WO2005005384A1

WO2005005384A1 - Process for the preparation of amortphous atorvastatin calcium without interconversion of any crystalline form

Info

Publication number: WO2005005384A1
Application number: PCT/TR2003/000062
Authority: WO
Inventors: Kadir Dabak; Hulya Keskin
Original assignee: Eos Eczacibasi Ozgun Kimyasal Urunler Sanyi Ve Ticaret A.S.
Priority date: 2003-07-15
Filing date: 2003-07-15
Publication date: 2005-01-20
Also published as: AU2003247327A1

Abstract

The invention relates to a novel process for the preparation of amorphous atorvastatin calcium salt (2:1) from atorvastatin tert-butyl ester (Figure 1). The preparation comprises: (a) dissolving atorvastatin tert-butyl ester (Figure 1) in a solvent, (b) adding an aqueous alkaline or alkaline earth metal hydroxide solution, (c) removing of the solvent, b) adding water and a water non soluble solvent, e) adding an aqueous calcium salt solution, f) separation of the phases and removing of the solvent to obtain desired amorphous atorvastatin calcium and hydrates thereof. The process disclosed herein gives amorphous form directly without interconversion of any crystalline form into amorphous form.

Description

PROCESS FOR THE PREPARATION OF AMORPHOUS ATORVASTATIN CALCIUM WITHOUT INTERCONVERS ON OF ANY CRYSTALLINE FORM

The accompanying drawings show as follows: Fig.l shows the formula of [R-(R*,R*)]-2-(4-fluorophenyι)-β,δ-dihydroxy-5-(l- methylethyl)-3 -phenyl-4- [(phenylamino)carbonyl] - 1 H-pyrrole- 1 -tert-butylheptanoate .

Fig.2 shows the formula of [R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(l- methylethyl)-3 -phenyl-4- [(phenylamino)carbonyl]- 1 H-pyrrole- 1 -heptanoic acid hemi calcium salt (Atorvastatin calcium).

Fig.3 demonstrates the X-Ray diffractogram of amorphous form of atorvastatin calcium wherein the horizantal axis presents 2Θ and the vertical axis corresponds to peak intensity.

Atorvastatin calcium, the substance known by the chemical name [R-(R*, R*)]-2-(4- fluorophenyl)-β,δ-dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]- 1 H-pyrrole- 1 -heptanoic acid hemi calcium salt is a synthetic HMGA-CoA reductase inhibitor which is used for the treatment of hyperlipidemia and hypercholesterolemia. Atorvastatin in the pharmaceutical compositions is usually prepared as its calcium salt since it enables atorvastatin to be conveniently formulated in the pharmaceutical formulations.

Process for the preparation of atorvastatin and key intermediates are disclosed in the US patent numbers: 5,003,080; 5,097,045; 5,103,024; 5,124,482; 5,149,837; 5,155,251; 5,216,174; 5,245,047; 5,248,793; 5,280,126; 5,342,952; 5,397,792. All these process give mixtures of crystalline and amorphous forms with unsuitable filtration and drying characteristics rendering them unsuitable for large scale production. Atorvastatin calcium can exist in an amorphous form or in one of the crystalline forms, which are disclosed in the patent applications WO 97/3958, WO 97/3959, WO 97/3960. These studies provided more favorable filtration and drying characteristics.

Atorvastatin calcium is the substance which is sparingly soluble in water, with pKa

4,5 and it has been found that the crystalline forms are less soluble than the amorphous form, which may cause problems in bioavailabilty of atorvastatin in the body. It is very important to ensure uniformity of the substance being employed in a pharmaceutical formulation.

There are basically two different known routes in the literature to prepare amorphous atorvastatin calcium;

(1) from the crystalline form of atorvastatin calcium, which comprise: dissolving crystalline form of atorvastatin in a solvent and removing of solvent (US 6,087,511) or alternatively adding a non solvent and filtering the precipitated amorphous form (WO 97/03960, US 6,274,740, US 6,087,311, US 6,528,660).

(2) from a reaction mixture of an intermediate of atorvastatin calcium, which comprise:

(2i) hydrolysis of atorvastatin lactone and having atorvastatin calcium in a solvent such as halogenated hydrocarbons, aliphatic esters or aromatic hydrocarbon, adding an anti-solvent such as ether or non-polar hydrocarbons and filtering the desired amorphous atorvastatin calcium (WO 03/018547).

(2ii) A similar process is described in the 2i (WO03/018547), but the amorphous form is obtained from aqueous phase by filtration (WO02/083637, WO02/083638,

WO02/059087).

We report here a process for the preparation of the amorphous atorvastatin calcium and hydrates thus consist of: a) dissolving atorvastatin tert-butyl ester (Figure 1) in a solvent, b) adding an aqueous alkaline or alkaline earth metal hydroxide solution to the reaction mixture, c) removing of the solvent, d) adding water and a water non soluble solvent, e) adding an aqueous calcium salt solution to the reaction mixture, f) separation of the phases and removing of the solvent to obtain desired amorphous atorvastatin calcium and hydrates thereof. The process disclosed herein gives amorphous form of atorvastatin calcium in a simple process without interconversion of any crystalline form. Additional solvents are not necessary to precipitate amorphous form. Additionally to these, the problem of removal of water from the product is not observed.

EXAMPLE

5 g of atorvastatin tert-butyl ester (Fig.l) was dissolved in 100 ml of methanol, and a solution of 0.390 g of NaOH / 15 ml of water was added. Reaction mixture was stirred for 1 h at 50°C. After 1 h, TLC showed no starting material (TLC was performed on silica plate, eluent: Hexane/ethyl acetate: 1/1). Methanol was removed under reduced pressure. 100 ml of water and 100 ml of ethyl acetate were added. A solution of 0.870 g of Ca(CH₃COO) . X H₂O / 20 ml of water was added. Reaction mixture was stirred for 1 h at 50°C. Mixture was cooled to room temperature and the phases were seperated. The organic phase was washed with 2X50 ml of water. The organic phase was concentrated under vacuo at 50 °C to give desired amorphous atorvastatin calcium.

Claims

1. An improved process for the preparation of amorphous atorvastatin calcium, having formula of Figure 2 which comprises; i) dissolving atorvastatin tert-butyl ester having formula of Figure 1 in a solvent, ii) adding an aqueous solution of alkaline or alkaline earth metal hydroxide, iii) removing of the solvent, iv) adding water and a water non soluble solvent, v) adding an aqueous solution of a calcium salt, vi) separation of the phases and removing of the solvent to obtain desired amorphous atorvastatin calcium and hydrates thereof.

2. The process of Claim li, wherein solvent is methanol.

3. The process of Claim lii wherein alkaline or alkaline earth metal hydroxide is sodium hydroxide.

4. The process of Claim liv wherein the solvent is ethyl acetate,

5. The process of Claim lv wherein calcium salt is, calcium acetate.