PL199228B1 - Improved method of crystallization of cephuroxime salt - Google Patents

Abstract

The invention relates to a method for carrying out the process of crystallization of a cefuroxime salt, consisting in carrying out the process of crystallization of the sodium salt of cefuroxime from a water-acetone solution in the presence of crystal growth modifying substances selected from the group of a tetraalkylammonium halide, a tetraalkylammonium propanesulfonate, an amine, an amino acid selected from the group consisting of L-threonine, L-lysine, a salt of a succinic acid derivative selected from the group of a sulfosuccinic acid salt, a dodecylbenzylsulfonic acid salt or urea, wherein the crystal growth modifying substance is used in an amount of from about 0.01 to about 1% by weight relative to the weight of the cefuroxime salt.

Description

Description of the invention

The present invention relates to a process for the crystallization of cefuroxime salt.

One of the most difficult problems in the production of semi-synthetic cephalosporins, including cefuroxime, is the preparation of substances with an appropriate crystalline form. The products of the crystallization process are characterized not only by the natural physical and chemical properties of the separated substance, but also by the presence of impurities, the granulometric composition of the population and the external shape of the crystals. The combination of all these properties determines the behavior of the crystals during further processing, e.g. separation from the solution, drying, confectioning. The type and size of the crystals have a very large, often fundamental, impact on the quality of the obtained cefuroxime and some elements of the technological process. The basic condition for good technology should be good filterability in the process of separating the crystals from the mother liquor. It is known that the size and type of crystals largely depend on the filtration rate and, consequently, the quality of the products obtained. Prolonged filtration has an adverse effect on some product parameters, such as color, or the content of undesirable contaminants that may be occluded on the surface of the crystals. Then a product is obtained that does not meet pharmacopoeial requirements, usually very high. Despite the fact that the crystallization processes in their various aspects are described theoretically, in general, the conditions for their conduct are to a large extent determined experimentally.

The subject of the presence of trace amounts of crystal habit modifying substances is known from the technical and patent literature and is based mainly on experimental work.

Various surfactants are known, the addition of which in the process of crystallization significantly modifies the type and shape of the crystals. These compounds are adsorbed on the surface of the crystals, thus reducing the growth rate of their individual walls, especially as a result of changes in the surface energy at the interface and mass transfer inhibition. The most frequently mentioned additives in the literature (see e.g. Zbigniew Rojkowski and Jerzy Synowiec, Krystalizacja i crystalizatory, Wydawnictwa Naukowo-Techniczne, Warsaw, 1991) include, among others such as fatty acids, alkylamines, polymethacrylic acid, polyvinylamine, sodium dodecylbenzyl sulfonate. In most cases, they were used in the crystallization processes of inorganic compounds. In contrast, WO9855484A1 discloses the use of additives such as organic carboxylic acid esters, polymeric glycols, polyacrylic compounds, polyamines, amines, melamine-formaldehyde resins and amino acids in the crystallization process of 7-aminocephalosporanic acid.

According to the invention, the method of crystallization of the cefuroxime salt consists in the fact that the process of crystallization of the sodium salt of cefuroxime is carried out from a water-acetone solution in the presence of crystal growth modifying substances selected from the group of tetraalkylammonium halide, tetraalkylammonium propane sulfonate, amine, amino acid selected from L-threonine, L-lysine, a salt of a succinic acid derivative selected from a salt of a sulfosuccinic acid, a salt of dodecylbenzylsulfonic acid, or a urea, wherein the crystal growth modifier is used in an amount of from about 0.01 to about 1% by weight based on cefuroxime salt weight.

In the process according to the invention, the tetraalkylammonium halide is selected from the group consisting of hexadecyltrimethylammonium bromide, tetraheptylammonium bromide, tetrabutylammonium bromide, decametonium bromide, cetyldimethylethylpyridinium bromide, hexadecylpyridinium chloride. It has been found that dimethyldioctadecylammonium bromide and other alkyltrimethylammonium bromides can also be used. Crystallization modifiers such as tetraalkylammonium propanesulfonate is selected from the group consisting of N-decyl-N, N-dimethyl-3-ammonium-1-propanesulfonate, 3 - [(3-cholamidopropyl) dimethyl] -ammonium-1-propanesulfonate, N- 1-propanesulfonate. hexadecyl-N, N-dimethyl-3-ammonium. It has been found that it is also possible to use N-octyl-N, N-dimethyl-3-ammonium 1-propanesulfonate, N-octadecyl-N, N-dimethyl-3-ammonium 1-propanesulfonate. Another modifier - the amine is selected from the group consisting of N, N-dibenzylethylenediamine diacetate, where it has also been found possible to use triethylenetetramine. The modifier according to the invention salt of the sulfosuccinic acid derivative is selected from the group consisting of sodium dihexyl sulfosuccinate, sodium dioctyl sulfosuccinate, and dodecylbenzylsulfonic acid salt is selected from the group consisting of sodium salt of this acid.

Particularly preferred crystal growth modifiers are tetraalkylammonium propanesulfonates, such as e.g. N-hexadecyl-N, N-dimethyl-3-ammonium-1-propanesulfonate and 1-propanesulfonate

PL 199 228 B1

3 - [(3-cholamidopropyl) dimethyl] ammonium, and certain sulfosuccinic acid derivatives such as sodium dihexyl sulfosuccinate and sodium dioctyl sulfosuccinate.

As a criterion for assessing the effect of the addition of a crystal growth modifier, the reduction of the filtration time of the precipitated crystals of cefuroxime sodium salt was adopted.

The rate of filtration often has a decisive influence on the quality of the crystalline cephalosporin produced. This is especially noticeable in the case of cefuroxime sodium, which crystallizes in the form of very fine, hardly draining crystals. Long filtering time has a decisive negative impact on the quality of the product due to the occlusion of impurities always present in the solution on the crystal surface. Washing of such impurities often causes delamination of the cefuroxime salt crystals.

It was found that the minimal addition of various crystal growth modifying substances allows for a multiple shortening of the filtration time, both during the separation from the mixture and during washing of the precipitate. The results for the various crystal growth modifiers are shown in Table 1.

The data presented there show that the addition of about 0.05% of the crystal growth modifier leads to the most preferred modifiers, such as, for example, sodium dihexyl sulfosuccinate or 3- [3- (cholamidopropyl) dimethyl] ammonium-1-propanesulfonate, to more than ten-fold reduction in the filtration time of cefuroxime sodium. In addition, the washing time of the filtered salt precipitate is reduced three times.

The amount of crystal growth modifier added may be, as already mentioned, from about 0.01 to about 1% based on the weight of the cephalosporin, preferably not more than about 0.05%. It was found that the added modifiers remained in the solution after filtration and their presence was practically not detected in the crystalline product.

The crystallization process in the presence of crystal growth modifying substances can be carried out over a fairly wide temperature range, e.g. at -10 ° C to 30 ° C. The choice of the most appropriate temperature practically does not depend on the type of modifier used.

By the process according to the invention, a highly pure product meeting the pharmacopoeial requirements is obtained with clearly shaped, non-flowing crystals.

The invention is illustrated in the following non-limiting examples.

P r z l a d y l - XVII

To a solution of 6.0 g of anhydrous sodium acetate in 90 ml of water, 15 g of cefuroxime acid, 180 ml of acetone, the amount of crystal growth modifier in the amount given in Table 1 and 0.15 g of the Na salt of cefuroxime were successively added with stirring. To the resulting mixture, 500 ml of acetone were added dropwise over 2 hours. The precipitate formed was filtered off and the filtration time was recorded, then suspended in 50 ml of ethanol to remove impurities, filtered (filtration time in brackets) and dried. The sodium salt of cefuroxime was obtained in a yield of 82.6 - 93.4%. The purity of the product obtained meets the pharmacopoeial requirements. The filter times for the crystal growth modifying substances used are shown in Table 1.

T a b e l a 1

Example Crystal growth modifier Filtration time [min] Amount [mg] 1 2 3 4 l no add-on 45 (12) - II L-threonine 15 (5) 7 III L-lysine 12 (7) 11 (7) 7 15 IV hexadecyltrimethylammonium bromide 6 (4) 5 (4) 7 15 V Na dodecylbenzylsulfonate 14 (6) 7 VI N, N-dibenzylethylenediamine diacetate 6 (4) 7 (4) 7 5 VII urea 8 (13) 60

Table 1 continues

1 2 3 4 VIII Na salt of dihexyl sulfosuccinate 4 (3) 7 IX N-decyl-N, N-dimethyl-3-ammonium 1-propanesulfonate 7.5 (6) 7 X Na salt of dioctyl sulfosuccinate 5 (3) 7 XI 3 - [(3-cholamidopropyl) dimethyl] ammonium 1-propanesulfonate 4 (3) 7 XII hexadecylpyridinium chloride 6 (4) 7 XIII decamethonium bromide 8 (6) 7 XIV N-hexadecyl-1-propanesulfonate N, N-dimethyl-3-ammonium 5 (3) 7 XV tetrabutylammonium bromide 11 (5) 7 XVI tetraheptylammonium bromide 11 (5) 7 XVII cetyldimethylethylpyridinium bromide 7 (4) 7

Example XVIII (A) 15 g of cefuroxime acid was suspended in 90 ml of water, and 10% sodium hydroxide solution was added with stirring until the suspension was completely dissolved.

Separately, 0.15 g of cefuroxime sodium was suspended in a solution of 4 g of sodium acetate in 20 ml of water. The previously prepared solution of cefuroxime sodium and a solution of 40 g of sodium acetate in 100 ml of water were simultaneously added dropwise over 3 hours to the above suspension heated at 50 ° C. After completion of the dropwise addition, the mixture was cooled to 5 ° C, the precipitate was filtered off, washed with 150 ml of ethanol and dried under reduced pressure.

Filter time 38 minutes, filter time after washing with ethanol 51 minutes. The sediment is very fine crystalline, sticky.

(B) The procedure of (A) was repeated except that 7 mg of N, N-dibenzylethylidenediamine was added to the suspension of 0.15 g of cefuroxime sodium. A product with clearly shaped, non-deliquescent and non-sticky crystals was obtained. Filter time 9 minutes, filter time after washing with ethanol 6 minutes.

(C) The procedure of (B) was repeated but 1.5 ml of a 1% solution of L-Lysine in water was added instead of N, N-dibenzyl-ethylenediamine diacetate. A product with clearly shaped, non-deliquescent and non-sticky crystals was obtained. Filter time 7 minutes, filter time after washing with ethanol 5 minutes. The purity of the product obtained meets the pharmacopoeial requirements.

Claims (2)

The method of crystallization of cefuroxime salt, characterized in that the process of crystallization of cefuroxime sodium salt is carried out from a water-acetone solution in the presence of crystal growth modifying substances selected from the group of tetraalkylammonium halide, tetraalkylammonium propane sulfonate, amine, amino acid selected from the group consisting of L- threonine, L-lysine, a salt of a succinic acid derivative selected from the group of sulfosuccinic acid salt, dodecylbenzylsulfonic acid salt, or urea, wherein the crystal growth modifier is used in an amount of from about 0.01 to about 1% by weight based on the weight of the cefuroxime salt. 2. The method according to p. 3. A process as claimed in claim 1, characterized in that the tetraalkylammonium halide is selected from the group consisting of hexadecyltrimethylammonium bromide, tetraheptylammonium bromide, tetrabutylammonium bromide, decametonium bromide, cetyl dimethylethylpyridinium bromide, N-N-tetraalkylsulfonate, hexadecyl sulfonate, hexadecyl sulfonate, hexadecylsulfonate, 3 - [(3-cholamidopropyl) dimethyl] ammonium 1-propanesulfonate, N-hexadecyl-N, N-dimethyl-3-ammonium 1-propanesulfonate, the amine is selected from the group consisting of N, N diacetate -dibenzylethylenediamine, the salt of the sulfosuccinic acid derivative is selected from the group consisting of sodium dihexyl sulfosuccinate, sodium dioctyl sulfosuccinate, and dodecylbenzylsulfonic acid salt is selected from the group consisting of sodium salt of this acid.