The following specification describes the invention:

AMORPHOUS CABAZITAXEL

INTRODUCTION
Aspects of the present application provide amorphous cabazitaxel and processes for its preparation.

The drug compound known as “cabazitaxel” has chemical names: (2a,5ß,7ß,10ß,13a)-4-acetoxy-13-({(2R,3S)-3[(tertbutoxycarbonyl)amino]-2-hydroxy-3phenylpropanoyl}oxy)-1-hydroxy-7,10-dimethoxy-9-oxo-5,20-epoxytax-11-en-2-yl benzoate; or 4-acetoxy-2a-benzoyloxy-5ß,20-epoxy-1ß-hydroxy,7ß,10ß-dimethoxy-9-oxo-11-taxen-13a-yl-(2R,3S)-3-t-butoxycarbonylamino-3-phenyl-2-hydroxy propionate; or dimethoxydocetaxel. It has the structure of formula (I).

Cabazitaxel is an antineoplastic agent belonging to the taxane class. The commercial product sold as JEVTANA® Injection contains, as the active ingredient, an acetone solvate of cabazitaxel having the chemical name (2a,5ß,7ß,10ß,13a)-4-acetoxy-13-({(2R,3S)-3[(tertbutoxycarbonyl)amino]-2-hydroxy-3-phenylpropanoyl} oxy)-1-hydroxy-7,10-dimethoxy-9-oxo-5,20-epoxytax-11-en-2-yl benzoate-propan-
2 -one(1:1).

U.S. Patent No. 5,847,170 discloses (2a,5ß,7ß,10ß,13a)-4-acetoxy-13-({(2R,3S)-3[(tertbutoxycarbonyl)amino]-2-hydroxy-3-phenylpropanoyl}oxy)-1-hydroxy-7,10-dimethoxy-9-oxo-5,20-epoxytax-11-en-2-yl benzoate and a process for its purification by preparative thin-layer chromatography, using methanol and dichloromethane (5:95 by volume) as the eluent mixture, and the product is obtained in the form of an ivory-coloured foam.

U.S. Patent No. 7,241,907 discloses an acetone solvate of (2a,5ß,7ß,10ß,13a)-4-acetoxy-13-({(2R,3S)-3[(tertbutoxycarbonyl)amino]-2-hydroxy-3-phenylpropanoyl}oxy)-1-hydroxy-7,10-dimethoxy-9-oxo-5, 20-epoxytax-11-en-2-yl benzoate, its X-ray powder diffraction pattern, and a process for its preparation by crystallization from a mixture of water and acetone, followed by drying the isolated product under reduced pressure.

International Application Publication No. WO 2009/115655 A2 discloses anhydrides, solvates, ethanol hetero-solvates and hydrates of dimethoxydocetaxel or 4-acetoxy-2a-benzoyloxy-5ß,20-epoxy-1ß-hydroxy,7ß,10ß-dimethoxy-9-oxo-11-taxen-13a-yl-(2R,3S)-3-t-butoxycarbonylamino-3-phenyl-2-hydroxypropionate, which are designated as anhydrous Form B, anhydrous Form C, anhydrous Form D, anhydrous Form E, anhydrous Form F, ethanol/water hetero-solvate form F, ethanolate form B, ethanolate Form D, ethanolate form E, monohydrate Form C, and a dihydrate form. Further, the publication discloses processes for preparing the polymorphic forms.

There remains a need for additional polymorphic forms of cabazitaxel, and processes for making them.

SUMMARY

In an aspect, the present application provides an amorphous cabazitaxel.

In an aspect, the present application provides a process for the preparation of an amorphous cabazitaxel, embodiments comprising:

a) providing a solution of cabazitaxel in a solvent; and

b) isolating an amorphous cabazitaxel.

In an aspect, the present application provides an amorphous cabazitaxel, characterized by a powder X-ray diffraction (PXRD) pattern, substantially as illustrated by one or more of Fig. 1, Fig. 2, Fig. 3, and Fig. 4.

In an aspect, the present application provides pharmaceutical compositions comprising amorphous cabazitaxel, together with one or more pharmaceutically acceptable excipients.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 is an illustration of a powder X-ray diffraction (PXRD) pattern of an amorphous cabazitaxel prepared according to Example 1.

Fig. 2 is an illustration of a PXRD pattern of an amorphous cabazitaxel prepared according to Example 2.

Fig. 3 is an illustration of a PXRD pattern of an amorphous cabazitaxel prepared according to Example 3.

Fig. 4 is an illustration of a PXRD pattern of an amorphous cabazitaxel prepared according to Example 4.

DETAILED DESCRIPTION

In an aspect, the present application provides an amorphous cabazitaxel.

In an aspect, the present application provides processes for the preparation of an amorphous cabazitaxel, embodiments comprising:

a) providing a solution of cabazitaxel in a solvent; and

b) isolating an amorphous cabazitaxel.

Step a) involves providing a solution of cabazitaxel in a solvent. Providing a solution in step a) includes:

i) direct use of a reaction mixture containing cabazitaxel that is obtained in the course of its synthesis; or

ii) dissolving cabazitaxel in a suitable solvent.

Any physical form of cabazitaxel may be utilized for providing the solution of cabazitaxel in step a).

Cabazitaxel that may be used as the input for the process of the present application may be obtained by any process, including the processes described in the literature. For example, cabazitaxel may be prepared by the processes described in U.S. Patent No. 5,847,170.

Suitable solvents that may be used in step a) include, but are not limited to, polar aprotic solvents such as for example, dimethylsulphoxide, acetone, acetonitrile, and mixtures of two or more thereof.

The dissolution temperatures may range from about -20°C to about the reflux temperature of the solvent, depending on the solvent used for dissolution, as long as a clear solution of cabazitaxel is obtained without affecting its quality. The solution may optionally be treated with carbon, flux-calcined diatomaceous earth (e.g., Hyflow™), or any other suitable material, to remove color and/or to clarify the solution.

Optionally, the solution may be filtered to remove any insoluble particles. The insoluble particles may be removed suitably by filtration, centrifugation, decantation, or any other suitable techniques. The solution may be filtered by passing through paper, glass fiber, or other membrane material, or a bed of a clarifying agent such as Celite® or Hyflow. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature crystallization.

Step b) involves isolation of an amorphous form of cabazitaxel from the solution of step a).

In embodiments, the isolation may be effected by removing solvent. Suitable techniques that may be used for the removal of solvent include using a rotational distillation device such as a Büchi® Rotavapor®, spray drying, thin film drying, freeze drying (lyophilization), ball milling, and the like, or any other suitable techniques.

The solvent may be removed, optionally under reduced pressures, at temperatures less than about 200°C, less than about 150°C, less than about 100°C, less than about 60°C, less than about 40°C, less than about 20°C, less than about 0°C, less than about -20°C, less than about -40°C, less than about -60°C, less than about -80°C, or any other suitable temperatures.

Freeze drying (lyophilization) may be carried out by freezing a solution of cabazitaxel at low temperatures and reducing the pressure as required to remove the solvent from the frozen solution of cabazitaxel. Temperatures that may be required to freeze the solution, depend on the solvent chosen to make the solution of cabazitaxel, may range from about -80°C to about 0°C, or up to about 20°C. Temperatures that may be required to remove the solvent from the frozen solution may be less than about 20°C, less than about 0°C, less than about -20°C, less than about -40°C, less than about -60°C, less than about -80°C, or any other suitable temperatures.

The solid obtained from step b) may be collected using techniques such as scraping, shaking the container, or other techniques specific to the equipment used. The product thus obtained may be optionally further dried.

Drying may be suitably carried out in a tray dryer, vacuum oven, Büchi® Rotavapor®, air oven, fluidized bed dryer, spin flash dryer, flash dryer, and the like. The drying may be carried out at atmospheric pressure or under reduced pressures, at temperatures less than about 100°C, less than about 60°C, less than about 40°C, less than about 20°C, less than about 0°C or any other suitable temperatures. The drying may be carried out for any time periods required for obtaining a desired quality, such as from about 15 minutes to several hours.

The dried product may be optionally milled to obtain desired particle sizes. Milling or micronization may be performed before drying, or after the completion of drying of the product. Techniques that may be used for particle size reduction include, without limitation, ball, roller, and hammer mills, and jet mills.

In an aspect, the present application provides an amorphous cabazitaxel, characterized by a PXRD pattern, substantially as illustrated by any one or more of Fig. 1, Fig. 2, Fig. 3, and Fig. 4.

All PXRD data reported herein are obtained using a Bruker AXS D8 Advance Powder X-ray Diffractometer, or a PANalytical X-ray Diffractometer, using copper Ka radiation.

In an aspect, the present application provides pharmaceutical compositions comprising amorphous cabazitaxel, together with one or more pharmaceutically acceptable excipients.

In embodiments, the pharmaceutical compositions may be formulated as: liquid dosage forms, such as, for example, syrups, suspensions, dispersions, and emulsions; and injectable preparations for intravenous, intradermal, intrathecal, and intramuscular depot administration, for example, solutions, dispersions, and freeze dried compositions. Pharmaceutical compositions according to the present application comprise one or more pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients include, but are not limited to, suitable surface modifiers. Such excipients include various polymers, low molecular weight oligomers, natural products, and surfactants.

DEFINITIONS

The following definitions are used in connection with the present application unless the context indicates otherwise. Celite® is a flux-calcined diatomaceous earth, and Celite® is a registered trademark of World Minerals Inc. Hyflow is a flux-calcined diatomaceous earth treated with sodium carbonate. Hyflo Super Cel® is a registered trademark of the Manville Corp.

Certain specific aspects and embodiments of the present application will be explained in more detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the present application in any manner.

EXAMPLES

Example 1: Preparation of amorphous cabazitaxel.

Cabazitaxel (0.5 g) and acetonitrile (9 mL) are placed into a round-bottom flask at 25-35°C and stirred to form a solution. The solution is evaporated completely in a Büchi® Rotavapor® at 45°C under reduced pressure, to afford the title compound. PXRD: Fig. 1.

Example 2: Preparation of amorphous cabazitaxel.

Cabazitaxel (1.0 g) and acetone (8 mL) are placed into a round-bottom flask at 25-35°C and stirred to form a solution. The solution is evaporated completely in a Büchi® Rotavapor® at 45°C under reduced pressure, to obtain the solid. A 150 mg portion of the solid was dried in an air oven at 50°C under vacuum for 6 hours, to afford 130 mg of the title compound. PXRD: Fig. 2.

Example 3: Preparation of amorphous cabazitaxel.

Cabazitaxel (0.5 g) and N,N-dimethylsulphoxide (12 mL) are placed in a glass beaker at 25-35°C and stirred to form a solution. The solution is filtered and the filtrate is subjected to freeze drying in a VirTis® AdVantage™ 2.0 bench top freeze dryer, at -50°C to -3°C and 300 mTorr vacuum, to afford the title compound. PXRD: Fig. 3.

Example 4: Preparation of amorphous cabazitaxel.

Cabazitaxel (0.5 g) and acetonitrile (10 mL) are placed in a glass beaker at 25-35°C and stirred to form a solution. The solution is filtered and the filtrate is subjected to freeze drying in a VirTis® AdVantage™ 2.0 bench top freeze dryer, at -50°C to -3°C and 300 mTorr vacuum, to afford the title compound. PXRD: Fig. 4.

CLAIMS:

1. A process for the preparation of an amorphous cabazitaxel comprising:

a) providing a solution of cabazitaxel in a solvent selected from dimethylsulphoxide, acetone, acetonitrile and mixtures thereof; and

b) isolating an amorphous cabazitaxel.

2. The process according to claim 1, wherein the solution in step a) is provided at temperatures about 0°C to about reflux temperature of the solvent used.

3. The process according to claim 1, wherein the isolation in step b) is effected by removing the solvent from the solution of step a).

4. The process according to claim 1, wherein the isolation in step b) is effected by removing the solvent using rotational distillation device such as a Buchi® Rotavapor®, spray drying, thin film drying or freeze drying.