U.S. patent application number 16/742326 was filed with the patent office on 2020-05-21 for novel polymorphs of dolutegravir and salts thereof.
The applicant listed for this patent is Laurus Labs Limited. Invention is credited to Satyanarayana Chava, Rajesh Edupuganti, Venkata Sunil Kumar Indukuri, Srihari Raju Kalidindi, Ram THAIMATTAM.
Application Number | 20200157118 16/742326 |
Document ID | / |
Family ID | 58051103 |
Filed Date | 2020-05-21 |
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United States Patent
Application |
20200157118 |
Kind Code |
A1 |
THAIMATTAM; Ram ; et
al. |
May 21, 2020 |
NOVEL POLYMORPHS OF DOLUTEGRAVIR AND SALTS THEREOF
Abstract
The present invention relates to novel crystalline forms of
dolutegravir, process for its preparation and pharmaceutical
composition comprising them.
Inventors: |
THAIMATTAM; Ram; (Hyderabad,
IN) ; Edupuganti; Rajesh; (Hyderabad, IN) ;
Indukuri; Venkata Sunil Kumar; (Hyderabad, IN) ;
Kalidindi; Srihari Raju; (Hyderabad, IN) ; Chava;
Satyanarayana; (Hyderabad, IN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Laurus Labs Limited |
Hyderabad |
|
IN |
|
|
Family ID: |
58051103 |
Appl. No.: |
16/742326 |
Filed: |
January 14, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15750595 |
Feb 6, 2018 |
10597404 |
|
|
PCT/IB2016/054974 |
Aug 19, 2016 |
|
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16742326 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07B 2200/13 20130101;
A61K 31/5365 20130101; C07D 498/14 20130101; A61K 9/2018
20130101 |
International
Class: |
C07D 498/14 20060101
C07D498/14; A61K 31/5365 20060101 A61K031/5365 |
Foreign Application Data
Date |
Code |
Application Number |
Aug 19, 2015 |
IN |
4334/CHE/2015 |
Claims
1-29. (canceled)
30. Dolutegravir morpholine solvate.
31. Crystalline Form-I of dolutegravir morpholine solvate,
characterized by a powder X-Ray diffraction pattern having one or
more peaks at about 6.30, 7.28, 8.86, 9.90, 10.52, 11.44, 12.14,
13.76, 14.62, 15.04, 15.76, 16.50, 17.24, 18.00, 19.88, 20.76,
21.08, 22.48, 23.24, 23.84, 24.62, 25.04, 26.46, 26.94, 28.60,
29.58 and 32.14.+-.0.2.degree. 2.theta..
32. Crystalline Form-I of dolutegravir morpholine solvate of claim
31, further characterized by one or more of a powder X-Ray
diffraction (PXRD) pattern substantially in accordance with FIG.
13, a differential scanning calorimetry (DSC) substantially in
accordance with FIG. 14, and a thermo gravimetric analysis (TGA)
substantially in accordance with FIG. 15.
33. A process for preparation of crystalline Form-I of dolutegravir
morpholine solvate, which comprise of: a) dissolving dolutegravir
in a suitable chloro solvent; b) adding morpholine to step a)
solution; c) adding a suitable anti-solvent to step b) solution;
and d) isolating the dolutegravir crystalline Form-I.
34. The process of claim 33, wherein the suitable chloro solvent is
selected from methylene chloride, chloroform or mixtures thereof;
and the suitable anti-solvent is selected from diethylether,
diisopropylether, methyl tertiary butyl ether, ethyl tertiary butyl
ether or mixtures thereof.
35. The process of claim 33, wherein the solvent is methylene
chloride and the anti-solvent is methyl tertiary butyl ether.
36. (canceled)
37. Crystalline Form-II of dolutegravir morpholine solvate,
characterized by a powder X-Ray diffraction pattern having one or
more peaks at about 6.78, 8.80, 11.56, 13.76, 14.80, 16.64, 17.56,
18.48, 19.34, 19.66, 20.40, 20.80, 21.48, 21.90, 22.74, 23.38,
25.24, 25.72, 27.56, 28.44, 29.54, 30.48 and 31.88.+-.0.2.degree.
2.theta..
38. Crystalline Form-II of dolutegravir morpholine solvate of claim
37, further characterized by one or more of a powder X-Ray
diffraction (PXRD) pattern substantially in accordance with FIG.
16, a differential scanning calorimetry (DSC) substantially in
accordance with FIG. 17, and a thermo gravimetric analysis (TGA)
substantially in accordance with FIG. 18.
39. A process for the preparation of crystalline Form-II of
dolutegravir morpholine solvate, which comprise of a) dissolving
dolutegravir in morpholine; and b) isolating the dolutegravir
crystalline Form-II.
40-46. (canceled)
47. A pharmaceutical composition comprising: dolutegravir
morpholine solvate; and at least one pharmaceutically acceptable
excipient, wherein the dolutegravir morpholine solvate is one of
crystalline Form-I of dolutegravir morpholine solvate characterized
by a powder X-Ray diffraction pattern having one or more peaks at
about 6.30, 7.28, 8.86, 9.90, 10.52, 11.44, 12.14, 13.76, 14.62,
15.04, 15.76, 16.50, 17.24, 18.00, 19.88, 20.76, 21.08, 22.48,
23.24, 23.84, 24.62, 25.04, 26.46, 26.94, 28.60, 29.58 and
32.14.+-.0.2.degree. 2.theta., and crystalline Form-II of
dolutegravir morpholine solvate characterized by a powder X-Ray
diffraction pattern having one or more peaks at about 6.78, 8.80,
11.56, 13.76, 14.80, 16.64, 17.56, 18.48, 19.34, 19.66, 20.40,
20.80, 21.48, 21.90, 22.74, 23.38, 25.24, 25.72, 27.56, 28.44,
29.54, 30.48 and 31.88.+-.0.2.degree. 2.theta..
Description
PRIORITY
[0001] This application claims the benefit under Indian Provisional
Application No. 4334/CHE/2015 filed on Aug. 19, 2015, the content
of which is incorporated by reference herein.
FIELD OF THE INVENTION
[0002] The present invention relates to novel polymorphs of
dolutegravir and salts thereof, process for their preparation and
pharmaceutical composition comprising the same.
BACKGROUND OF THE INVENTION
[0003] Dolutegravir is chemically known as
(4R,12aS)-9-{[(2,4-difluorophenyl)methyl]carbamoyl}-4-methyl-6,8-dioxo-3,-
4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazino
[2,1-b][1,3]oxazin-7-olate and represented by the following
structural formula;
##STR00001##
[0004] Dolutegravir (DTG, GSK1349572) is an integrase inhibitor
being developed for the treatment of human immunodeficiency virus
(HIV)-1 infection. Sodium salt of dolutegravir was recently
approved by FDA and marketed under the brand name of TIVICAY by
ViiV Healthcare and manufactured by GlaxoSmithKline. TIVICAY is
administered orally as a tablet of 50 mg strength.
[0005] Tivicay is a human immunodeficiency virus type 1 (HIV-1)
integrase strand transfer inhibitor (INSTI) indicated in
combination with other antiretroviral agents for the treatment of
HIV-1 infection.
[0006] Dolutegravir and process for its preparation were first
described in U.S. Pat. No. 8,129,385. However this patent does not
discloses any characteristic details of dolutegravir or its salts
such as sodium.
[0007] WO2010068253 publication discloses anhydrous and monohydrate
crystalline form of dolutegravir sodium characterized by PXRD and
IR spectrum. Anhydrous dolutegravir sodium obtained by treating the
solution of dolutegravir in ethanol with aqueous sodium hydroxide
at 80.degree. C.; whereas the monohydrate form was obtained by
dissolving the anhydrous dolutegravir sodium in THF-water followed
by treatment with aqueous sodium hydroxide. This publication
further discloses the crystalline form of dolutegravir free acid
along with its PXRD.
[0008] WO 2013038407 publication discloses amorphous form of
dolutegravir sodium, process for its preparation and pharmaceutical
composition comprising the same.
[0009] IP.com journal, ID No. IPCOM000238311D discloses the
crystalline form of dolutegravir sodium characterized by PXRD,
which is obtained by treating dolutegravir in tetrahydrofuran with
aqueous sodium hydroxide at reflux temperature.
[0010] WO2015092752 publication discloses crystalline Form-M1 of
dolutegravir sodium and process for its preparation.
[0011] WO2015118460 publication discloses crystalline Form-M2.
Form-M3 and Form-M4 of dolutegravir sodium and process for their
preparation.
[0012] WO2015138933 publication discloses crystalline Form-II,
Form-III, Form-IV, Form-V, Form-VI, Form-VII, Form-VIII, Form-IX,
Form-X and Form-XI of dolutegravir sodium, process for their
preparation, pharmaceutical composition comprising them and uses
thereof.
[0013] WO2015139591 publication discloses polymorphic Form-A,
Form-B, Form-C, Form-D and Form-E of dolutegravir sodium and
pharmaceutical composition comprising them.
[0014] WO2016016279 publication discloses crystalline Form-HxA,
Form-Hy1B and Form-S.sub.ETOH,H2O of dolutegravir sodium, process
for their preparation and pharmaceutical composition comprising
them.
[0015] WO2016102078 publication discloses crystalline form of
dolutegravir sodium 1,2-propylene glycol solvate, process for its
preparation and pharmaceutical composition comprising the same.
[0016] Our co-pending IN application number 3105/CHE/2015 discloses
crystalline form of dolutegravir sodium designated as Form-L1,
Form-L2, Form-L3, Form-L4, Form-L5, Form-L6, Form-L7 and Form-L8,
amorphous form of dolutegravir, solid dispersion of dolutegravir
sodium with one or more pharmaceutically acceptable excipient and
crystalline benzyltrimethyl ammonium salt of dolutegravir.
[0017] Polymorphism is the occurrence of different crystalline
forms of a single compound and it is a property of some compounds
and complexes. Thus, polymorphs are distinct solids sharing the
same molecular formula, yet each polymorph may have distinct
physical properties. Therefore, a single compound may give rise to
a variety of polymorphic forms where each form has different and
distinct physical properties, such as different solubility
profiles, different melting point temperatures and/or different
x-ray diffraction peaks. Since the solubility of each polymorph may
vary, identifying the existence of pharmaceutical polymorphs is
essential for providing pharmaceuticals with predictable solubility
profiles. It is desirable to investigate all solid state forms of a
drug, including all polymorphic forms and solvates, and to
determine the stability, dissolution and flow properties of each
polymorphic form.
[0018] Dolutegravir is one of the important drugs available in the
market for the treatment of human immunodeficiency virus (HIV)-1
infection. Hence it's important to discover new polymorphic forms
of dolutegravir and its salt, which may provide a new opportunity
to improve the performance characteristics of a pharmaceutical
product. Hence the main object of the present invention is to
provide novel polymorphic forms of dolutegravir and salts thereof,
especially sodium.
SUMMARY OF THE INVENTION
[0019] The present invention provides novel polymorphic forms of
dolutegravir and salts thereof, especially sodium, process for
their preparation and pharmaceutical compositions comprising one or
more of the novel polymorphic forms of dolutegravir and its salts.
The polymorphic forms of dolutegravir sodium of the present
invention have advantageous properties selected from at least one
of: chemical purity, flowability, solubility, morphology or crystal
habit, stability--such as storage stability, stability to
dehydration, and stability to polymorphic conversion, low
hygroscopicity, and low content of residual solvents.
[0020] In one embodiment, the present invention provides novel
polymorphic forms of dolutegravir sodium; which are designated
herein as dolutegravir sodium Form-L9, dolutegravir sodium
Form-L10, dolutegravir sodium Form-L11 and dolutegravir sodium
Form-L12.
[0021] In another embodiment the present invention provides a
process for the preparation of novel polymorphic forms of
dolutegravir sodium Form-L9, Form-L10, Form-L11 and Form-L12 and
other crystalline forms of dolutegravir sodium.
[0022] In another embodiment, the present invention provides novel
solvates of dolutegravir such as morpholine solvate and
1-amino-2-propanol solvate.
[0023] In another embodiment, the present invention provides
polymorphic forms of morpholine and 1-amino-2-propanol solvate of
dolutegravir as well as process for their preparation.
[0024] In another embodiment, the present invention provides a
pharmaceutical composition comprising the novel polymorphic forms
of dolutegravir and salts thereof described above and at least one
pharmaceutically acceptable excipient.
BRIEF DESCRIPTION OF THE DRAWINGS
[0025] The accompanying drawings, which are incorporated in and
constitute a part of this specification, illustrate several
embodiments of the invention and together with the description,
serve to explain the principles of the invention.
[0026] FIG. 1 is the characteristic powder X-ray diffraction (XRD)
pattern of dolutegravir sodium Form-L9.
[0027] FIG. 2 is the characteristic differential scanning
calorimetric (DSC) thermogram of dolutegravir sodium Form-L9.
[0028] FIG. 3 is the characteristic thermo gravimetric analysis
(TGA) of dolutegravir sodium Form-L9.
[0029] FIG. 4 is the characteristic powder X-ray diffraction (XRD)
pattern of dolutegravir sodium Form-L10.
[0030] FIG. 5 is the characteristic differential scanning
calorimetric (DSC) thermogram of dolutegravir sodium Form-L10.
[0031] FIG. 6 is the characteristic thermo gravimetric analysis
(TGA) of dolutegravir sodium Form-L10.
[0032] FIG. 7 is the characteristic powder X-ray diffraction (XRD)
pattern of dolutegravir sodium Form-L11.
[0033] FIG. 8 is the characteristic differential scanning
calorimetric (DSC) thermogram of dolutegravir sodium Form-L11.
[0034] FIG. 9 is the characteristic thermo gravimetric analysis
(TGA) of dolutegravir sodium Form-L11.
[0035] FIG. 10 is the characteristic powder X-ray diffraction (XRD)
pattern of dolutegravir sodium Form-L12.
[0036] FIG. 11 is the characteristic differential scanning
calorimetric (DSC) thermogram of dolutegravir sodium Form-L12.
[0037] FIG. 12 is the characteristic thermo gravimetric analysis
(TGA) of dolutegravir sodium Form-L12.
[0038] FIG. 13 is the characteristic powder X-ray diffraction (XRD)
pattern of crystalline Form-I of dolutegravir morpholine
solvate.
[0039] FIG. 14 is the characteristic differential scanning
calorimetric (DSC) thermogram of crystalline Form-I of dolutegravir
morpholine solvate.
[0040] FIG. 15 is the characteristic thermo gravimetric analysis
(TGA) of crystalline Form-I of dolutegravir morpholine solvate.
[0041] FIG. 16 is the characteristic powder X-ray diffraction (XRD)
pattern of crystalline Form-II of dolutegravir morpholine
solvate.
[0042] FIG. 17 is the characteristic differential scanning
calorimetric (DSC) thermogram of crystalline Form-II of
dolutegravir morpholine solvate.
[0043] FIG. 18 is the characteristic thermo gravimetric analysis
(TGA) of crystalline Form-II of dolutegravir morpholine
solvate.
[0044] FIG. 19 is the characteristic powder X-ray diffraction (XRD)
pattern of crystalline form of dolutegravir 1-amino-2-propanol
solvate.
[0045] FIG. 20 is the characteristic differential scanning
calorimetric (DSC) thermogram of crystalline form of dolutegravir
1-amino-2-propanol solvate.
[0046] FIG. 21 is the characteristic thermo gravimetric analysis
(TGA) of crystalline form of dolutegravir 1-amino-2-propanol
solvate.
[0047] FIG. 22 is the characteristic powder X-ray diffraction (XRD)
pattern of crystalline dolutegravir sodium obtained as per
example-10.
[0048] FIG. 23 is the characteristic powder X-ray diffraction (XRD)
pattern of crystalline dolutegravir sodium obtained as per
example-11.
[0049] FIG. 24a shows overlaid powder X-ray diffraction (XRD)
pattern of dolutegravir sodium Form-L9 under thermal study.
[0050] FIG. 24b shows overlaid differential scanning calorimetric
(DSC) thermogram of dolutegravir sodium Form-L9 under thermal
study.
[0051] FIG. 25 shows overlaid powder X-ray diffraction (XRD)
pattern of dolutegravir sodium Form-L9 subjected to hygroscopic
study at 85% RH.
DETAILED DESCRIPTION OF THE INVENTION
[0052] The present invention provides novel polymorphic forms of
dolutegravir and salts thereof, process for their preparation and
pharmaceutical compositions comprising one or more of such
polymorphic forms.
[0053] The polymorphic forms of dolutegravir sodium and
dolutegravir of the present invention are characterized by one or
more analytical methods such as X-ray powder diffraction (XRPD)
patterns, Differential scanning calorimetry (DSC) and Thermo
gravimetric analysis (TGA).
[0054] In one embodiment, the present invention provides novel
polymorphic forms of dolutegravir sodium, which are designated as
dolutegravir sodium Form-L9, dolutegravir sodium Form-L10,
dolutegravir sodium Form-L11 and dolutegravir sodium Form-L12.
[0055] In another embodiment, the present invention provides
dolutegravir sodium Form-L9.
[0056] In another embodiment, the present invention provides
dolutegravir sodium Form-L9, characterized by a powder X-Ray
diffraction (PXRD) pattern substantially in 30 accordance with FIG.
1.
[0057] In another embodiment, the present invention provides
dolutegravir sodium Form-L9 characterized by a powder X-Ray
diffraction pattern having one or more peaks at about 6.1, 8.6,
12.1, 13.4, 17.1, 18.6, 19.3, 22.4, 23.8, 25.4 and 26.3+0.2.degree.
2.theta..
[0058] In another embodiment, the present invention provides
dolutegravir sodium Form-L9, characterized by a differential
scanning calorimetry (DSC) substantially in accordance with FIG.
2.
[0059] In another embodiment, the present invention provides
dolutegravir sodium Form-L9, characterized by a thermo gravimetric
analysis (TGA) substantially in accordance with FIG. 3.
[0060] In another embodiment, the present invention provides
dolutegravir sodium Form-L9, characterized by a powder X-Ray
diffraction (PXRD) pattern substantially in accordance with FIG. 1,
a differential scanning calorimetry (DSC) substantially in
accordance with FIG. 2, and/or a thermo gravimetric analysis (TGA)
substantially in accordance with FIG. 3.
[0061] In another embodiment, the present invention provides a
process for preparation of dolutegravir sodium Form-L9, which
comprise of de-solvating dolutegravir sodium 1-pentanol solvate
(Form-L12, characterized by a powder X-Ray diffraction pattern
having one or more peaks at about 5.32, 7.50, 9.16, 11.46, 12.98,
13.72, 15.02, 15.84, 16.42, 18.60, 19.58, 20.08, 20.50, 21.00,
21.98, 23.06, 23.90, 24.46, 25.78, 26.28, 27.18 and
28.36.+-.0.2.degree. 2.theta.) by heating at a suitable temperature
of about 110.degree. C. to about 135.degree. C., preferably at
about 120.degree. C. to about 125.degree. C. for a sufficient
period of time, preferably for 4 hrs to 12 hrs under vacuum to
provide dolutegravir sodium Form-L9.
[0062] In another embodiment, the present invention provides a
process for the preparation of Form-L9, which comprise of [0063] a)
suspending or mixing dolutegravir in 1-pentanol, [0064] b) adding
sodium hydroxide to step a) at a suitable temperature, [0065] c)
stirring the reaction mass at a suitable temperature, [0066] d)
isolating the dolutegravir sodium and drying the wet solid at a
suitable temperature, and [0067] e) exposing the dried compound
under atmosphere air or humid air to obtain dolutegravir sodium
Form-L9.
[0068] In step a) of the aforementioned process involves suspending
or mixing dolutegravir in 1-pentanol. The step of suspending or
mixing dolutegravir in 1-pentanol can be carried out by adding
dolutegravir to 1-pentanol at a suitable temperature of about
25.degree. C. to about 45.degree. C., preferably at about
25.degree. C. to about 35.degree. C. Then, sodium hydroxide is
added to form dolutegravir sodium salt. The addition of sodium
hydroxide is carried out at a temperature of about 25.degree. C. to
about 45.degree. C., preferably at about 25.degree. C. to about
35.degree. C. The sodium hydroxide may be taken as in the form of
solid or as an aqueous solution or as a solvent containing
solution; preferably aqueous sodium hydroxide solution is used.
[0069] The step c) of stirring the reaction mass is carried out for
a sufficient period of time at about 25.degree. C. to about
45.degree. C. Then, the precipitated solid dolutegravir sodium can
be separated by filtration. The obtained solid dolutegravir sodium
may be dried at about 25.degree. C. to about 120.degree. C. for
sufficient period of time under atmospheric pressure or under
reduced pressure, until traces of 1-pentanol solvent substantially
removed. For example, the wet dolutegravir sodium can be dried
initially at 25-35.degree. C., further at 50-55.degree. C. and
finally at 100-110.degree. C. under vacuum.
[0070] The step e) of exposing dolutegravir sodium of step d) under
atmosphere air or humid air can be carried out by keeping the
compound in atmospheric air chambers or in a humidity chambers at a
temperature of about 25.degree. C. to about 35.degree. C. for a
sufficient period of about 2 hrs to 36 hrs, preferably for about 4
hrs to 16 hrs, more preferably for about 6 hrs to obtain
dolutegravir sodium Form-L9.
[0071] In another embodiment, the present invention provides
dolutegravir sodium Form-L10.
[0072] In another embodiment, the dolutegravir sodium Form-L10 of
the present invention is an isopentanol solvate.
[0073] In another embodiment, the present invention provides
dolutegravir sodium Form-L10, characterized by a powder X-Ray
diffraction (PXRD) pattern substantially in accordance with FIG.
4.
[0074] In another embodiment, the present invention provides
dolutegravir sodium Form-L10 characterized by a powder X-Ray
diffraction pattern having one or more peaks at about 5.94, 6.30,
7.22, 8.10, 10.58, 12.20, 13.08, 14.12, 15.74, 16.48, 17.88, 18.40,
19.74, 21.72, 23.40, 24.72, 25.24, 26.44, 27.02, 28.60 and
29.54.+-.0.2.degree. 2.theta..
[0075] In another embodiment, the present invention provides
dolutegravir sodium Form-L10, characterized by a differential
scanning calorimetry (DSC) substantially in accordance with FIG.
5.
[0076] In another embodiment, the present invention provides
dolutegravir sodium Form-L10, characterized by a thermo gravimetric
analysis (TGA) substantially in accordance with FIG. 6.
[0077] In another embodiment, the present invention provides
dolutegravir sodium Form-L10, characterized by a powder X-Ray
diffraction (PXRD) pattern substantially in accordance with FIG. 4,
a differential scanning calorimetry (DSC) substantially in
accordance with FIG. 5 and/or a thermo gravimetric analysis (TGA)
substantially in accordance with FIG. 6.
[0078] In another embodiment, the present invention provides a
process for preparation of dolutegravir sodium Form-L10, which
comprise of [0079] a) suspending or mixing dolutegravir in
isopentanol or its aqueous solution, [0080] b) adding sodium
hydroxide to step a) at a suitable temperature, and [0081] c)
isolating the dolutegravir sodium Form-L10.
[0082] In the aforementioned process of dolutegravir sodium
Form-L10, suspending or mixing dolutegravir in isopentanol or its
aqueous solution, preferably in aqueous isopentanol is carried out
at a suitable temperature of about 25.degree. C. to about
45.degree. C., preferably at about 25.degree. C. to about
35.degree. C. Addition of sodium hydroxide of step b) can be used
directly as a solid or as aqueous solution; preferably as an
aqueous solution and added to step a) suspension at a suitable
temperature of about 25.degree. C. to about 45.degree. C.,
preferably at about 25.degree. C. to about 35.degree. C. and
stirred for a sufficient period of time, preferably for 2 hrs to 10
hrs. Then the isolation of dolutegravir sodium Form-L10 from the
reaction mass can be carried out by any conventional techniques
known in the art, for example filtration and followed by
drying.
[0083] In another embodiment, the present invention provides
dolutegravir sodium Form-L11.
[0084] In another embodiment, dolutegravir sodium Form-L11 of the
present invention may be an isobutanol solvate.
[0085] In another embodiment, the present invention provides
dolutegravir sodium Form-L11, characterized by a powder X-Ray
diffraction (PXRD) pattern substantially in accordance with FIG.
7.
[0086] In another embodiment, the present invention provides
dolutegravir sodium Form-L11, characterized by a powder X-Ray
diffraction pattern having one or more peaks at about 6.08, 6.92,
11.20, 12.48, 14.00, 16.04, 18.24, 19.08, 20.20, 20.90, 22.12,
22.70, 22.96, 23.54, 24.08, 25.84, 26.92, 29.84 and
31.68.+-.0.2.degree. 2.theta..
[0087] In another embodiment, the present invention provides
dolutegravir sodium Form-L11, characterized by a differential
scanning calorimetry (DSC) substantially in accordance with FIG.
8.
[0088] In another embodiment, the present invention provides
dolutegravir sodium Form-L11, characterized by a thermo gravimetric
analysis (TGA) substantially in accordance with FIG. 9.
[0089] In another embodiment, the present invention provides
dolutegravir sodium Form-L11, characterized by a powder X-Ray
diffraction (PXRD) pattern substantially in accordance with FIG. 7,
a differential scanning calorimetry (DSC) substantially in
accordance with FIG. 8 and/or a thermo gravimetric analysis (TGA)
substantially in accordance with FIG. 9.
[0090] In another embodiment, the present invention provides a
process for preparation of dolutegravir sodium Form-L11, which
comprise of [0091] a) suspending or mixing dolutegravir in
isobutanol or its aqueous solution, [0092] b) adding sodium
hydroxide to step a) at a suitable temperature, [0093] c)
optionally heating the suspension, and [0094] d) isolating
dolutegravir sodium Form-L11.
[0095] In the aforementioned process of dolutegravir sodium
Form-L11, suspending or mixing dolutegravir in isobutanol or its
aqueous solution, preferably in isobutanol can be carried out at a
suitable temperature of about 25.degree. C. to about 45.degree. C.,
preferably at about 25.degree. C. to about 35.degree. C. In step b)
sodium hydroxide can be used directly as a solid or as aqueous
solution, preferably as aqueous sodium hydroxide solution and added
to step a) suspension at a suitable temperature of about 25.degree.
C. to about 45.degree. C., preferably at about 25.degree. C. to
about 35.degree. C. and stirred for a sufficient period of time,
preferably for 2 hrs to 20 hrs. Then the isolation of dolutegravir
sodium Form-L11 from the reaction mass can be carried out by any
conventional techniques known in the art, for example filtration
and followed by drying.
[0096] In forgoing process, if heating the suspension in step c) is
involved, then the reaction mass is heated to about 40.degree. C.
to about 70.degree. C., preferably about 60.degree. C. to about
65.degree. C. and stirred for a sufficient period of time,
preferably for 30 mins to 4 hrs. Then isolation of dolutegravir
sodium Form-L11 can be carried out by any conventional techniques
known in the art, for example cooling the reaction mass to about
25.degree. C. to about 35.degree. C., stirring followed by
filtration and drying.
[0097] In another embodiment, the present invention provides
dolutegravir sodium Form-L12.
[0098] In another embodiment, dolutegravir sodium Form-L12 of the
present invention is a 1-pentanol solvate.
[0099] In another embodiment, the present invention provides
dolutegravir sodium Form-L12, characterized by a powder X-Ray
diffraction (PXRD) pattern substantially in accordance with FIG.
10.
[0100] In another embodiment, the present invention provides
dolutegravir sodium Form-L12 characterized by a powder X-Ray
diffraction pattern having one or more peaks at about 5.32, 7.50,
9.16, 11.46, 12.98, 13.72, 15.02, 15.84, 16.42, 18.60, 19.58,
20.08, 20.50, 21.00, 21.98, 23.06, 23.90, 24.46, 25.78, 26.28,
27.18 and 28.36.+-.0.2.degree. 2.theta..
[0101] In another embodiment, the present invention provides
dolutegravir sodium Form-L12, characterized by a differential
scanning calorimetry (DSC) substantially in accordance with FIG.
11.
[0102] In another embodiment, the present invention provides
dolutegravir sodium Form-L12, characterized by a thermo gravimetric
analysis (TGA) substantially in accordance with FIG. 12.
[0103] In another embodiment, the present invention provides
dolutegravir sodium Form-L12, characterized by a powder X-Ray
diffraction (PXRD) pattern substantially in accordance with FIG.
10, a differential scanning calorimetry (DSC) substantially in
accordance with FIG. 11 and/or a thermo gravimetric analysis (TGA)
substantially in accordance with FIG. 12.
[0104] In another embodiment, the present invention provides a
process for preparation of dolutegravir sodium Form-L12, which
comprise of [0105] a) suspending or mixing dolutegravir in
1-pentanol or its aqueous solution, [0106] b) adding sodium
hydroxide to step a) at a suitable temperature, and [0107] c)
isolating dolutegravir sodium Form-L12.
[0108] In the aforementioned process of dolutegravir sodium
Form-L12, suspending or mixing dolutegravir in 1-pentanol or its
aqueous solution can be carried out at a suitable temperature of
about 25.degree. C. to about 45.degree. C., preferably at about
25.degree. C. to about 35.degree. C. In step b) sodium hydroxide
can be used directly as a solid or as aqueous solution; preferably
as aqueous solution and added to step a) suspension at a suitable
temperature of about 25.degree. C. to about 45.degree. C.,
preferably at about 25.degree. C. to about 35.degree. C. and
stirred for a sufficient period of time, preferably for 2 hrs to 10
hrs. Then the isolation of dolutegravir sodium Form-L12 from the
reaction mass can be carried out by any conventional techniques
known in the art, for example filtration and followed by
drying.
[0109] In another embodiment, the present invention provides a
process for preparation of crystalline dolutegravir sodium
characterized by a powder X-Ray diffraction pattern having one or
more peaks at about 5.98, 7.76, 8.52, 12.88, 14.88, 15.90, 16.84,
18.26, 19.20, 20.40, 20.86, 21.80, 23.44, 26.24, 27.72 and
30.16.+-.0.2.degree. 2.theta. or characterized by a powder X-Ray
diffraction (PXRD) pattern substantially in accordance with FIG.
22, which comprise of: de-solvating dolutegravir sodium isopentanol
solvate (Form-L10, characterized by a powder X-Ray diffraction
pattern having one or more peaks at about 5.94, 6.30, 7.22, 8.10,
10.58, 12.20, 13.08, 14.12, 15.74, 16.48, 17.88, 18.40, 19.74,
21.72, 23.40, 24.72, 25.24, 26.44, 27.02, 28.60 and
29.54.+-.0.2.degree. 2.theta.) by heating at a suitable temperature
of about 110.degree. C. to about 135.degree. C., preferably at
about 120.degree. C. to about 125.degree. C. for a sufficient
period of time, preferably for 4 hrs to 12 hrs under vacuum.
[0110] In another embodiment, the present invention provides a
process for preparation of crystalline dolutegravir sodium
characterized by a powder X-Ray diffraction pattern having one or
more peaks at about 6.2, 7.94, 12.66, 14.18, 15.46, 16.42, 18.26,
19.02, 20.92, 21.52, 22.18, 23.92, 24.68, 27.4, 28.28 and
30.68.+-.0.2.degree. 2.theta. or characterized by a powder X-Ray
diffraction (PXRD) pattern substantially in accordance with FIG.
23, which comprise of de-solvating dolutegravir sodium isobutanol
solvate (Form-L11, characterized by a powder X-Ray diffraction
pattern having one or more peaks at about 6.08, 6.92, 11.20, 12.48,
14.00, 16.04, 18.24, 19.08, 20.20, 20.90, 22.12, 22.70, 22.96,
23.54, 24.08, 25.84, 26.92, 29.84 and 31.68.+-.0.2.degree.
2.theta.) by heating at a suitable temperature of about 110.degree.
C. to about 135.degree. C., preferably at about 120.degree. C. to
about 125.degree. C. for a sufficient period of time, preferably
for 4 hrs to 12 hrs under vacuum.
[0111] In another embodiment, the present invention provides novel
solvates of dolutegravir and their polymorphic forms.
[0112] In another embodiment, the present invention provides
morpholine solvate of dolutegravir.
[0113] In another embodiment, the present invention provides
morpholine solvate of dolutegravir in crystalline form.
[0114] In another embodiment, the present invention provides
crystalline Form-I of dolutegravir morpholine solvate.
[0115] In another embodiment, the present invention provides
crystalline Form-I of dolutegravir morpholine solvate,
characterized by a powder X-Ray diffraction (PXRD) pattern
substantially in accordance with FIG. 13.
[0116] In another embodiment, the present invention provides
crystalline Form-I of dolutegravir morpholine solvate,
characterized by a powder X-Ray diffraction pattern having one or
more peaks at about 6.30, 7.28, 8.86, 9.90, 10.52, 11.44, 12.14,
13.76, 14.62, 15.04, 15.76, 16.50, 17.24, 18.00, 19.88, 20.76,
21.08, 22.48, 23.24, 23.84, 24.62, 25.04, 26.46, 26.94, 28.60,
29.58 and 32.14.+-.0.2.degree. 2.theta..
[0117] In another embodiment, the present invention provides
crystalline Form-I of dolutegravir morpholine solvate,
characterized by a differential scanning calorimetry (DSC)
substantially in accordance with FIG. 14.
[0118] In another embodiment, the present invention provides
crystalline Form-I of dolutegravir morpholine solvate,
characterized by a thermo gravimetric analysis (TGA) substantially
in accordance with FIG. 15.
[0119] In another embodiment, the present invention provides
crystalline Form-I of dolutegravir morpholine solvate,
characterized by a powder X-Ray diffraction (PXRD) pattern
substantially in accordance with FIG. 13, a differential scanning
calorimetry (DSC) substantially in accordance with FIG. 14 and/or a
thermo gravimetric analysis (TGA) substantially in accordance with
FIG. 15.
[0120] In another embodiment, the present invention provides a
process for preparation of crystalline Form-I of dolutegravir
morpholine solvate, which comprise of [0121] a) dissolving
dolutegravir in a suitable chloro solvent, [0122] b) adding
morpholine to step a) solution, [0123] c) adding a suitable
anti-solvent to step b) solution, and [0124] d) isolating the
dolutegravir crystalline Form-I.
[0125] In the aforementioned process of crystalline Form-I of
dolutegravir morpholine solvate, dissolution of dolutegravir in a
suitable chloro solvents such as methylene chloride, chloroform and
the like; preferably methylene chloride, can be carried out at a
suitable temperature of about 25.degree. C. to about 45.degree. C.,
preferably at about 25.degree. C. to about 35.degree. C. In step b)
morpholine was added to step a) solution at about 25.degree. C. to
about 35.degree. C. The suitable anti-solvents selected from ether
solvents such as diethylether, diisopropylether, methyl tertiary
butyl ether, ethyl tertiary butyl ether, and the like; preferably
methyl tertiary butyl ether, was added to step b) solution at about
25.degree. C. to about 35.degree. C. and the obtained suspension
was stirred for 1 hrs to 2 hrs. Then the isolation of crystalline
Form I from the reaction mass can be carried out by any
conventional techniques known in the art, for example filtration
and followed by drying.
[0126] In another embodiment, the present invention provides
crystalline Form-II of dolutegravir morpholine solvate.
[0127] In another embodiment, the present invention provides
crystalline Form-II of dolutegravir morpholine solvate,
characterized by a powder X-Ray diffraction (PXRD) pattern
substantially in accordance with FIG. 16.
[0128] In another embodiment, the present invention provides
crystalline Form-II of dolutegravir morpholine solvate,
characterized by a powder X-Ray diffraction pattern having one or
more peaks at about 6.78, 8.80, 11.56, 13.76, 14.80, 16.64, 17.56,
18.48, 19.34, 19.66, 20.40, 20.80, 21.48, 21.90, 22.74, 23.38,
25.24, 25.72, 27.56, 28.44, 29.54, 30.48 and 31.88.+-.0.2.degree.
2.theta..
[0129] In another embodiment, the present invention provides
crystalline Form-II of dolutegravir morpholine solvate,
characterized by a differential scanning calorimetry (DSC)
substantially in accordance with FIG. 17.
[0130] In another embodiment, the present invention provides
crystalline Form-II of dolutegravir morpholine solvate,
characterized by a thermo gravimetric analysis (TGA) substantially
in accordance with FIG. 18.
[0131] In another embodiment, the present invention provides
crystalline Form-II of dolutegravir morpholine solvate,
characterized by a powder X-Ray diffraction (PXRD) pattern
substantially in accordance with FIG. 16, a differential scanning
calorimetry (DSC) substantially in accordance with FIG. 17 and/or a
thermo gravimetric analysis (TGA) substantially in accordance with
FIG. 18.
[0132] In another embodiment, the present invention provides a
process for the preparation of crystalline Form-II of dolutegravir
morpholine solvate, which comprise of [0133] a) dissolving
dolutegravir in morpholine, and [0134] b) isolating the
dolutegravir crystalline Form-II.
[0135] In the aforementioned process of crystalline Form-II of
dolutegravir morpholine solvate, dissolution of dolutegravir in
morpholine can be carried out at a suitable temperature of about
25.degree. C. to about 45.degree. C., preferably at about
25.degree. C. to about 35.degree. C. and the reaction mass is
stirred for 15 to 30 mins at about 25.degree. C. to about
35.degree. C. Then the isolation of crystalline Form II from the
reaction mass can be carried out by any conventional techniques
known in the art, for example filtration and followed by drying.
Advantageously before the isolation step b), suitable ether
solvents such as diethylether, diisopropylether, methyl tertiary
butyl ether, ethyl tertiary butyl ether, and the like; was added to
the reaction mass at about 25.degree. C. to about 35.degree. C.,
stirred for an hour and then filtered.
[0136] In another embodiment, the present invention provides
1-amino-2-propanol solvate of dolutegravir.
[0137] In another embodiment, the present invention provides
1-amino-2-propanol solvate of dolutegravir in crystalline form.
[0138] In another embodiment, the present invention provides
crystalline form of dolutegravir 1-amino-2-propanol solvate,
characterized by a powder X-Ray diffraction (PXRD) pattern
substantially in accordance with FIG. 19.
[0139] In another embodiment, the present invention provides
crystalline form of dolutegravir 1-amino-2-propanol solvate,
characterized by a powder X-Ray diffraction pattern having one or
more peaks at about 6.26, 7.58, 9.64, 12.04, 12.44, 15.18, 17.62,
18.20, 18.58, 19.22, 20.10, 21.76, 24.16, 25.34, 26.08, 26.34,
26.96, 29.10, 29.74 and 34.30+0.2.degree. 2.theta..
[0140] In another embodiment, the present invention provides
crystalline form of dolutegravir 1-amino-2-propanol solvate,
characterized by a differential scanning calorimetry (DSC)
substantially in accordance with FIG. 20.
[0141] In another embodiment, the present invention provides
crystalline form of dolutegravir 1-amino-2-propanol solvate,
characterized by a thermo gravimetric analysis (TGA) substantially
in accordance with FIG. 21.
[0142] In another embodiment, the present invention provides
crystalline form of dolutegravir 1-amino-2-propanol solvate,
characterized by a powder X-Ray diffraction (PXRD) pattern
substantially in accordance with FIG. 19, a differential scanning
calorimetry (DSC) substantially in accordance with FIG. 20 and/or a
thermo gravimetric analysis (TGA) substantially in accordance with
FIG. 21.
[0143] In another embodiment, the present invention provides a
process for the preparation of crystalline form of dolutegravir
1-amino-2-propanol solvate, which comprise of [0144] a) dissolving
dolutegravir in a suitable solvent, [0145] b) adding
1-amino-2-propanol to step a) solution; and [0146] c) isolating the
crystalline form of dolutegravir 1-amino-2-propanol solvate.
[0147] In the aforementioned process of crystalline form of
dolutegravir 1-amino-2-propanol solvate, dissolution of
dolutegravir in a suitable solvent such as N-methyl-2-pyrrolidone
or methylene chloride, can be carried out at a suitable temperature
of about 25.degree. C. to about 45.degree. C., preferably at about
25.degree. C. to about 35.degree. C. In step b) 1-amino-2-propanol
was added to step a) solution at about 25.degree. C. to about
35.degree. C. and the obtained suspension stirred for a sufficient
period of time, preferably for 30 mins to 2 hrs. Then the isolation
of crystalline dolutegravir 1-amino-2-propanol solvate from the
reaction mass can be carried out by any conventional techniques
known in the art, for example filtration and followed by drying.
Advantageously water was added to the reaction mass at about
25.degree. C. to about 35.degree. C. before the isolation step and
stirred for an hour then filtered.
[0148] As used herein above, the dolutegravir which is used as a
starting material is known in the art and can be prepared by any
known method. The starting dolutegravir may be in any form such as
crude obtained directly from the reaction mass, crystalline,
amorphous or other forms of dolutegravir, including various
solvates and hydrates known in the art.
[0149] The novel polymorphs of dolutegravir sodium and solvates of
dolutegravir of the present invention are stable even at
accelerated conditions and having higher dissolution rate when
compared to known solid forms of dolutegravir sodium.
[0150] In another embodiment, the present invention provides a
pharmaceutical composition comprising novel polymorphic forms of
dolutegravir sodium and solvates of dolutegravir of the present
invention and at least one pharmaceutically acceptable
excipient.
[0151] In a preferred embodiment, the present invention provides a
pharmaceutical composition comprising crystalline dolutegravir
sodium Form-L9 and at least one pharmaceutically acceptable
excipient.
[0152] The X-Ray powder diffraction of novel polymorphs of the
present invention can be measured by an X-ray powder Diffractometer
equipped with a Cu-anode ([.lamda.]=1.54 .ANG.), X-ray source
operated at 30 kV, 15 mA and a Ni filter is used to strip K-beta
radiation. The sample was analyzed using the following instrument
parameters: measuring range=3-45.degree. 2.theta.; step
width=0.020.degree.; and scan speed=5.degree./minute.
[0153] All DSC data reported herein were analyzed in hermitically
sealed aluminium pan with pin hole, with a blank hermitically
sealed aluminium pan with pin hole as the reference and were
obtained using DSC (DSC Q200, TA instrumentation, Waters) at a scan
rate of 10.degree. C. per minute with an Indium standard.
[0154] All TGA data reported herein were analyzed using TGA Q500 V
20.2 build 27 in platinum pan with a temperature rise of about
10.degree. C./min in the range of about 30.degree. C. to about
250.degree. C.
[0155] Other embodiments of the invention include composition
containing one or more polymorphic forms of dolutegravir or salts
thereof as described above. The pharmaceutical composition
includes, but is not limited to tablets, capsules, solutions,
suspensions and injections. Such pharmaceutical compositions
contains one or more excipients, including, without limitation,
binders such as binders such as acacia, guar gum, tragacanth,
gelatin, polyvinylpyrrolidone, hydroxypropyl celluloses,
hydroxypropyl starch, hydroxypropylmethyl celluloses,
pregelatinized starch and the like; diluents/fillers such as
starch, pregelatinized starch, lactose, powdered cellulose,
microcrystalline cellulose, silicified microcrystalline cellulose,
dicalcium phosphate, tricalcium phosphate, magnesium oxide,
magnesium carbonate, calcium carbonate, mannitol, sorbitol,
xylitol, sugar, and the like; lubricants such as stearic acid,
talc, magnesium stearate, calcium stearate, zinc stearate, sodium
stearyl fumarate and the like; disintegrants such as starch, sodium
starch glycolate, pregelatinized starch, crospovidone, polacrilin
potassium, croscarmellose sodium, colloidal silicon dioxide and the
like; glidants such as colloidal silicon dioxide, talc and the
like; wetting agents such as sodium lauryl sulfate, sodium dodecyl
sulfate, tween and the like; emulsifiers, suspending agents,
sweeteners, flavorings, preservatives, buffers, effervescent
agents, and other conventional excipients and additives.
[0156] The following examples are provided by way of illustration
only, and are not intended to be limiting of the present invention.
Further, the present invention covers all the possible combinations
of particular and preferred embodiments indicated herein.
EXAMPLES
Example-1: Preparation of Dolutegravir Sodium Form-L9
[0157] Dolutegravir sodium Form-L12 (1 g) was dried at
120-125.degree. C. for 8 hrs under vacuum yielded dolutegravir
sodium Form-L9. Yield: 880 mg The XRPD is set forth in FIG. 1; The
DSC is set forth in FIG. 2; The TGA is set forth in FIG. 3.
Example-2: Preparation of Dolutegravir Sodium Form-L9
[0158] Dolutegravir (100 g) was added to 1-pentanol (1500 ml) at
25-35.degree. C. To this mixture, 6.6N sodium hydroxide solution
(39.73 ml) was slowly added at 22-28.degree. C., then the reaction
mass was stirred for about 40 hrs at 22-28.degree. C. The solid
obtained was filtered, washed with 1-pentanol and suck dried. The
suck dried material was initially dried at 25-35.degree. C. for 2
hrs under vacuum, further at 50-55.degree. C. for 10 hrs under
vacuum and finally dried at 100-110.degree. C. for 16 hrs under
vacuum. The dried compound was kept in a air tray drier at
25-35.degree. C. for about 6 hrs yielded dolutegravir sodium
Form-L9. Yield: 90 grams
Example-3: Preparation of Dolutegravir Sodium Form-L10
[0159] Dolutegravir (1 g) was added to 10% aqueous isopentanol (10
ml) at 25-35.degree. C. To this suspension, aqueous sodium
hydroxide (6.75N, 0.1 ml) was added at 25-35.degree. C. and stirred
for 8 hrs. The solid obtained was filtered, washed with
isopentanol, suck dried and finally dried at 50-55.degree. C. for 4
hrs under vacuum to get the title compound. Yield: 1.1 g
[0160] The XRPD is set forth in FIG. 4; The DSC is set forth in
FIG. 5; The TGA is set forth in FIG. 6.
Example-4: Preparation of Dolutegravir Sodium Form-L11
[0161] Dolutegravir (2 g) was added to isobutanol (30 ml) at
25-35.degree. C. To this suspension, aqueous sodium hydroxide
(6.75N, 0.8 ml) was added and heated to 60-65.degree. C. The
reaction mass was stirred for 3 hrs at 60-65.degree. C. and then
cooled to 25-35.degree. C. The solid obtained was filtered, washed
with isobutanol and dried at 50-55.degree. C. for 2 hrs under
vacuum to get the title compound. Yield: 2.2 g
[0162] The XRPD is set forth in FIG. 7; The DSC is set forth in
FIG. 8; The TGA is set forth in FIG. 9.
Example-5: Preparation of Dolutegravir Sodium Form-L11
[0163] Dolutegravir (2 g) was added to isobutanol (30 ml) at
25-35.degree. C. To this suspension, aqueous sodium hydroxide
(6.75N, 0.8 ml) was added at 25-35.degree. C. and stirred for 15
hrs. The solid obtained was filtered, washed with isobutanol, suck
dried and finally dried at 50-55.degree. C. for 2 hrs under vacuum
to get the title compound. Yield: 2.4 g
Example-6: Preparation of Dolutegravir Sodium Form-L12
[0164] Dolutegravir (1 g) was added to 1-pentanol (10 ml) at
25-35.degree. C. To this suspension, aqueous sodium hydroxide
(6.75N, 0.4 ml) was added at 25-35.degree. C. and stirred for 8
hrs. The solid obtained was filtered, washed with 1-pentanol and
dried at 50-55.degree. C. for 4 hrs under vacuum to get the title
compound. Yield: 1.2 g
[0165] The XRPD is set forth in FIG. 10; The DSC is set forth in
FIG. 11; The TGA is set forth in FIG. 12.
Example-7: Preparation of Crystalline Form-I of Dolutegravir
Morpholine Solvate
[0166] Dolutegravir (1 g) was dissolved in methylene chloride (10
ml) at 25-35.degree. C. To this solution, morpholine (0.4 ml) was
added and stirred for 10 mins. Methyl tertiary butyl ether (30 ml)
was added to the reaction mass at 25-35.degree. C. and stirred for
75 mins. The solid obtained was filtered, washed with methyl
tertiary butyl ether and dried at 50-55.degree. C. for 3 hrs to get
the title compound. Yield: 1.2 g
[0167] The XRPD is set forth in FIG. 13; The DSC is set forth in
FIG. 14; The TGA is set forth in FIG. 15.
Example-8: Preparation of Crystalline Form-II of Dolutegravir
Morpholine Solvate
[0168] Dolutegravir (10 g) was dissolved in morpholine (100 ml) at
25-35.degree. C. and stirred for 15 mins. Methyl tertiary butyl
ether (500 ml) was added to the reaction mass at 25-35.degree. C.
and stirred for an hour. The solid obtained was filtered, washed
with methyl tertiary butyl ether and suck dried to get the title
compound. Yield: 12.9 g
[0169] The XRPD is set forth in FIG. 16; The DSC is set forth in
FIG. 17; The TGA is set forth in FIG. 18.
Example-9: Preparation of Crystalline Form of Dolutegravir
1-Amino-2-Propanol Solvate
[0170] Dolutegravir (3 g) was dissolved in N-methyl-2-pyrollidone
(15 ml) at 25-35.degree. C. To this solution, 1-amino-2-propanol
(1.1 ml) was added and the obtained suspension was stirred for 10
mins at 25-35.degree. C. DM water (30 ml) was added to the reaction
mass at 25-35.degree. C. and stirred for 1.5 hr. The solid obtained
was filtered, washed with water and dried at 50-55.degree. C. under
vacuum for 4 hrs to get the title compound. Yield: 2.4 g
[0171] The XRPD is set forth in FIG. 19; The DSC is set forth in
FIG. 20, The TGA is set forth in FIG. 21.
Example-10: Preparation of Crystalline Dolutegravir Sodium
[0172] Dolutegravir sodium Form-L10 (1 g) was dried at
120-125.degree. C. for 8 hrs under vacuum yielded crystalline
dolutegravir sodium. Yield: 894 mg
[0173] The XRPD is set forth in FIG. 22.
Example-11: Preparation of Crystalline Dolutegravir Sodium
[0174] Dolutegravir sodium Form-L11 (2 g) was dried at
120-125.degree. C. for 10 hrs under vacuum yielded crystalline
dolutegravir sodium. Yield: 1.8 g
[0175] The XRPD is set forth in FIG. 23.
Example-12: Stability Data for Dolutegravir Sodium Form-L9
[0176] Dolutegravir sodium Form-L9 was packed in a Low density
polyethylene (LDPE) bag with a strip seal, which is again kept in a
second low density polyethylene bag with strip seal. The LDPE bag
is kept in a high density polyethylene (HDPE) container and well
closed and loaded for stability chamber.
[0177] The stability data performed at 40.+-.2.degree. C./75.+-.5%
RH ensures that the dolutegravir sodium Form-L9 of the present
invention retained the same polymorphic and chemical identity at
least up to three months. This indicates that dolutegravir sodium
Form-L9 is physically and chemically stable.
[0178] Table-1 shows chemical and polymorphic stability data of
dolutegravir sodium Form-L9 when stored at 40.+-.2.degree.
C./75.+-.5% RH:
TABLE-US-00001 TABLE 1 Parameters Initial 1 month 2 month 3 month
Water content (% w/w) 2.2 1.9 2 2.3 Purity by HPLC (% w/w) 99.8
99.9 99.9 99.8 Des fluoro 0.09 0.08 0.09 0.10 dolutegravir (% w/w)
PXRD Form-L9 Form-L9 Form-L9 Form-L9
[0179] The purity of dolutegravir sodium was analysed using high
performance liquid chromatography ("HPLC") with the conditions is
tabulated below:
TABLE-US-00002 Column Kinetex Phenyl Hexyl (250 .times. 4.6) mm,
5.0 .mu.m Column temp 27.degree. C. Mobile phase A: Buffer, THF and
acetonitrile; B: Methanol, water, THF and acetonitrile. Diluent
Acetonitrile and water Flow rate 0.8 ml/min Wavelength 258 nm
Injection Volume 10 .mu.l
Example-13; Thermal Stability of Dolutegravir Sodium Form-L9
[0180] Dolutegravir sodium Form-L9 was kept in an oven at
60.degree. C. and 100.degree. C. for 24 hrs. The samples were
analyzed by PXRD and DSC and observed that same polymorphic nature
retained after the studies. Table-2 shows polymorphic nature of the
dolutegravir sodium Form-L9 at 60.degree. C. and 100.degree. C. for
24 hrs by PXRD and DSC.
TABLE-US-00003 TABLE 2 Form after heating Initial Form Temperature
Hours PXRD DSC Form-L9 60.degree. C. 24 hrs Form-L9 Form-L9 Form-L9
100.degree. C. 24 hrs Form-L9 Form-L9
[0181] The analytical data provided in Table-2 suggest that the
dolutegravir sodium Form-L9 is stable even at elevated
temperatures. Overlaid PXRD pattern and DSC thermogram of
dolutegravir sodium Form-L9 subjected to thermal stress study at
60.degree. C. and 100.degree. C. for 24 hours is represented as
Figure-24a and Figure-24b respectively.
Example-14: Hygroscopic Study of Dolutegravir Sodium Form-L9
[0182] Dolutegravir sodium Form-L9 was exposed to 85% relative
humidity at room temperature for one week and was analyzed by PXRD
at different time intervals such as 24 hours, 48 hours, 72 hours
and 168 hours. The samples were analyzed by PXRD and DSC and
observed that same polymorphic nature retained after the studies.
The overlaid PXRD pattern of dolutegravir sodium Form-L9 subjected
to hygroscopic study at 85% RH is represented as Figure-25.
Example-15; Solubility Studies of Dolutegravir Sodium Form L9
[0183] Aqueous solubility was performed for dolutegravir sodium
anhydrous form (prepared according to Ex-11 of WO2010/068253) and
Form-L9 of the present invention at different pH buffers and
solubility profile was found to be comparable. The results of
aqueous solubility profile after 24 hours by UV quantification was
shown in the following Table-3:
TABLE-US-00004 TABLE 3 S. No Aqueous buffer solution Anhydrous Form
Form L9 1 Water 0.56 0.54 2 pH buffer 1.2 0.53 0.54 3 pH buffer 4.5
0.39 0.33 4 pH buffer 6.8 0.38 0.54
Example-16
[0184] Composition for the preparation of dolutegravir sodium
tablets with dolutegravir sodium Form L9.
TABLE-US-00005 S. No Ingredients % w/w 1 Dolutegravir Sodium 15-20
2 D-Mannitol 45-65 3 Microcrystalline Cellulose 15-20 4 Sodium
Starch Glycolate 2-8 5 Povidone 2-8 6 Sodium Stearyl Fumarate
0.5-3.sup.
[0185] Tablets are prepared by using direct compression process and
the dissolution of dolutegravir sodium tablets are performed in
0.01M pH-6.8 Phosphate buffer+0.25% Sodium lauryl sulfate, 900 mL,
Paddle, 50 rpm and the results are as follows:
TABLE-US-00006 Test Time (Tablets prepared Ref Product (Min) using
Form-L9) (Tivicay) 5 34 30 10 68 61 15 88 85 20 93 92 30 97 98 45
99 99
Example 17: Intrinsic Dissolution Study of Dolutegravir Sodium Form
L9
[0186] Dissolution experiments were carried out in ELECTROLAB-8
dissolution apparatus equipped with an ETC-112 temperature
controller. An intrinsic dissolution apparatus (Woods apparatus)
was used. Samples were compressed at 2.0 metric tons for 1 min in
KBr hydraulic press, giving a sample surface of 0.50 cm.sup.2. A
dissolution medium consisting of 0.01M pH-6.8 Phosphate
buffer+0.25% Sodium lauryl sulfate, 900 mL, Paddle, 50 rpm, was
used for each experiment. The results of dissolution studies were
shown in Table-4:
TABLE-US-00007 TABLE 4 Time (Min) Form- L9 Anhydrous Form 15 1.17
0.18 30 1.56 0.24 45 1.64 0.26 60 1.77 0.23 120 1.98 0.43 480 2.23
1.72 1440 4.36 3.97
[0187] While the invention has been described with reference to
above detailed description and the preferred examples, it is not
intended to be limited thereto. Therefore the above description
should not be construed as limiting, but merely as exemplifications
of preferred embodiments. For example, the functions described
above and implemented as the best mode for operating the present
invention are for illustration purposes only. Other arrangements
and methods may be implemented by those skilled in the art without
departing from the scope and spirit of this invention. Moreover,
those skilled in the art will envision other modifications within
the scope and spirit of the specification appended hereto.
* * * * *