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(21)Application Number: KE/P/2010/ 001110

(22) Filing Date: 15/01/2009

(30) Priority data: 08/00,243  17/01/2008  FR

(86) PCT data PCT/FR09/000042 15/01/2009 wo 2009/115655 24/09/2009

(73) Owner: Aventis Phanna S.A. of 20, Avenue Raymond Aron, 92160 ANTONY, France

(72) Inventors: BILLOT, Pascal of c/o Sanofi-Aventis, D6partement Brevets, 174 avenue de France, F-75013 Paris, France;  DUFRAJGNE, Marielle of c/o Sanofi-Aventis, D6partement Brevets, 174 avenue de France, F-75013 Paris, France; ELMALEH, Hagitofc/o Sanofi-Aventis,  Departement Brevets, 174 avenue de France, F-75013 Paris,France; GUILJANI, Alexandre of c/o Sanofi-Aventis, D6partement Brevets, 174 avenue de France, F-75013 Paris, France; MANGIN, Fabrice of c/o Sanofi-Aventis, D6partement Brevets, 174 avenue de France, F-75013 Paris, France; RORTAIS, Patricia of c/o Sanofi-  Aventis, D6partement Brevets, 174 avenue de France, F-750 13 Paris, France and ZASKE, Lionel of c/o Sanofi-Aventis, Departement Brevets, 174 avenue de France, F-75013 Paris, France

(74) Agent/address for correspondence:  Kaplan & Stratton Advocates, P.O. Box 40111-00100, Nairobi

(54) Title: CRYSTALLINE FORMS OF DIMETHOXY DOCETAXEL AND METHODS FOR PREPARING SAME.

(57) 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-2a.-benzoyloxy-5!3, 20-epoxy-1-hydroxy-713,1013-dimethoxy-9-oxo-tax-I I- ene-13a.-yle, and to the preparation thereof.
 
CRYSTALLINE FORMS OF DIMETHO}..'Y DOCETAXEL AND METHODS FOR PREPARING THE SAME

The present invention relates to crystalline forms of dimethoxy docetaxel or

4-acetoxy-2ct-benzoyloxy-5~,20-epoxy-1-hydroxy-7~,10~-dimethoxy-9-oxotax-

11-en-13ct-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate and

to methods for the preparation thereof.

4-Acetoxy-2ct-benzoyloxy-5~,20-epoxy-1-hydroxy-7~,10~-dimethoxy-

9-oxotax-11-en-13ct-yl    (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenyl-

propionate exhibits notable anticancer and antileukaemic properties.

10    4-Acetoxy-2ct-benzoyloxy-5~,20-epoxy-1-hydroxy-7~,10~-dimethoxy-

9-oxotax-11-en-13ct-yl    (2R,3S)-3-tert-butoxycarbonylarnino-2-hydroxy-3-phenyl-

propionate 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

15    is not crystallized and is not characterized.

It was found that the acetone solvate of 4-acetoxy-2ct-benzoyloxy-5~,20-epoxy-1-hydroxy-7 ~. 1O~-dimethoxy-9-oxotax-11-en-13ct-yl (2R,3S)-3-tert-but~xy­

carbonylamino-2-hydroxy-3-phenylpropionate  (called  form  A)   was  completely

determined  and  characterized  according  to  the  patent  published  under  number

20    W02005/028462.

The present invention relates to new crystalline fonns, with the exclusion of

the acetonate form, the only one known to date.

According  to  the  present invention,  it has  now  been  found  that  certain

anhydrous forms, certain ethanolic solvates or heterosolvates and hydrated fonns have

25    been completely characterized from a physical and chemical structure point of view.

According to the invention, among the anhydrous fonns of 4-acetoxy-2a.-

benzoyloxy-5~,20-epoxy-1-hydroxy-7~,1 O~-dimethoxy-9-oxotax-11-en-13ct-yl

(2R,3S)-3-tert-butoxycarbonylarnino-2-hydroxy-3-phenylpropionate,   five   different

fonns  have  been  identified,  among  the  ethanolic  solvates  or  heterosolvates  of

30    4-acetoxy-2ct-benzoyloxy-5~,20-epoxy-1-hydroxy-7~,10~-dimethoxy-9-oxotax-

11-en-13ct-yl    (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate,

four different forms have been identified and among the hydrates of 4-acetoxy-2a.-

benzoyloxy-5~,20-epoxy-l-hydroxy-7~, 1O~-dimethoxy-9-oxotax-11-en-13ct-yl
 




2

(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate,   two   different

forms have been identified.

The  five  anhydrous  forms  identified  were  obtained  according  to  the

following methods:

The anhydrous form B by a method which consists in heating the acetone fonn or form A obtained according to the patent mentioned above, between 100 and
ll0°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

10    150'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.

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'C

15    and maintaining between 0 and 5% RH at ambient temperature. Its melting point by DSC is approximately 146'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  :1::  0.2 degrees 2-theta. It is,  among the various

anhydrous forms,  the least stable of all the forms  described in the present

20    invention. In the presence of a relative humidity of greater than 5%, it changes to a hydrated form.

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 25 consists in leaving a solution of 4-acetoxy-2a-benzoyloxy-5p,20-epoxy-1-

hydroxy-7p, I Op-dimethoxy-9-oxotax-ll-en-13a-yl    (2R,3 S)-3-tert-

butoxycarbonylarnino-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

30    approximately 175'C (cf. Figure I) and is found to be the highest of all the anhydrous forms isolated. The PXRD diagram of the anhydrous form D (cf. Figure 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, 35            1249, 1488, 1716, 1747, 3436 ±I  em•' (cf. Figure 3). Among all the forms
 





described in the present invention, it is the most stable anhydrous form.

TI1e anhydrous fonn E is obtained at ambient temperature by maturation of the acetone form or fonn A in ethanol so as to intennediately form an ethanolic fonn which is subsequently desolvated under nitrogen sweeping or by heating
at    approximately  100°C  for  2 hours.  Its  melting  point  by  DSC  is

approximately 157°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.

The  anhydrous  form  F  is  obtained  by  desolvating  the  ethanol/water

10    heterosolvate at 120°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°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.

15

There are four crystalline fonns identified in ethanolic solvate or heterosolvate form:

The ethanolate form B is obtained at ambient temperature by maintaining the anhydrous form B in an ethanol-vapour-saturated environment. The PXRD

20    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.

The ethanolate fonn 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. Figure 4) exhibits characteristic lines

25    located at 3.8, 7.5, 7.7, 8.4, 9.4, 10.3, 10.5, 11.1, ll.5 and 11.9 ± 0.2 degrees 2-theta.

The ethanolate formE is obtained at ambient temperature by maturation of the acetonate form A in ethanol. The PXRD diagram of the ethanolate formE (cf.
Figure 5) exhibits characteristic lines located at 7.1, 8.1, 8.8, 10.2, 10.7, 12.5,

30    13.2, 13.4, 13.9 and 14.2 ± 0.2 degrees 2-theta.

The ethanol/water heterosolvate fonn 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 ethanoVwater heterosolvate fonn F exhibits characteristic lines located at
 




4

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.

There are two crystalline forms identified in hydrate form:

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.

-    The dihydrate form C is obtained at ambient temperature by maintaining the

10    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, I 0.9, 11.7, 12.3, 12.6 and 13.2 ± 0.2 degrees 2-theta.

Other,  nonethanolic,  solvates  of the  form  B  were  prepared,  such  as  in

particular those obtained with the following solvents: dichloromethane, diisopropyl

15    ether, n-propanol, isopropanol, toluene, methyl isobutyl ketone, tetrahydrofuran, dimethylfonnamide, ethyl acetate, etc.

The present invention will be described more fully by means of the following examples which should not be considered to limit the invention.

Experimental analysis conditions:

20

Differential Scanning Calorimetry (DSCl:

The measurements were carried out on a T.A. Instruments DSC2010 thermal analyser.

The sample is subjected to temperature progranuning from  25°C to 225°C with a

25    heating rate of 5°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 rniJmin is used in the oven chamber.


30    Powder X-Ray Diffraction (PXRD):
 





The analyses were carried out on a Panalytical X'Pert Pro diffractometer with a reflection-mode Bragg-Brentano focusing geometry (8-28) assembly. The product analysed is deposited as a thin layer on a silicon single crystal. A copper anticathode
tube (45 kV/40 rnA) supplies an incident radiation CuKa, (1. = 1.5406 A). 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 28,
counting time from 100 to 500 seconds per step with a step of0.017'.

10

Fourier Transform InfraRed (FTIR.) spectrometry:

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

15    the company Thermo (single reflection diamond crystal ATR accessory). The spectral

range swept is between 4000 and 400 cm"1 with a resolution of 2 cm"1 and an accumulated scan number of20.

Example 1

20 Two tests of dissolution of approximately 550 mg of 4-acetoxy-2a-benzoyloxy-5p,20-epoxy-1-hydroxy-7p, 1op-dimethoxy-9-oxotax-11-en-13a-y1 (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate in 14 g of Miglyol 812 Neutral oil, Sasol are carried out. Magaetic stirring is carried out at 500 rpm for 24 hours at ambient temperature.

25    After one week, the samples are vacuum-filtered and rinsed with heptane.

Each sample is analysed by PXRD for confirmation of the fom1 obtained. After filtration, between 300 and 350 mg of anhydrous fonm D are obtained.


Approximately 3 g of 4-acetoxy-2a-benzoyloxy-5p,20-epoxy-1-hydroxy-30 7P,10P-dimethoxy-9-oxotax-11-en-13a-y1 (2R,3S)-3-tert-butoxycarbonylamino-
 





2-hydroxy-3-phenylpropionate 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.

A  comparative stability study was carried out between the  acetone  solvate

form A and the anhydrous form D. The comparison ofthe PXRD analyses carried out

on the A and D fonns immediately after production and after having maintained said

forms at 40°C for one month gives the following results:

10    -   Form  A:  partial desolvation resulting in a mixture of the  acetone  solvate

form A and of !he anhydrous form B being obtained.

-    Form D: no change detected after maintaining at 40°C for one month.
 






CLAIMS

1.- Crystalline forms of 4-acetoxy-2o:-benzoyloxy-5~,20-epoxy-l-hydroxy-

7~, I 0~-dimethoxy-9-oxotax-11-en-!3o:-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-2o:-benzoyloxy-5~,20-epoxy-1-hydroxy-7~,10~-dimethoxy-

9-oxotax-11-en-13o:-yl    (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenyl-

propionate.

3.    -   Anhydrous  form  B  of  4-acetoxy-2o:-benzoyloxy-5~,20-epoxy-1-

10    hydroxy-?~, I O~-dimethoxy-9-oxotax-11-en-13o:-yl  (2R,3S)-3-tert-butoxycarbonyl-

amino-2-hydroxy-3-phenylpropionate according to Claim 2, characterized by a PXRD diagram exhibiting 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.

4.    -   Anhydrous  form   C  of  4-acetoxy-2o:-benzoyloxy-5~,20-epoxy-1-

15    hydroxy-?~, I O~-dimethoxy-9:oxotax-11-en-!3o:-yl    (2R,3S)-3-tert-butoxycarbonyl-

arnino-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 !3.1 ± 0.2 degrees 2-theta.

5.    -   Anhydrous  form  D  of  4-acetoxy-2o:-benzoyloxy-5~,20-epoxy-1-

20    hydroxy-?~, I 0~-dimethoxy-9-oxotax-11-en-!3o:-yl    (2R,3S)-3-tert-butoxycarbonyl-

amino-2-hydroxy-3-phenylpropionate according to Claim 2, characterized by a PXRD diagram exhibiting 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.

6.-   Anhydrous   form   E   of  4-acetoxy-2o:-benzoyloxy-5~,20-epoxy-1-

25 hydroxy-?~, I O~-dimethoxy-9-oxotax-11-en-13o:-yl (2R,3S)-3-tert-butoxycarbonyl-amino-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 !3.9 ± 0.2 degrees 2-theta.

7.    -   Anhydrous  form  F  of  4-acetoxy-2o:-benzoyloxy-5~,20-epoxy-1-

30    hydroxy-?~,! O~-dimethoxy-9-oxotax-ll-en-13o:-yl  (2R,3S)-3-tert-butoxycarbonyl-

amino-2-hydroxy-3-phenylpropionate according to Claim 2, characterized by a PXRD
 





diagram exhibiting characteristic lines located at 4.4, 7.2, 8.2, 8.8, 9.6, 10:2, 10.9,

1 1.2, 12.1 and 12.3 ± 0.2 degrees 2-theta.

8.- Forms according to Claim 1, characterized in that they are ethanolic solvate or heterosolvate forms of 4-acetoxy-2a.-benzoyloxy-5~,20-epoxy-1-hydroxy-

7~, 1op-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-5 p,20-epoxy-1-hydroxy-7p, 1Op-dimethoxy-9-oxotax-11-en-13a.-yl (2R,3S)-3-tert-butoxycarbonylarnino-2-hydroxy-3-phenylpropionate according to Claim 8, characterized by a PXRD
10    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-5p,20-epoxy-

1-hydroxy-7p,1 op-dimethoxy-9-oxotax-11-en-13a.-yl  (2R,3S)-3-tert-butoxycarbonyl-

amino-2-hydroxy-3-phenylpropionate according to Claim 8, characterized by a PXRD

15    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.

1 I. - Ethanolate form E of 4-acetoxy-2a.-benzoyloxy-5p,20-epoxy-1-hydroxy-7p,1 Op-dimethoxy-9-oxotax-ll-en-13a.-y1 (2R,3S)-3-tert-butoxycarbonyl-

amino-2-hydroxy-3-phenylpropionate according to Claim 8, characterized by a PXRD

20    diagram exhibiting 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.

12.  -  EthanoUwater  heterosolvate  fonn  F of 4-acetoxy-2a.-benzoyloxy-

5p,20-epoxy-l-hydroxy-7p, I Op-dimethoxy-9-oxotax-11-en-13a.-yl    (2R,3S)-3-tert-

butoxycarbonylamino-2-hydroxy-3-phenylpropionate    according    to    Claim 8,

25    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, I 1.2 and 12.2 ± 0.2 degrees 2-theta.

13.- Fonns according to Claim 1, characterized  in that they are hydrate

forms of 4-acetoxy-2a.-benzoyloxy-5p,20-epoxy-1-hydroxy-7p,!Op-dimethoxy-9-oxotax-11-en-13a.-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenyl-

30    propionate.

14.-  Monohydrate  form  C  of  4-acetoxy-2a.-benzoyloxy-5p,20-epoxy-

1-hydroxy-7~,1 op-dimetl10xy-9-oxotax-11-en-13a.-yl (2R,3S)-3-tert-butoxycarbonyl-arnino-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 fonn C of 4-acetoxy-2u-benzoyloxy-5p,20-epoxy-1-hydroxy-7p,!OP-dimethoxy-9-oxotax-11-en-13u-yl (2R,3S)-3-tert-butoxycarbonyl-amino-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,
II. 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,

10 which consists in heating the acetone solvate form A between 100 and ll0°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,

15    followed by drying up to approximately 50'C and then maintaining at ambient temperature at a relative humidity ofless 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.

20    19. -Method for preparing the anhydrous fonn 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 fonn D according to Claim 5, by crystallization of a solution of 4-acetoxy-2u-benzoyloxy-5p,20-epoxy-1-hydroxy-
25    7p, I Op-diruethoxy-9-oxotax-11-en-13u-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 formE according to Claim 6, by

30    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
 




10

heating  at  approximately  JOO'C  for  2 hours  and  then  returning  to  ambient

temperature.

22. -Method for preparing the anhydrous fonn F according to Claim 7, by

desolvating the ethano1/water heterosolvate at l20°C under a nitrogen atmosphere for

24 hours and then maintaining at a relative humidity of 0% at ambient temperature.

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