SI22542A - Stable formulation of amorphous salts of perindopril, procedure for its preparation in industrial scale and its application for treatmentof hypertensia - Google Patents

Abstract

The submitted invention deals with the preparation of a stable formulation of alkaline and earth alkaline salts of perindopril in amorphous form by neutralising perindopril in the form of a free acid, dissolved in alcohol, with water solution of an alkaline or earth alkaline base, then spraying this solution on inert substances for preparation of granulate and drying in the stream of warm air at 30 to 50 degrees Celsius or in vacuum. Substances for easier tabletting or additional active substances such as diuretics, preferably indapamid, are added to this granulate and the mixture is tabletted.

Description

FIELD OF THE INVENTION

The present invention is in the field of pharmaceutical chemistry and relates to the stable formulation of the amorphous salts of perindopril of formula I:

wherein B ⁺ is an alkali metal or alkaline earth metal cation, a process for its industrial scale preparation and its use for the treatment of hypertension.

A technical problem

The best known and most used salt of perindopril is erbumin, which is a salt with tertiary butylamine, which is a very effective vasodilator and antihypertensive agent. However, this salt is due to the low boiling point of tert. butylamine very thermally sensitive and prone to decomposition at elevated temperatures. Therefore, especially in countries with average high daily temperatures, the shelf life is relatively short. For this reason, there was a need for a process for the preparation of a more stable formulation of pharmaceutical preparations.

The state of the art

In known formulations, the active component is perindopril erbumine in various polymorphic forms of formula II:

These polymorphic forms are protected by the corresponding patent applications: α-form with application WO 01 / 87835A1, β-form with application WO 01 / 87836A1 and γ-form with application WO 01 / 83439A1.

To increase the stability of preparations with perindopril erbumine, it is also known to use additives of slightly basic components, preferably sodium hydrogen carbonate in solid form, as indicated in pat. report WO 2005 / 094793A and DE 10 2004 019 845A1. In doing so, perindopril remains in the form of erbumine and does not react with alkaline additives.

U.S. Patent No. 6,696,481 addresses perindopril salt with arginine, which is more stable than erbumine. At the same time, it also states the disadvantages of erbumine and also mentions that the perindopril sodium salt in its pure form is useless for formulation because it passes into oil and decomposes.

Our prior patent application PCT / SI2006 / 000034 addresses the preparation of a stable formulation of perindopril in the form of an amorphous sodium salt, otherwise on an inert carrier, derived from perindopril erbumine or perindopril erbumin hydrate.

Description of solution to a technical problem.

According to the present invention, stable formulations of perindopril amorphous salts are prepared directly from perindopril (acid) without an intermediate step of the erbumine salt. Perindopril in free acid form (is (2S, 3aS, 7aS) -1 - {{(1S) -1- (ethoxycarbonyl) butyl} amino-1-oxopropyl} octahydro-1H-indole-carboxylic acid of formula III:

In synthesis, it is formed as a dense oily substance, which is reluctant to crystallize but to be converted to a solid form by drying under high vacuum.

It has been found that salts of perindopril with alkali and alkaline earth alkalis can be directly formed by dissolving it in alcohol and adding a solution of the corresponding base in water in a molar ratio of 1: 1 during vigorous stirring. This solution is then sprayed onto the calculated amount of inert tabletting ingredients ( lactose, starch, cellulose) and dried under warm air at 30-50 ° C or under vacuum.

The solids thus obtained (first granulate) are then mixed by trituration with the other auxiliaries, and if necessary other ingredients (diuretics), to obtain the final mixture - the second granulate, which is then tableted.

This process is better and more advanced than our previous PCT / SI 2006/000034 process because it allows higher yields of the valuable active substance and is therefore less expensive. The combination of perindopril with diuretics, such as indapamide, is well known for the effective treatment of hypertension.

This procedure can also be used to prepare this composition by triturating the first granulate obtained with the other necessary ingredients after the granulation phase in the air stream, where at the same time micronized indapamide is added. The usual ratio of perindopril to indapamide is 4: 1.25.

The invention is illustrated by the following embodiments, but which are by no means limited thereto:

Example 1.

Particularly dissolve 7.9 g (21.4 mmol) of perindopril (free acid) in 35 ml of ethanol (96%). A solution of 2.0 g (23.8 mmol) of sodium hydrogen carbonate in 35 ml of water is prepared separately. The two solutions were combined and stirred for 10 min, with a pH of 7.0 to a maximum of 7.5.

This mixture is then sprayed in a stream of warm air at a temperature of 30-50 ° C to a pre-prepared mixture consisting of 142 g of lactose, 6 g of corn starch and 42.6 g of microcrystalline cellulose. Dry with warm air to a humidity of 0.5 - 1.5% water (K. Fischer method). About 200 g of the first granulate are obtained containing 4.17% of the sodium salt of perindopril.

By trituration, 5.8 g of corn starch, 4.7 g of talc and 2.4 g of magnesium stearate are added to this mixture and homogenized well. The (second) granulate obtained is used for tabletting and tablets of 90 mg containing 3.53 mg of the sodium salt of perindopril are prepared, which corresponds to the usual therapeutic dose of 4.0 mg perindopril erbumine.

Example 2.

7.9 g (21.4 mmol) of perindopril was dissolved in 35 ml of ethanol (96%). A solution of 0.86 g (21.4 mmol) of sodium hydroxide in 30 ml of water is prepared separately. Combine the two solutions, mix well and adjust the pH to 7.0 -7.5.

In the following, the solution, together with the other ingredients, is processed into granulate and tablets as described in Example 1.

Example 3.

7.9 g (21.4 mmol) of perindopril was dissolved in 35 ml of ethanol (96%) and this solution was slowly added to a suspension of 0.95 g (12.8 mmol) of calcium hydroxide during intensive stirring and stirred for 30 min. The pH should be 7.0 - 7.5. The resulting slightly cloudy solution was filtered to clarify.

In the following, this solution is processed into granulate and tablets according to the procedure described in Example 1.

Example 4.

7.9 g (21.4 mmol) of perindopril was dissolved in 35 ml of ethanol (96%). A solution of 2.0 g (23.8 mmol) of sodium hydrogen carbonate in 35 ml of water is prepared separately. The two solutions were combined and stirred for 10 min, pH 7.0 - 7.5. This mixture is then sprayed in a stream of warm air at a temperature of 30-50 ° C to a pre-prepared mixture consisting of: 140.0 g of lactose, 5.9 g of corn starch and 41.75 g of microcrystalline cellulose. The air stream is dried to a water content of 0.5 - 1.5%.

196 g of the granulate is obtained, which is then homogeneously mixed with:

2.95 g of indapamide, 5.9 g of corn starch, 4.7 g of talc and 2.4 g of magnesium stearate. This final granulate is used to make 90 mg tablets containing 3.53 mg perindopril sodium salt (equivalent to 4.0 mg perindopril erbumine) and 1.25 mg indapamide.

Claims (5)

Patent claims. A process for the preparation of a stable formulation of the amorphous salts of perindopril of formula I: C00 'B ⁺ I where B ⁺ is an alkali metal or alkaline earth metal cation, characterized in that perindopril is a free acid of formula lil: dissolved in alcohol and neutralized with an alkaline or alkaline earth alkaline aqueous solution, and the resulting neutral salt solution sprayed onto a homogeneous mixture of inert granulate constituents, dried in vacuo or in warm air, added to facilitate tableting or other active substances, preferably diuretics, homogenized and tableted. Process according to claim 1, characterized in that the alkaline earth metal is calcium or magnesium, and the alkali metal is sodium or potassium, preferably sodium. Process according to claims 1 and 2, characterized in that alkali or alkaline earth metal hydroxide, oxide, carbonate or hydrogen carbonate are used as the base. Process according to claims 1 to 3, characterized in that the drying is carried out at a temperature of from 30 to 50 ° C. Process according to claims 1 to 4, characterized in that a diuretic substance, preferably indapamide, is used as the second active substance in the final phase of granulate mixing. o 5 as antihypertensive and vaso-