or homogeneous phase.
[0378] In an embodiment, the mixture of Selinexor and glycerol may
be optionally filtered to make particle free solution, in case the
mixture forms a homogenous clear solution and may be treated with a
decolorizing agent, such as carbon, before filtration.
[0379] In an embodiment, Selinexor that may be used in step a) of
this aspect may be amorphous form of Selinexor.
[0380] In an embodiment, the mixture of Selinexor and glycerol at
step b) may be stirred for sufficient time to complete formation of
crystalline Form-Lambda of Selinexor. In an embodiment, the mixture
of Selinexor and glycerol may be stirred for at least 5 minutes or
more.
[0381] In an embodiment, the mixture of Selinexor and glycerol may
be stirred at suitable temperature for the formation of crystalline
Form-Lambda of Selinexor. In an embodiment, the mixture of
Selinexor and glycerol may be stirred at 0.degree. C. and above,
preferably between 0.degree. C. to reflux temperature of the
reaction mixture.
[0382] In an embodiment, isolation of crystalline Form-Lambda of
Selinexor may be carried out by any methods known in the art or
procedures described in the present application. In an embodiment,
crystalline Form-Lambda of Selinexor may be isolated by employing
any of the techniques, but not limited to: decantation, filtration
by gravity or suction, centrifugation, adding solvent to make
slurry followed by filtration, or other techniques specific to the
equipment used and the like, and optionally washing with a
solvent.
[0383] In an embodiment, isolated crystalline Form-Lambda of
Selinexor may be dried in a suitable drying equipment such as tray
dryer, vacuum oven, rotatory cone dryer, air oven, fluidized bed
dryer, spin flash dryer, flash dryer, or the like. The drying may
be carried out at atmospheric pressure or under reduced pressures
at temperatures of less than about 100.degree. C., less than about
60.degree. C., less than about 40.degree. C., or any other suitable
temperatures. Drying can be carried out at temperatures and times
sufficient to achieve desired quality of product. Drying may be
carried out for any time period required for obtaining a desired
quality, such as from about 15 minutes to 10 hours or longer.
[0384] In another aspect, the present application provides process
for preparing a crystalline Form-Mu of Selinexor, which comprises:
[0385] a) combining Selinexor with dimethyl formamide; [0386] b)
stirring the mixture of step a); [0387] c) isolating crystalline
Form-Mu of Selinexor.
[0388] In an embodiment, Selinexor may be combined with dimethyl
formamide at any suitable temperatures, such as at about 0.degree.
C. to about the reflux temperature of the reaction mixture. The
mixture of Selinexor and dimethyl formamide may be prepared
preferably at about 0.degree. C. to 60.degree. C.
[0389] In an embodiment the mixture of Selinexor and dimethyl
formamide may be either a heterogeneous or homogeneous phase.
[0390] In an embodiment, the mixture of Selinexor and dimethyl
formamide may be optionally filtered to make particle free
solution, in case the mixture forms a homogenous clear solution and
may be treated with a decolorizing agent, such as carbon, before
filtration.
[0391] In an embodiment, Selinexor that may be used in step a) of
this aspect may be amorphous or crystalline form of Selinexor.
[0392] In an embodiment, the mixture of Selinexor and dimethyl
formamide at step b) may be stirred for sufficient time to complete
formation of crystalline Form-Mu of Selinexor. In an embodiment,
the mixture of Selinexor and dimethyl formamide may be stirred for
at least 5 minutes or more.
[0393] In an embodiment, the mixture of Selinexor and dimethyl
formamide may be stirred at suitable temperature for the formation
of crystalline Form-Mu of Selinexor.
[0394] In an embodiment, the mixture of Selinexor and dimethyl
formamide may be stirred at 0.degree. C. and above, preferably
between 0.degree. C. to reflux temperature of the reaction
mixture.
[0395] In an embodiment, the mixture of Selinexor and dimethyl
formamide may be optionally evaporated either under atmospheric
pressure or reduced pressure. In an embodiment, the mixture of
Selinexor and dimethyl formamide may be subjected to slow solvent
evaporation.
[0396] In an embodiment, isolation of crystalline Form-Mu of
Selinexor may be carried out by any methods known in the art or
procedures described in the present application. In an embodiment,
crystalline Form-Mu of Selinexor may be isolated by employing any
of the techniques, but not limited to: decantation, filtration by
gravity or suction, centrifugation, adding solvent to make slurry
followed by filtration, or other techniques specific to the
equipment used and the like, and optionally washing with a
solvent.
[0397] In another aspect, the present application provides process
for preparing a crystalline Form-Nu of Selinexor, which comprises:
[0398] a) combining Selinexor with dimethyl acetamide; [0399] b)
stirring the mixture of step a); [0400] c) isolating crystalline
Form-Nu of Selinexor.
[0401] In an embodiment, Selinexor may be combined with dimethyl
acetamide at any suitable temperatures, such as at about 0.degree.
C. to about the reflux temperature of reaction mixture. The mixture
of Selinexor and dimethyl acetamide may be prepared preferably at
about 0.degree. C. to 60.degree. C.
[0402] In an embodiment the mixture of Selinexor and dimethyl
acetamide may be either a heterogeneous or homogeneous phase.
[0403] In an embodiment, the mixture of Selinexor and dimethyl
acetamide may be optionally filtered to make particle free
solution, in case the mixture forms a homogenous clear solution and
may be treated with a decolorizing agent, such as carbon, before
filtration.
[0404] In an embodiment, Selinexor that may be used in step a) of
this aspect may be amorphous or crystalline form of Selinexor.
[0405] In an embodiment, the mixture of Selinexor and dimethyl
acetamide at step b) may be stirred for sufficient time to complete
formation of crystalline Form-Nu of Selinexor. In an embodiment,
the mixture of Selinexor and dimethyl acetamide may be stirred for
at least 5 minutes or more.
[0406] In an embodiment, the mixture of Selinexor and dimethyl
acetamide may be stirred at suitable temperature for the formation
of crystalline Form-Nu of Selinexor. In an embodiment, the mixture
of Selinexor and dimethyl acetamide may be stirred at 0.degree. C.
and above, preferably between 0.degree. C. to reflux temperature of
reaction mixture.
[0407] In an embodiment, the mixture of Selinexor and dimethyl
formamide may be optionally evaporated either under atmospheric
pressure or reduced pressure. In an embodiment, the mixture of
Selinexor and dimethyl formamide may be subjected to slow solvent
evaporation.
[0408] In an embodiment, isolation of crystalline Form-Nu of
Selinexor may be carried out by any methods known in the art or
procedures described in the present application. In an embodiment,
crystalline Form-Nu of Selinexor may be isolated by employing any
of the techniques, but not limited to: decantation, filtration by
gravity or suction, centrifugation, adding solvent to make slurry
followed by filtration, or other techniques specific to the
equipment used and the like, and optionally washing with a
solvent.
[0409] In another aspect, the present application provides process
for preparing a crystalline Form-Xi of Selinexor, which comprises
the step of drying Form-kappa of Selinexor.
[0410] In an embodiment, drying Form-kappa of Selinexor may be
carried out in suitable drying equipment such as a tray drier
optionally under reduced pressure or other drying conditions known
in the art such as Buchi rotavapour vacuum drying, rotatory cone
vacuum drying; fluid bed drying optionally under nitrogen
atmosphere, thin film drying; or the like.
[0411] In an embodiment, drying Form-kappa of Selinexor may be
carried out at suitable temperatures of about 25.degree. C. and
above, optionally under reduced pressure.
[0412] In an embodiment, drying Form-kappa of Selinexor may be
carried out for sufficient time to complete its conversion to
Form-Xi of Selinexor. Drying can be carried out at temperatures and
times sufficient to achieve desired quality of product. Drying may
be carried out for any time period required for obtaining a desired
quality, such as from about 15 minutes to 1 hour or longer.
[0413] In another aspect, the present application provides process
for preparing a crystalline Form-Kappa of Selinexor, which
comprises: [0414] a) providing a solution of Selinexor in methanol
or a mixture thereof; [0415] b) contacting the solution of step a)
with water; [0416] c) isolating crystalline Form-Kappa of
Selinexor.
[0417] In an embodiment, Selinexor that may be used in step a) may
be any other crystalline or amorphous form. In an embodiment,
solution of step a) may be provided by combining Selinexor with
methanol or a mixture thereof, optionally heating the mixture to
obtain a homogeneous solution. The solution may be filtered to make
it particle free, after optionally treating with carbon.
[0418] Step b) of this aspect may be carried out by contacting the
solution of step a) with water. In an embodiment, the solution of
step a) may be contacted with water at a suitable temperature of
about 0.degree. C. and above. In an embodiment, the solution of
step a) may be optionally cooled either before or after contacting
it with water.
[0419] In an embodiment, either the solution of step a) may be
added to water or water may be added to it. The ratio of methanol
to water that may be used vary between about 1:1 and 1:50. In
embodiment, addition may be carried out at a suitable temperature
of about 0.degree. C. and above for sufficient time to nucleate and
stabilize crystalline form kappa.
[0420] In an embodiment, the mixture of step b) may be stirred for
sufficient time to obtain crystalline form kappa of Selinexor for
at least 5 minutes or more at about 0.degree. C. or above.
[0421] In an embodiment, isolation of crystalline Form-kappa of
Selinexor at step c) may be carried out by any methods known in the
art or procedures described in the present application. In an
embodiment, crystalline Form-kappa of Selinexor may be isolated by
employing any of the techniques, but not limited to: decantation,
filtration by gravity or suction, centrifugation, adding solvent to
make slurry followed by filtration, or other techniques specific to
the equipment used and the like, and optionally washing with a
solvent.
[0422] Selinexor that is used any of the aspects of present
application may be purified by any methods known in the art such as
column chromatography, fractional distillation, acid-base
treatment, slurring or re-crystallization, before using.
[0423] Selinexor that is used any of the aspects of present
application may be either in amorphous form or any other
crystalline form of Selinexor or by directly taking a synthetic
reaction mixture comprising Selinexor.
[0424] In embodiments, for the preparation of the crystalline from
of Selinexor selected from the group comprising Form-Alpha,
Form-Delta, Form-Epsilon, Form-Zeta, Form-Eta, Form-Theta,
Form-Iota, Form-Kappa, Form-Lambda, Form-Mu, Form-Nu and Form-Xi or
mixtures thereof, at least one additional solvent may be optionally
used, other than the solvent mentioned in their respective
aspects.
[0425] In another aspect, the present application provides a
process for the preparation of an amorphous form of Selinexor,
comprising the steps of: [0426] a) providing a solution of
Selinexor in a solvent or a mixture thereof; [0427] b) removing the
solvent from the solution obtained in step a); and [0428] c)
isolating the amorphous form of Selinexor. [0429] d) optionally
combining amorphous form of step c) with at least one
pharmaceutically acceptable excipient
[0430] In an embodiment, Selinexor that is used in step a) may be
purified by any methods known in the art such as column
chromatography, fractional distillation, acid-base treatment,
slurring or re-crystallization, before using.
[0431] In an embodiment, Selinexor that is used in step a) of this
aspect may be either a crystalline form of Selinexor or by directly
taking a synthetic reaction mixture comprising Selinexor and a
solvent or a mixture of solvents.
[0432] In an embodiment, solvent at step a) of this aspect may be
selected from C1-C6 alcohols, C3-C6 ketones, C5-C8 aliphatic or
aromatic hydrocarbons, C3-C6 esters, C2-C6 aliphatic or cyclic
ethers, C2-C6 nitriles, halogenated hydrocarbons, water or mixtures
thereof.
[0433] In preferred embodiment, the solvent may be selected from
the group comprising of alcohol solvents such as methanol, ethanol,
2-propanol, 1-butanol, 2-butanol, 1-pentanol, 2-pentanol,
3-pentanol; ketone solvents such as acetone, methyl ethyl ketone,
methyl isobutyl ketone; esters solvents such as methyl acetate,
ethyl acetate, isopropyl acetate; water and mixtures thereof.
[0434] In an embodiment, providing a solution at step a) may be
carried out by dissolving Selinexor in a solvent or by taking the
reaction mixture containing Selinexor directly. In an embodiment, a
solution of Selinexor can be prepared at any suitable temperatures,
such as about 0.degree. C. to about the reflux temperature of the
solvent used. Stirring and heating may be used to reduce the time
required for the dissolution process.
[0435] In an embodiment, a solution of Selinexor may be filtered to
make it clear, free of unwanted particles. In embodiments, the
obtained solution may be optionally treated with an adsorbent
material, such as carbon and/or hydrose, to remove colored
components, etc., before filtration.
[0436] In an embodiment, removal of solvent at step b) may be
carried out by methods known in the art or any procedure disclosed
in the present application. In preferred embodiments, removal of
solvent may include, but not limited to: solvent evaporation under
atmospheric pressure or reduced pressure/vacuum such as a
rotational distillation using Buchi.RTM. Rotavapor.RTM., spray
drying, freeze drying, thin film drying, agitated thin film drying
and the like.
[0437] In preferred embodiment, the solvent may be removed under
reduced pressures and at temperatures of less than about
100.degree. C., less than about 60.degree. C., less than about
40.degree. C., less than about 20.degree. C., less than about
0.degree. C., less than about -20.degree. C., less than about
-40.degree. C., less than about -60.degree. C., less than about
-80.degree. C., or any other suitable temperatures.
[0438] In an embodiment, the isolation of an amorphous form of
Selinexor at step c) involves recovering the solid obtained in step
b). The solid obtained from step b) may be recovered using
techniques such as by scraping, or by shaking the container, or
adding solvent to make slurry followed by filtration, or other
techniques specific to the equipment used. In an embodiment, the
amorphous form of Selinexor obtained from step b) may be optionally
dried before or after isolating it at step c).
[0439] Amorphous form of Selinexor obtained at step c) may be
optionally combined with at least one pharmaceutically acceptable
excipient at step d).
[0440] In an embodiment, amorphous form of Selinexor may be
combined with excipient using a technique known in art or by the
procedures disclosed in the present application.
[0441] In preferred embodiment, amorphous form of Selinexor may be
combined with excipient either by physical blending of both the
solid components or by suspending both the components in a suitable
solvent and conditions, such that both the components remain
unaffected. Blending may be carried out using techniques known in
art such as rotatory cone dryer, fluidized bed dryer or the like
optionally under reduced pressure/vacuum or inert atmosphere such
nitrogen at suitable temperature and sufficient time to obtain
uniform composition of amorphous form of Selinexor and at least one
pharmaceutically acceptable excipient.
[0442] In an embodiment, amorphous form of Selinexor may be
combined with the excipient by evaporating the suspension or
solution of amorphous form of Selinexor and at least one
pharmaceutically acceptable excipient.
[0443] In an embodiment, pharmaceutically acceptable excipient may
include, but not limited to an inorganic oxide such as SiO.sub.2,
TiO.sub.2, ZnO.sub.2, ZnO, Al.sub.2O.sub.3 and zeolite; a water
insoluble polymer is selected from the group consisting of
cross-linked polyvinyl pyrrolidinone, cross-linked cellulose
acetate phthalate, cross-linked hydroxypropyl methyl cellulose
acetate succinate, microcrystalline cellulose,
polyethylene/polyvinyl alcohol copolymer, polyethylene/polyvinyl
pyrrolidinone copolymer, cross-linked carboxymethyl cellulose,
sodium starch glycolat, and cross-linked styrene divinyl benzene or
any other excipient at any aspect of present application.
[0444] In preferred embodiment, pharmaceutically acceptable
excipient may be selected from the group consisting of silicon
dioxide, e.g. colloidal or fumed silicon dioxide or porous silica;
copolymers, such as polyethylene/polyvinyl alcohol copolymer,
polyethylene/polyvinyl pyrrolidinone copolymer; and cellulose,
preferably microcrystalline cellulose.
[0445] Amorphous form of Selinexor isolated at step c) or d) may be
dried in suitable drying equipment such as vacuum oven, rotatory
cone dryer, air oven, fluidized bed dryer, spin flash dryer, flash
dryer, or the like. The drying may be carried out at atmospheric
pressure or under reduced pressures at temperatures of less than
about 100.degree. C., less than about 60.degree. C., less than
about 40.degree. C., or any other suitable temperatures. The drying
may be carried out for any time period required for obtaining a
desired quality, such as from about 15 minutes to 10 hours or
longer.
[0446] In an aspect, the present application provides
pharmaceutical composition comprising amorphous form of Selinexor
and at least one pharmaceutically acceptable excipient.
[0447] In another aspect, the present application provides a
process for the preparation of an amorphous solid dispersion of
Selinexor, comprising the steps of: [0448] a) providing a solution
of Selinexor and at least one pharmaceutically acceptable excipient
in a solvent or a mixture thereof; [0449] b) removing the solvent
from the solution obtained in step a), and [0450] c) isolating the
amorphous solid dispersion of Selinexor. [0451] d) optionally
combining amorphous solid dispersion of step c) with at least one
additional pharmaceutically acceptable excipient.
[0452] In an embodiment, Selinexor that is used in step a) may be
purified by any methods known in the art such as column
chromatography, fractional distillation, acid-base treatment,
slurring or re-crystallization, before using.
[0453] In an embodiment, Selinexor that is used in step a) of this
aspect may be either a crystalline form of Selinexor or by directly
taking a synthetic reaction mixture comprising Selinexor and a
solvent or a mixture of solvents.
[0454] In an embodiment, solvent at step a) of this aspect may be
selected from C1-C6 alcohols, C3-C6 ketones, C5-C8 aliphatic or
aromatic hydrocarbons, C3-C6 esters, C2-C6 aliphatic or cyclic
ethers, C2-C6 nitriles, halogenated hydrocarbons, water or mixtures
thereof.
[0455] In preferred embodiment, the solvent may be selected from
the group consisting of alcohol solvents such as methanol, ethanol,
2-propanol, 1-butanol, 2-butanol, 1-pentanol, 2-pentanol,
3-pentanol; ketone solvents such as acetone, methyl ethyl ketone,
methyl isobutyl ketone; esters solvents such as methyl acetate,
ethyl acetate, isopropyl acetate; water and mixtures thereof.
[0456] In an embodiment, at least one pharmaceutically acceptable
excipient of this aspect may be selected from the group consisting
of polyvinyl pyrrolidone, povidone K-30, povidone K-60, Povidone
K-90, polyvinylpyrrolidone vinylacetate, co-povidone NF,
polyvinylacetal diethylaminoacetate (AEA.RTM.), polyvinyl acetate
phthalate, polysorbate 80, polyoxyethylene-polyoxypropylene
copolymers (Poloxamer.RTM. 188), polyoxyethylene (40) stearate,
polyethyene glycol monomethyl ether, polyethyene glycol, poloxamer
188, pluronic F-68, methylcellulose, methacrylic acid copolymer
(Eudragit), hydroxypropylmethyl cellulose phthalate,
hydroxypropylmethyl ellulose acetate succinate, hydroxypropyl
methyl ellulose, hydroxypropyl cellulose SL, hydroxyethyl
cellulose, gelucire 44/14, ethyl cellulose, D-alpha-tocopheryl
polyethylene glycol 1000 succinate, cellulose acetate phthalate,
carboxymethylethylcellulose and the like; cyclodextrins, gelatins,
hypromellose phthalates, sugars, polyhydric alcohols, and the like;
water soluble sugar excipients, preferably having low
hygroscopicity, which include, but are not limited to, mannitol,
lactose, fructose, sorbitol, xylitol, maltodextrin, dextrates,
dextrins, lactitol and the like; polyethylene oxides,
polyoxyethylene derivatives, polyvinyl alcohols, propylene glycol
derivatives and the like; organic amines such as alkyl amines
(primary, secondary, and tertiary), aromatic amines, alicyclic
amines, cyclic amines, aralkyl amines, hydroxylamine or its
derivatives, hydrazine or its derivatives, and guanidine or its
derivatives, or any other excipient at any aspect of present
application. The use of mixtures of more than one of the
pharmaceutical excipients to provide desired release profiles or
for the enhancement of stability is within the scope of this
invention. Also, all viscosity grades, molecular weights,
commercially available products, their copolymers, and mixtures are
all within the scope of this invention without limitation.
[0457] In an embodiment, providing a solution at step a) may be
carried out by dissolving Selinexor and at least one
pharmaceutically acceptable excipient in a solvent simultaneously
or by dissolving components in a solvent separately to form
individual solutions and combining those solutions later.
[0458] In an embodiment, a solution of Selinexor and the excipient
may be prepared at any suitable temperatures, such as about
0.degree. C. to about the reflux temperature of the solvent used.
Stirring and heating may be used to reduce the time required for
the dissolution process.
[0459] In an embodiment, a solution of Selinexor and the excipient
may be filtered to make it clear, free of unwanted particles. In
embodiments, the obtained solution may be optionally treated with
an adsorbent material, such as carbon and/or hydrose, to remove
colored components, etc., before filtration.
[0460] In an embodiment, removal of solvent at step b) may be
carried out by methods known in the art or any procedure disclosed
in the present application. In preferred embodiments, removal of
solvent may include, but not limited to: solvent evaporation under
atmospheric pressure or reduced pressure/vacuum such as a
rotational distillation using Buchi.RTM. Rotavapor.RTM., spray
drying, freeze drying, agitated thin film drying and the like.
[0461] In preferred embodiment, the solvent may be removed under
reduced pressures, at temperatures of less than about 100.degree.
C., less than about 60.degree. C., less than about 40.degree. C.,
less than about 20.degree. C., less than about 0.degree. C., less
than about -20.degree. C., less than about -40.degree. C., less
than about -60.degree. C., less than about -80.degree. C., or any
other suitable temperatures.
[0462] In an embodiment, the isolation of an amorphous solid
dispersion of Selinexor and excipient at step c) involves
recovering the solid obtained in step b). The solid obtained from
step b) may be recovered using techniques such as by scraping, or
by shaking the container, or adding solvent to make slurry followed
by filtration, or other techniques specific to the equipment
used.
[0463] In an embodiment, the amorphous solid dispersion of
Selinexor and excipient obtained from step b) may be optionally
dried before or after isolating at step c).
[0464] Amorphous solid dispersion of Selinexor obtained at step c)
may be optionally combined with at least one additional
pharmaceutically acceptable excipient at step d).
[0465] In an embodiment, amorphous solid dispersion of Selinexor
may be combined with additional excipient using a technique known
in art or by the procedures disclosed in the present
application.
[0466] In preferred embodiment, amorphous solid dispersion of the
present application may be combined with additional excipient
either by physical blending of both the solid components or by
suspending both the components in a solvent and conditions, such
that both the components remain unaffected. Blending may be carried
out using techniques known in art such as rotatory cone dryer,
fluidized bed dryer or the like optionally under reduced
pressure/vacuum or inert atmosphere such nitrogen at suitable
temperature and sufficient time to obtain uniform composition of
amorphous solid dispersion of Selinexor with pharmaceutically
acceptable excipient and at least one additional pharmaceutically
acceptable excipient.
[0467] In an embodiment, amorphous solid dispersion of the present
application may be combined with additional excipient by
evaporating the suspension or solution of amorphous solid
dispersion of Selinexor and additional excipient.
[0468] In an embodiment, pharmaceutically acceptable additional
excipient may be same or different from the excipient used in the
preparation of amorphous solid dispersion of Selinexor. Additional
excipient may include, but not limited to an inorganic oxide such
as SiO.sub.2, TiO.sub.2, ZnO.sub.2, ZnO, Al.sub.2O.sub.3 and
zeolite; a water insoluble polymer is selected from the group
consisting of cross-linked polyvinyl pyrrolidinone, cross-linked
cellulose acetate phthalate, cross-linked hydroxypropyl methyl
cellulose acetate succinate, microcrystalline cellulose,
polyethylene/polyvinyl alcohol copolymer, polyethylene/polyvinyl
pyrrolidinone copolymer, cross-linked carboxymethyl cellulose,
sodium starch glycolat, and cross-linked styrene divinyl benzene or
any other excipient at any aspect of present application.
[0469] In preferred embodiment, pharmaceutically acceptable
additional excipient may be selected from the group consisting of
silicon dioxide, e.g. colloidal or fumed silicon dioxide or porous
silica; copolymers, such as polyethylene/polyvinyl alcohol
copolymer, polyethylene/polyvinyl pyrrolidinone copolymer; and
cellulose, preferably microcrystalline cellulose.
[0470] Amorphous solid dispersion of Selinexor isolated at step c)
or d) may be dried in a suitable drying equipment such as tray
dryer, vacuum oven, rotatory cone dryer, air oven, fluidized bed
dryer, spin flash dryer, flash dryer, or the like. The drying may
be carried out at atmospheric pressure or under reduced pressures
at temperatures of less than about 100.degree. C., less than about
60.degree. C., less than about 40.degree. C., or any other suitable
temperatures. The drying may be carried out for any time period
required for obtaining a desired quality, such as from about 15
minutes to 10 hours or longer.
[0471] In an aspect, the present application provides
pharmaceutical composition comprising amorphous solid dispersion of
Selinexor with at least one pharmaceutically acceptable excipient
and at least one additional pharmaceutically acceptable
excipient.
[0472] In an aspect, the present application provides
pharmaceutical compositions comprising amorphous Selinexor and at
least one pharmaceutically acceptable excipient, in particular in
the form of solid dispersions and adsorbates, and a process for
preparing the same. In embodiments, the pharmaceutically acceptable
excipient is selected from the excipients at any aspect of present
application.
[0473] In embodiments, the present application provides adsorbates,
wherein Selinexor is associated with a substrate. Substrate may be
a particulate and/or porous substrate, wherein this substrate has
an outer and/or inner surface onto which the API may be adsorbed.
This means that if the substrate has pores, these pores are filled
by the Selinexor and the substrate remains unaffected, it does not,
at least not essentially, change during and/or after the
adsorption. In embodiments, the substrate is selected from the
excipients at any aspect of present application.
[0474] Amorphous form of Selinexor or its solid dispersion may be
obtained alternatively either by employing a melt-extrusion
technique or by combining a solution of Selinexor as obtained any
of the aspects of present application with a anti-solvent. In
embodiment, amorphous product may be obtained by employing suitable
melt-extrusion conditions or any of the procedures known in the art
for obtaining amorphous product by melt-extrusion technique. In
embodiment, solution of Selinexor may be combined with the
anti-solvent at suitable temperature and for sufficient time to
obtain amorphous product. Anti-solvent is a solvent, wherein
Selinexor has low solubility and it may include, but not limited to
aliphatic or cyclic ethers solvents, aliphatic or aromatic
hydrocarbons or the like.
[0475] In an aspect, the present application provides
pharmaceutical composition comprising Selinexor and at least one
pharmaceutically acceptable excipient, wherein Selinexor may be
selected from group comprising of crystalline Form-Alpha,
Form-Beta, Form-Gamma, Form-Delta, Form-Epsilon, Form-Zeta,
Form-Eta, Form-Theta, Form-Iota, Form-Kappa, Form-Lambda, Form-Mu,
Form-Nu and Form-Xi of Selinexor or mixtures thereof.
[0476] In another aspect, the present application provides
Selinexor or its pharmaceutical composition comprising Selinexor
having a chemical purity of at least 99% by HPLC or at least 99.5%
by HPLC or at least 99.9% by HPLC. In embodiment, Selinexor may be
selected from group comprising of crystalline Form-Alpha,
Form-Beta, Form-Gamma, Form-Delta, Form-Epsilon, Form-Zeta,
Form-Eta, Form-Theta, Form-Iota, Form-Kappa, Form-Lambda, Form-Mu,
Form-Nu, Form-Xi and amorphous form of Selinexor or mixtures
thereof.
[0477] In another aspect, the present application provides
Selinexor or its pharmaceutical composition comprising Selinexor
having particle size (D.sub.90) of less than 100 microns or less
than 50 microns or less than 20 microns. In embodiments, Selinexor
may be selected from group comprising of crystalline Form-Alpha,
Form-Beta, Form-Gamma, Form-Delta, Form-Epsilon, Form-Zeta,
Form-Eta, Form-Theta, Form-Iota, Form-Kappa, Form-Lambda, Form-Mu,
Form-Nu and amorphous form of Selinexor or mixtures thereof.
[0478] X-ray powder diffraction patterns described herein were
generated using a Bruker AXS D8 Advance powder X-ray diffractometer
or PANalytical X'pert pro X-ray diffractometer with a copper
K-alpha radiation source. Generally, a diffraction angle (2.theta.)
in powder X-ray diffractometry may have an error in the range of
.+-.0.2.degree.. Therefore, the aforementioned diffraction angle
values should be understood as including values in the range of
about .+-.0.2.degree.. Accordingly, the present invention includes
not only crystals whose peak diffraction angles in powder X-ray
diffractometry completely coincide with each other, but also
crystals whose peak diffraction angles coincide with each other
with an error of about .+-.0.2.degree.. Therefore, in the present
specification, the phrase "having a diffraction peak at a
diffraction angle (2.theta.).+-.0.2.degree. of 6.3.degree. " means
"having a diffraction peak at a diffraction angle (2.theta.) of
6.1.degree. to 6.5.degree.. Although the intensities of peaks in
the x-ray powder diffraction patterns of different batches of a
compound may vary slightly, the peak relationships and the peak
locations are characteristic for a specific polymorphic form. The
relative intensities of the PXRD peaks may vary somewhat, depending
on factors such as the sample preparation technique, crystal size
distribution, various filters used, the sample mounting procedure,
and the particular instrument employed. Moreover, instrumental
variation and other factors may slightly affect the 2-theta values.
Therefore, the term "substantially" in the context of PXRD is meant
to encompass that peak assignments may vary by plus or minus about
0.2.degree.. Moreover, new peaks may be observed or existing peaks
may disappear, depending on the type of the machine or the settings
(for example, whether a filter is used or not).
[0479] Certain specific aspects and embodiments of the present
application will be explained in greater detail with reference to
the following examples, which are provided only for purposes of
illustration and should not be construed as limiting the scope of
the application in any manner. Variations of the described
procedures, as will be apparent to those skilled in the art, are
intended to be within the scope of the present application.
Definitions
[0480] The term "about" when used in the present application
preceding a number and referring to it, is meant to designate any
value which lies within the range of .+-.10%, preferably within a
range of .+-.5%, more preferably within a range of .+-.2%, still
more preferably within a range of .+-.1% of its value. For example
"about 10" should be construed as meaning within the range of 9 to
11, preferably within the range of 9.5 to 10.5, more preferably
within the range of 9.8 to 10.2, and still more preferably within
the range of 9.9 to 10.1.
[0481] The term "solvent" when used in the present application is a
solvent that does not react with the reactants or reagent s under
conditions that cause the chemical reaction indicated to take
place.
[0482] The terms "crystalline form of Selinexor" or "crystalline
Selinexor" includes solvates, hydrates, and anhydrates of
Selinexor. The percent crystallinity of any of the crystalline
forms of Selinexor described herein can vary with respect to the
total amount of Selinexor. In particular, certain embodiments
provide for the percent crystallinity of a crystalline form of
Selinexor being at least 10%, at least 20%, at least 30%, at least
40%, at least 50%, at least, 60%, at least 70%, at least 80%, at
least 90%, at least 95%, or at least 99%. In some embodiments, the
percent crystallinity can be substantially 100%, where
substantially 100% indicates that the entire amount of Selinexor
appears to be crystalline as best can be determined using methods
known in the art.
[0483] The terms "amorphous form of Selinexor" and "amorphous
Selinexor" indicate that the Selinexor is present in substantially
amorphous state in the composition (e.g. solid dispersion,
adsorbate or pharmaceutical composition). "Substantially" amorphous
denotes that 90%, preferably 95% or 99%, more preferably all of the
Selinexor being present in the solid dispersion, on the adsorbate
or in the pharmaceutical composition is amorphous. In other words,
an "amorphous" Selinexor composition denotes a Selinexor-containing
composition, which does not contain substantial amounts, preferably
does not contain noticeable amounts, of crystalline portions of
Selinexor e.g. measurable upon X-ray powder diffraction
analysis.
[0484] The term "solid dispersion" when used in the present
application, denotes a state where most of the Selinexor,
preferably 90%, 95% or all of the Selinexor of the solid
dispersion, is homogeneously molecularly dispersed in a solid
polymer matrix. Preferably solid dispersion, relates to a molecular
dispersion where the API (active pharmaceutical ingredient) and
polymer molecules are uniformly but irregularly dispersed in a
non-ordered way. In other words, in a solid dispersion, the two
components (polymer and API) form a homogeneous one-phase system,
where the particle size of the API in the solid dispersion is
reduced to its molecular size. In a preferred embodiment, in the
solid dispersion according to the present invention no chemical
bonds can be detected between the API and the polymer. In order to
arrive at such a solid dispersion, preferably solid solution, it is
required to have a substantial amount of API dissolved in a solvent
at least at one time point during preparation of said solid
dispersion.
[0485] The term "adsorbate" when used in the present application,
specifies that the Selinexor is, preferably evenly, and preferably
homogeneously, distributed on the inner and/or outer surface of the
particulate substrate.
[0486] An "alcohol" is an organic compound containing a carbon
bound to a hydroxyl group. "C1-C6 alcohols" include, but are not
limited to, methanol, ethanol, 2-nitroethanol,2-fluoroethanol,
2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene
glycol, 1-propanol, 2-propanol (isopropyl alcohol),
2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl
alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol,
neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl
ether, diethylene glycol monoethyl ether, cyclohexanol, phenol,
glycerol, or the like.
[0487] An "aliphatic hydrocarbon" is a liquid hydrocarbon compound,
which may be linear, branched, or cyclic and may be saturated or
have as many as two double bonds. A liquid hydrocarbon compound
that contains a six-carbon group having three double bonds in a
ring is called "aromatic." Examples of "C5-C8aliphatic or aromatic
hydrocarbons" include, but are not limited to, n-pentane,
isopentane, neopentane, n-hexane, isohexane, 3-methylpentane,
2,3-dimethylbutane, neohexane, n-heptane, isoheptane,
3-methylhexane, neoheptane, 2,3-dimethylpentane,
2,4-dimethylpentane, 3,3-dimethylpentane, 3-ethylpentane,
2,2,3-trimethylbutane, n-octane, isooctane, 3-methylheptane,
neooctane, cyclohexane, methylcyclohexane, cycloheptane, benzene,
toluene, ethylbenzene, m-xylene, o-xylene, p-xylene,
trimethylbenzene, chlorobenzene, fluorobenzene, trifluorotoluene,
anisole, or any mixtures thereof.
[0488] An "ester" is an organic compound containing a carboxyl
group --(C.dbd.O)--O-- bonded to two other carbon atoms.
"C3-C6esters" include, but are not limited to, ethyl acetate,
n-propyl acetate, n-butyl acetate, isobutyl acetate, t-butyl
acetate, ethyl formate, methyl acetate, methyl propanoate, ethyl
propanoate, methyl butanoate, ethyl butanoate, or the like.
[0489] An "ether" is an organic compound containing an oxygen atom
--O-- bonded to two other carbon atoms. "C2-C6 ethers" include, but
are not limited to, diethyl ether, diisopropyl ether, methyl
t-butyl ether, glyme, diglyme, tetrahydrofuran,
2-methyltetrahydrofuran, 1,4-dioxane, dibutyl ether, dimethylfuran,
2-methoxyethanol, 2-ethoxyethanol, anisole, or the like.
[0490] A "halogenated hydrocarbon" is an organic compound
containing a carbon bound to a halogen. Halogenated hydrocarbons
include, but are not limited to, dichloromethane,
1,2-dichloroethane, trichloroethylene, perchloroethylene,
1,1,1-trichloroethane, 1,1,2-trichloroethane, chloroform, carbon
tetrachloride, or the like.
[0491] A "ketone" is an organic compound containing a carbonyl
group --(O.dbd.O)-- bonded to two other carbon atoms. "C3-C6
ketones" include, but are not limited to, acetone, ethyl methyl
ketone, diethyl ketone, methyl isobutyl ketone, ketones, or the
like.
[0492] A "nitrile" is an organic compound containing a cyano
--(C.ident.N) bonded to another carbon atom. "C2-C6Nitriles"
include, but are not limited to, acetonitrile, propionitrile,
butanenitrile, or the like.
EXAMPLES
Example-1: Preparation of Isopropyl
(Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylate
##STR00016##
[0494] 3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazole (250 g)
was dissolved in tetrahydrofuran (2 I) under nitrogen atmosphere at
27.degree. C. and cooled to -5.degree. C.
1,4-diazabicyclo[2.2.2]octane (DABCO, 199.5 g) was added to the
reaction mixture at -5.degree. C. and stirred at the same
temperature for 40 minutes. Isopropyl (Z)-3-iodoacrylate (234.8 g
in 500 mL of tetrahydrofuran) was added drop wise to the reaction
mixture in 1 hour 10 minutes at -5.degree. C. and stirred at the
same temperature for 2 hours. After the completion of the reaction,
the reaction mixture was added to ice cold water (2 I) and
separated the organic layer. The aqueous layer was extracted with
ethyl acetate (2.times.1 I). The combined organic layer was washed
with brine solution (1 I) and dried over sodium sulphate. The dried
solution was evaporated completely under vacuum at 40.degree. C. to
obtain crude product with HPLC purity of 93.53% The crude product
was triturated with hexane (700 mL) and stirred for 20 minutes at
-30.degree. C. and filtered the solid. Trituration of crude product
with hexane was repeated for three times and dried under vacuum to
obtain the title compound with HPLC purity of 97.46% and
trans-isomer content of 0.66%. Yield: 297 g
Example-2: Preparation of
(Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic
acid
##STR00017##
[0496] To a mixture of tetrahydrofuran (300 mL) and water (300 mL),
Isopropyl
(Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl-
)acrylate (30 g) was added and cooled to 0.degree. C. Lithium
hydroxide monohydrate (16.03 g) under cooling condition at
0.degree. C. was added to the reaction mixture and stirred the
reaction mixture at same temperature for 7 hours. After completion
of the reaction, 2 N HCl (180 mL) was added to adjust the pH of the
reaction mixture to 2 and extracted it with ethyl acetate (300 mL).
Organic layer was dried over sodium sulphate and evaporated under
vacuum at 40.degree. C. The crude compound was stirred with hexane
(150 mL) and filtered the solid. Dried the compound under vacuum at
40.degree. C. for 0.5 hour to obtain the title compound with HPLC
purity of 97.25% with trans-isomer content of 3%. Yield: 24 g
Example-3: Purification of
(Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic
acid
##STR00018##
[0498] A mixture of
(Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic
acid (24 g) and acetone (240 mL) was stirred for complete
dissolution at 30.degree. C. Dicyclohexyl amine (15 mL) was added
drop wise for 20 minutes under stirring at the same temperature.
Acetone (50 mL) was added to the reaction mixture and stirred for 2
hours at 27.degree. C. Filtered the solid and washed with hot
acetone (150 mL) and dried in vacuum drier at 30.degree. C. for 1
hour to obtain the Dicyclohexyl amine salt of
(Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic
acid. To the above salt, dichloromethane (150 mL) and water (100
mL) was added and stirred for complete dissolution at 30 and
adjusted the pH of the solution with 2 N sulphuric acid (100 mL) to
2. Filtered the reaction mixture and washed the product with water
(100 mL) and then with hexane (150 mL). The solid was dried under
vacuum at 40.degree. C. for 0.5 hour to obtain title compound with
HPLC purity 99.98% with no detectable content of trans-isomer.
Yield: 17 g
Example-4: Preparation of Selinexor
##STR00019##
[0500]
(Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acr-
ylic acid (10 g) was combined with a mixture of acetonitrile (100
mL) and ethyl acetate (50 mL) then added the 2-hydrazinylpyrazine
(3.76 g) and stirred for 5 min. Reaction mixture was cooled to
0.degree. C. and diisopropyl ethyl amine (16.63 ml) and then
Propylphosphonic anhydride (T.sub.3P, 33.31 mL) was added at
0.degree. C. and stirred the reaction mixture for 2.5 hours at the
same temperature. After completion of the reaction, the reaction
mixture was quenched with cold water (100 mL) and extracted the
product with ethyl acetate (2.times.150 mL). The combined organic
layer was dried over sodium sulphate and evaporated the solvent
under vacuum at 40.degree. C. to obtain the crude product as yellow
syrup. The obtained crude product was combined with dichloromethane
(100 mL) and filtered the solid and washed with dichloromethane
(2.times.50 mL). The solid was dried under vacuum at 40.degree. C.
to obtain the title compound with purity by HPLC of 99.86%. Yield:
7 g
Example-5: Preparation of Form-Alpha of Selinexor
[0501] A mixture of amorphous Selinexor (0.2) and 9:1 acetone:water
(1 mL) was stirred at 25.degree. C. for 54 hours and filtered the
solid and dried in air tray drier at 40.degree. C. for 1 hour 20
minutes to obtain the title compound.
Example-6: Preparation of Form-Beta of Selinexor
[0502] A mixture of amorphous Selinexor (0.2) and ethanol (1 mL)
was stirred at 25.degree. C. for 54 hours and filtered the solid
and dried in air tray drier at 40.degree. C. for 1 hour to obtain
the title compound.
Example-7: Preparation of Form-Gamma of Selinexor
[0503] A mixture of amorphous Selinexor (0.2) and water (1 mL) was
stirred at 25.degree. C. for 55 hours and filtered the solid and
dried in air tray drier at 40.degree. C. for 1 hour 10 minutes to
obtain the title compound.
Example-8: Preparation of Form-Delta of Selinexor
[0504] A mixture of amorphous Selinexor (500 mg) and methanol (1
mL) was stirred at 25.degree. C. for 45 minutes. Filtered the solid
and dried in air tray drier at 30.degree. C. for 1 hour to obtain
the title compound.
Example-9: Preparation of Form-Epsilon of Selinexor
[0505] A mixture of amorphous Selinexor (500 mg) and ethanol (1 mL)
was stirred at 25.degree. C. for 10 minutes. Filtered the solid and
dried in air tray drier at 30.degree. C. for 1 hour to obtain the
title compound.
Example-10: Preparation of Form-Zeta of Selinexor
[0506] A mixture of amorphous Selinexor (1 g), acetic acid (15 mL)
and water (25 mL) was stirred at 25.degree. C. for 4.5 hours.
Filtered the solid and dried in air tray drier at 30.degree. C. for
1 hour to obtain the title compound.
Example-11: Preparation of Form-Eta of Selinexor
[0507] A mixture of Selinexor (1 g) and nitromethane (25 mL) was
stirred at 25.degree. C. for 22 hours. Filtered the solid and dried
in air tray drier at 30.degree. C. for 1 hour to obtain the title
compound.
Example-12: Preparation of Form-Theta of Selinexor
[0508] Selinexor (1 g) was dissolved in formic acid (1 mL) at
25.degree. C. to obtain a clear solution. Methyl tert. Butyl ether
(25 mL) and hexane (30 mL) were added to the above solution at
25.degree. C. Stirred the reaction mixture for 23 hours at
25.degree. C. and the solid was filtered. The solid was dried in
air tray drier at 30.degree. C. for 1 hour to obtain the title
compound.
Example-13: Preparation of Form-Iota of Selinexor
[0509] A mixture of Selinexor (1 g) and nitromethane (35 mL) was
stirred at 25.degree. C. for 3 days. The solid was filtered and
dried in air tray drier at 40.degree. C. for 1 hour, 50.degree. C.
for 3 hours and 70.degree. C. for 3 hours to obtain the title
compound.
[0510] Alternate method: A mixture of Selinexor (1 g) and
nitromethane (25 mL) was stirred at 25.degree. C. for 18.5 hours.
Filtered the solid and dried in air tray drier at 70.degree. C. for
3 hour to obtain the title compound.
Example-14: Preparation of Form-Kappa of Selinexor
[0511] A mixture of amorphous Selinexor (1 g) and water (5 mL) was
stirred at 25.degree. C. for 30 minutes and filtered the solid to
obtain the title compound.
[0512] Alternate method: Selinexor (20 g) was dissolved in methanol
(200 mL) at 50.degree. C. and filtered the solution to make it
particle free. The clear solution was added in to chilled water
(1000 mL) at 8.degree. C. and stirred at the same temperature for
30 minutes. Water (300 mL) was added to the reaction mixture and
stirred for 15 minutes. The solid was filtered under nitrogen
atmosphere to obtain title compound. Yield: 16.5 g
Example-15: Preparation of Form-Lambda of Selinexor
[0513] A mixture of amorphous Selinexor (1 g) and glycerol (10 mL)
was stirred at 25.degree. C. for 30 minutes. The solid was filtered
and dried in air tray drier at 70.degree. C. for 6 hours to obtain
the title compound.
Example-16: Preparation of Form-Mu of Selinexor
[0514] Selinexor (500 mg) was dissolved in dimethyl formamide (2
mL) at 25.degree. C. and stirred the mixture for 24 hours at
25.degree. C. and the mixture was kept open at 25.degree. C. under
atmospheric pressure for slow solvent evaporation for 4 days. The
solid was filtered to obtain the title compound.
Example-17: Preparation of Form-Nu of Selinexor
[0515] Selinexor (500 mg) was dissolved in dimethyl formamide (2
mL) at 25.degree. C. and stirred the mixture for 24 hours at
25.degree. C. and the mixture was kept open at 25.degree. C. under
atmospheric pressure for slow solvent evaporation for 8 days. The
solid was filtered to obtain the title compound.
Example-18: Preparation of Form-Xi of Selinexor
[0516] A mixture of amorphous Selinexor (1 g) and water (5 mL) was
stirred at 25.degree. C. for 30 minutes. Water (5 ml) was added to
the mixture at 25.degree. C. and continued stirring at the same
temperature for 1 hour. The solid was filtered to obtain form-kappa
and dried in air tray drier at 30.degree. C. for 2.5 hours to
obtain title compound. Alternate method: A mixture of amorphous
Selinexor (500 mg) and a mixture of water (4.5 mL) and methanol
(0.5 mL) was stirred for 15 minutes at 25.degree. C. A mixture of
water (2.7 mL) and methanol (0.3 mL) was added to reaction mixture
at 25.degree. C. and stirred for 1.5 hours at the same temperature.
The solid was filtered to obtain form-kappa and dried in air tray
drier at 30.degree. C. for 3 hours to obtain title compound.
Example-19: Preparation of Amorphous Form of Selinexor
[0517] Selinexor (0.3 g) was dissolved in methanol (10 mL) at
50.degree. C. The clear solution was evaporated in a rotavapour at
60.degree. C. under vacuum to obtain the title compound. XRD:
Amorphous
Example-20: Preparation of Amorphous Form of Selinexor
[0518] Selinexor (0.3 g) was dissolved in acetone (10 mL) at
50.degree. C. The clear solution was evaporated in a rotavapour at
60.degree. C. under vacuum to obtain the title compound. XRD:
Amorphous
Example-21: Preparation of Amorphous Solid Dispersion of Selinexor
and Povidone
[0519] Selinexor (0.3 g) and povidone K-30 (0.3 g) was dissolved in
methanol (15 mL) at 60.degree. C. The clear solution was evaporated
in a rotavapour at 60.degree. C. under vacuum to obtain the
amorphous solid dispersion. Above obtained solid dispersion (150
mg) was combined with Syloid (75 mg) by gently grinding the mixture
in a mortar and pestle for 10 minutes. XRD: Amorphous
Example-22: Preparation of Amorphous Solid Dispersion of Selinexor
and HPMC Phthalate
[0520] Selinexor (0.3 g) and HPMC phthalate (0.3 g) was dissolved
in methanol (15 mL) at 60.degree. C. The clear solution was
evaporated in a rotavapour at 60.degree. C. under vacuum to obtain
the amorphous solid dispersion. Above obtained solid dispersion
(500 mg) was combined with Syloid (500 mg) by gently grinding the
mixture in a mortar and pestle for 10 minutes. XRD: Amorphous
Example-23: Preparation of Amorphous Form of Selinexor
[0521] Selinexor (1 g) was dissolved in methanol (30 mL) at
55.degree. C. and evaporated the solution under reduced pressure in
rotavapour at the same temperature to obtain amorphous Selinexor.
Amorphous Selinexor (0.7 g) was combined with Syloid (0.7 g) and
blended the mixture in rotavapour at 28.degree. C. for 30 minutes.
XRD: Amorphous
Example-24: Preparation of Amorphous Form of Selinexor
[0522] Selinexor (10 g) was dissolved in methanol (300 mL) at
25.degree. C. and evaporated the solution under reduced pressure in
rotavapour at the 50.degree. C. to obtain amorphous Selinexor and
dried the solid at 60.degree. C. for 10 minutes to obtain title
compound.
* * * * *