Good understanding of the interactions between drug stubstances and excipients, that may occur during the manufacture or storage of a drug product, is crucial for successful development of a drug product. Very common are interactions of drug substances with reactive impurities from excipients. Reactive impurities presence in drug products may result from the manufacturing process of the excipient or, as in the case of polyethylene glycol 6000, from degradation of the excipient. Low molecular weight aldehydes and organic acids formed during degradation are especially problematic for low dose drug substances that contain amine functional groups. Factors influencing the rate of polyethylene glycol degradation in solid dosage forms are not fully elucidated, which we attribute mainly to two reasons. First one being the lack of attempts at mechanistic understanding of degradation reactions in solid dosage forms and second the lack of appropriate methods for compatibility testing. In the case of primary amine functionality containing drug substance saxagliptin, which is for its better stability present in the tablet film coating, we performed a comprehensive stability testing of the final dosage form. With minimal variation in the proportion of plasticizer polyethylene glycol 6000, different distribution of saxagliptin degradation products was achieved. Using statistical methods, quantum mechanical calculations and modeling of the kinetics of chemical reactions, we were able to explain and link the degradation of the excipient and the drug substance. We established that in addition to the concentration of reactants and environmental factors such as temperature and relative humidity, the distribution of degradation products is mainly influenced by micro-environmental pH. Formation of acidic organic compounds resulting from the degradation of polyethylene glycol slows down the main degradation pathway of saxagliptin % intramolecular cyclization with further epimerization. In contrast, parallel N-formylation reaction in which N-formyl saxagliptin impurity is formed, is acid catalyzed. In addition to understanding the mechanism of degradation, the kinetic parameters determined by regression enable us to predict the concentrations of individual degradation products as a function of temperature, relative humidity and tablet composition over time. The findings led to the development of a stable final dosage form, which was further supported by stability testing of simple binary mixtures. Second reason for the deficient understanding of the interactions of amine functionality containing drug substances and reactive impurities from accidents is the lack of appropriate methods for compatibility testing. Oxidation reactions resulting in methanal and methanoic acid formation and consequent reactions of N- Abstract IV methylation and N-formylation of drug substances are among those that are difficult to predict by standard compatibility testing methods. The conditions to which the excipient and the drug substance are exposed during standard testing differ from those in the final dosage forms. We propose a new approach to compatibility testing that is fast, simple, and based on the actual proportions of the components in the drug product. Proposed method was used to test the secondary amine functionality containing drug substance paroxetine and was able to produce comparable levels of degradation products as in the original tablet formulation. The wide applicability of the proposed stress testing method was confirmed through testing of larger number of amine drug substances, whereby in addition to the overall reactivity of the amine group to this type of reactions, their tendency to N-methylation or N-formylation was also assessed. The influence of iron oxide on polyethylene glycol degradation rate was also explained using simulations based on the constructed kinetic model.
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