NO165247B - TOEY LAUNDRY FOR AA WASH AND SOFT TOUCH TOEY. - Google Patents

Description

Procedure for the production of a

crystalline, containing water of crystal

calcium salt of phenoxymethylpenicillin.

This invention relates to a new process for producing a crystalline, water-of-crystal calcium salt of phenoxymethylpenicillin.

It is known that phenoxymethylpenicillin has a marked stability against acids compared to many other penicillins, e.g. benzylpenicillin. It has therefore been used extensively in oral penicillin therapy. As an ingredient in tablets, phenoxymethylpenicillin can be used in the form of the free acid, but its salts, i.a. the calcium salt, is preferred.

Some methods for producing the calcium salt of phenoxymethylpenicillin have previously been described in the literature. In one of the methods described, free phenoxymethylpenicillin acid is released from an aqueous solution of its alkali metal salt and extracted with an organic solvent, from which the calcium salt is obtained by extracting the organic solution with an aqueous solution containing calcium ions. This particular method is laborious and entails a great risk of deactivation of the penicillin, particularly in the release of the phenoxymethylpenicillin acid from the alkali metal salt by means of an acid. It is also known to prepare the calcium salt of phenoxymethylpenicillin by double reaction (metathesis) of a water-soluble alkali metal salt of the penicillin dissolved in water with a calcium salt or calcium hydroxide, whereby the slightly soluble calcium phenoxymethylpenicillinate containing crystal water is precipitated from the solution. Instead of the water-soluble alkali metal salt, the free acid dissolved in an organic solvent can also be used. In the above-mentioned method, the reaction is carried out in the presence of water and with solutions of phenoxymethylpenicillin, both of which entail a high risk of loss of active penicillin during or before the desired reaction.

Furthermore, it is desirable to carry out the reaction at as high a concentration as possible. In addition to saving materials, a better utilization of the device's capacity is achieved. However, it is known that difficulties often arise in carrying out a chemical reaction when one or more of the reacting components are present in solid form or are slightly soluble in the reaction medium. This difficulty is emphasized if one of the reaction products is also slightly soluble. This problem has been attempted to be solved by treating the solid potassium salt of phenoxymethylpenicillin with calcium chloride in an anhydrous, aliphatic alcohol, e.g. ethanol, and in this case one encounters the further difficulty that the alcoholic reaction mixture assumes a gelatinous consistency which makes it difficult to handle.

According to the present invention is provided

a method for producing a crystalline, water-of-crystal calcium salt of phenoxymethylpenicillin, where the potassium salt of phenoxymethylpenicillin in solid form is treated with an anhydrous alcohol solution while stirring, the alcohol being an aliphatic alcohol with no more than 4 carbon atoms, preferably

ethanol or methanol, of a calcium salt of an acid whose potassium salt is slightly soluble in the aliphatic alcohol, preferably calcium chloride or bromide, and after complete conversion a small amount of water or an aqueous solution of a neutral salt is added to the reaction mixture, f .ex. calcium or sodium chloride, so that the crystalline, water-of-crystal calcium salt of phenoxymethylpenicillin is precipitated. The method is characterized by the fact that the reaction of the potassium salt of phenoxymethylpenicillin with the calcium salt is carried out in the presence of at least one mole of urea per moles of the potassium salt of phenoxymethylpenicillin.

Despite the high concentration of salts in the reaction mixture, the reaction mixture remains at all times in an easily stirred state. By using a solution of e.g. calcium or sodium chloride, in the added water, the solubility of the calcium salt of phenoxymethylpenicillin is reduced. The reaction is preferably carried out at no more than 30°C. The calcium salt of phenoxymethylpenicillin can be obtained with a very high yield, more than 90%.

The exact mechanism of the reaction in the presence of urea and the reason for the beneficial effect of urea are not known at present, but it is likely that an addition compound between the calcium salt of phenoxymethylpenicillin and urea is formed.

The invention and the beneficial effect of urea shall be illustrated by the following examples.

EXAMPLE 1

3.1 g of urea and 15 ml of a 10% solution of calcium chloride in anhydrous ethanol were added to 5 g of potassium phenoxymethylpenicillinate. The reaction mixture was allowed to stand for 20 minutes with stirring and was then filtered. Even after this short reaction time, the precipitate, 1.0 g, contained only 2% of the amount of penicillin used, while the rest was potassium chloride. This shows that practically all the penicillin dissolved as a calcium salt. If the experiment is repeated in the same way, but with the same amount of anhydrous ethanol instead of a solution of calcium chloride, the amount of phenoxymethylpenicillin salt used could be found quantitatively in the solid phase. The same result was obtained if urea was also omitted.

This shows that the potassium salt as such is not soluble in the solvent, even in the presence of urea.

EXAMPLE 2

5.01 g solid potassium salt of phenoxymethylpenicillin

and 3.1 g of urea was added to 15 ml of a 10% calcium chloride solution in anhydrous ethanol. The reaction mixture was stirred at room temperature until all the potassium salt had reacted. With continued stirring, 15 ml of a 36% calcium chloride solution in water was then added. The precipitate formed, consisting of crystalline calcium salt of phenoxymethylpenicillin, was isolated by filtration, washed with water and acetone and then dried. The yield was 4.65 g. Its water content was determined by titration according to Karl Fischer, and 4.7% by weight was found.

EXAMPLE 3

0.77 g of urea and 10 ml of a 15% solution of calcium chloride in anhydrous ethanol were added to 4.98 g of potassium phenoxymethylpenicillinate. The reaction mixture was allowed to stand at room temperature until all the potassium salt had reacted. Then 20 ml of a 36% solution of calcium chloride in water and 1 ml of saturated calcium acetate solution were added. After continuing the treatment as described in example 2, 4.72 g of the crystalline calcium salt of phenoxymethylpenicillin were obtained.

EXAMPLE 4

5 g of solid potassium salt of phenoxymethylpenicillin and 3.1 g of urea were added to 15 ml of a 15% solution of calcium chloride in anhydrous ethanol. The reaction mixture was stirred at room temperature until all the potassium salt had reacted. Then 50 ml of a 20% solution of potassium chloride in water was added. The precipitate of the penicillin salt thus formed was filtered, washed with water and acetone and dried. The yield was 4.57 g.

EXAMPLE 5

5 g of solid potassium salt of phenoxymethylpenicillin and 3.1 g of urea were added to 15 ml of a 10% solution of calcium chloride in anhydrous ethanol. The reaction mixture was stirred until all the potassium salt had reacted. Then 15 ml of water was added. The precipitate of the crystalline calcium salt of phenoxymethylpenicillin thus formed was filtered, washed with water and acetone and dried. The yield was 4.20 g.

EXAMPLE 6

5.00g solid potassium salt of phenoxymethylpenicillin and

3.1 g of urea was added to 18 ml of a 15% calcium bromide solution in anhydrous ethanol. The reaction mixture was stirred until all the potassium salt had reacted. Then 15 ml of water was added. The resulting precipitate of a crystalline calcium salt of phenoxymethylpenicillin was isolated by filtration, washed with water and acetone and then dried. The yield was 4.05 g.

EXAMPLE 7

5.00 g of solid potassium salt of phenoxymethylpenicillin and 3.1 g of urea were added to 15 ml of a 10% solution of calcium chloride in anhydrous n-propanol. The reaction mixture was stirred until all the potassium salt had reacted. Then 15 ml of water was added. The resulting precipitate of crystalline calcium salt of phenoxymethylpenicillin was isolated by filtration, washed with water and acetone, and dried. The yield was 4.10 g.

By means of the method according to the invention, the following advantages are achieved. As the potassium salt of phenoxymethylpenicillin is used in solid form, and anhydrous alcohol, preferably ethanol or methanol, is used in the reaction, the risk of loss of active penicillin is small. On the basis of the fact that the reaction takes place in an alcohol, which is present in high concentration even after the addition of water, one has favorable conditions with regard to sterility, which is of great importance when working with penicillin. With the method according to the invention, a product is also obtained which has a crystal size which is particularly suitable for tablet production.

Claims (1)

Method for producing a crystalline, water-of-crystal calcium salt of phenoxymethylpenicillin, where the potassium salt of phenoxymethylpenicillin in solid form is treated with an anhydrous alcohol solution while stirring, the alcohol being an aliphatic alcohol with no more than 4 carbon atoms, preferably ethanol or methanol, of a calcium salt of an acid whose potassium salt is slightly soluble in the aliphatic alcohol, preferably calcium chloride or bromide, and after completion of the conversion a small amount of water or an aqueous solution of a neutral salt is added to the reaction mixture, e.g. calcium or sodium chloride, so that the crystalline, water-of-crystal calcium salt of phenoxymethylpenicillin is precipitated, characterized in that the reaction of the potassium salt of phenoxymethylpenicillin with the calcium salt is carried out in the presence of at least one mole of urea per moles of the potassium salt of phenoxymethylpenicillin.