Abstract:
The present invention provides (2α,5β,7β,10β,13α)-4-acetoxy-13-({(2R,3S)-3[ (tert-butoxy carbonyl) amino] -2-hydroxy-3 -phenylpropanoyl} oxy)-1 -hydroxy-7,10-dimethoxy-9-oxo-5,20-epoxytax-1 l-en-2-yl benzoate or Cabazitaxel (I) stable crystalline Form-SC and process for its preparation.
The present application also provides Cabazitaxel (I) crystalline Form-SC useful as an active pharmaceutical ingredient in pharmaceutical composition comprising thereof and having anti-cancer activity.
Get Free WhatsApp Updates!
Notices, Deadlines & Correspondence
PROCESS FOR PREPARING CABAZITAXEL AND ITS SOLVATE
The following specification particularly describes the invention and the manner in which it is to be performed.
FIELD OF THE INVENTION
The present invention provides (2a,5p,7p,10p,13a)-4-acetoxy-13-({(2R,3S)-3[ (tert-butoxy carbonyl) amino] -2-hydroxy-3 -phenylpropanoyl} oxy)-1 -hydroxy-7,10-dimethoxy-9-oxo-5,20-epoxytax-1 l-en-2-yl benzoate or Cabazitaxel (I) stable crystalline Form-SC and process for its preparation,
The present application also provides Cabazitaxel (I) crystalline Form-SC useful as an active pharmaceutical ingredient in pharmaceutical composition comprising thereof and having anti-cancer activity.
INTRODUCTION
(2a,5p,7p, 1 Op, 13a)-4-acetoxy-l 3-({(2R,3 S)-3 [(tert-butoxycarbonyl) amino]-2-hydroxy-3 -phenylpropanoyl} oxy)-1 -hydroxy-7,10-dimethoxy-9-oxo-5,20-epoxytax-11 -en-2-yl benzoate (I) is the chemical name of Cabazitaxel -
(.)
Cabazitaxel as its acetone solvate was approved by USFDA as JEVTANA™ and is chemically mentioned in the label as (2a,5p,7p,10p,13a)-4-acetoxy-13-({(2R,3S)-3[(tert-butoxy-carbonyl) 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) solvatomorph ( Cabazitaxel : acetone).
Cabazitaxel is a white to off-white powder and is lipophilic in nature, practically insoluble in water.
Bouchard et al in US5847170 provides the first disclosure of (2a,5p,7p,10p,13a)-4-acetoxy-13-({(2R,3S)-3[(tertbutoxycarbonyl) amino]-2-hydroxy-3-phenylpropanoyl}oxy)-l-hydroxy-7,10-dimethoxy-9-oxo-5,20-epoxytax-ll-en-2-yl benzoate (also known as Cabazitaxel), which also describes the process for preparing Cabazitaxel.
Kung Liang-Rern et al in US2012149925Al disclose process for preparing Cabazitaxel by reacting beta-lactam side chain with a protected baccatin derivative in the presence of one or more Lewis acids and a base agent, wherein Lewis acid may be selected from LiBr, MgBr2, CsBr, ZnBr2, ZnCl2, CuBr, Cu(CF3S04)2, BF3.OEt2, KBr, T1CI4, SnCl2, ScCl3, VC13, A1C13, InCl3, A12C03, CeCl3, Ag20, ZnC104, LiC104, Ti{OCH(CH3)2}4 or any combination thereof.
According to applicant of US20120149925Al, use of Lewis acid is one of inventive merit of the application. Applicant in the specification mentions that - comparing to the reaction carried out without Lewis acid, the presence of Lewis acid provides a more selective reaction, characterized by higher reaction rate, higher yield, more selective product, higher purity of the desired product and less side products.
Other disclosures related to Cabazitaxel process viz, - CN102532065A, CN102675256A and CN1023367268 also disclose similar processes however, either involving organometallic bases selected from n-BuLi, NaHMDS, KHMDS, KH & NaH and extremely low temperature conditions for the coupling reaction or different protecting groups on beta lactam side chains with varying bases and extremely low temperature conditions.
Subsequent to process of Cabazitaxel, the concern has remained for the solid form isolated for Cabazitaxel. As mentioned earlier, the Cabazitaxel form mentioned in the label as (2a,5p,7p, 1 Op, 13a)-4-acetoxy-13-({(2R,3 S)-3 [(tert-butoxy-carbonyl) amino]-2-hydroxy-3-phenylpropanoyl}oxy)-l-hydroxy-7,10-dimethoxy-9-oxo-5,20-epoxytax-ll-en-2-yl benzoate -propan-2-one (1:1) solvatomorph ( Cabazitaxel : acetone) is designated as Form-A in EMEA scientific discussion as well as in the subsequent patent US7241907.
Further, it appears from the literature that in order to achieve therapeutic role, it is Cabazitaxel base molecule that has to play the role and not necessarily its solvates as long as stable solvate or base form known to exists. In line with this, applicant in US 20120301425A1 (Eq. WO 2011051894A1) on page 2 mentions that Cabazitaxel may be administered in base form (cf. above formula), or in the form of a hydrate. It may also be a solvate, i.e. a molecular complex characterized by the incorporation of the crystallization solvent into the crystal of the molecule of the active principle (see in this respect page 1276 of J. Pharm. Sci. 1975, 64(8), 1269-1288). In particular, it may be an acetone solvate, and, more particularly, may be the solvate described in WO 2005/02846. It may be an acetone solvate of cabazitaxel containing between 5% and 8% and preferably between 5% and 7% by weight of acetone (% means content of acetone/content of acetone + cabazitaxelx 100). An average value of the acetone content is 7%, which approximately represents the acetone stoichiometry, which is 6.5% for a solvate containing one molecule of acetone.
Didier et al in US7241907 (An equivalent patent of WO 2005/02846A1) describes a crystalline form as acetone solvate of dimethoxy-docetaxel or 4-acetoxy-2