U.S. patent application number 13/128157 was filed with the patent office on 2011-12-22 for polymorphs of darunavir.
This patent application is currently assigned to HETERO RESEARCH FOUNDATION. Invention is credited to Dasari Muralidhara Reddy, Bandi Parthasaradhi Reddy, Rapolu Raji Reddy, Kura Rathnakar Reddy, Kesireddy Subash Chander Reddy, Bandi Vamsi Krishna.
Application Number | 20110313035 13/128157 |
Document ID | / |
Family ID | 44166823 |
Filed Date | 2011-12-22 |
United States Patent
Application |
20110313035 |
Kind Code |
A1 |
Parthasaradhi Reddy; Bandi ;
et al. |
December 22, 2011 |
POLYMORPHS OF DARUNAVIR
Abstract
The present invention provides novel solvated forms of darunavir
and processes for there preparation. The present invention also
provides novel process for preparation of darunavir amorphous form
and pharmaceutical composition comprising it. Thus, for example,
darunavir 2-methyl-2-butanol solvate was dissolved in methylene
dichloride, distilled under vacuum at 45.degree. C. to obtain a
residue, cyclohexane was added to the residue and stirred for 30
hours at 20 to 25.degree. C., and the separated solid was filtered,
washed with cyclohexane and dried under vacuum at 50.degree. C. for
12 hours to yield darunavir amorphous form.
Inventors: |
Parthasaradhi Reddy; Bandi;
(Hyderabad, IN) ; Rathnakar Reddy; Kura;
(Hyderabad, IN) ; Muralidhara Reddy; Dasari;
(Hyderabad, IN) ; Raji Reddy; Rapolu; (Hyderabad,
IN) ; Subash Chander Reddy; Kesireddy; (Hyderabad,
IN) ; Vamsi Krishna; Bandi; (Hyderabad, IN) |
Assignee: |
HETERO RESEARCH FOUNDATION
Hyderabad, Andhrapradesh
IN
|
Family ID: |
44166823 |
Appl. No.: |
13/128157 |
Filed: |
December 16, 2009 |
PCT Filed: |
December 16, 2009 |
PCT NO: |
PCT/IN09/00724 |
371 Date: |
July 6, 2011 |
Current U.S.
Class: |
514/470 ;
549/464 |
Current CPC
Class: |
A61P 31/12 20180101;
A61K 9/2054 20130101; A61K 31/34 20130101; C07D 493/04 20130101;
A61K 9/2027 20130101; A61P 31/18 20180101 |
Class at
Publication: |
514/470 ;
549/464 |
International
Class: |
A61K 31/34 20060101
A61K031/34; A61P 31/12 20060101 A61P031/12; A61P 31/18 20060101
A61P031/18; C07D 493/04 20060101 C07D493/04 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 16, 2009 |
IN |
PCT/IN2009/000724 |
Claims
1. A darunavir C.sub.5-C.sub.8 alcohol solvate.
2. A process for the preparation of darunavir C.sub.5-C.sub.8
alcohol solvate as defined in claim 1, which comprises
crystallizing darunavir C.sub.5-C.sub.8 alcohol solvate from a
solution of darunavir in C.sub.5-C.sub.8 alcohol solvent.
3. The solvate according to claim 1, wherein the ratio of darunavir
to C.sub.5-C.sub.8 alcohol solvent ranges between 1:0.3 and
1:1.3.
4. The solvate according to claim 3, wherein the ratio of darunavir
to C.sub.5-C.sub.8 alcohol solvent is about 1:1.
5. The process according to claim 2, wherein the C.sub.5-C.sub.8
alcohol solvent is selected from 2-methyl-2-butanol or
n-pentanol.
6. A process for the preparation of darunavir amorphous form, which
comprises: a. dissolving darunavir in a solvent; b. removing the
solvent from the solution obtained in step (a) to obtain a residue;
c. slurrying the residue obtained in step (b) with aliphatic
solvent or aromatic solvent; and d. isolating darunavir amorphous
form.
7. The process according to claim 6, wherein the darunavir used in
step (a) is darunavir in any solvated or hydrated or anhydrous
form.
8. The process according to claim 7, wherein the darunavir used in
step (a) is darunavir C.sub.5-C.sub.8 alcohol solvate such as
2-methyl-2-butanol solvate or n-pentanol solvate.
9. The process according to claim 6, wherein the solvent used in
step (a) is a solvent or mixture of solvents selected from
dichloromethane, ethylene dichloride, chloroform and ethyl
acetate.
10. The process according to claim 9, wherein the solvent is
dichloromethane.
11. The process according to claim 6, wherein the aliphatic solvent
or aromatic solvent used in step (c) is a solvent or mixture of
solvents selected from cyclohexane, hexane, n-heptane, toluene and
xylene.
12. The process according to claim 11, wherein the aliphatic
solvent is cyclohexane.
13. A pharmaceutical composition comprising a darunavir amorphous
form and a pharmaceutically acceptable excipient.
14. The pharmaceutical composition as claimed in claim 13, wherein
the pharmaceutical composition is used in a solid dosage forms.
15. The pharmaceutical composition as claimed in claim 14, wherein
the solid dosage forms for oral administration is include capsules,
tablets, pills, powders and granules.
Description
FIELD OF THE INVENTION
[0001] The present invention provides novel solvated forms of
darunavir and processes for there preparation. The present
invention also provides novel process for preparation of darunavir
amorphous form and pharmaceutical composition comprising it.
BACKGROUND OF THE INVENTION
[0002] Virus-encoded proteases, which are essential for viral
replication, are required for the processing of viral protein
precursors. Interference with the processing of protein precursors
inhibits the formation of infectious virions. Accordingly,
inhibitors of viral proteases may be used to prevent or treat
chronic and acute viral infections. Darunavir has HIV protease
inhibitory activity and is particularly well suited for inhibiting
HIV-1 and HIV-2 viruses. Among them darunavir, chemically
(1S,2R,3'R,3'aS,6'
aR)-[3'-hexahydrofuro[2,3-b]furanyl-[3-(4-aminobenzenesulfonyl)isobutylam-
ino]-1-benzyl-2-hydroxypropyl]carbamate. Darunavir is represented
by the following structure:
##STR00001##
[0003] Processes for the preparations of darunavir were disclosed
in EP 715618, WO 99/67417, U.S. Pat. No. 6,248,775, and in
Bioorganic and Chemistry Letters, Vol. 8, pp. 687-690, 1998,
"Potent HIV protease inhibitors incorporating high-affinity
P2-igands and (R)-(hydroxyethylamino)sulfonamide isostere", all of
which are incorporated herein by reference.
[0004] Polymorphism is defined as "the ability of a substance to
exist as two or more crystalline phases that have different
arrangement and/or conformations of the molecules in the crystal
Lattice. Thus, in the strict sense, polymorphs are different
crystalline forms of the same pure substance in which the molecules
have different arrangements and/or different configurations of the
molecules". Different polymorphs may differ in their physical
properties such as melting point, solubility, X-ray diffraction
patterns, etc. Although those differences disappear once the
compound is dissolved, they can appreciably influence
pharmaceutically relevant properties of the solid form, such as
handling properties, dissolution rate and stability. Such
properties can significantly influence the processing, shelf life,
and commercial acceptance of a polymorph. It is therefore important
to investigate all solid forms of a drug, including all polymorphic
forms, and to determine the stability, dissolution and flow
properties of each polymorphic form. Polymorphic forms of a
compound can be distinguished in the laboratory by analytical
methods such as X-ray diffraction (XRD), Differential Scanning
calorimetry (DSC) and Infrared spectrometry (IR).
[0005] Darunavir can exist in different polymorphic forms, which
differ from each other in terms of stability, physical properties,
spectral data and methods of preparation.
[0006] U.S. Patent Application No. 2005/0250845 described Amorphous
Form, Form A (ethanolate), Form B (hydrate), Form C (methanolate),
Form D (acetonate), Form E (dichloromethanate), Form F
(ethylacetate solvate), Form G (1-ethoxy-2-propanolate), Form H
(anisolate), Form I (tetrahydrofuranate), Form J (isopropanolate)
and Form K (mesylate) of darunavir.
[0007] One object of the present invention is to provide novel
solvated forms of darunavir and processes for their
preparation.
[0008] Another object of the present invention is to provide a
novel process for preparation of darunavir amorphous form and
pharmaceutical compositions comprising them.
SUMMARY OF THE INVENTION
[0009] In one aspect, the present invention provided darunavir
C.sub.5-C.sub.8 alcohol solvate.
[0010] In another aspect, the present invention provides a process
for preparing darunavir C.sub.5-C.sub.8 alcohol solvate, which
comprises crystallizing darunavir C.sub.5-C.sub.8 alcohol solvate
from a solution of darunavir in C.sub.5-C.sub.8 alcohol
solvent.
[0011] In another aspect, the present invention provides a process
for preparing darunavir amorphous form, which comprises: [0012] a)
dissolving darunavir in a solvent; [0013] b) removing the solvent
from the solution obtained in step (a) to obtain a residue; [0014]
c) slurrying the residue obtained in step (b) with aliphatic
solvent or aromatic solvent; and [0015] d) isolating darunavir
amorphous form.
[0016] In yet another aspect, the present invention provides a
pharmaceutical composition comprising darunavir amorphous form and
a pharmaceutically acceptable excipient.
BRIEF DESCRIPTION OF THE DRAWING
[0017] FIG. 1 is X-ray powder diffraction spectrum of darunavir
2-methyl-2-butanol solvate.
[0018] FIG. 2 is X-ray powder diffraction spectrum of darunavir
n-pentanol solvate.
[0019] FIG. 3 is X-ray powder diffraction spectrum of darunavir
amorphous form.
[0020] X-ray powder diffraction spectrum was measured on a bruker
axs D8 advance X-ray powder diffractometer having a copper-K.alpha.
radiation. Approximately 1 gm of sample was gently flattered on a
sample holder and scanned from 2 to 50 degrees two-theta, at 0.02
degrees to theta per step and a step of 10.4 seconds. The sample
was simply placed on the sample holder. The sample was rotated at
30 rpm at a voltage 40 KV and current 35 mA.
DETAILED DESCRIPTION OF THE INVENTION
[0021] According to one aspect of the present invention, there is
provided darunavir C.sub.5-C.sub.8 alcohol solvate.
[0022] According to another aspect of the present invention, there
is provided a process for preparing darunavir C.sub.5-C.sub.8
alcohol solvate, which comprises crystallizing darunavir
C.sub.5-C.sub.8 alcohol solvate from a solution of darunavir in
C.sub.5-C.sub.8 alcohol solvent.
[0023] Solvates can occur in different ratios of solvation. The
ratio of darunavir to the C.sub.5-C.sub.8 alcohol solvent may range
between 1:0.3 and 1:1.3. In particular, the ratio may range from
about 0.5 to about 1 molecules of C.sub.5-C.sub.8 alcohol solvent
per 1 molecule of darunavir, preferably the ratio is 1 molecule of
C.sub.5-C.sub.8 alcohol solvent per 1 molecule of darunavir.
[0024] The C.sub.5-C.sub.8 alcohol solvent is selected from
2-methyl-2-butanol or n-pentanol.
[0025] Darunavir 2-methyl-2-butanol solvate characterized by peaks
in the powder x-ray diffraction spectrum having 2.theta. angle
positions at about 6.8, 8.8, 11.1, 13.7, 16.3, 16.7, 19.6, 20.9 and
22.3.+-.0.2 degrees. The powdered x-ray diffractogram (PXRD) of
darunavir 2-methyl-2-butanol solvate is shown in FIG. 1.
[0026] Darunavir n-pentanol solvate characterized by peaks in the
powder x-ray diffraction spectrum having 2.theta.angle positions at
about 6.9, 9.1, 11.2, 13.7, 16.4, 17.1, 20.3, 20.6, 21.1 and
22.6.+-.0.2 degrees. The powdered x-ray diffractogram (PXRD) of
darunavir n-pentanol solvate is shown in FIG. 2.
[0027] The solvates of the present invention are useful
intermediates for obtaining pure darunavir. The solvates of
darunavir of the present invention can be used to obtain known
polymorphs of darunavir.
[0028] According to another aspect of the present invention, there
is provided a process for the preparation of darunavir amorphous
form, which comprises: [0029] a) dissolving darunavir in a solvent;
[0030] b) removing the solvent from the solution obtained in step
(a) to obtain a residue; [0031] c) slurrying the residue obtained
in step (b) with aliphatic solvent or aromatic solvent; and [0032]
d) isolating darunavir amorphous form.
[0033] Darunavir used in step (a) is darunavir in any solvated or
hydrated or anhydrous form.
[0034] Preferably, darunavir used in step (a) is darunavir
C.sub.5-C.sub.8 alcohol solvate such as 2-methyl-2-butanol solvate
or n-pentanol solvate.
[0035] The solvent used in step (a) may be a solvent or mixture of
solvents selected from the group consisting of a dichloromethane,
ethylene dichloride, chloroform and ethyl acetate. Preferable
solvent is dichloromethane.
[0036] The distillation of the solvent may be carried out in step
(b) at atmospheric pressure or at reduced pressure. The
distillation may preferably be carried out until the solvent is
almost completely distilled off.
[0037] The aliphatic solvent or aromatic solvent used in step (c)
may be a solvent or a mixture of solvents selected from the group
consisting of a cyclohexane, hexane, n-heptane, toluene and xylene.
Preferable aliphatic solvent is cyclohexane.
[0038] The isolation of darunavir amorphous form may be performed
by conventional techniques such as centrifugation and
filtration.
[0039] According to another aspect of the present invention, there
is provided a pharmaceutical composition comprising a darunavir
amorphous form and a pharmaceutically acceptable excipient.
[0040] The pharmaceutically acceptable inert carrier which can be
used may be a solid dosage forms.
[0041] The solid dosage forms for oral administration may include
capsules, tablets, pills, powders and granules.
[0042] The invention will now be further described by the following
examples, which are illustrative rather than limiting.
Preparative Example
Preparation of Darunavir
[0043] To a mixture of (3R,3aS,6aR)-hexandrofuro[2,3-b]furan-3-ol
(25 gm) and acetonitrile (180 ml) was added disuccinimidyl
carbonate (56 gm) and pyridine (46 gm) at 25 to 30.degree. C. The
mixture was stirred for 1 hour at 25 to 30.degree. C. and cooled to
0.degree. C. A solution of
4-amino-N-((2R,3S)-3-amino-2-hydroxy-4-phenylbutyl)-N-(isobutyl)benzene
sulfonamide (70 gm) in acetonitrile (300 ml) was added to the
reaction mass at 0 to 5.degree. C. for 30 minutes. To the reaction
mass was added triethylamine (19 gm) and monomethylamine (3 gm) at
0 to 5.degree. C., the temperature was slowly raised to 25 to
30.degree. C. and stirred for 22 hours. Distilled off the solvent
completely under vacuum at 45.degree. C. to obtain a residue and to
the residue was added ethyl acetate (250 ml). The ethyl acetate
layer was washed with 10% sodium bicarbonate (100 ml), 2% sulfuric
acid (100 ml), 10% sodium sulfate (100 ml) and 10% sodium chloride
solution (100 ml). The layer was dried over sodium sulfate. The
layer was treated with carbon and distilled off the solvent under
vacuum at below 45.degree. C. to obtain 85 gm of darunavir.
EXAMPLES
Example 1
Preparation of darunavir 2-methyl-2-butanol solvate
[0044] Darunavir (85 gm) as obtained in preparative example was
added to 2-methyl-2-butanol (50 ml) and distilled off the solvent
under vacuum at below 45.degree. C. to obtain a residue. To the
residue was added 2-methyl-2-butanol (150 ml) and heated to
50.degree. C. The reaction mass was slowly cooled to room
temperature and stirred for 24 hours. The reaction mass further
cooled to 0.degree. C. and stirred for 1 hour at 0 to 5.degree. C.
The separated solid was filtered, washed with 2-methyl-2-butanol
and dried the solid under vacuum at 50.degree. C. to obtain 60 gm
of darunavir 2-methyl-2-butanol solvate.
Example 2
Preparation of Darunavir N-Pentanol Solvate
[0045] Darunavir (85 gm) as obtained in preparative example was
added to n-pentanol (50 ml) and distilled off the solvent under
vacuum at below 45.degree. C. to obtain a residue. To the residue
was added n-pentanol (150 ml) and heated to 50.degree. C. The
reaction mass was slowly cooled to room temperature and stirred for
24 hours. The reaction mass further cooled to 0.degree. C. and
stirred for 1 hour at 0 to 5.degree. C., filtered. The solid
obtained was washed with n-pentanol and dried the solid under
vacuum at 50.degree. C. to obtain 61 gm of darunavir n-pentanol
solvate.
Example 3
Preparation of Darunavir Amorphous Form
[0046] Darunavir 2-methyl-2-butanol solvate (5 gm) as obtained in
example 1 was dissolved in methylene dichloride (50 ml), methylene
dichloride layer was dried over sodium sulfate. The layer was
treated with carbon and distilled off the solvent under vacuum at
45.degree. C. to obtain foam like residue. Cyclohexane (2.times.25
ml) was added to the residue, distilled off the solvent and the
residue was collected. To the residue obtained was added
cyclohexane (50 ml), stirred for 30 hours at 20 to 25.degree. C.
The separated solid was filtered, washed with cyclohexane and then
dried under vacuum at 50.degree. C. for 12 hours to obtain 4.2 gm
of darunavir amorphous form.
Example 4
Preparation of Darunavir Amorphous Form
[0047] Darunavir n-pentanol solvate (5 gm) as obtained in example 2
was dissolved in methylene dichloride (50 ml), methylene dichloride
layer was dried over sodium sulfate. The layer was treated with
carbon and distilled off the solvent under vacuum at 45.degree. C.
to obtain foam like residue. Cyclohexane (2.times.25 ml) was added
to the residue, distilled off the solvent and the residue was
collected. To the residue obtained was added cyclohexane (50 ml),
stirred for 30 hours at 20 to 25.degree. C., filtered, washed with
cyclohexane and dried under vacuum at 50.degree. C. for 12 hours to
obtain 4.2 gm of darunavir amorphous form.
Example 5
Preparation of Darunavir Amorphous Form
[0048] Example 3 was repeated using darunavir ethanolate form A
instead of darunavir 2-methyl-2-butanol solvate to obtain darunavir
amorphous form.
Example 6
Preparation of Darunavir Amorphous Form
[0049] Example 3 was repeated using darunavir hydrated form B
instead of darunavir 2-methyl-2-butanol solvate to obtain darunavir
amorphous form.
* * * * *