HU204570B - Process for purifying adriamycin-hydrochloride - Google Patents

Abstract

Fermented or synthesised raw adriamycin-hydrochloride antibiotic is purified for pharmaceutical use, as follows. A mixt of an 1-4C aliphatic ketone and 1-5C aliphatic alcohol is added to raw adriamycin soln till incipient turbidity at 25-50deg.C. The soln is cooled to room temp and phased out tarry substances are removed. Pure adriamycin is pptd from the remaining soln by diluting it with a 1-4C aliphatic ketone. Opt. the isolated cpd. is resuspended in ketone, agitated, filtered and dri

Description

The present invention relates to a novel process for the preparation of high purity adriamycin hydrochloride for pharmaceutical use starting from crude adriamycin hydrochloride obtained by fermentation or synthesis.

Adriamycin, an antibiotic with antitumor activity, is one of the most commonly and successfully used components in the complex chemotherapy treatment of cancers. It may be prepared by fermentation (for example, Hungarian Patent No. 157,650); semisynthetically, by chemical conversion of daunomycin (e.g., Hungarian Patent No. 158,639), or by the total synthesis of a suitably protected magic icon and a sugar component (e.g., German Patent Publication Nos. 2,510,866 and 2,519,157). However, whatever the route of preparation of the adriamycin hydrochloride, the final product requires further purification to obtain USP XXH. adriamycin hydrochloride, 97 to 102% by weight of the active ingredient, suitable for pharmaceutical use, can be prepared. For the preparation of this high purity composition, only one process has been known so far (British Patent No. 2,133,005) which provides two successive chromatographic (ion exchange and then adsorption) chromatography of the crude product to the desired quality of thiamamicin hydrochloride. In addition to the high loss of material (about 65% yield), binary chromatography has the disadvantage of using expensive ion exchange resin (Kastell S 112) and of working with and evaporating large volumes of solvent.

In addition, during the reproduction of the above process, it has been found that the ion exchange resin and / or the ion exchange resin used in the chromatography. absorbent can only be used once as it cannot be regenerated. And the desired quality of adriamycin hydrochloride can be achieved only by starting from a relatively pure product (> 95% purity). In the case of lower quality crude product, it is necessary to repeat the purification process, which reduces the yield to less than 30%.

SUMMARY OF THE INVENTION It is an object of the present invention to provide a purification process which is free from the disadvantages of the prior art and which can optionally convert an adriamycin hydrochloride of less than 95% purity to a pharmaceutical grade product containing up to 31% impurities. 45

It has been found in our experiments that crude adriamycin is generally contaminated with tarry by-products, the solubility of which differs from that of adriamycin hydrochloride and can therefore be selectively removed from the drug by solvent precipitation. Further, it has been found that mixtures of C 1-4 aliphatic aliphatic aliphatic alcohols with C 1-5 aliphatic alcohols are excellent for selective precipitation. The precipitate of 55 riamycin hydrochloride is converted into a microcrystalline form which is very advantageous for processing and pharmaceutical preparation.

Accordingly, the present invention provides a process for the preparation of pharmaceutical grade 60 adriamycin hydrochloride containing up to 3% impurities, starting from crude adriamycin hydrochloride obtained by fermentation or synthesis, wherein the crude adriamycin hydrochloride is between 40 ° C and 65 ° C. A solution of a C 1 -C 4 aliphatic ketone and a C 1 -C 5 aliphatic alcohol is added to the aqueous solution of the mixture at a temperature ranging from 25 ° C to 50 ° C until the solution is clouded to room temperature. removed, the adriamycin hydrochloride in the remaining solution was precipitated by dilution with a C 1-4 aliphatic ketone and separated, resuspended in a C 1-4 aliphatic ketone, stirred at room temperature, then filtered and dried.

The final product thus obtained meets all the requirements for pharmaceutical preparation.

In a preferred embodiment of the process according to the invention, crude adriamycin hydrochloride is dissolved in water at 40 ° C to 65 ° C, preferably 55 ° C, or heated to 55 ° C with crude adriamycin hydrochloride, and then adding a mixture of a C 1 -C 4 aliphatic ketone and a C 1 -C 5 aliphatic alcohol, preferably a 3: 1 mixture of acetone-isopropanol or ethanol, until the solution is cloudy to a temperature of 25 ° C to 50 ° C. between. The mixture is then allowed to cool to room temperature and the precipitated dark tarry precipitate is removed by filtration or centrifugation using a filter aid, preferably Supercell.

The remaining solution is precipitated with adriamycin hydrochloride by addition of an additional 1-4 carbon aliphatic ketone, preferably acetone, left overnight in the refrigerator, filtered, washed with ketone and dried. If desired, the resulting product can be further purified by suspending it in a C 1 -C 4 ketone, preferably acetone, and stirring the suspension at room temperature.

The main advantage of the present invention over the known process is that it allows the preparation of adriamycin hydrochloride of a suitable pharmaceutical grade without the use of an ion exchange resin in a simple and economical manner.

The process of the invention is illustrated by the following examples, without limiting the invention thereto.

l.példa

2.1 g of adriamycin hydrochloride (HPLC purity 93% purity) were dissolved in 27 ml of 55 ° C water with stirring, and a mixture of 90 ml of acetone and 30 ml of isopropanol was added to bring the solution to 25 ° C. Set between 'C and 45' C. The solution becomes cloudy and after 10 minutes at room temperature a dark, fluffy precipitate forms. The precipitate was directly filtered through a 2.7 cm diameter G-3 filter through a 3 mm thick supercell filter layer with water to 54 ml of acetone,

204570 Β then wash the filter with 13 mL of acetone / isopropanol (3: 1). The precipitate immediately precipitates out of the filtrate. The precipitated solution was stored overnight at + 5 ° C. During this time, the precipitate becomes microcrystalline. This was filtered and washed with acetone (27 mL). The product thus obtained is air-dried and then suspended in 25 ml of acetone and stirred at room temperature for 2 hours. The suspension is filtered, washed with 20 ml of acetone, and the material is dried in air at room temperature and then at 40 [deg.] C. over phosphorus pentoxide in vacuo for 2 hours. The resulting 2.2 g adriamycin hydrochloride contains 97% purity (by HPLC), less than 0.5% daunomycin and less than 1.5% other anthracycline impurities. The yield of the purification process was 81%.

Example 2 To a solution of 0.3 g of 71% pure Adriamycin hydrochloride in water was added a mixture of 9 ml of acetone and 3 ml of isopropanol at 55 ° C. The supernatant was centrifuged at room temperature and the supernatant was decanted and poured into 48 ml of acetone. The precipitate was treated as in Example 1 to give 88% pure Adriamycin hydrochloride in 73% yield. Further purification of this material as in the first example gives the product of the purity indicated therein. The yield for further cleaning is 75%.

Example 5

Adriamycin hydrochloride (0.3 g, 87% purity) was dissolved in 3 mL of 55 ° C water with stirring, then a mixture of 28 mL of acetone and 7 mL of ethanol was added. The fine fluffy precipitate is removed and further processed as described in Examples 1. The resulting adriamycin hydrochloride was 975% pure and the purification yield was 62%.

Claims (6)

PATIENT INDIVIDUAL POINTS A process for the preparation of adriamycin hydrochloride of a quality suitable for the manufacture of a medicament containing up to 3% of contamination, starting from crude adriamycin hydrochloride produced by fermentation or synthesis, wherein the crude adriamycin hydrochloride is dissolved in an aqueous solution at a temperature of from 40 ° C to 65 ° C, starting at a cloudiness. 4-C aliphatic ketone and a mixture of C 1-5 aliphatic alcohols are added such that the temperature of the resulting solution is between 25 ° C and 50 ° C and the solution is cooled to room temperature to remove the tarry materials removed from the solution and the pure adriamycin from the remaining solution. Hydrochloride is precipitated by dilution with a C 1-4 aliphatic ketone and separated and resuspended in a C 1-4 aliphatic ketone at room temperature, then filtered and dried. Process according to claim 1, characterized in that starting from an aqueous adriamycin hydrochloride solution heated to 55 ° C. The process according to claim 1 or 2, wherein the C 1-4 aliphatic ketone is acetone, the C 1-5 aliphatic alcohol is isopropanol or ethanol. 4. The method of claim 3, wherein the precipitation is effected with a 3: 1 mixture of acetone-isopropanol. 5. Method according to one of claims 1 to 3, characterized in that the tar-like by-products are removed by filtration or centrifugation in the presence of a filtering aid. The method of claim 5, wherein the filtering aid is Supercell.