T h e Thermal Stability of Sodium Penicillin . K. IS. IloDfîi·:,
MURRAY SENKUS, AND JOHN
A.
RIDDICK
Research and Development Department, Commercial Solvents Corp., Terre Haute, Ind.
H ERETOFORE the thermal stability of crystalline sodium penicillin has been largely a matter of academic interest, with the exception of its use for standardization purposes, inasmuch as only the amorphous form of this product has been available commercially. T h e thermal stability of the amorphous form is such that a substantial deterioration occurs «•veil at ordinary temperatures and refrigeration below 15° C. is required to make practical use of the product on a large scale, Randall, Welch, and Hunter (V) reported stability data on amorphous sodium penicillin for temperatures up to 56° C., and a t that temperature found an average potency lo.ss of 6 0 % for ten commercial lots over a period of three months. T h e y found no loss in one month at 56° C. with crystalline sodium penicillin anil no loss in two hours for crystalline sodium penicillin "G" at 10O°C. The limited tests of Randall, Welch, and Hunter (2) have been greatly extended to show the remarkable stability of the crystalline form of the sodium salt of penicillin. The recently announced commercial production of crystalline penicillin, therefore, assumes a very important and practical significance in view of the data submitted herewith. Comparative data on the thermal stability of amorphous sodium penicillin and the crystalline salt at G0° C and 100° C. are exhibited in the chart. The curves for amorphous sodium penicillin represent the average of results from stability tests of samples from each of 11 different manufacturers. The curves for crystalline sodium penicillin were plotted from data obtained on nine samples, two of which were prepared in the laboratory and seven of which were made in the plant. T h e samples under test were stored at the stated temperatures in open 20-ee. size glass vials. Penicillin assays were mai le by the biological method of the Food and Drug Administration (J). With the commercial amorphous preparations, no correlation was found between potencies and the rales of inactivation, although the potencies varied from 700 to 1,500 units per mg. T h e distribution of the various penicillin species was determined only for the samples assaying
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approximately 1,500 units per mg., and of the penicillin contained i n these samples at least 9 0 % was indicated to be "G" by chromatographic data, differential assays, and other tests. The following experiment gave further evidence regarding the relation between tin; physical state and iho stability of sodium penicillin. In order to compare crystalline and amorphous salts of the same composition, crystalline sodium salt of a potency of 1,500 units per mg. was tested at 100° C. in comparison with a portion of the same salt which had been dissolved in water, frozen, and dried from the frozen state in order to produce an amorphous material. The time required for 15% loss of potency was found to be 0.5 day in the case of the amorphous form and 28 days for t he crystalline, form. T h e reverse
procedure, in which a portion of a n amorphous salt was converted to the crystalline state without change in composition and the two products stored at 100 e C. gave essentially the same result. Preliminary data on rates of inactivaHon Indicate that the energy of activation for the inactivation reaction of crysta;.mc sodium penicillin is about 15,000 cal/mole greater than for t h e amorphous form. This is in conformity with the greatly enhanced stability of the crystalline form over the amorphous state. IAl
