US3044936A - Process of producing solutions of chloramphenicol in aqueous liquids, and composition - Google Patents

Description

United States Patent PROCESS OF PRODUCING SOLUTIONS OF CHLOR- AMPHENICOIL IN AQUEOUS LIQUIDS, AND COMPOSITION Johann Daniel Achelis, Heidelberg, Rndi Gall, Mannheim-Kae'fertai, Erich Haack, Heidelberg, and Wolfgang Voemel, -Mannheim, Germany, assignors to C. F. Boehringer & Soehne G.rn.b.H., Mannheim-Waidhof, Germany, a corporation of Germany No Drawing. Filed Dec. 2, 1958, Ser. No. 777,602

Claims priority, application Germany Dec. 7, 1957 5 Claims. (Cl. 167-65) The present invention relates to solutions of chloramphenicol in aqueous liquids, and to a process of preparing such solutions.

The antibiotic chloramphenicol is readily absorbed by the body on oral administration. For this reason it is usually given per os, for instance, in the form of gelatine capsules or dragees. In some instances, however, oral administration cannot be used or is ineffective because the patient is not able to swallow the drug, respectively, to absorb it. It is also frequently necessary for medical reasons to avoid the passage of the drug through the digestive tract, for instance, during or before an operation. In some cases it is desirable to achieve a rapid increase of the antibiotic level in the blood. Thus, there is a considerable demand for injectable solution of this valuable antibiotic. However, the preparation of such solutions meets with great difficulties.

Chloramphen-icol is soluble in water at room temperature only up to 0.4%. This concentration is by far insufiicient for administration by intramuscular or intravenous injection. It has been found that non-aqeous solvents for chloramphenicol, which have been used for the preparation of more concentrated solutions, cause severe damage to the tissue in the form of painful swellings and frequently of serious necroses, even if the solvent as such is physiologically inert. This disadvantage is especially encountered on intramuscular injection. The same applies to aqueous mixtures with said solvents because the solvent content required to provide stable solutions by far exceeds the limit of compatibility.

It is, therefore, understandable that injection solutions of chloramphenicol, as they have been prepared heretofore, for instance solutions in solvents containing a high percentage of glycols and substituted fatty acid amides (see, for instance, German Patent No. 852,123) have not found applicationin therapy. As pharmacological tests have shown, such solutions cannot be used for intramuscular administration on account of their damaging effect on the tissue. The same applies to the known crystal suspensions of chloramphenicol in water or oil. These suspensions are highly unsatisfactory for their low blood levels. Unsatisfactory blood levels are also obtained by administering water soluble chloramphenicol esters which were proposed for injection purposes. Such esters, for instance, the preferably investigated 3-succinate, are water-soluble in the form of their neutral salts, such as their sodium salts. Their solutions may be injected almost without causing harmful reactions. However, the biological efiiciency test shows that, for instance, the succinate produces a much lower blood level than the same amount of chloramphenicol. This is probably due to the poor hydrolysis of the succinate within the body to produce the effective chloramphenicol.

It is one object of the present invention to provide solutions for parenteral administration which contain a high percentage of chloramphenicol, which may be diluted with water without precipitation of the chloramphenicol, and which have no damaging effect upon the tissue when injected in therapeutically useful amounts.

Another object of the present invention is to provide a simple and effective process of producing such highly concentrated chloramphenicol solutions.

A further object of the present invention is to provide phenicol is increased considerably by the addition of lower chloramphenicol esters. Solutions of chloramphenicol containing such esters can be diluted with water without precipitation of chloramphenicol. The application of this principle permits parenteral administration of chloramphenicol, preferably intramuscular administration thereof, which, in .many' cases, is highly desirable, in an amount sufficient to produce the desired antibiotic eifects without causing damage to the body, such as necrotic changes of the tissue.

The term lower esters indica-ta esters having a maximum of 10 carbon atoms Within the ester group and will be used hereinafter and in the claims annexed hereto. With higher esters a significant decrease in antibiotic efiiciency is observed. Suitable esters are not only the mono-esters of chloramphenicol but also the di-esters and mixtures thereof. The esters may be esters of monoor polyvalent organic acids and their substitution products as well as of inorganic acids, such as nitric acid, hydrochloric acid, phosphoric acid, and the like. Especially effective esters are the following esters of organic acids:

Esters of lower aliphatic monoor'polycarboxylic acids such as the following esters:

O -acetate, O ,O -diaceta'te, O -maleate, 0 -succin'ate. Esters of esterified and etherified hydroxy lower fatty acids such as the following esters:

-O -ethox-y acetate, O -ethoxy acetate, O ,O -di-(ethoxy acetate), O -methoxy ethoxy acetate, o O -di-(methoxy ethoxy acetate), O -rnethoxy ethoxy ethoxy acetate, O ,O -di-(methoxy ethoxy ethoxy acetate),

O -tetrahydrofurfuryloxy acetate, O ,O di-(tetrahydrofurfuryloxy acetate), O -1,3-dimethoxy isopropoxy acetate, O -methoxy acetate, O ,O '-di-(methoxy acetate), O acetoxy acetate, O -diacetyl tartrate. 1 Esters of partly esterified aliphatic polycarboxylic acids,

such as the followingesters:

O -mono-methyl succinate, O -mono-methyl malonate.- Esters of lower aliphatic keto carboxylic acids, such as the following ester: O -aceto acetate. Esters of 'monocyclic aromatic 'dicarboxylic esters, such as the following ester: o -p'hthalate.

The solubility increasing and stabilizing effect of such esters lis apparently not principally connected with their, own solubility in wateror, respectively, with the solubility of their salts in water; most of them are, in fact, only difliculty soluble therein. However, in carrying out the solvents'must be inert to chloramphenicol and its esters.

They must :also be physiologically inert, at least in the 3,044,936 I Patented July 17, 196 2 j 3 concentrations in which they are used therapeutically. Solvents which meet with these conditions are, among others, the following:

Polyethylene glycol ethers, such as diethylene glycol dimethyl ether;

Dimethyl sulfoxide;

N,N-di-(lower alkyl) lower alkanoic acid amides such as dimethyl formamide, dimethyl acetamide, diethyl formamide, diethyl acetamide;

Glycerol methyl ether;

Tetrahydrofurfuryl methyl ether; and others.

To carry out the present invention it is not necessary to use the solubilizing or, respectively, stabilizing ester as such. The ester may also be formed-and this is the preferred method in some cases-when preparing the chloramphenicol solution, whereby, of course, an excess of chloramphenicol is used. For this purpose the corresponding acid anhydride is added to the mixture of solvent and chloramphenicol. If esters of acids are used which contain a salt-forming group, it is the preferred procedure to form the salt by adding an equivalent amount of an alkali hydroxide or another basic substance, for instance, of a physiologically inert amine. In certain special instances it might be advisable to use additionally a known solubilizing agent to cause further stabilization of the resulting solution, such as urea or its substitution products, or urethanes. This elfect is very surprising because such known solubilizing aids alone do not produce any substantial increase in solubility of chloramphenicol in aqueous liquids.

The process of increasing the solubility of chloramphenicol in aqueous liquids by means of lower chloramphenicol esters according to the present invention is, as stated above, of considerable importance for the preparation of injectable solutions of this valuable antibiotic. The resulting injectable solutions which may contain 30% and more of the effective drug, are well tolerated especially by the tissue because their content of organic solvents, if they are used for preparing the initial ester solution, is always within the limit of compatibility, whereas the esters of chloramphenicol are physiologically inert and contribute to the desired therapeutieal effect due to their more or less rapid hydrolysis to chloramphenicol.

The injectable liquids according to the present invention are quite stable. However, due to the sensitivity of most esters against hydrolysis, it is advisable to first prepare a solution containing the chloramphenicol and the ester and, if necessary, the solubilizing aid in an anhydrous organic solvent of the above mentioned type. This solution, which can be stored for an unlimited period of time, represents the stock solution. It is diluted with water shortly before its use. The physician may prepare the final dilution. Further handling of the injectable solutions according to the present invention, for instance, adjustment of its pH-value, sterilization, and the like is effected with the usual care.

The following examples serve to illustrate the present invention without, however, limiting the same thereto.

Example 1 A suspension containing 4 g. of chloramphenicol in a solution of 5.5 g. of chloramphenicol-Ownccinate in the form of its sodium salt in 100 cc. of water is caused to dissolve by heating for a short period of time. The resulting solution remains clear after cooling whereas a solution of 0.6 g. of chloramphenicol in 100 cc. of warm water shows immediate precipitation of crystals when cooled.

Example 2 When a solution containing 1.0 g. of chloramphenicol in 2.0 cc. of dimethyl sulfoxide is diluted with cc. of water, chloramphenicol precipitates immediately. However, if 1.4 g. of the sodium salt of chloramphenicol-O succinate are added to the starting solution, a clear solution results on the addition of the same amount of water. This solution does not precipitate even after several days.

Example 3 A solution containing 1.89 g. of chloramphenicol, 2.0 g. of dimethyl urea, and 0.15 g. of chloramphencol-O methoxy ethoxy acetate in 2 cc. of dimethyl sulfoxide remains clear after dilution with water whereas, without the addition of the chloramphenicol ester, the chloramphenicol is precipitated by the addition of water.

Example 4 500 mg. of chloramphenicol and 635 mg. of chloram- PhBIIlCOl-O -SUCClHQlfi are dissolved in a mixture of 0.4 cc. of dimethyl sulfoxide and 0.2 cc. of diethylene glycol dimethyl ether. Upon addition of 160 mg. of sodium carbonate and distilled water in an amount sufiicient to yield a volume of 4 cc., a clear solution containing 25% of chloramphenicol is obtained.

Example 5 10 g. of chloramphenicol and 13.8 g. of the sodium salt of chloramphenicol-O -succinate are dissolved in 16 cc. of tetrahydrofurfuryl methyl ether. In order to obtain a 25% chloramphenicol solution, water is added to a volume of cc.

Example 6 A solution containing 2.0 g. of chloramphenicol and 0.206 g. of succinic acid anhydride in 1.4 cc. of N,N- dimethyl methoxy acetamide is heated at 110 C. for 60 minutes. Upon adding 5.1 cc. of a 4.3% sodium carbonate solution, a clear solution is obtained with a total chloramphenicol content of 25 Example 7 A solution of 2.0 g. of chloramphenicol in 1.6 cc. of diethylene glycol dimethyl ether sold under the trademark Diglyme is mixed with 0.3 g. of succinic acid anhydride. The resulting mixture is heated to 110 C. for minutes. By adding a solution of 350 mg. of sodium carbonate in 4.9 cc. of water thereto, a clear solution is obtained.

Example 8 A solution of 2.0 g. of chloramphenicol in 0.9 cc. of diethylene glycol dimethyl ether and 0.5 cc. of dimethyl acetamide is mixed with 0.25 g. of maleic acid anhydride. The mixture is heated to C. for 60 minutes. By adding a solution of 300 mg. of sodium carbonate in 5.1 cc. of water, a clear solution is obtained.

Example 9 0.5 g. of chloramphenicol and 0.69 g. of chloramphenicol-3-N,N-dimethy1 glycinate hydrochloride correspond ing to 0.5 g. of chloramphenicol, are dissolved in 1.0 cc. of dimethyl methoxy acetamide. The resulting solution is diluted with water to a volume of 4 cc. A clear solution with a total chloramphenicol content of 25% is obtained.

The same results are obtained When chloramphenicol- 3-glycinate sulfate or chloramphenicol-3-betainate hydrochloride are used in place of chloramphenicol-LEN- dimethyl glycinate hydrochloride.

Of course, other lower esters of chloramphenicol may be employed for solubilizing chloramphenicol and stabilizing its aqueous solutions as they have been mentioned hereinabove, may be used by those skilled in the art in accordance with the principles set forth herein and in the claims annexed hereto.

If esters of acids are used which contain a salt-forming group, it is preferred to form the salts by addition of a basic substance. In that case, not only alkali hydroxides or carbonates can be used but also ammonia or organic amines, e.g. butyl amine, methoxy propyl amine etc;

We claim:

1. The stable solution of chloramphenicol in an aqueous liquid containing dissolved therein choramphenicol and, as solubilizing agent, the sodium salt of chlorarnphenico1-3-succinate, the molar ratio of chlorarnphenicol to sodium salt being between about 1:1 and about 2: l.

2. The solution of chloramphenicol in dimethyl sulfoxide containing dissolved therein the sodium salt of chloramphenicol-3-succinate, the molar ratio of chloramphenicol to sodium salt being between about 1:1 and about 2: 1, said solution being miscible with water to yield a highly concentrated, stable, aqueous chloramphenicol solution.

3. The solution of chloramphenicol in tetrahydrofurfuryl methyl ether containing dissolved therein the sodium salt of chloramphenicol-3-succinate, the molar ratio of chloramphenicol to sodium salt being between about 1:1 and about 2:1, said solution being miscible with water to yield a highly concentrated, stable, aqueous chloramphenicol solution.

. 4. The stable solution of chloramphenicol in an aqueone liquid containing dissolved therein chloramphenicol and, as solubilizing agent, a salt of chloramphenicol-3- succinate selected from the group consisting of its alkali metal salts and its ammonium salt, the molar ratio of 1 chloramphenicol to salt being between about 1:1 and References Cited in the file of this patent UNITED STATES PATENTS 2,586,661 Jacob Feb. 19, 1952 2,838,552 Gansau June 10, 1958 2,852,430 Goebel Sept. 16, 1958 FOREIGN PATENTS 852,123 Germany Oct. 13, 1952

Claims (1)

1. THE STABLE SOLUTION OF CHLORAMPHENICOL IN AN AQUEOUS LIQUID CONTAINING DISSOLVED THEREIN CHORAMPHENICOL AND, AND SOLUBILIZING AGENT, THE SODIUM SALT OF CHLORAMPHENICOL-3-SUCCINATE, THE MOLAR RATIO OF CHLORAMPHENICOL TO SODIUM SALT BEING BETWEEN ABOUT 1:1 AND A BOUT 2:1.