CZ201038A3 - Method of industrial production of amorphous form of (3R,5R) 7-[3-phenyl-4-phenylcarbamoyl-2-(4-fluorophenyl)-5-isopropylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid hemicalcium salt (atorvastatin) with low specific surface and use thereof in medicamento - Google Patents

Abstract

The present invention relates to a new, large-scale process for the production of an amorphous form of (3R, 5R) 7- [3-phenyl-4-phenylcarbamoyl-2- (4-fluorophenyl) -5-isopropylpyrrol-1-yl] hemi-calcium salt. 3,5-dihydroxyheptanoic acid (atorvastatin of formula I) with a low specific surface area based on controlled precipitation and its use in dosage form.

Description

Technical field

The present invention relates to a novel process for the production of larger quantities of a suitable process for the production of the amorphous form of the hemicalcium salt of (3R, 5R) 7- [3-phenyl-4-phenylcarbamoyl-2- (4-fluorophenyl) -5-isopropylpyrrol-1-yl] -3 5-dihydroxyheptanoic acid (atorvastatin-I) with a low specific surface area based on controlled precipitation and its use in dosage form.

BACKGROUND OF THE INVENTION

Atorvastatin of formula I is a prominent representative of hypolipidemic and hypocholesteric drugs and has been the subject of numerous patents.

According to an embodiment, atorvastatin is obtained in any of the crystalline forms, or amorphous atorvastatin. The original patents US 4,681,893 and US 5,273,995 do not mention the form of the substance obtained according to these patents. Later patents 5,969,156 and 6,121,461 describing crystalline forms of atorvastatin indicate that the substance obtained according to the original patents was amorphous. In EP 0 839 132 describing a new process for obtaining an amorphous form of atorvastatin, by dissolving crystalline atorvastatin and drying it again, the original patents lead to amorphous atorvastatin, but that this process is poorly reproducible. The possibility of obtaining amorphous atorvastatin by dissolving crystalline atorvastatin in a suitable solvent, evaporation and grinding described in EP 0 839 132 has the drawback of considerable thermal stress on the substance resulting in a number of decomposition products resulting in unsatisfactory purity of the amorphous atorvastatin thus obtained.

Egis's application (WO 01/28999 A1) describes the recovery of amorphous atorvastatin by crystallization from lower alcohols, but repeatedly this procedure yielded partially crystalline samples.

Another attractive possibility of obtaining amorphous atorvastatin is by spray drying a solution of atorvastatin in a suitable solvent using an inert carrier gas such as nitrogen,

OF.

described in PV 2005-094. The disadvantage of this procedure is the necessity of investment-intensive spray driers and considerable consumption of inert gas.

A number of different crystal modifications are currently patented (eg, US 5,969,156; US 6,121,461; WO 01/36384 A1; WO 03/004470), yet is suitable for some applications (EP 0 839 132) or suitable use amorphous forms of atorvastatin. Already in the original U.S. Pat. No. 4,681,893, the possibility of purification of an unsatisfactory substance by dissolution in ethyl acetate and precipitation with hexane is already mentioned. In substantially the same way, using various solvents for dissolving atorvastatin and anti-coagulating solvents, amorphous atorvastatin is also obtained according to Lek (WO 01/42209 A1), Ranbaxy (WO 00/71116 A1), Biocon (WO 02 / 057228 A1), Chadila (WO 02/08367 A1; WO 02/08368 A1) and Morepen (WO 03/018547 A2). In some cases, the opposite possibility is also indicated where a solution of atorvastatin in a suitable solvent is added dropwise to a solvent in which atorvastatin is not dissolved or only to a limited extent (anti-solvent) (WO 02/057228 A1, CZ 2002-413).

In some cases, a concentrated solution of atorvastatin in a suitable solvent is not obtained by dissolving crystalline or semi-crystalline atorvastatin, but is obtained directly in the last reaction stage of atorvastatin production (CZ 2002-413, WO 03/018547 A2), thereby not infringing the patent claims describing the respective crystal forms. In our patent (CZ 296967; WO 03/068739; EP 1 470 106; US 7 208 608; AU 2003/213986; UA 76826), we have started from (3Λ, 5Λ) tert-butyl (6) to produce atorvastatin solution in a suitable solvent. - {2- [3-phenyl-4-phenylcarbamoyl-2- (4-fluorophenyl) -5-isopropylpyrrol-1-yl] -ethyl} -2,2-dimethyl- [1,3] dioxan-4-yl) -acetate of formula II.

(Π)

Thus, the precipitation method discussed above appears to be the most advantageous industrially applicable method. However, a considerable disadvantage of the above processes for obtaining amorphous atorvastatin by precipitation is the fact that the production of larger quantities (of the order of kilograms) makes it difficult to achieve the homogeneity of the amorphous atorvastatin obtained. In addition, in some cases a poorly filterable product is formed, or residual solvents are difficult to remove from the amorphous product obtained. Most of these disadvantages have been solved by PV 2003-987 (UV CZ 13296) protecting process based on the precipitation of amorphous atorvastatin by injecting a solution of atorvastatin in a suitable solvent into a suitable anti-solvent under pressure of a suitable gas using a special device. Thus, when the atorvastatin so produced is suitable for currently manufactured dosage forms, it has been shown that amorphous atorvastatin with a lower specific surface area is more suitable for other types of dosage forms. These are, in particular, sustained-release dosage forms.

The present invention describes a new, improved process for the production of the amorphous form of the hemicalcium salt of (3R, 5R) 7- [3-phenyl-4-phenylcarbamoyl-2- (4-fluorophenyl) -5-isopropylpyrrolidin-3-yl] -3,5-dihydroxyheptanoic acid ( atorvastatin of formula (I) having a low specific surface area suitable for industrial use, which would not have the disadvantages mentioned, and its use in a dosage form.

SUMMARY OF THE INVENTION

SUMMARY OF THE INVENTION The present invention provides a novel process for the preparation of an amorphous form of the hemicalcium salt of (3Λ, 5Λ) 7- [3-phenyl-4-phenylcarbamoyl-2- (4-fluorophenyl) -5-isopropylpynol-1-yl] -3,5-dihydroxyheptanoic acid. a surface suitable for industrial use, based on precipitation and optimized insulation, and its use in pharmaceutical form. The low surface area amorphous form of atorvastatin is particularly suitable for dosage forms where slow release of the active ingredient is desired.

This whole process includes:

(a) obtaining a solution of atorvastatin in a suitable solvent or solvent mixture, either by dissolving crystalline or amorphous atorvastatin, or obtaining this solution directly in the last step of atorvastatin production;

b) adding a certain amount of water to the atorvastatin solution prior to precipitation

c) precipitation of amorphous atorvastatin by injecting this solution of atorvastatin in a suitable solvent into a suitable anti-solvent under pressure of a suitable gas using the apparatus described in PV 2003-987 (UV CZ 13296) under precisely defined conditions

d) washing the obtained product so that the residual solvent content of the filter cake is within a defined range of 0 to 4% by weight.

(e) standard drying of the product

It has been surprisingly found that addition of a certain amount of water to coagulated atorvastatin solution leads to precipitation of the amorphous product has a low specific surface area ^of from 2 m / g to 10 m ^z / g.

DETAILED DESCRIPTION OF THE INVENTION.

In the production of atorvastatin according to PV 2003-987, it was shown that amorphous atorvastatin usually exhibited specific surface values of 15 to 39 m ² / g (Table 1). Experimental measurement of the surface of the substance showed association with the residual solvent content of the filter cake before drying the finished product. Conversely, the effect of mixing or nozzle size on the product surface was not demonstrated. It has been shown that the amorphous surface differences in the existing atorvastatin production are due to the content of residual solvents before product isolation, in our case the ratio of ethyl acetate to pentane. If the isolated product contained a large amount of ethyl acetate, the drying process resulted in selective drying of pentane and a decrease in the amorphous atorvastatin surface (Table 2).

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Table 1:

Batch Sg m2 / g 1 130606 28.8 1 140606 38.8 1 150606 34.2 1 160606 29.4 1 170706 33.4 1 180706 28.0 1 010907 32.8 1 010508 16.6 1 020508 15.6 1 030608 15.3

S _g ..... total specific surface area

Table 2:

Try Specific surface area m ² / g EtAc / pentane mass ratio (%) 61 15.5 7.8 62 28.4 6.8 63 19.3 8.0 64 58.4 4.0 65 67.5 3.4 66 54.9 4.4 67 46.4 4,5 68 42.7 4.9

Description of experiment 61-68: Atorvastatin (0.3 kg) dissolved in ethyl acetate (1 L) was precipitated under nitrogen pressure into pentane (7 L), the product was isolated on suction and washed with pentane, the pentane / ethyl acetate mass ratio was measured before drying in a filter cake. The product was dried under vacuum and the specific surface area was measured.

Although a specific surface area reduction can be achieved when drying, when the ratio of ethyl acetate to pentane is higher, such a process is not reproducible, since at a weight ratio greater than 10% there is a risk of forming a gel product which can no longer be used. When measuring the solubility of atorvastatin in the ethyl acetate / pentane system, it has been shown that atorvastatin begins to dissolve in the system when the ethyl acetate / pentane ratio exceeds 0.5 (Table 3).

Table 3:

EtAc / pentane (l / l) Solubility g / l 0.25 0 0.33 0 0.5 0 1 0.5 1.13 2.1 1,27 4 1.33 5.2 1.5 14

In further experiments, exposure of precipitated atorvastatin with a specific surface area of about 22 m ² / g of the solvent system in which atorvastatin begins to dissolve has been shown to reduce the specific surface area of the product (Table 4).

Table 4:

Sample Input specific surface m ² / g Pentane / Ethyl acetate (L / L) Time stirs her Specific surface area m ² / g AS 139 22.5 1,2 2h 10.1 AS 140 22.5 1.4 2h 13.6 AS 141 22.6 1.6 2h 15.2 AS 142 22.6 1 2h 5.2 AS 143 22.6 1 1h 5.0

Description of the experiment: amorphous atorvastatin (100 g) was stirred in ethyl acetate / pentane, diluted after 2 h (1h) with pentane to a 2: 1 ratio (pentane / EtAc) and aspirated, washed with pentane (2 x 500 ml) and dried under vacuum. The ethyl acetate / pentane weight ratio in the filter cake after washing was always below 3%.

Although a reproduced preparation of atorvastatin with a low surface area can be achieved in this way, the handling of flammable materials during manufacture and thus an increased risk of fire is unpleasant. Surprisingly, experiments investigating the effect of water content on the surface of precipitated atorvastatin under otherwise standard conditions have surprisingly found that the surface area of precipitated atorvastatin drops sharply from a certain water content (Table 5).

Table 5:

Try Water content (water / atv w / w) Surface area m ² / g 1020105/31 2% 58.4 1020105/31/1 3.5% 61.3 1020105/31/2 4.7% 54.3 1020105/31/3 5.2% 38.4 1020105/32 8,60% 5.4 1020105/33 17,50% 2.4 1020105/34 21,60% 3.8

Description of the experiment

Atorvastatin (0.3 kg) dissolved in ethyl acetate (1 L) with added water was precipitated under nitrogen pressure into pentane (7 L), the product was isolated on suction and washed with pentane (4 x 3 L), dried under vacuum and measured surface .

Thus, the production of low surface amorphous atorvastatin involves only adding water to the solution prior to precipitation.

The specific surface area S _g was measured after treatment of the sample by a volume flow of helium

1.5 l / h. The measurement of the total specific surface area was performed on a commercial Pulse Chemisorb 2700 from Micromeritics, which operates on the principle of a dynamic, chromatographic method. The total specific surface area was determined from the measured nitrogen physisorption data at three different partial pressures in the BET equation at 77 K. The linearized form of the BET equation was used to mathematically process the measured data and determine the total specific surface area.

The invention is illustrated by the following examples. These examples, which illustrate preferred alternatives to the production of atorvastatin according to the invention, are illustrative only and do not limit the scope of the invention in any way.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Atorvastatin (0.3 kg) dissolved in ethyl acetate (1 L) with added water (25.8 g) was precipitated under nitrogen pressure into pentane (7 L), the product was isolated on suction and washed with pentane (4x3 L), Product dried under vacuum to give 279 g of an amorphous product with a surface area of 5.4 m ² / g.

Example 2

Atorvastatin (0.3 kg) dissolved in ethyl acetate (1 L) with added water (52.5 g) was precipitated under nitrogen pressure into pentane (7 L), the product was isolated on suction and washed with pentane (4 x 3 L), Product dried under vacuum to give 264 g of an amorphous product with a surface area of 2.4 m ² / g.

Claims (8)

PATENT CLAIMS A process for the preparation of the amorphous form of the hemi-calcium salt of (3R, 5R) 7- [3-phenyl-4-phenylcarbamoyl-2 (4-fluorophenyl) -5-isopropylpyrrol-1-yl] -3,5-dihydroxyheptanoic acid known under the unprotected name Atorvastatin of formula (I), characterized in that a solution of atorvastatin in a water-containing solvent is blown into the anti-solvent by means of a gas, preferably nitrogen, and the precipitated amorphous atorvastatin is filtered off, washed with anti-solvent and dried. Process according to claim 1, characterized in that the solvent used is a solvent or mixture of solvents, wherein the solubility of atorvastatin is greater than 1 g per liter. Method according to claim 1, characterized in that the anti-solvent used is a solvent or solvent mixture in which less than 0.1 g of atorvastatin per 1 l is dissolved. The process according to claim 2, wherein the solvent is ethyl acetate or a mixture thereof with tetrahydrofuran, The method of claim 3, wherein the anti-solvent is pentane. The method of claim 1, wherein the water content, expressed as a weight ratio of water and atorvastatin, in the solution prior to precipitation is in the range of 6 to 25%. The amorphous form of the atorvastatin hemi-calcium salt of (3R, 5R) 7- [3-phenyl-4-phenylcarbamoyl-2- (4-fluorophenyl) -5-isopropylpyrrol-1-yl] -3,5-dihydroxyheptanoic acid of the formula I Claims 1 to 6 with a specific surface area in the range of 2 to 10 m ² / g. 8. A pharmaceutical oral composition comprising from 1 to 80 wt. amorphous forms of the atorvastatin hemi-calcium salt (3 R, 5 R) 7- [3-phenyl-4-phenylcarbamoyl-2- (4-fluorophenyl) -5-isopropylpyrrol-1-yl] -3,5-dihydroxyheptanoic acid of the formula I according to claims 1 to 7.