WO2014115168A2

WO2014115168A2 - Novel solvate forms of cabazitaxel and process for preparation thereof

Info

Publication number: WO2014115168A2
Application number: PCT/IN2014/000049
Authority: WO
Inventors: Kocherlakota Chandrashekhar; Banda Nagaraju; Pullagurla Manik REDDY
Original assignee: Leiutis Pharmaceutials LLP
Current assignee: Leiutis Pharmaceutials LLP
Priority date: 2013-01-23
Filing date: 2014-01-23
Publication date: 2014-07-31
Anticipated expiration: 2015-07-23
Also published as: WO2014115168A3

Abstract

The present invention relates to novel solvate forms of cabazitaxel and preparation thereof. The invention further relates to tertiary-butyl alcohol solvate form of Cabazitaxel, and process of preparation thereof, and pharmaceutical compositions comprising of the novel solvate form of cabazitaxel.

Description

NOVEL SOLVATE FORMS OF CABAZITAXEL AND PROCESS FOR

PREPARATION THEREOF

FIELD OF THE INVENTION

The invention relates to novel solvate forms of dimethoxydocetaxel or 4-acetoxy-2a.- benzoyloxy-5p 20-epoxy- l -hydroxy-7p , Ι Οβ -dimethoxy-9-oxotax-l l -en-13a-yl(2R,3S)- 3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate and methods ^' for the preparation thereof.

BACKGROUND OF THE INVENTION

Cabazitaxel is chemically described as ( \ S,2S,3RAS, 7R,9S, \ 0S, \ 2R, \ 55)-4-(Acetyloxy)- 15- { [(2R,3S)-3- { [(tert-butoxy) carbonyl]amino} -2-hydroxy-3-phenylpropanoyl]oxy} - 1 - hydroxy-9, 12-dimethoxy- 10, 14, 17, 17-tetramethyl- 1 1 -oxo-6-oxatetracyclo

[ l l .3.1.0³'¹⁰.0⁴'⁷]heptadec- 13 -ene-2-yl benzoate. Cabazitaxel is an antineoplastic agent belonging to the taxane class, exhibits anticancer and antileukemic properties and used for the treatment of hormone-refractory prostate cancer.lt is prepared by semi-synthesis with a precursor extracted from yew needles. Cabazitaxel is a microtubule inhibitor. It acts by binding to tubulin and promotes its assembly into microtubules while simultaneously inhibiting disassembly. This leads to the stabilization of microtubules, which results in the inhibition of mitotic and interphase cellular functions. Cabazitaxel has the following chemical structure:

Prostate cancer is a form of cancer that develops in the prostate gland in the male reproductive system. Most prostate cancers are slow growing; however, there are cases of aggressive prostate cancers. The cancer cells may metastasize (spread) from the prostate to other parts of the body, particularly the bones and lymph nodes.

Cabazitaxel is white to almost-white powder with a molecular formula of C45H57 O14.C3H6O and a molecular weight of 894.01 (for the acetone solvate) / 835.93 (for the solvent free). It is lipophilic, practically insoluble in water and soluble in alcohol.

Cabazitaxel is marketed in the US under the trade name JEVTANA by SANOFI AVENTIS US. JEVTANA is available as single 60 mg injections for intravenous use. JEVTANA (Cabazitaxel) Injection 60 mg/1.5 mL is a sterile, non-pyrogenic, clear yellow to brownish-yellow viscous solution and is available in single-use vials containing 60 mg Cabazitaxel (anhydrous and solvent free) and 1 .56 g Polysorbate 80. Each mL contains 40 mg Cabazitaxel (anhydrous) and 1 .04 g Polysorbate 80. JEVTANA requires two dilutions prior to intravenous infusion. JEVTANA injection should be diluted only with the supplied DILUENT (clear, colorless, sterile, and non-pyrogenic solution containing 13% (w/w) ethanol in water for injection, approximately 5.7 mL) for JEVTANA, followed by dilution in either 0.9% sodium chloride solution or 5% dextrose solution.This formulation is indicated in combination with prednisone for the treatment of patients with hormone- refractory metastatic prostate cancer previously treated with a docetaxel-containing treatment regimen.

U.S Patent No. 5438072 discloses new injectable form containing taxoids such as taxol, taxotere or derivatives. U.S Patent No. 5847170discloses Cabazitaxel and its process of preparation and pharmaceutical compositions containing them.

U.S Patent No. 7241907 by Sanofi discloses acetone solvate form of Cabazitaxel and its method of preparation.

U.S. Patent Application No. 201 10144362 by Sanofi Aventis Pharma discloses various crystalline forms of dimethoxydocetaxel such as anhydrous form D, anhydrous form B, anhydrous form C, anhydrous form E, anhydrous form F, ethanolate form D, ethanolate form E, ethanolate form B, ethanol/water heterosolvate form F, monohydrated forms C and dihydrate form C and methods for preparing the same.

WO2012/1421 1 7 by Teva Pharmaceuticals discloses various solid state forms of Cabazitaxel such as crystalline Cabazitaxel form 1, Amorphous Cabazitaxel in a powdery, non-foamy form, crystalline Cabazitaxel form II, crystalline Cabazitaxel form III, crystalline Cabazitaxel form IV, crystalline Cabazitaxel form V and processes for preparation thereof. Polymorphism, the occurrence of different crystal forms, is a property of some molecules and molecular complexes. A single molecule, like Cabazitaxel, may give rise to a variety of polymorphs having distinct crystal structures and physical properties like melting point, thermal behaviors (e.g. measured by thermogravimetric analysis - "TGA", or differential scanning calorimetry - "DSC"), powder X-ray diffraction (PXRD) pattern, infrared absorption fingerprint, and solid state NMR spectrum. One or more of these techniques may be used to distinguish different polymorphic forms of a compound. Discovering new polymorphic forms and solvates of a pharmaceutical product can provide materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, and ease of purification or as desirable. New polymorphic forms and solvates of a pharmaceutically useful compound or salts thereof can also provide an opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for formulation optimization, for example by providing a product with different properties, e.g., better processing or handling characteristics, improved dissolution profile, or improved shelf- life.

In particular, it would be desirable to find other novel forms of Cabazitaxel and to find alternate processes for making useful solvate forms of Cabazitaxel having desirable properties.

It has surprisingly been found that by using solvents or solvent mixture such as tertiary- butyl alcohol or in combination with other solvents such as ethyl acetate in a suitable proportion resulted in a novel form of Cabazitaxel having desirable properties. OBJECTS OF THE INVENTION

The primary object of the invention is to provide novel solvate forms of Cabazitaxel. Another object of the invention is to provide process for preparation of such novel solvate forms of Cabazitaxel.

SUMMARY OF THE INVENTION Accordingly, the present invention provides novel solvate forms of Cabazitaxel, process for the manufacture thereof and pharmaceutical compositions comprising the said novel solvate forms of Cabazitaxel.

One aspect of the invention relates, to novel solvate forms of Cabazitaxel such as tertiary- butyl alcohol solvate form of Cabazitaxel.

Another aspect of the invention relates to novel solvate forms of Cabazitaxel comprising tertiary butyl alcohol or a mixture of tertiary-butyl alcohol and ethyl acetate and the process of preparation thereof.

Another aspect of the present invention relates to tertiary-butyl alcohol solvate form of Cabazitaxel preparation comprising mixture of solvents such as tertiary-butyl alcohol (TBA) and ethyl acetate (EA) in varied proportions. Yet another aspect of the invention provides the lyophilization process by using a suitable solvent or mixtures of solvents to obtain the novel solvate form of Cabazitaxel.

Yet another aspect of the invention relates to pharmaceutical compositions of Cabazitaxel comprising novel solvate form of Cabazitaxel and method of preparation thereof. BRIEF DESCRIPTION OF THE DRAWINGS:

Figure 1 shows a powder X-ray diffraction pattern ("Powder XRD" or "PXRD") of novel solvate form (TBA Solvate form) of Cabazitaxel.

Figure 2 shows a Differential Scanning Calorimetry ("DSC") thermogram of novel solvate(TBA Solvate form) form of Cabazitaxel

Figure 3 shows a Thermogravimetric analysis ("TGA") thermogram of novel solvate form(TBA Solvate form) of Cabazitaxel

Figure 4 shows a' H NMR spectrum of novel solvate form(TBA Solvate form) of Cabazitaxel Figure 5 shows the Infrared Spectrum of novel solvate(TBA Solvate form)form of Cabazitaxel.

DETAILED DESCRIPTION OF THE INVENTION In one preferred embodiment, the invention provides tertiary-butyl alcohol solvate form of Cabazitaxel, processes for preparation and pharmaceutical compositions thereof.

A "solvate" may be defined as a compound formed by solvation, for example as a combination of solvent molecules with molecules or ions of a solute. Well known solvent molecules include water, alcohols and other polar organic solvents. Suitable solvents include the following but are not limited to methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, ethyl acetate and other lower alkanols, glycerine, acetone, Ethoxy ethanol dichloromethane, Dimethyl sulphoxide (DMSO), Dimethyl acetate (DMA), dimethyl formamide (DMF), isopropyl ether, methyl ethyl ketone, acetonitrile, toluene, N-methylpyrrolidone (NMP), tetrahydrofuran (THF), tetrahydropyran, water, other cyclic mono-, di- and tri-ethers, polyalkylene glycols '(e. g., polyethylene glycol, polypropylene glycol, propylene glycol) and mixtures thereof in suitable proportions. Preferably a mixture of solvents such as tertiary butyl alcohol (t-butanol), and ethyl acetate optionally in the presence of water in varied proportions may be used.

To characterize individual crystal forms of a particular compound, and/or to detect the presence of a particular form in a complex composition techniques known to those of skill in the art, such as that X-ray diffraction patterns, differential scanning calorimeter thermograms, thermal gravimetic analyzer thermograms, melting point information, polarized light microscopy, hotstage microscopy photomicrographs, dynamic vapor sorption/desorption information, water content, IR spectra, NMR spectra, and hygroscopicity profiles, to name a few, are used.

Cabazitaxel tertiary butyl alcohol solvate can be characterized by any one or combination of the following data:

XRD : Characteristic peaks at (°2 theta + 0.2) : 7.3, 7.8, 10.1 1 , 14.3, 1 7.6, 19.4

IR (cm^"' ): 2975, 1720, 1250, 1 170, 1 103, 1072

Powder X-ray Diffraction (PXRD) method:

Powder X-ray Diffraction was performed on an X-Ray powder diffractometer:

PANalytical; X'pert Pro.

Measurement parameters:

Scan range: 3 - 40 degrees 2-theta;

Scan mode: continuous;

Step size: 0.0167 degrees;

Scan Type: Continues

Time per step: 42 s;

Sample spin: yes;

Sample holder: zero background silicon plate.

Differential Scanning Calorimetry (DSC) method:

DSC measurements were performed on a Differential Scanning Calorimeter: TA instruments; (Q20) in Aluminum crucibles 40 with pin-holed lids were used for sample preparation. Typical sample weight was between 1 and 5 mg. Program parameters: temperature range at least 30 - 250°C; heating rate 10°C/min; nitrogen flow 50 ml/min.

Thermo gravimetric analysis (TGA) method:

TGA measurements were performed on a Thermogravimetric analyzer: TA instruments (Q50).

TGA measurements were performed using temperature range from least 30-250°C; heating rate: 10°C/min. 'HNMR

' HN R was performed on an Agilent Varian (400MHz). ATB probe was employed. Samples were prepared in cdcl₃ and data was analyzed with Agilent VN R 3.2 version.

Infrared Spectrum

Infrared spectra measurement was performed on a PerkinElmer instrument (Spectrum one: model). 2-3 mg sample was taken and mixed with 250mg of KBr and a pellet was made which is used for the IR analysis.

The present invention also relates to a process of manufacture of Cabazitaxel tertiary butyl alcohol solvate.

In one embodiment Cabazitaxel tertiary butyl alcohol solvate (TBA Solvatre) is prepared by dissolving Cabazitaxel in a mixture of ethyl acetate and tertiary butanol in varied ratios, preferably 1 : 4 ratioand raising the temperature to 85-92 °C followed by cooling to 0-5°C.

In some embodiments, the solvate form is prepared by lyophilization from a solution. In particular embodiments, the solvate form is prepared by lyophilization from a mixture of t- butanol/ethyl acetate in the presence of water. Lyophilization (also called freeze-drying) refers to a process that uses low temperature and pressure to remove a solvent, from a liquid formulation by the process of sublimation (i.e., a change in phase from solid to vapor without passing through a liquid phase). Lyophilization helps stabilize drug by reducing the solvent component or components to levels that no longer support chemical reactions or biological growth. Since drying during lyophilization takes place at a low temperature, chemical decomposition is also reduced. The freeze-drying process comprises steps of freezing, annealing, primary drying and secondary drying under various conditions such that the bulking agent is maintained in a substantially amorphous state or is maintained in a substantially crystalline state. The primary goal of the freezing process is to solidify at least the solvent component of the formulation. In the freezing process, the liquid formulation is therefore cooled to a sufficiently low temperature to allow for solidification of at least the solvent component. An annealing process results in the removal of solvent crystals smaller than a critical size and generation of larger solvent crystals. Annealing also reduces freezing-induced drying rate heterogeneity. During the primary drying process, the solvent is removed from the liquid formulation by a process of sublimation. The solvate forms obtained are characterized by suitable analytical techniques known in the art. Another aspect of the present invention is to provide pharmaceutical compositions of Cabazitaxel comprising: a)Cabazitaxel tertiary butyl alcohol solvate; and b) a pharmaceutically acceptable carrier.One embodiment of the invention relates to a parenteral compositioncompnsing: a)Cabazitaxel tertiary butyl alcohol solvate; and b) a pharmaceutically acceptable carrier. Pharmaceutically acceptable carrier or adjuvants can be selected from complexing agents, preservatives, anti-oxidants; stabilizers, tonicity modifiers, buffering agents and any other suitable adjuvants thereof.

Stabilizing agents are typically added to a formulation to improve stability of the protein formulation, for example, by reducing denaturation, aggregation, deamidation and oxidation of the protein during the freeze-drying process as well as during storage. Suitable stabilizers include the following, but are not limited to Saccharides, including monosaccharides such as glucose, disaccharides such as sucrose (glucose+fructose), lactose (glucose+galactose), maltose (glucose+glucose), and trehalose (alpha-D- glucopyranosyl alpha-D-glucopyranoside), and polysaccharides such as dextran (polysaccharide containing glucose monomers and the like. Surfactants also act as suitable stabilizers such as polyoxyethylenesorbitanmonolaurate (Tween.TM. 20, Tween.TM. 80), pluronic F-68, Triton.TM. X- 100, and sodium dodecyl sulfate (SDS), polysorbate or any other suitable surfactant can be selected. Cyclodextrins can also be used as a stabilizer. Preferably stabilizers could be surfactants in suitable proportion.

Tonicity modifiers are those pharmaceutically acceptable inert substances that can be added to the formulation to provide an isotonity of the formulation. Tonicity modifiers suitable for this invention include the following, but are not limited to mannitol, dextrose, sucrose, glycine, glycerol, sodium chloride, salts and amino acids and the like. Tonicity modifier can also be a component of diluent used for dilution of the prepared parenteral formulation.

Buffers are typically included in pharmaceutical formulations to maintain the pH of the formulation at a physiologically acceptable pH. The desirable pH for a formulation may also be affected by the active agent. Examples of suitable buffers include but are not limited to buffers derived from an acid such as phosphate, aconitic, citric, tartaric, aleic, glutaric, malic, succinic, carbonic acid, alkali or alkaline earth salt of one of these acids, Tris buffer, glycine, histidine buffers, meglumine, Sodium acetate, Ammonium acetate, and other acetates or any suitable buffer thereof. pH adjusting agents such as, but are not limited to sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, ammonium carbonate, hydrochloric acid, citric acid, lactic acid, phosphoric acid, sodium phosphate, sulfuric acid, and the like can also be used.

Components of the diluent may include the following but are not limited to ethanol, polyethylene glycols or blends containing one or more polyethylene glycols of different grades, propylene glycol, polyvinylpyrrolidone, or agents to adjust solution osmolarity or other parenterally acceptable sugars, polyols, mannitol solution, sodium chloride, dextrose solution, electrolytes or any suitable adjuvant thereof.

The compositions of the present invention can be prepared by the following process; Required amount of solvent was taken was taken in a S.S vessel to which drug was added and dissolved. Then required quantity of buffer was added and stirred well to get a uniform solution. Then required quantity of surfactant was added and stirred well. The final volume was made to q.s with the solvent. The prepared bulk solution prepared was filled in to a suitable container and the solvent was removed by rotary evaporation and the solution was filtered and desired quantity was filled in vials. Alternately the prepared bulk solution after filtration can be filled in vials and vaccuum can be applied to remove the solvent. The vials are then stoppered and sealed. Suitable sterilization techniques are used to keep the composition sterile.

Having described the invention with reference to certain preferred embodiments, other embodiments will become apparent to one skilled in the art from consideration of the specification, ft is to be understood that the examples are given by way of illustration only and are not intended to limit the scope of the invention in any manner.

EXAMPLES

Example 1 : Preparation of TBA solvate form of Cabazitaxel.

Brief manufacturing procedure:

Required quantity of Ethyl acetate & Tertiary butanol was taken in a SS manufacturingvessel and stirred well to get homogeneous solution. 80% of the above solvent mixture was takenin a mixing vessel and required quantity of Cabazitaxel was added and stirred well till it dissolves completely. Required quantity of water for injection was added and stirred well to get a homogenous solution. Finally the volume was made up with the remaining solvent mixture. Filter the bulk solution prepared and desired quantity was filled into vials and stoppered. Alternately the solution can be filled in trays. Vials or trays were loaded in alyophilizer and freeze dried as follows: (i) The product was frozento temperature below -40°C with optional annealing steps. (ii) The primary drying was performed at temperatures above -45°C at a vacuum rarrging from 10-700 millitorrs.(iii) The primary drying steps may contain one or more annealing steps, (iv) The freeze drying steps shall be performed in inert gas (N2, argon etc) or air.After completion of cycle the vacuum of chamber was released with Nitrogen and vials are sealed. Example 2: Preparation of Cabazitaxel Injection.

*Removed during the process by evaporation

Brief manufacturing procedure:

Required quantity of Cabazitaxel was added in required amount of ethanoi (80%) followed by buffer i.e., citric acid anhydrous and stirred till it dissolves. Required quantity of Polysorbate 80 was added to the above solution and stirred until it dissolves. Final volume was made up with ethanoi (20%). Ethanoi was removed from the solution by rotary evaporation. The solution was filtered and desired quantity was filled in vials and the vials arethen stoppered and sealed andstored at 25°C (77°F).

Example 3: Preparation of Cabazitaxel Injection.

*Removed during the process by evaporation

Brief manufacturing procedure:

Required quantity of Cabazitaxel was added in required amount of ethanoi (80%) followed by buffer i.e., citric acid anhydrous and stirred tillit dissolves. Required quantity of Polysorbate 80 was added to the above solution and stirred well until it dissolves. The final volume was made up with remaining ethanoi (20%) and stirred well to get a uniform solution. The solution was filtered and desired quantity of the solution was filled in the vials. The vials were partially stoppered with rubber stoppers and loaded in a lyophilizer/vacuum dryer and vacuum was applied to remove solvent.After completion of vacuum drying, the vials were stoppered completely under inert atmosphere (Eg.N₂). The vials were then sealed and stored at 25°C (77°F).

Example 4: Preparation of Cabazitaxel Injection.

* Removed during the process by evaporation

Brief manufacturing procedure:

Required quantity of cabazitaxelwas added in required amount of ethanol (80%) followed by buffer i.e., glycine and stirred until it dissolves. Required quantity of polysorbate 80 was added to the above solution and stirred until it dissolves. Final volume was made up with ethanol (20%). Ethanol was removed from the solution by rotary evaporation. The solution was filtered and desired quantity was filled in vials and the vials were stoppered and sealed. The vials were Stored at 25°C (77°F)..

Example 5: Preparation of Cabazitaxel Injection.

*Removed during the process by evaporation Brief manufacturing procedure:

Required quantity of Cabazitaxel was added in required amount of ethanol (80%) followed by buffer i.e., glycine and stirred till it dissolves. Required quantity of Polysorbate 80 was added to the above solution and stirred well until it dissolves. The final volume was made up with remaining ethanol (20%) and stirred well to get a uniform solution. The solution was filtered and desired quantity of the solution was filled in the vials. The vials were partially stoppered with rubber stoppers and loaded in a lyophilizer/vacuum dryer and vacuum was applied to remove solvent. After completion of vacuum drying, the vials were stoppered completely under inert atmosphere (Eg.N₂). The vials were then sealed and stored at 25°C (77°F).

Example 6: Preparation of Cabazitaxel Injection.

*Removed during the process by evaporation Brief manufacturing procedure:

Required quantity of Cabazitaxel was added in required amount of ethanol (80%) followed by buffer i.e., Sodium acetate and stirred until it dissolves. Required quantity of Polysorbate 80 was added to the above solution and stirred until it dissolves. Final volume was made up with ethanol (20%). Ethanol was removed from the solution by rotary evaporation. The solution was filtered and desired quantity was filled in vials and the vials were stoppered and sealed. The vials were Stored at 25°C (77°F).

Example 7: Preparation of Cabazitaxel Injection.

*Removed during the process by evaporation Brief manufacturing procedure:

Required quantity of Cabazitaxel was added in required amount of ethanol (80%) followed by buffer i.e., Sodium acetate and stirred till it dissolves. Required quantity of Polysorbate 80 was added to the above solution and stirred well until it dissolves. The final volume was made up with remaining ethanol (20%) and stirred well to get a uniform solution. The solution was filtered and desired quantity of the solution was filled in the vials. The vials were partially stoppered with rubber stoppers and loaded in a lyophilizer/vacuum dryer and vacuum was applied to remove solvent. After completion of vacuum drying, the vials were stoppered completely under inert atmosphere (Eg.N₂). The vials were then sealed and stored at 25°C (77°F).

Example 8: Recrystallization of Cabazitaxel.

Brief crystallization procedure:

Required quantity of Cabazitaxel was added in required amount of ethylacetate and tertiary butyl alcohol (1 :4 ratio) in a RB flask at 25-30 °C. The reaction temperature is raised to 85-92 °C and the reaction mass is stirred for 30-40 minutes at that temperature. If clear solution is not obtained, additional mixture of Ethyl acetate and Tertiary butyl alcohol is added (1 : 4 ratio) until clear solution is obtained at 85-92 °C. The reaction mass is cooled to 25-30 °C during l -2.hr. It is further cooled to 0-5 °C during 1-2 hr. The reaction mass is stirred for reaction mass for 45-60 min at 0-5 °C. The solid is filtered at 0- 5 °C and dried. Yield 95%.

Claims

We Claim:

1. Cabazitaxel tertiary butyl alcohol solvate characterized by a powder X-ray diffraction pattern as shown in Fig. 1.

2. Cabazitaxel tertiary butyl alcohol solvate of claim 1 further characterized by IR spectrum as shown in Fig. 5.

3. A pharmaceutical composition comprising Cabazitaxel tertiary butyl alcohol solvate of claims 1 or 2 and at least one pharmaceutically acceptable excipient.

4. A parenteral formulation of Cabazitaxel comprising:

(i) Cabazitaxel tertiary butyl alcohol solvate;

(ii) Solubiliser and;

(iii) Buffer.

5. The formulation of claim 4 that is manufactured by lyophilisation or vacuum drying.

6. The formulation of claim 4 comprising Polysorbate-80 and a buffer selected from acid buffers such as acid such as phosphate, aconitic, citric, tartaric, maleic, glutaric, malic, succinic, carbonic acid, alkali or alkaline earth salt of one of these acids, glycine, Tris buffer, sodium acetate, glycine, histidine buffers, meglumine, Ammonium acetate, and other acetates.

7. Process for preparation of Cabazitaxel tertiary butyl alcohol solvate by dissolving in a solvent mixture of ethyl acetate and tertiary butyl alcohol in 1 : 4 ratio at temperature of 85-92 °C followed by cooling to 0-5 °C to isolate the crystallized compound.