CS254211B1 - Method of 7-(/2-thienyl/acetamido)cephaelosporanic acid's crystalline sterile sodium salt preparation - Google Patents

Abstract

The solution relates to the process of preparing the crystalline). sterile sodium salt of 7 - [(2- -thienyl) acetamidojcephalosporanic, which is rapidly soluble in conventional pharmaceuticals solvents for parenteral use. The substance is used in the treatment of bacterial infections. The crystalline salt is being prepared mixing sterile aqueous but aqueous alkanoic solutions with sterile akanol at a temperature of 5 ° C to 40 ° C and a pH of 4.5 to 8.5.

Description

The present invention relates to the preparation of crystalline sterile sodium salt of 7 - [(2-thienyl) acetamido cephalosporanoic acid, which is rapidly soluble in conventional pharmaceutical solvents suitable for parenteral use, and is used as an antibiotic in the treatment of infections caused by Gram positive and Gram negative bacteria.

The preparation of the sterile] sodium salt of 7 - [(2-thienyl jacetamldo) cephalosporanoic acid is described in U.S. Pat. No. 4,029,655 by lyophilization requiring more than 24 hours to complete one cycle. U.S. Pat. No. 4,132,848 discloses lyophilization. at which a vacuum of 0.16 kPa is required and the freezing is at -40 ° C.

National Res. Develop. Corp. discloses (British Pat. No. 1,232,656) the preparation of ultrapure cephalotin free of polymeric materials by dialysis, fractionation, and ultrafiltration. The sterile rapid-dissolving and crystalline cephalotin sodium may be prepared by lyophilization from a solvent mixture (belg. Pat. No. 861 135).

A disadvantage of the prior art processes for obtaining a sterile sodium salt of 7 - [(2-thienyl) acetamido ]cephalosporanoic acid is the necessity to achieve high vacuum and low temperatures, or the use of sophisticated equipment and auxiliaries, using sublimation techniques. .

SUMMARY OF THE INVENTION The present invention provides a process for the preparation of a sterile sodium salt of 7 - [(2-thienyl) acetamido ]cephalosporanoic acid in crystalline form from a sterile aqueous or aqueous-alkanol solution thereof wherein the alkanol has 1 to 3 carbon atoms. A pH of 4.5 to 8.5 and a temperature of 5 to 40 ° C gradually add sterile C 1 -C 3 alkanol in an amount of 1.43 to 12.42 L / kg of salt to form a metastable state and further addition of sterile alkanol. having from 1 to 3 carbon atoms at 15 to -10 ° C a sterile salt crystallizes.

The advantage of the process according to the invention, which is important from an industrial point of view, is the achievement of a high crystallinity of the sterile product compared to the preparation of a sterile salt by freeze-drying, reducing the apparatus, energy and personnel requirements. It provides sufficient stability while rapidly dissolving in suitable solvents for parenteral use.

The process of the invention is carried out by dissolving the non-sterile sodium salt of cephalotin in a water-alkanol system wherein the alkanol has 1 to 3 carbon atoms and the water content is 50 to 98% by volume or in water. The concentration of cephalotin sodium is chosen to form a 14-40% solution, with a 25-35% solution being preferred.

The percentages given refer to weight percent. The resulting solution may have a pH of 4.5 to 8.5, or obtaining optimal pH values of 4.5 to 8.5 is achieved by addition of buffering agents such as non-toxic salts of organic acids, e.g. sodium citrate, or non-toxic inorganic salts, e.g. sodium bicarbonate. The pharmaceutically acceptable salts may be added to the cephalotin sodium salt solution either in the form of an aqueous or aqueous-alkali solution, preferably without a solvent.

Sterilization of the aqueous or aqueous-alkali solution of sodium salt is accomplished by filtration through a sterile filter in a conventional manner, e.g. 0.45 μπι Millipore membrane filter for sterile crystallization equipment. Subsequently, to the sterile solution at 5 to 40 ° C is added with 1 to 3 carbon atoms in an amount and at a rate such that a metastable state is formed. Practically this means, according to the kind of alkanol, it added in an amount of 1.43 to 12.42 L / kg of cephalotin salt to form a metastable state.

Precipitation crystallization and metastatic formation are well known and discussed, e.g. in Sönel O., Chemical Industry 34 (59) 505 (1984), or Veverka, F., Nyvlt J., ibid. 34 (59) 623 (1984). In practical conversion, the width of the metastable region indicates supercooling with the appearance of crystallization seeds in solution, preferably slowly cooled, while continuously adding an additional portion of alkanol having a carbon number of 1 to 3 to the solution. After cooling to 5-10 ° C, the crystallization mass is stirred for a further 1-3 hours to complete the solidification. The precipitated product is isolated by a conventional method such as filtration or centrifugation, preferably subsequently washed with acetone to completely dry the crystalline product. Alternatively, to improve the rheological properties of the crystal prior to being filled into sterile ampoules, it is possible to wash the product with an alkanolic solution having a carbon number of 1 to 3, or acetone containing antistatic additives such as e.g. Cremophor 09, or Tween. The use of surfactants for this purpose is well known to those skilled in the art.

The prepared sterile cephalotin sodium salt does not crystallize as a hydrate and the loss on drying is less than 1.5%. The X-ray method determined crystallinity greater than 95% and crystal size · 10 to 60 μία. The details of the individual embodiments are given in the following examples without being limited to these.

Example 1

A solution of 2 kg of non-sterile sodium salt of 7 - [(2-thienyl) acetamido] cephalosporanoic acid and 0.053 kg of sodium bicarbonate CsL 3 in 7 L of water for injections of CsL 3 is injected into the boilers placed in the sterile part of the device through an animimrobial filter and pressure filter. To the stirring contents of the boiler was added (via an animicrobial filter) at 25 ° C 15 L of isopropyl alcohol, the solution was slowly cooled to 5 ° C and allowed to stand for 15 minutes, followed by 49 L of isopropyl alcohol while cooling to -10 ° C. The reaction mass is allowed to stand for 3 hours: The precipitated product is centrifuged and placed back in the boilers and suspended with 35 L of acetone and 0.0025 kg of Cremophor 09. The product is subsequently centrifuged and dried in a vacuum oven at 10 ° C and vacuum. 0.65 kPa to give 1.85 kg of sterile sodium salt.

Example 2

A solution of 2 kg of non-sterile sodium salt of 7 - [(2-thienyl) acetamido jcephalosporanoic acid and 0.004 kg of sodium citrate CsL 3 in 7 L of water for injections of Cs 3 and 7 L was transferred to the boilers placed in the sterile part of the device. isopropyl alcohol. 9 L of isopropyl alcohol is added to the stirring contents of the boiler at room temperature. Subsequently, 40 l of isopropanol were added to the opaque solution, and the contents of the boiler were gradually cooled to 5 ° C for 2 hours. The precipitated product is centrifuged, washed with 20 l of acetone and dried at 30 ° C in a vacuum oven under a vacuum of 0.6 kPa. 1.6 kg of sterile sodium salt are obtained. Crystallinity 95%.

Example 3

According to Example 2, 1.54 kilograms of sterile sodium salt was prepared using ethanol instead of isopropyl alcohol. Crystalline 96%.

Example 1 4

From a measuring cup, through an antimicrobial filter, it is forced into the boiler in the sterile part of the 9 L isopropyl alcohol apparatus. The contents of the boiler are heated to 40 ° C and a solution of 2 kg of 7 - [(2-thienyl) acetamidoycephalosporanoic acid salt in 7 L of water for injections of CsL 3 and 7 L of isopropanol is added through a pressure filter and an antimicrobial filter. After stirring for 1 hour in the reactor, it is stirred for a further 2 hours and the precipitated product is centrifuged and washed on a centrifuge with a dispersion of 0.0015 kilograms of Cremophor 09 in 1.5 1 of 70%. The product is thoroughly centrifuged and dried in a vacuum oven at a temperature of 30 ° C and a vacuum of 0.6 kPa to give 1.75 kg of sterile sodium salt.

Example 5

Follow the example. 2, using 7 L of water and 14.4 L of ethanol to form the sodium salt solution, and 1.35 kg of sterile sodium salt was prepared to eliminate 55 L of isopropyl alcohol. Crystallite 92%.

Claims (2)

SUBJECT A process for the preparation of crystalline sterile sodium salt of 7 - [(2-thienyl) acetamido ]cephalosporanoic acid from a sterile aqueous or aqueous alkanol solution thereof, wherein the alkanol has 1 to 3 carbon atoms, characterized in that 8.5 and a temperature of 5 to 40 ° C gradually added YN A I. EZU sterile C 1 -C 3 alkanol in an amount of 1.43 to 12.42 L / kg of salt to form a metastable state and further addition of sterile C 1 -C 3 alkanol at 15 to -10 ° C. Sterile sodium salt crystallizes.