How to stabilize cilazapril-containing solid dosage forms? The optimization of a final drug formulation

Cilazapril, a moisture-sensitive compound, is known to undergo rapid degradation which could be additionally facilitated by the presence of excipients that contain or absorb moisture. Hence we investigated the stability of cilazapril in two commercially-available dosage forms and in binary mixtures with the selected excipients used in the studied commercial formulations i.e.: hypromellose, lactose monohydrate, maize starch and talc in order to detect any possible, stability-affecting incompatibilities. Also the impact of the blister made of oriented polyamide/aluminum/polyvinyl chloride//aluminum on cilazapril-containing tablets was researched. A validated HPLC and HPLC-MS methods were used for analysis and the isothermal stress testing conditions were applied (temperature range 318-343 K, relative humidity 76.4% for tablets and temperature 333 K, relative humidity range 50.9-76.4% for binary mixtures). It was shown that the degradation of cilazapril in both, model mixtures and tablets follows the autocatalytic model kinetics and it is more rapid than that observed for pure substance, evidenced by higher degradation rate constants. The immediate packaging protects cilazapril in tablets from degradation only in case of the original drug while in its blistered generic counterpart a slight but statistically insignificant increase of cilazapril decay occurs when compared to bare tablets (p < 0.05). The degradation product of cilazapril in tablets and binary mixtures was identified as cilazaprilat. It was also observed that the increase of relative humidity or the presence of hypromellose, lactose and talc significantly impairs the stability of cilazapril in the aforementioned order. Only maize starch exhibited a positive effect on cilazapril stability (10.8% loss of cilazapril in binary mixture after 360 days of stressing compared to 35% loss of pure cilazapril in analogous test conditions) probably thanks to its moisture-scavenging properties. It was suggested that in the manufacture of cilazapril-containing solid dosage forms the procedure of wet granulation should be avoided while hygroscopic excipients should be substituted by their non-hygroscopic counterparts.