Importance of stability of pharmaceutical formulations

Stability is an essential quality attribute for pharmaceutical formulations. Evaluation of drug stability can prevent toxicity and increase safety, efficacy and quality of the final drug product. In this work, various factors affecting stability of both small molecule and biopharmaceutical compounds were investigated. In the first study, we initially hypothesized that albendazole, a poorly water soluble drug, could be prepared by melt extrusion to enhance its dissolution and bioavailability. However, it was found that albendazole was severely degraded by heat and shear during extrusion. When combined with methanesulfonic acid and Kollidon VA 64, amorphous albendazole solid dispersion was successfully prepared by an alternative process, spray drying, to enhance dissolution and shelf-stability. In the second study, the stability of a caveolin-1 scaffolding domain (CSP7), which is a newly developed peptide for the treatment of idiopathic pulmonary fibrosis, was investigated in order to achieve an optimal formulation for in vivo clinical studies. This study showed the physical instability of the peptide, which was aggregation induced by moisture, and the crystallization of bulking agent on its stabilizing effect. It was found that the moisture-induced aggregates were reversible and could be prevented by pH adjustment and incorporation of lactose in the composition. Lactose, a reducing sugar, stabilized the peptide possibly as a result of chemical interactions with CSP7 (e.g., formation of a Schiff base with the N-terminal amino group of CSP7). Based on these results, lactose stabilized CSP7 against moisture-induced aggregation in the solid state to a greater degree than mannitol. Additionally, stability of the CSP7-bulking agent formulations was not affected by nebulization using vibrating mesh nebulizers. Lastly, the effect of nebulization using vibrating mesh nebulizers on stability of tissue-type plasminogen activator (tPA) and single-chain urokinase plasminogen activator (scuPA), being studied for the treatment of inhalational smoke-induced acute lung injury (ISALI), was evaluated. For scuPA, the effect of lyophilization on its stability was also studied. The results showed that scuPA was stable after lyophilization (scuPA) and that both proteins were stable following reconstitution and nebulization. There were only slightly differences between the active and passive vibrating mesh nebulizers. In conclusion, from our work, the physical and chemical stability of small- and macromolecules was affected by formulation composition, processing and post-processing factors.