NO138144B - PROCEDURE FOR THE PREPARATION OF CRYSTALLINIC SODIUM AND POTASSIUM SALTS OF ALFA-CARBOXYBENZYLPENICILLIN - Google Patents

Description

This invention relates to a new, convenient and economical process for the production of crystalline sodium or "C". potassium salts of α-carboxybenzylpenicillin, which may be mono- or di-salts.

The valuable broad-spectrum penicillin, a-carboxy-berizylpenicillin, is described in U.S. Patent No. 3,142,673 and in British Patent No. 1,004,670 together with the preparation of various salts of this valuable penicillin, including the dialkali metal salts. .1 U.S. Patent No. 3,142,673 also describes the preparation of the mono-alkali metal salts. However, as the alkali metal salts are prepared by the methods of these two patents, they are amorphous and not crystalline materials.

The relatively highly polar nature of α-carboxybenzylpenicillin - together with its tendency to decompose, particularly at elevated temperatures and especially in alkaline solutions of pH.-9 or higher or in acidic solutions of pH 4 or lower, into such products as benzylpenicillin ,--penicilloic acid and penicillinic acid, and the presence of inorganic salts formed by the methods of preparation used - make formation of its crystalline alkali metal salts difficult.

An amorphous salt is generally less preferred than a . ' :> .crystalline form thereof with respect to manufacture, sale, storage :and use. The physical properties of an amorphous salt, such as ease of handling, dispersion in solution, dissolution rate, color of the salt and of the solution thereof, are generally - worse than for a crystalline form of the same salt. Amorphous forms of a salt are also often more hygroscopic than crystalline forms of the salt.

For pharmaceutical use, the above-mentioned poor properties of an amorphous salt, compared to the properties of a crystalline form of the salt, are particularly unfortunate. Formation of acceptable dosage forms such as solutions, suspensions, elixirs, tablets, capsules and various pharmaceutically beneficial preparations required and desirable is made difficult or impossible with an amorphous salt.

It has now been found that stable, crystalline forms of mono- and di-sodium or potassium salts of α-carboxybenzylpenicillin, including its epimers or stereoisomers, can conveniently be prepared from aqueous solutions of α-carboxybenzylpenicillin. The stable, crystalline products produced according to the invention are useful in the same dosage forms and quantities for the same purposes as the amorphous, previously known products, but are not affected by the above-mentioned disadvantages of the amorphous products.

According to the invention, a method is provided for the production of a crystalline sodium or potassium

salt of α-carboxybenzylpenicillin, and the method is characterized in that an aqueous solution of α-carboxybenzylpenicillin with a pH from 2 to 3.5 is extracted with n-butanebl or methyl isobutyl ketone, and the extract obtained is dried in a manner known per se to a water content from 3 to 20% by weight and treated with sodium or potassium 2-ethyl hexanoate.

For the purposes of the present invention, it is desirable that the aqueous solution of α-carboxybenzylpenicillin has a concentration corresponding to from 0.5 to 10% of the acid form by weight. It is preferred that the penicillin is present in a concentration of from 2 to 5% by weight in order to achieve optimal extraction of α-carboxybenzylpenicillin in the subsequent steps.

The pH value of the aqueous solution must be brought to a : value of from 2 to 3.5. The preferred pH range is from 2 to 3, and in particular the range from 2.,2' to 3;0..The regulation.of

The pH value is conveniently carried out using a mineral acid such as hydrochloric acid, sulfuric acid or hydrogen bromide. The acid solution is then extracted with n-butanol or methyl isobutyl ketone. which , have favorable partition coefficients for α-carboxybenzylpenicillin. When methyl isobutyl ketone is used as solvent, a pH value of approx. 2.2, and when n-butanol is used, the preferred pH value is approx. 3.0.

The extraction can be carried out as a batch or continuous process. Regardless of the type of method used, it has been found that a total volume of solvent. equal to approximately one-half to one-third of the volume of the aqueous acid solution allows satisfactory extraction of the α-carboxybenzylpenicillin. Larger volumes can of course be used,

but will necessitate treatment and recycling•of unnecessary

large volumes of solvent. Smaller volumes are not desirable, since the recovery of the desired product is then reduced. The volume of the organic solvent is regulated appropriately so that a concentration of α-carboxybenzylpenicillin in the extract is obtained from 10 to 20%.

Extracts of α-carboxybenzylpenicillin stored in n-butanol or methyl isobutyl ketone contain a certain

amount of water. However, it has been found that

if too much water is present in the extract, i.e. if it is too wet, the crystalline product is difficult to filter apparently due to a very small crystal size. ' If, on the other hand, the extract is too dry, the salts tend to separate out as amorphous instead of crystalline products.

A certain amount of water is necessary to achieve optimal excretion of the crystalline sodium or potassium salts.

It has been found that a water content of from 3 to 20% in the organic solvent extract leads to crystal formation,

and the preferred" range is from 7 to 15% water. This degree of dryness is easily and conveniently achieved by drying the organic solvent extract with anhydrous sodium sulfate which is the preferred drying agent for this process. Other drying agents, such as anhydrous calcium sulfate and anhydrous magnesium sulfate , can also be used. When magnesium sulfate is used, it is desirable to

monitor the drying process to prevent the water content from falling below the above. In addition, mechanical methods such as filtration through cotton, centrifugation and "

azeotropic drying..

The "dried" organic solvent extract is then treated with the appropriate mole fraction of sodium or potassium 2-ethyl hexanoate to form the desired crystalline mono- or di-sodium or potassium salt of α-carboxybenzylpenicillin.

Sodium or potassium 2-ethyl hexanoate is added j

IN

suitably in the form of a solution in acetone, methyl isobutyl ketone, ethyl acetate, n-butanol, isopropanol or another organic solvent in which it is soluble to the extent of at least 0.05%. The preferred solvent is acetone. When you want to prepare a mono-sodium or potassium salt, up to 1 mol of sodium or potassium 2-ethyl hexanoate is used per mol of a-carboxybenzylpenicillin. A molar ratio much above 1:1 at this stage tends to reduce the yield of the mono-) salt due to formation of the di-salt. A moi ratio of significantly less than 1:1 also results in reduced yields due to j incomplete turnover. A moi ratio of from 0.8:1 to 1.2:1 j

i is preferred for formation of mono-salt. j

Formation of the crystalline di-sodium or -potassium salts is achieved by using a molar ratio of at least 2:1 of sodium or potassium 2-ethyl hexanoate to α-carboxybenzylpenicillin. In practice, it is preferred to use up to a 20% excess of sodium or potassium 2-ethyl hexanoate to ensure as complete precipitation of the disalt as possible.

The crystalline sodium or potassium salt (mono- or di-salt, depending on the quantity ratio of sodium or potassium 2-ethyl hexanoate to α-carboxybenzylpenicillin) which precipitates is separated, for example by filtration, and washed or treated again with an organic solvent such as acetone or isopropanol, and then dried. Other solvents such as n-butanol and methyl isobutyl ketone can be used in this precipitation step, but . j-are not preferred since they are difficult to remove from the [ crystalline product. r j

The products are dried appropriately at approx. 40 to 65°C. j Other methods that are common in the art can also be used, e.g. air drying, drying under nitrogen or drying in vacuum.j Although higher temperatures can be used, such treatment will require careful monitoring to avoid decomposition of the product and/or! loss of crystal water. A certain amount of crystal water is desirable for reasons of stability of the crystalline disodium salt.

The crystalline disodium salt thus obtained is somewhat hygroscopic, but considerably less hygroscopic than the amorphous disodium salt. It appears to be a monohydrate. The crystalline mono-sodium and mono-potassium salts are considerably less soluble in water than the corresponding disodium and dipotassium salts1

The temperature. at which these various operations are performed is not particularly critical. However, due to the instability of α-carboxybenzylpenicillin in aqueous acid or aqueous alkaline solutions, it is convenient to carry out the entire process, with the exception of the drying step at the end, at a temperature of from 0 to 30°C, and the preferred range is from 5 to 25°C. The only step in the process where the temperature can fall outside this range without damaging the product is the drying step at the end with drying of the crystalline salts.

The following examples shall serve to further illustrate the invention.

Example 1 Crystalline disodium α-carboxybenzylpenicillin

An aqueous solution of α-carboxybenzylpenicillin

(content approx. 8%), prepared from 250 g of crude disodium-α-carboxybenzylpenicillin, n-butanol (650 ml) is added, and the mixture is cooled to 5-8°C and adjusted to pH 3.0 using 2N hydrochloric acid -.•„■-(850 ml). The mixture is stirred carefully, the n-butanol phase is separated, and the aqueous phase is extracted twice more with 400 and 250 ml of n-butanol respectively. The n-butanol extracts are then collected, dried with anhydrous sodium sulfate (600 g) and - , ^ filtered first through filter paper and then through a millipore filtration unit (solvent resistant membrane type, porosity 2.2 y).

Sodium 2-ethyl hexanoate is then added to the filtrate

(2.1 equivalents in 950 mL of acetone) over a period of 1 1/2 hours. Acetone is added as needed to maintain an easily stirrable suspension (total volume added is 2300 ml). Stirring is continued

for 1 hour at room temperature after the addition of sodium 2-ethyl hexanoate, after which the product is removed by filtration. Filter-

the cake is reslurried in acetone at room temperature for 45 minutes, then filtered, and the reslurry is repeated. The crystalline disodium salt is dried overnight under a stream of nitrogen. Further drying is achieved by heating the product to approx. 65°C in a drying oven. Total yield equals 178.5 g, 71%.

Example' 2 ../ V ' ■

Cross tal linsTc dihatfium-a-carboxybenzylpenicillin from rat

a- carboxybenzylpenicillin

One sample of crude α-carboxybenzylpenicillin (7.5 g) is dissolved in water (75 ml) to give a 10% solution of the crude acid,

"and cooled to 10°C. <X> The pH value is adjusted to 2.2 using 2N sulfuric acid, the solution is extracted with methyl isobutyl ketone (3 x 20 ml)..., and the combined extract is dried with anhydrous calcium sulfate. The dried extract filtered, cooled to 8°C and treated dropwise with 18 ml of an acetone solution of sodium 2-ethylhexanoate (containing 0.2075 mg sodium salt per ml).

Acetone is added as needed to allow effective stirring.

After 1 hour at 8 to 10°C. the crystalline disodium salt is removed by filtration, washed with acetone and dried at 40°C.

Example 3

Crystalline disodium salt of α-carboxybenzylpenicillin

An approx. 8% aqueous solution of carboxybenzylpenicillin (content about 42.6 g), prepared by hydrolysis of 97 g of α-carbo-phenoxybenzylpenicillin-N-ethylpiperidine salt, n-butanol (100 ml) is added, and the mixture is stirred and cooled to 0 to 10 °C. Sufficient 2N hydrochloric acid is added to bring the mixture to

pH 3.0, the mixture is allowed to separate, and the butanol layer is collected. The acidic aqueous liquid is extracted twice with 75 mL of butanol each time, the combined butanol solutions (250 mL) are dried over anhydrous sodium sulfate (300 g) for 1 hour and then filtered into a 100.0 mL 3-necked flask equipped with a mechanical stirrer and an addition funnel. An acetone solution of sodium 2-ethyl hexanoate (169 ml containing 207.5 mg of salt per ml) is added dropwise over a period of 20 to 30 minutes. When approximately half of

the solution has been added, crystallization seed of crystalline disodium salt is added to the mixture. The mixture is stirred for 30 minutes after the addition of the sodium ethyl hexanoate, then acetone (225 ml) is added, and the mixture is stirred for a further 15 minutes. The crystalline disodium salt is collected by filtration on a sintered glass funnel under a dry atmosphere. nitrogen, and

. The filter cake is washed with acetone (500 ml). The cake is suspended in fresh acetone (1000 ml), the suspension is stirred at room temperature for 30 minutes, filtered as described above and allowed to dry on

the filter in a stream of dry nitrogen. for 16 hours. The product .is

a white, free-flowing, crystalline powder soin is somewhat hygroscopic and easily soluble in water.

Yield = 25.6 g (60%), .sm.p. i?8-201°C, cleavage.

Example 4

An aqueous solution of α-carboxybenzylpenicillin (content approx. 3%), prepared by hydrolysis of 97 g of 2-carbo-phenoxybenzylpenicillin-N-ethylpiperidine salt, is adjusted to pH .7 by the addition of 2N hydrochloric acid and then extracted with n-butanol

(3 x 200 ml). The n-butanol extract is then discarded, and n-butanol (100 ml) is added to the aqueous phase, the mixture is stirred, cooled

to 5-10°C and brought to pH 2.2 using 2N hydrochloric acid. The phase with n-butanol is allowed to separate, collected, and the aqueous layer is extracted twice again with n-butanol (75 ml each time)

The combined n-butane extracts are dried over anhydrous sodium sulfate, filtered and treated at 10°C with sodium 2-ethyl.l-

hexanoate (16 9 ml acetone solution containing 207.5 mg sodium,

salt per ml) over a period of 30 minutes. The mixture is stirred for 1/2 hour, 250 ml of acetone is added and stirring is continued for a further 15 minutes. The crystalline disodium salt is collected and dried under nitrogen.

Example 5

Crystalline monosodium-α-carboxybenzylpenicillin'

Butanol solutions of α-carboxybenzylpenicillin,

prepared according to the procedure from Example 3 is dried over anhydrous sodium sulfate and then treated with sodium 2-ethyl hexanoate in an organic solvent to give the mono-sodium salt." -The conditions appear in the table. ' .

Claims (1)

Process for the preparation of a crystalline sodium or potassium salt of α-carboxybenzylpenicillin, characterized in that an aqueous solution of α-carboxybenzylpenicillin with a pH from 2 to 3.5 is extracted with n-butanol or methyl isobutyl ketone, and the extract obtained dried in a known manner to a water content of 3 to 20% by weight and treated with sodium or potassium 2-ethyl hexanoate.