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Polymorphs of (2R,3S)-N-carboxy-3-phenylisoserine, N-tert-butyl ester, 13-ester with 5(β)-20-epoxy-1,2(α), 4,7(beta),10(β), 13(α)-hexahydroxytax-11-en-9-one 4-acetate 2-benzoate

IP.com Disclosure Number: IPCOM000131707D
Publication Date: 2005-Nov-16
Document File: 6 page(s) / 182K

Publishing Venue

The IP.com Prior Art Database

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Polymorphs of (2R,3S)-N-carboxy-3-phenylisoserine, N-tert-butyl ester, 13-ester with 5(β)-20-epoxy-1,2(α), 4,7(beta),10(β), 13(α)- hexahydroxytax-11-en-9-one 4-acetate 2-benzoate

    (2R,3S)-N-carboxy-3-phenylisoserine, N-tert-butyl ester, 13-ester with 5(β)-20-epoxy-1,2(α), 4,7(beta),10(β), 13(α)-hexahydroxytax-11-en-9-one 4- acetate 2-benzoate (referred to as DCX) is an antineoplastic agent belonging to the taxoid family. DCX is a semi-synthetic anticancer drug deriving from chemical modification of a taxane core (named 10-deacetylbaccatin III or 10-DAB) extracted from leaves and bark of European or Indian yew trees.

DCX represented by the following formula

O

HN

O

O

OH

OH

     O O

HO

H

   O HO

H

O

O

O

O

is marketed under the name TAXOTERE® as a concentrated injection. TAXOTERE® injection is a clear yellow to brownish-yellow viscous solution. TAXOTERE® injection is available in single-dose vials containing 20 mg (0.5 ml) or 80 mg (0.2 ml) DCX (anhydrous).

  Two crystalline forms of DCX were found, and are described herein below. Form D

Figure 1: The crystalline form, denominated Form D, has main X-ray powder diffraction peaks at about 8.0, 11.3, 12.5, 15.5 and 16.9 ±0.2 degrees two-theta. Form D may be further characterized by X-ray powder diffraction peaks at about 4.7, 9.2,
13.9, 20.4 and 23.5 degrees two-theta, ±0.2 degrees two-theta.

1

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Figure 2: Form D may further be characterized by a DSC thermogram showing a small endotherm at a temperature of about 30ºC to about 50ºC and another endotherm at a temperature of about 140ºC to about 180ºC.

_

Integral -9.71 mJ

1 normalized -3.88 Jg^-1 Peak 32.48 °C Left Limit 27.94 °C Right Limit 48.91 °C

Integral -30.09 mJ

normalized -12.04 Jg^-1 Peak 166.91 °C Left Limit 150.09 °C Right Limit 174.24 °C

mW

Method: 25-200C 10C/min 40ml/min N2

25.0-200.0°C 10.00°C/min N2 40.0 ml/min

40 60 80 100 120 140 160 180

0 2 4 6 8 10 12 14 16

°C

min

Form D exists as an anhydrous form.

Trihydrate form

Figure 3: The crystalline form, denominated Trihydrate form, has main X-ray powder diffraction peaks at about 4.6, 9.1, 10.6, 14.2 and 17.9 ±0.2 degrees two-theta. Trihydrate form may be further characterized by X-ray powder diffraction peaks at about 11.3, 12.5, 15.5, 19.5 and 21.5 degrees two-theta, ±0.2 degrees two-theta.

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Figure 4: The Trihydrate form may further be characterized by a DSC thermogram showing a broad endotherm at a temperature of about 50ºC to about 100ºC and a small endotherm at a temperature of about 110ºC to about 140ºC and an endothermic peak at a temperature of about 171ºC.

_

Integral -442.51 mJ

normalized -95.16 Jg^-1 Onset 53.86 °C Peak 77.36 °C Left Limit 46.01 °C Right Limit 100.47 °C

Integral -46.87 mJ

normalized -10.08 Jg^-1 Onset 166.56 °C Peak 171.21 °C Left Limit 161.22 °C Right Limit 177.83 °C

mW

Integral -12.76 mJ

normalized -2.74 Jg^-1 Onset 107...