DK145824B - PROCEDURE FOR PREPARING A VANDU-SOLUBLE CRYSTALLINIC FORM OF CEPHALEXIN MONO HYDRATE - Google Patents

Description

U5824

The present invention relates to a particular process for preparing a water-insoluble crystalline form of cephalexin monohydrate.

Cephalexin, 7- (D-α-aminophenylacetamido) -3-methyl-3-cephem-4-05 -carboxylic acid, is an antibacterial agent used in human therapy and is marketed as the free acid monohydrate (i.e., the zwitterion). It is e.g. described in J. Med. Chem. 12, 310-313 (1969), J. Org. Chem. 36 (9), 1259-1267 (1971) and J. Org.

Chem. 37 (17), 2765-2767 (1972) [see Belgian Patent Specification No. 765,596; 10 Farmdoc 67,511S] and in U.S. Patent No. 3,507,861, British Patent No. 1,174,335, and Canadian Patent No. 856,786.

There are numerous descriptions of alternative methods for the preparation and purification of cephalexin (such as the free acid). Examples thereof include U.S. Patent No. 3,634,416; U.S. Patent No. 3,668,201; U.S. Patent No. 3,668,202; U.S. Patent No. 3,671,449 (Example 3); U.S. Patent No. 3,676,434; U.S. Patent No. 3,676,437 and U.S. Patent No. 3,689,483 and U.S. Patent No. 3,694,437.

Various descriptions of crystal forms and hydrates 20 are given for cephalexin, e.g. by Pfeiffer et al. in Journal of Pharmaceutical Sciences, 59 (12), 1809-1814 (1970), by Bond et al. in the Pharmaceutical Journal, 210-214 (August 22, 1970) in U.S. Patent Nos. 3,502,663; 3,531,481; Nos. 3,655,656 and 3,692,781 and Belgian Patent Nos. 753,910 (Farmdoc 8214S) and Belgian Nos.

25,777,789 (Farmdoc 48556T) and in French Patent No. 2,096,117.

In particular, U.S. Pat. No. 3,531,481 discloses a process for preparing cephalexin monohydrate in crystalline form, according to which an aqueous solution of an acid addition salt of cephalexin is heated to at least 58 ° C, and the solution is neutralized with a base. , and the precipitated product is separated. Exposure of cephalexin to a temperature of at least 58 ° C involves a risk of decomposition of the product, but it is not possible in the known method to use a lower temperature because this will precipitate a dihydrate which is weathering and unstable.

The process of the present invention is similar to preparing a concentrated, acidic aqueous solution of cephalexin having a pH less than 2.4, adding an adequate amount of n-butanoi to form two liquid phases. , and also add seed crystals of the insoluble form of cephalexin monohydrate, and then, at a temperature of not more than 45 ° C, slowly neutralizes the two-phase system up to a pH of approx. 4.0 to approx. 5.0 to precipitate the water-insoluble crystalline form of cephalexin monohydrate.

Thus, in the process of the present invention, a two-phase system is used by adding n-butanol to a concentrated, acidic, aqueous solution of cephalexin in an amount sufficient to form two liquid phases, and then slowly neutralizing the two-phase system to precipitation of the cephalexin monohydrate. The use of such a two-phase system with n-butanol offers significant advantages, avoiding the decomposition at higher temperatures at a temperature of not more than 45 ° C. It is even possible to carry out the process according to the invention at room temperature, and a preferred embodiment of the invention is therefore characterized by neutralizing the two-phase system at a temperature in the range of approx. 20 ° C to approx. 25 ° C.

The X-ray diffraction properties of the product obtained by the method of the invention are not identical to the X-ray diffraction properties of the products obtainable by the above-described known method. The water content of this known monohydrate should be between 4 and 8%, while according to the following Examples 1 and 3 it amounts to 3.6, respectively. 3.9%.

The water-insoluble crystalline form of cephalexin monohydrate obtained by the process of the invention exhibits the following X-ray diffraction data:

Interplanar distance d (Å): Relative intensities l / l ^ 05 16.01 0.19 12.07 1.00 10.82 0.13 9.64 0.03 8.83 0.07 8.53 0.13 8.10 0.26 7.07 0.08 6.10 0.14 5.60 0.22 5.43 0.64 4.98 0.17 «4.76 0.09 lb 4.57 0.17 4.39 0, 18 4.23 0.18 4.02 0.30 3.94 0.13 3.86 0.19 20 3.79 0.04 3.70 0.05 3.61 0.18 3.44 0.08 3.24 0.10 3, 0.05 0.05 3.11 0.13 2.99 0.08 2.91 0.09 2.80 0.07 2.73 0.07 2.67 0.09 U5824 4

In the process of the invention, it is preferred that triethylamine, sodium hydroxide, potassium hydroxide or ammonium hydroxide be used to neutralize the two-phase system.

During the neutralization, the pH values are determined with a glass electrode inserted into the two-phase system, which is stirred, as well as in the separated aqueous phase at the end of the titration.

The water-insoluble form of cephalexin monohydrate, referred to herein, has an approximate solubility of 10 mg / ml. This was determined by the following approximate method. 30 mg was suspended in 1.0 ml of deionized water and shaken for 5 minutes; some solid remained in suspension. Further addition of 1.0 ml of water was made and not all solids dissolved after 5 minutes of shaking. Further addition of water of 1.0 ml (total 3.0 ml H 2 O) was made and at this point a clear solution was obtained.

The solubility is therefore between 10 and 15 mg per day. ml.

The present invention provides, as mentioned, a particularly crystalline form of water-insoluble cephalexin monohydrate. The usefulness of this crystalline form is identical to that of cephalexin products fully disclosed in the prior scientific and medical literature. As a result, this crystalline form of cephalexin monohydrate is a useful antibacterial agent in the therapy of humans and animals, it has good stability, and it provides effective blood levels by oral administration. Its precise and reproducible chemical and physical nature makes it extremely suitable for efficient, commercial production and subsequent formulation.

The process according to the invention is illustrated in the following by way of example.

Example 1

30 Cephalexin monohydrate in insoluble form with BuOH - HgO system at 20-25 ° C

25.0 g of premium cephalexin was slowly added to 60 ml of H2 O.

Then 6N HCl (9.8 ml) was added dropwise to give a final pH of 1.7. The solution was slightly foggy. 2.5 g of carbon was added for bleaching ("Darko KB"). The mixture was stirred for 15 minutes and filtered. 20 g of NaOH was dissolved in enough water to form 100 ml of 20% NaOH solution.

The carbon was washed with water to give a final filtrate volume of 110 ml. With stirring at 20-25 ° C, 3.5 ml of 20% NaOH was added over ca. 2 minutes; the final pH was 2.3. A seed crystal of insoluble cephalexin monohydrate was then added to the solution. Then 50 ml of n-BuOH was added and the mixture was stirred at 23 ° C while a further 8.65 ml of 20% NaOH was added in portions (about 0.5 ml) over 4½ hours.

Thus, the pH was maintained at 2.4 or slightly higher with a final pH of 4.5, and the temperature maintained at 20-25 ° C.

Analyzes gave K.F. H 2 O = 3.6%. IPA = 0.089%. BuOH = 0.72%. Chemical activity = 898 mcg / mg; bioactivity = 920 mcg / mg.

The precipitated, insoluble cephalexin monohydrate was collected in 1R

by filtration, washed successively with n-BuOH (50 ml), water (40 ml), n-BuOH (50 ml) and IPA (100 ml) and then dried for 22 hours at 53-55 ° C (atmospheric oven pressure) to obtain 20.0 g of dry, crystalline, insoluble pharmaceutical grade cephalexin monohydrate.

20

Example 2

Cephalexin monohydrate (insoluble form) over butanol-water recrystallization The following procedure has been found to give a very white product of high purity as well as the desired crystal form. The butanol layer removes dimethylaniline (DMA) residue and stained items, while the aqueous layer removes the water-soluble contaminants.

1. Slowly add 1000 g of premium cephalexin to 2400 ml

OA

deionized water containing 40 ml of 6N HCl. The addition is carried out slowly for a period of approx. 15 minutes while maintaining the pH of 1.6-1.8 by the addition of 6N HCl. The pH is constantly checked and a total of 390-400 ml of 6 N HCl is required for complete dissolution. The temperature is kept at approx. 20 ° C.

2. 100 g of pale carbon ("Darco KB") are added to the solution and the slurry is stirred for 30 minutes. The slurry is filtered on a pre-coated filter.

6 The filter cake is washed out with deionized water enough to bring the volume of the filtrate to 4.0 liters. Larger volumes would lead to a greater loss of maternal volume.

05 4. The filtrate is adjusted to pH 2.1-2.2 with approx. 30-35 ml of triethylamine (TEA). The pH value must be monitored. A slight haze may appear.

5. Add the chemical-rich aqueous solution to 2000 ml of n-buta-1Q nol and bring the temperature to 40 ° C. Add approx. 100 ml of TEA and the mixture is seeded. This will give a good crystal slurry.

6. TEA is constantly added over an approx. 5 minute period (while keeping the temperature at 40 ° C) to pH 4.4-4.6. The total amount of TEA needed will be approx. 345-350 * ml. The temperature is then lowered to 20 ° C over a 30 minute period. The slurry is stirred at 15-20 ° C for 3 hours.

7. The slurry is filtered on a Buchner funnel and the filter cake 20 is washed out with 2 liters of butanol or until the filter washout butanol begins to pass through colorlessly.

8. The filter cake is then washed out with 1500 ml of deionized water at 0-5 ° C.

25 9. Wash the cake with 1500 ml of butanol and store these leaching liquids and the mother liquor and use the aqueous phase to repeat the cycle.

Finally, wash the filter cake with 2000 ml of isopropanol. It is then dried at 53-55 ° C overnight (about 16-24 hours): yields of 800-820 g of insoluble form of cephalexin monohydrate per ml. 1000 g of starting material were obtained.

% 35 As a check on its concentration, a sample of 6N HCl should be titrated with TEA first to see how much TEA is required to achieve pH 4.5. The hydrochloric acid should be diluted with 8 volumes of deionized. water before performing the titration. In this way one can avoid adding too much TEA during crystallization.

7 145824

Example 3

Cephalexin monohydrate (insoluble form) by direct crystallization with the BuOH-H 2 O system of the aqueous solution from pilot plant 05 1000 ml of partially concentrated aqueous acidic solution of cephalexin from a pilot plant was evaporated in vacuo to ca. 200 ml. The pH of the concentrate was 1.1. Temperature = 22 ° C. The pH was adjusted to 2.1 with 10.0 ml of TEA. The solution was seeded with 1.0 g of cephalexin monohydrate (insoluble form) and 150 ml of n-butanol was added. A thick crystal mass formed very easily. The slurry was stirred and triplicate was added in small portions of ca. 1.0 ml for a period of 3 hours TEA (8.0 ml) until the pH 4.5.

The slurry was stirred for 1 hour at 20 ° C, then the solid was collected by filtration and the filter cake washed with 200 ml of wet butanol followed by 100 ml of cold (0-5 ° C) deionized water. The filter cake was then washed out with 100 ml of dry butanol followed by 100 ml of isopropanol. The filter cake was dried at 50 ° C. A yield of 30.0 g of cephalexin monohydrate (insoluble form) was obtained, which was 29.0 g of cephalexin monohydrate corrected for the addition of 1.0 g of graft crystal.

Analysis: K.F. H 2 O = 3.9% IPA = 0.15% BuOH = 0.57%

Chemical activity = 892 mcg / mg.