Compatibility studies, drug substances

It was recognized quite some time ago that DTA analysis could be used to deduce the compatibility between a drug substance and its excipients in a formulation. The effect of lubricants on performance was as problematic then as it is now, and DTA proved to be a powerful method in the evaluation of possible incompatibilities. Jacobson and Reier used DTA to study the interaction between various penicillins and stearic acid [17]. For instance, the addition of 5% stearic acid to sodium oxacillin monohydrate completely obliterated the thermal events associated with the antibiotic. Since that time, many workers employed DTA analysis in the study of drug-excipient interactions, although the DTA method has been largely replaced by differential scanning calorimetry technology. 

It is recommended that drug substances be evaluated as a solid in a solid-state mixture with potential excipients as part of normal excipient compatibility studies. 

A compatibility study focuses on a binary mixture of drug substance and some selected excipients in a fixed ratio with or without added moisture. The... 

In contrast to the common practice of studying the interaction between a drug substance and excipients as described in the previous section, a proposal had been made that the preparation of initial formulations for stability screening of dosage forms is more meaningful and economical than the test for excipient compatibility in powder mixtures. ... 

The problem of preformulation studies for screening of excipients to know their compatibility with the drug substance, given in table 2.8, is here simplified by reducing the number of possibilities in each class of excipient (factor) to 2 (9). For this illustration we will also eliminate the final variable, the presence or not of a gelatine capsule shell. The excipients tested and their concentrations are therefore those of table 2.10. 

Consider a problem where we want to study the compatibility of a drug substance with 4 classes of excipient, each at 3 levels, as in table 2.13. The measured response here is the degradation observed after 1 month at 50°C (50% relative humidity). 

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