Abstract
The development of new anticancer drugs can be divided into six phases: characterization of the API (structural and analytical), solubility- and stability studies, design of the formulation, manufacturing, quality control analysis, and (bio)compatibility studies. Structural and analytical characterization of the API is required before solubility- and stability studies are performed.
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Subsequently, solubility- and stability studies are performed. Because anticancer drugs are mainly compounds with a decreased solubility in aqueous solutions, formulations have to be developed which increase the solubility of the API. This thesis showed that the use of the organic solvent tert-butyl alcohol (TBA) in combination with freeze drying is a suited technique to elucidate both solubility- and stability problems. Furthermore, it was found with DSC analysis that during freeze drying of 40% v/v TBA three different crystals are formed: TBA hydrate (containing 70% w/w TBA)-ice crystals, pure TBA hydrate crystals (containing 70% w/w TBA), and TBA hydrate crystals containing 90-95% w/w TBA. Furthermore, it was seen that crystallization of TBA was inhibited when both mannitol and sodium bicarbonate were present. Another technique to solve dissolution problems is the use of complexing agents. In this thesis the use of the complexation agent 2-hydroxypropyl-?-cyclodextrin (HP?CD) is described. It was shown that this agent can be very useful for complexation of drugs even if the complexation constant is relatively low. Furthermore, it was seen that the addition of HP?CD can result in different stability profiles, indicating that the presence of excipients can influence the stability profile dramatically. Based on the results of the solubility- and stability studies the final formulation is developed. Subsequently, further research is performed to be able to guarantee a formulated product of good quality. Therefore, compatibility studies have to be performed to determine the stability of the product in the primary packaging material, in the clinic (after dilution prior to administration) and in the physiological environment (i.e. simulation of the “in vivo” situation). Meanwhile, specification limits of the newly developed final product have to be defined. After these studies a final formulation is selected and manufacturing is performed on small scale for phase I and II clinical trials. However, before this is performed, possible interactions between the drug substance and/or excipients with the manufacturing materials should be investigated (e.g. extraction of lipophile compounds from silicone tubing by complexing agents). Furthermore, because only a limited amount of batches is manufactured in this stage of development, it is not possible to perform risk assessment of the manufacturing process per product. Therefore, we performed risk assessment using mixed effects analysis. This method was shown to be a suitable technique for risk assessment in this early stage of development. Overall it can be concluded that all the items discussed in this thesis are of importance during pharmaceutical development experimental agents to obtain a final pharmaceutical product of good quality. Neglecting one step may result in an undesired decrease in product quality.
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