Terramycin Intravenous

Scientific Edition

JOURNAL OF THE A M E R I C A N P H A RMACELJTICAL ASSOCIATION VOLUME XLI

JANUARY, 1952

NUMBER 1

CONSECUTIVE No. 2

Terramycin Intravenous* By W. W. ARMSTRONG, C. I. JAROWSKI, and C. J. SALIVARt The preparation, properties, and stability of terramycin intravenous both in the dry form and in solution are presented.

the applicability of the latter to proper parenteral dosage formulating was recognized. Several methods for obtaining the solubilization of terramycin at pH 7 were studied. Efforts were made to utilize concentrated aqueous solutions of nicotinamide, urea, and urethane. A mixture of betaine, acetamide, and triethanolamine was tried. None of these combinations could be used to dissolve adequate quantities of terramycin at neutral PH. Mixtures of the crystalline hydrochloride salt with various buffers were then investigated. The most favorable resuIts were obtained with dry mixtures of amino acid sodium salts. It was essential that the buffering agent, in combination with terramycin hydrochloride, produce a solution of pH 9 or greater in order to effect and maintain complete solution of the antibiotic. A satisfactory preparation was resolved to be a mixture of ten parts of terramycin hydrochloride and nine parts of sodium glycinate. Upon the addition of an appropriate quantity of distilled water to this mixture, a clear solution a t pH 9.0 to 9.25 containing 100 mg. of terramycin activity per milliliter was obtained. Extensive pharmacological animal testing indicated this buffered mixture to be entirely satisfactory as an intravenous preparation. Reports from extended clinical evaluation of this product have continued to be excellent. Sodium glycinate from commercial sources was found to vary in purity and alkalinity. I n order

ERRAMYCIN, newest of the broad spectrum Tantibiotics, is a chemical substance whose chemical properties permit the preparation of a large number of acid and basic salts, organic derivatives, and complexes with organic and inorganic salts (1). Shortly after the discovery of terramycin, efforts were made to produce a dosage form of the drug suitable for intravenous administration. From the solubility data presented in Table I, it is evident that a simple parenteral solution of high concentration is to be obtained only at high pH values. Thus the preparation of crystalline water-soluble alkali metal salts of terramycin would appear to offer a ready solution to the problem of preparing an intravenous dosage form. However, this approach does not utilize the superior stability and handling properties of crystalline terramycin hydrochloride. It was not until after careful study had been made of the comparative keeping properties of various dosage form mixtures containing the alkali salts and the hydrochloride, respectively, that

*

Received September 7, 1951, from the Research Laboratories, Chas. Pfizer and Co., Inc., Brooklyn, N.Y. The authors are grateful to Mr. R. Kersey for the biolog~calassays, to Dr. K. Murai for the solubility figures in Table I, and to Mr. M. Marmo and Mr. J. Shaw for their technical assistance.

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JOURNAL OF THE

AMERICAN PHARMACEUTICAL ASSOCIATION

TABLEI.-sOLUBILITY O F TERRAMYCIN I N DISTILLED WATERAT VARIOUS p H LEVELS

m

PH

Potency per Milliliter, pg

1.25 2 3 4 5.05 6 7 8 9

31,400” 4,600 1,400 850 525 700 1,050 28,260 38,600

1 Mg. of terramyan is equivalent to 1,000 pg. activity.

to obtain consistently t h e desired $€I range of the buffered terramycin solution, it was found necessary t o provide sodium glycinate of maximum purity and consistent PH. Parenteral grade sodium glycinate was conveniently prepared by adjustment of an aqueous solution of U. S. P. glycine to pH 11 with sodium hydroxide, and freeze-drying the resultant sterile alkaline solution.

VOl. XLI, No. 1

TABLE 111.--STABILITYOF A N AQUEOUSSOLUTION CONTAINING ‘10 PARTS OF TERRAMYCIN A N D 9 PARTS OF SODIUM GLYCINATE AT A CONCENTRATION OF PER ML. 100 MG. OF TERRAMYCIN

Storage Time, Hr.

Temperature,

2 4 6 8 24 24 48 72

Room Room

c.

Room Room Room

5 5 5

Original Potency (Bioassay), %

98 96 94 94 92 97 93 92

Table 111, 92 per cent of terramycin activity remains after seventy-two hours. In addition t o water for injection U. S. P. XIV, acceptable diluents for preparation and a d ministration of this terramycin dosage form are normal saline U. S. P. XIV and dextrose injection U. S. P. XIV.

TABLE 1 1 . 4 T A B I L I T Y O F A DRY MIXTUREOF 10 EXPERIMENTAL PARTS OF CRYSTALLINE TERRAMYCIN HYDROCHLORIDE WITH 9 PARTS OF SODIUM GLYCINATE Preparation of Parenteral Grade Terramycin Hydrochloride.-A solution of terramycin hydroOriginal Potency chloride in pyrogen-free distilled water is sterilized Temperature, (Bioassay). by filtration. Under asceptic conditions, the filStorage Time c. % trate is titrated with a sterile caustic solution to PH 1 hr. 100 100 5 and the slightly soluble base is separated by filtra100 18 hr. 96 tion and washed with pyrogen-free, sterile, distilled 100 hr. 100 90 50 1 hr. 100 water. The amphoteric terramycin base suspended 50 100 18 hr. in sterile methanol is dissolved by the gradual addi100 hr. 50 100 tion of conccntrated hydrochloric acid. Crystalliza11 mo. 50 93 tion of sterile terramycin hydrochloride is brought 37 11 mo. 96 about by the addition of excess acid. The sterile 11 mo. Room 100 crystalline salt is separated, washed with sterile methanol and dried in vawo. Preparation of Parenteral Grade Sodium GlyThe excellent stability of a dry mixture of cinate.-One part of U. S. P. glycine is dissolved in sodium glycinafe and crystalline terramycin three parts of pyrogen-free water and sufficient hydrochloride is evident from the figures i n sodium hydroxide solution added to bring the soluTable I1 and from t h e d a t a in Table 111. It is tion alkalinity to pH 11 by the alkali “blue” elcct o be noted t h a t prepared intravenous solutions trode. The solution is sterile-filtercd. The sterile filtrate is freeze-dried to a moisture content of less are slow t o lose potency under ordinary temperathan 1% and milled. The sterile sodium glycinate ture conditions. From the latter information i t is then ready for use. Preparation of Terramycin Intravenous.-Under is evident, therefore, that a minimal time allowance for preparation and administration of the asceptic conditions, ten parts of parenteral grade dosage is not necessary. Progressive darkening terramycin hydrochloride and nine parts of parenteral grade sodium glycinate are combined and of prepared aqueous solutions will be observed, thoroughly blended. This ratio of components in however, during prolonged holding periods. This 20% aqueous solution has a pH of 9.0 to 9.25. result of slow oxidative change, on the other hand, is not a direct indication of potency loss. REFERENCE A change in solution color from yellow-amber t o (1) Finlay A. C. Hobby G. L. P’an S . Y. Regna P. P. mahogany-brown may be observed during stor- Routien, J. B,, Seiley, D . ’ R . , Sdull, G. M.,’Sobin,’B.A,: Solomons. I. A., Vinsou, J. W., and Kane, J. H., Science. 3, age under refrigeration, and as indicated in 85(1950).