U.S. patent application number 16/188687 was filed with the patent office on 2019-05-16 for crystalline forms of dimethoxy docetaxel and methods for preparing the same.
The applicant listed for this patent is Aventis Pharma S.A.. Invention is credited to Pascal BILLOT, Marielle DUFRAIGNE, Hagit ELMALEH, Alexandre GIULIANI, Fabrice MANGIN, Patricia RORTAIS, Lionel ZASKE.
Application Number | 20190144406 16/188687 |
Document ID | / |
Family ID | 39712334 |
Filed Date | 2019-05-16 |
United States Patent
Application |
20190144406 |
Kind Code |
A1 |
BILLOT; Pascal ; et
al. |
May 16, 2019 |
CRYSTALLINE FORMS OF DIMETHOXY DOCETAXEL AND METHODS FOR PREPARING
THE SAME
Abstract
The invention relates to anhydrides, solvates and ethanol
hetero-solvates and hydrates of dimethoxy docetaxel or
(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenyl-propionate of
4-acetoxy-2.alpha.-benzoyloxy-5.beta.,20-epoxy-1-hydroxy-7.beta.,
10.beta.-dimethoxy-9-oxo-tax-11-ene-13.alpha.-yle, and to the
preparation thereof.
Inventors: |
BILLOT; Pascal; (Montreuil,
FR) ; DUFRAIGNE; Marielle; (Brunoy, FR) ;
ELMALEH; Hagit; (Ormesson sur Marne, FR) ; MANGIN;
Fabrice; (Paris, FR) ; RORTAIS; Patricia;
(Bourg La Reine, FR) ; ZASKE; Lionel; (Saint
Maurice, FR) ; GIULIANI; Alexandre; (Boissy Saint
Leger, FR) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Aventis Pharma S.A. |
Antony |
|
FR |
|
|
Family ID: |
39712334 |
Appl. No.: |
16/188687 |
Filed: |
November 13, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15646375 |
Jul 11, 2017 |
10160739 |
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16188687 |
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14453087 |
Aug 6, 2014 |
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15646375 |
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13767966 |
Feb 15, 2013 |
8846959 |
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14453087 |
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12837559 |
Jul 16, 2010 |
8378128 |
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13767966 |
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PCT/FR2009/000042 |
Jan 15, 2009 |
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12837559 |
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Current U.S.
Class: |
549/510 ;
549/457 |
Current CPC
Class: |
A61P 35/00 20180101;
C07D 305/14 20130101; A61P 35/02 20180101 |
International
Class: |
C07D 305/14 20060101
C07D305/14 |
Foreign Application Data
Date |
Code |
Application Number |
Jan 17, 2008 |
FR |
0800243 |
Claims
1. Crystalline forms of
4-acetoxy-2a-benzoyloxy-5b,20-epoxy-1-hydroxy-7.beta.,10.beta.-dimethoxy--
9-oxotax-11-en-13a-yl
(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate,
with the exception of the acetonate form.
2. Forms according to claim 1, characterized in that they are
anhydrous forms of
4-acetoxy-2a-benzoyloxy-5b,20-epoxy-1-hydroxy-7.beta.,10.beta.-d-
imethoxy-9-oxotax-11-en-13a-yl
(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate.
3. (canceled)
4. Anhydrous form C of
4-acetoxy-2.alpha.-benzoyloxy-5b,20-epoxy-1-hydroxy-7.beta.,10.beta.-dime-
thoxy-9-oxotax-11-en-13a-yl
(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate
according to claim 2, characterized by a PXRD diagram exhibiting
characteristic lines located at 4.3, 6.8, 7.4, 8.7, 10.1, 11.1,
11.9, 12.3, 12.6 and 13.1.+-.0.2 degrees 2-theta.
5. (canceled)
6. Anhydrous form E of
4-acetoxy-2a-benzoyloxy-5b,20-epoxy-1-hydroxy-7.beta.,10.beta.-dimethoxy--
9-oxotax-11-en-13a-yl
(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate
according to claim 2, characterized by a PXRD diagram exhibiting
characteristic lines located at 7.1, 8.1, 8.9, 10.2, 10.8, 12.5,
12.7, 13.2, 13.4 and 13.9.+-.0.2 degrees 2-theta.
7. (canceled)
8. Forms according to claim 1, characterized in that they are
ethanolic solvate or heterosolvate forms of
4-acetoxy-2a-benzoyloxy-5b,20-epoxy-1-hydroxy-7.beta.,10.beta.-dimethoxy--
9-oxotax-11-en-13a-yl
(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate.
9. Ethanolate form B of
4-acetoxy-2a-benzoyloxy-5b,20-epoxy-1-hydroxy-7.beta.,10.beta.-dimethoxy--
9-oxotax-11-en-13a-yl
(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate
according to claim 8, characterized by a PXRD diagram exhibiting
characteristic lines located at 7.3, 7.8, 8.8, 10.2, 12.6, 12.9,
13.4, 14.2, 14.7 and 15.1.+-.0.2 degrees 2-theta.
10. Ethanolate form D of
4-acetoxy-2a-benzoyloxy-5b,20-epoxy-1-hydroxy-7.beta.,10.beta.-dimethoxy--
9-oxotax-11-en-13a-yl
(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate
according to claim 8, characterized by a PXRD diagram exhibiting
characteristic lines located at 3.8, 7.5, 7.7, 8.4, 9.4, 10.3,
10.5, 11.1, 11.5 and 11.9.+-.0.2 degrees 2-theta.
11. (canceled)
12. Ethanol/water heterosolvate form F of
4-acetoxy-2a-benzoyloxy-5b,20-epoxy-1-hydroxy-7.beta.,10.beta.-dimethoxy--
9-oxotax-11-en-13a-yl
(2R,3S)-3-tert-butoxy-carbonylamino-2-hydroxy-3-phenylpropionate
according to claim 8, characterized by a PXRD diagram exhibiting
characteristic lines located at 4.4, 7.2, 8.2, 8.3, 8.8, 9.6, 10.3,
10.9, 11.2 and 12.2.+-.0.2 degrees 2-theta.
13. Forms according to claim 1, characterized in that they are
hydrate forms of
4-acetoxy-2a-benzoyloxy-5b,20-epoxy-1-hydroxy-7p,10.beta.-dimeth-
oxy-9-oxotax-11-en-13a-yl
(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate.
14. Monohydrate form C of
4-acetoxy-2a-benzoyloxy-5b,20-epoxy-1-hydroxy-7.beta.,10.beta.-dimethoxy--
9-oxotax-11-en-13a-yl
(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate
according to claim 13, characterized by a PXRD diagram exhibiting
characteristic lines located at 4.3, 6.8, 7.4, 8.6, 10.1, 11.1,
11.9, 12.2, 12.6 and 13.3.+-.0.2 degrees 2-theta.
15. Dihydrate form C of
4-acetoxy-2a-benzoyloxy-5b,20-epoxy-1-hydroxy-7.beta.,10.beta.-dimethoxy--
9-oxotax-11-en-13a-yl
(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate
according to claim 13, characterized by a PXRD diagram exhibiting
characteristic lines located at 4.2, 6.9, 7.5, 8.4, 9.9, 10.9,
11.7, 12.3, 12.6 and 13.2.+-.0.2 degrees 2-theta.
16. Method for preparing the anhydrous form B according to claim 3,
which consists in heating the acetone solvate form A between 100
and 110.degree. C. under vacuum or nitrogen sweeping, preferably
for at least 9 hours, and then returning to ambient
temperature.
17. Method for preparing the anhydrous form C according to claim 4,
by maturation of the acetone solvate form A, or of the anhydrous
form B, in water, followed by drying up to approximately 50.degree.
C. and then maintaining at ambient temperature at a relative
humidity of less than 5%.
18. Method for preparing the anhydrous form D according to claim 5,
by maturation, at ambient temperature, of the acetone solvate form
A in ethanol and drying under nitrogen or under vacuum.
19. Method for preparing the anhydrous form D according to claim 5,
by crystallization, at ambient temperature, of the acetone solvate
form A from an oil, followed by rinsing with an alkane.
20. Method for preparing the anhydrous form D according to claim 5,
by crystallization of a solution of
4-acetoxy-2a-benzoyloxy-5b,20-epoxy-1-hydroxy-7.beta.,10.beta.-dimethoxy--
9-oxotax-11-en-13a-yl
(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate in
a mixture of Polysorbate 80, pH 3.5, ethanol and water (preferably,
a 25/25/50 mixture) for approximately 48 hours at ambient
temperature.
21. Method for preparing the anhydrous form E according to claim 6,
by maturation of the acetone solvate form A in ethanol so as to
intermediately form an ethanolic form which is subsequently
desolvated under nitrogen sweeping or by heating at approximately
100.degree. C. for 2 hours and then returning to ambient
temperature.
22. Method for preparing the anhydrous form F according to claim 7,
by desolvating the ethanol/water heterosolvate at 120.degree. C.
under a nitrogen atmosphere for 24 hours and then maintaining at a
relative humidity of 0% at ambient temperature.
Description
[0001] This application is a divisional of U.S. patent application
Ser. No. 15/646,375, filed Jul. 11, 2017, which is a divisional
application of U.S. patent application Ser. No. 14/453,087, filed
Aug. 6, 2014, which is a divisional application of U.S. patent
application Ser. No. 13/767,966, filed Feb. 15, 2013, now U.S. Pat.
No. 8,846,959, which is a divisional application of U.S. patent
application Ser. No. 12/837,559 filed Jul. 16, 2010, now U.S. Pat.
No. 8,378,128, which is a continuation of International Patent
Application PCT/FR2009/000042 filed Jan. 15, 2009, all of which are
incorporated herein by reference; and which claim priority to
French Patent Application No. 0800243 filed on Jan. 17, 2008.
[0002] The present invention relates to crystalline forms of
dimethoxy docetaxel or
4-acetoxy-2.alpha.-benzoyloxy-5.beta.,20-epoxy-1-hydroxy-7.beta.,
10.beta.-dimethoxy-9-oxotax-11-en-13.alpha.-yl
(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate and
to methods for the preparation thereof.
BACKGROUND OF THE INVENTION
[0003] 4-Acetoxy-2.alpha.-benzoyloxy-5.beta.,
20-epoxy-1-hydroxy-7.beta.,
10.beta.-dimethoxy-9-oxotax-11-en-13.alpha.-yl
(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate
exhibits notable anticancer and antileukaemic properties.
[0004] 4-Acetoxy-2.alpha.-benzoyloxy-5.beta.,
20-epoxy-1-hydroxy-7.beta., 10.beta.-di
methoxy-9-oxotax-11-en-13.alpha.-yl
(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate is
prepared according to the method which is described more
particularly in PCT International Application WO 96/30355 or PCT
International Application WO 99/25704. According to the method
described in these applications, the product is not crystallized
and is not characterized.
[0005] It was found that the acetone solvate of
4-acetoxy-2.alpha.-benzoyloxy-5.beta.,20-epoxy-1-hydroxy-7.beta.,
10.beta.-dimethoxy-9-oxotax-11-en-13.alpha.-yl
(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate
(called form A) was completely determined and characterized
according to the patent published under number WO2005/028462.
BRIEF SUMMARY OF THE INVENTION
[0006] The present invention relates to new crystalline forms, with
the exclusion of the acetonate form, the only one known to
date.
[0007] According to the present invention, it has now been found
that certain anhydrous forms, certain ethanolic solvates or
heterosolvates and hydrated forms have been completely
characterized from a physical and chemical structure point of
view.
BRIEF DESCRIPTION OF THE DRAWINGS
[0008] FIG. 1 depicts a Differential Scanning calorimetry (DSC)
analysis for anhydrous form D.
[0009] FIG. 2 depicts a Powder X-Ray Diffraction (PXRD) analysis
for anhydrous form D.
[0010] FIG. 3 depicts Fourier Transform InfraRed (FTIR)
spectrometry analysis for anhydrous form D.
[0011] FIG. 4 depicts a Powder X-Ray Diffraction (PXRD) analysis
for ethanolate form D.
[0012] FIG. 5 depicts a Powder X-Ray Diffraction (PXRD) analysis
for ethanolate form E.
DETAILED DESCRIPTION OF THE INVENTION
[0013] According to the invention, among the anhydrous forms of
4-acetoxy-2.alpha.-benzoyloxy-5.beta.,20-epoxy-1-hydroxy-7.beta.,10.beta.-
-dimethoxy-9-oxotax-11-en-13.alpha.-yl(2R,3S)-3-tert-butoxycarbonylamino-2-
-hydroxy-3-phenylpropionate, five different forms have been
identified, among the ethanolic solvates or heterosolvates of
4-acetoxy-2.alpha.-benzoyloxy-5.beta.,20-epoxy-1-hydroxy-7.beta.,10.beta.-
-dimethoxy-9-oxotax-11-en-13.alpha.-yl(2R,3S)-3-tert-butoxy c arb
onyl amino-2-hydroxy-3-phenylpropionate, four different forms have
been identified and among the hydrates of
4-acetoxy-2.alpha.-benzoyloxy-5.beta.,20-epoxy-1-hydroxy-7.beta.,10.beta.-
-dimethoxy-9-oxotax-11-en-13.alpha.-yl
(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate,
two different forms have been identified.
[0014] The five anhydrous forms identified were obtained according
to the following methods: [0015] The anhydrous form B by a method
which consists in heating the acetone form or form A obtained
according to the patent mentioned above, between 100 and
110.degree. C. under vacuum or nitrogen sweeping. This treatment is
preferably carried out for at least 9 hours before a return to
ambient temperature without inducing chemical decomposition. Its
melting point by DSC is approximately 150.degree. C. The PXRD
diagram of the anhydrous form B exhibits characteristic lines
located at 7.3, 8.1, 9.8, 10.4, 11.1, 12.7, 13.1, 14.3, 15.4 and
15.9.+-.0.2 degrees 2-theta. [0016] The anhydrous form C is
obtained by maturation of the acetone solvate form A, or of the
anhydrous form B, in water followed by drying at up to 50.degree.
C. and maintaining between 0 and 5% RH at ambient temperature. Its
melting point by DSC is approximately 146.degree. C. The PXRD
diagram of the anhydrous form C exhibits characteristic lines
located at 4.3, 6.8, 7.4, 8.7, 10.1, 11.1, 11.9, 12.3, 12.6 and
13.1.+-.0.2 degrees 2-theta. It is, among the various anhydrous
forms, the least stable of all the forms described in the present
invention. In the presence of a relative humidity of greater than
5%, it changes to a hydrated form. [0017] The anhydrous form D is
obtained according to a first method by crystallization of the form
A in an oil (especially Miglyol), following by rinsing with an
alkane, for example heptane; the second preparation method consists
in leaving a solution of
4-acetoxy-2.alpha.-benzoyloxy-5.beta.,20-epoxy-1-hydroxy-7.beta.,10.beta.-
-dimethoxy-9-oxotax-11-en-13.alpha.-yl
(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate in
a mixture of Polysorbate 80, pH 3.5, ethanol and water (preferably
a 25/25/50 mixture) to crystallize for approximately 48 hours. Its
boiling point by DSC is approximately 175.degree. C. (cf. FIG. 1)
and is found to be the highest of all the anhydrous forms isolated.
The PXRD diagram of the anhydrous form D (cf. FIG. 2) exhibits
characteristic lines located at 3.9, 7.7, 7.8, 7.9, 8.6, 9.7, 10.6,
10.8, 11.1 and 12.3.+-.0.2 degrees 2-theta. The FTIR spectrum of
the anhydrous form D exhibits characteristic bands located at 979,
1072, 1096, 1249, 1488, 1716, 1747, 3436.+-.1 cm.sup.-1 (cf. FIG.
3). Among all the forms described in the present invention, it is
the most stable anhydrous form. [0018] The anhydrous form E is
obtained at ambient temperature by maturation of the acetone form
or form A in ethanol so as to intermediately form an ethanolic form
which is subsequently desolvated under nitrogen sweeping or by
heating at approximately 100.degree. C. for 2 hours. Its melting
point by DSC is approximately 157.degree. C. The PXRD diagram of
the anhydrous form E exhibits characteristic lines located at 7.1,
8.1, 8.9, 10.2, 10.8, 12.5, 12.7, 13.2, 13.4 and 13.9.+-.0.2
degrees 2-theta. [0019] The anhydrous form F is obtained by
desolvating the ethanol/water heterosolvate at 120.degree. C. under
a nitrogen atmosphere for 24 hours and then maintaining in a dry
environment at 0% RH at ambient temperature. Its melting point by
DSC is approximately 148.degree. C. The PXRD diagram of the
anhydrous form F exhibits characteristic lines located at 4.4, 7.2,
8.2, 8.8, 9.6, 10.2, 10.9, 11.2, 12.1 and 12.3.+-.0.2 degrees
2-theta.
[0020] There are four crystalline forms identified in ethanolic
solvate or heterosolvate form: [0021] The ethanolate form B is
obtained at ambient temperature by maintaining the anhydrous form B
in an ethanol-vapour-saturated environment. The PXRD diagram of the
ethanolate form B exhibits characteristic lines located at 7.3,
7.8, 8.8, 10.2, 12.6, 12.9, 13.4, 14.2, 14.7 and 15.1.+-.0.2
degrees 2-theta. [0022] The ethanolate form D is obtained at
ambient temperature by maintaining the anhydrous form D in an
ethanol-vapour-saturated environment. The PXRD diagram of the
ethanolate form D (cf. FIG. 4) exhibits characteristic lines
located at 3.8, 7.5, 7.7, 8.4, 9.4, 10.3, 10.5, 11.1, 11.5 and
11.9.+-.0.2 degrees 2-theta. [0023] The ethanolate form E is
obtained at ambient temperature by maturation of the acetonate form
A in ethanol. The PXRD diagram of the ethanolate form E (cf. FIG.
5) exhibits characteristic lines located at 7.1, 8.1, 8.8, 10.2,
10.7, 12.5, 13.2, 13.4, 13.9 and 14.2.+-.0.2 degrees 2-theta.
[0024] The ethanol/water heterosolvate form F is obtained by
maintaining the form B in a minimum amount of ethanol at reflux,
slow cooling and isolation at ambient temperature and ambient
relative humidity. The PXRD diagram of the ethanol/water
heterosolvate form F exhibits characteristic lines located at 4.4,
7.2, 8.2, 8.3, 8.8, 9.6, 10.3, 10.9, 11.2 and 12.2.+-.0.2 degrees
2-theta.
[0025] There are two crystalline forms identified in hydrate form:
[0026] The monohydrated forms C are obtained at ambient temperature
by maintaining the anhydrous form C in an atmosphere containing at
least 10% relative humidity. The PXRD diagram of the monohydrate
form C exhibits characteristic lines located at 4.3, 6.8, 7.4, 8.6,
10.1, 11.1, 11.9, 12.2, 12.6 and 13.3.+-.0.2 degrees 2-theta.
[0027] The dihydrate form C is obtained at ambient temperature by
maintaining the anhydrous form C in an atmosphere containing at
least 60% relative humidity. The PXRD diagram of the dihydrate form
C exhibits characteristic lines located at 4.2, 6.9, 7.5, 8.4, 9.9,
10.9, 11.7, 12.3, 12.6 and 13.2.+-.0.2 degrees 2-theta.
[0028] Other, nonethanolic, solvates of the form B were prepared,
such as in particular those obtained with the following solvents:
dichloromethane, diisopropyl ether, n-propanol, isopropanol,
toluene, methyl isobutyl ketone, tetrahydrofuran,
dimethylformamide, ethyl acetate, etc.
[0029] The present invention will be described more fully by means
of the following examples which should not be considered to limit
the invention.
[0030] Experimental Analysis Conditions:
[0031] Differential Scanning Calorimetry (DSC):
[0032] The measurements were carried out on a T.A. Instruments
DSC2010 thermal analyser. The sample is subjected to temperature
programming from 25.degree. C. to 225.degree. C. with a heating
rate of 5.degree. C./min. The product is placed in a crimped
aluminium capsule and the amount of product analysed is between 2
and 5 mg. Constant nitrogen sweeping at 55 mL/min is used in the
oven chamber.
[0033] Powder X-Ray Diffraction (PXRD):
[0034] The analyses were carried out on a Panalytical X'Pert Pro
diffractometer with a reflection-mode Bragg-Brentano focusing
geometry (.theta.-2.theta.) assembly. The product analysed is
deposited as a thin layer on a silicon single crystal. A copper
anticathode tube (45 kV/40 mA) supplies an incident radiation Cu
K.alpha..sub.1 (.lamda.=1.5406 .ANG.). The beam is collimated using
Sollers slits which improve the parallelism and variable slits
which limit scattering. An X'Celerator detector completes the
device. The diagram recording characteristics are the following:
sweeping from 2 to 30 degrees 2.theta., counting time from 100 to
500 seconds per step with a step of 0.017.degree..
[0035] Fourier Transform InfraRed (FTIR) Spectrometry:
[0036] The solid samples were analysed using a Nicolet Nexus
spectrometer. The analysis is carried out by attenuated total
reflectance (ATR) using a Smart Orbit accessory from the company
Thermo (single reflection diamond crystal ATR accessory). The
spectral range swept is between 4000 and 400 cm.sup.-1 with a
resolution of 2 cm.sup.-1 and an accumulated scan number of 20.
Example 1
[0037] Two tests of dissolution of approximately 550 mg of
4-acetoxy-2.alpha.-benzoyloxy-5.beta.,20-epoxy-1-hydroxy-7.beta.,10.beta.-
-dimethoxy-9-oxotax-11-en-13.alpha.-yl
(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate in
14 g of Miglyol 812 Neutral oil, Sasol are carried out. Magnetic
stirring is carried out at 500 rpm for 24 hours at ambient
temperature.
[0038] After one week, the samples are vacuum-filtered and rinsed
with heptane. Each sample is analysed by PXRD for confirmation of
the form obtained. After filtration, between 300 and 350 mg of
anhydrous form D are obtained.
Example 2
[0039] Approximately 3 g of
4-acetoxy-2.alpha.-benzoyloxy-5.beta.,20-epoxy-1-hydroxy-70,100-dimethoxy-
-9-oxotax-11-en-13.alpha.-yl
(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenyl-propionate
are dissolved in a mixture of 50 mL ethanol+50 mL Polysorbate 80,
pH 3.5. 100 mL of water are added to the previous mixture and the
whole is homogenized. After storage for 48 hours at ambient
temperature, crystals of anhydrous form D appeared. The amount of
crystallized product recovered by filtration is approximately 2.45
g.
[0040] A comparative stability study was carried out between the
acetone solvate form A and the anhydrous form D. The comparison of
the PXRD analyses carried out on the A and D forms immediately
after production and after having maintained said forms at
40.degree. C. for one month gives the following results: [0041]
Form A: partial desolvation resulting in a mixture of the acetone
solvate form A and of the anhydrous form B being obtained. [0042]
Form D: no change detected after maintaining at 40.degree. C. for
one month.
* * * * *