PRODUCTION AND MECHANISTIC EVALUATION OF THE STABILITY OF POLYMORPHIC ACTIVE PHARMACEUTICAL INGREDIENTS APIS INCORPORATED INTO TABLETS AND EXTRUDATES TO PSYCHIATRIC PATIENTS

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Production and mechanistic evalution of the stability of polymorphic olanzapine in solid dosage forms

Publication . Paisana, Maria de Castro; Pinto, João Fernandes de Abreu, 1963-; Wahl, M. A.

Research related to drug polymorphism is an important aspect in drug product development since the properties of a formulated product, such as its stability and bioavailability, are often directly related to the physicochemical properties of the existing polymorph in the formulation. Olanzapine (OLZ) belongs to a new generation of benzodiazepines for the treatment of schizophrenia and other related psychoses and may exist in several crystalline forms, including polymorphic anhydrates, hydrates and solvates. Consequently, the physical treatments and technological processes undergone by the drug may have an impact on its solid-state, which in turn may affect its performance in terms of dissolution rate, absorption and therapeutic activity and response. OLZ Form I is the form used in marketed tablets and the most stable form at room temperature. The work presented in this Thesis aimed to provide an in-depth understanding of the conversion of olanzapine polymorphic forms into hydrated forms when exposed to different processing conditions. To perform this study we used several techniques, such as a combination of thermal analysis (differential scanning calorimetry (DSC), thermogravimetry (TGA) and hot stage microscopy (HSM)) with spectroscopic (infrared spectroscopy – DRIFT; FTIR), diffraction analysis (XRPD) and surface measurements (contact angle and surface free energy). Dissolution performance and impact of polymorphism on the mechanical characteristic of solid dosage forms was also evaluated. At first, a thorough investigation of the solid state stability of olanzapine forms I and II was performed. Aspects such as the interaction with water and the conversion of both forms into different dihydrates were fully explored. This allowed the successful clarification of the higher hygroscopic nature and easier ability of olanzapine Form II to undergo hydrate formation. On the other hand, Form I showed to hydrate into the lowest soluble form of olanzapine - dihydrate D – when subjected to high RH environments. The interaction of Form I with humidity and excipients was fully investigated. Form I was found to hydrate at different rates depending on the excipients in which it is formulated. Polymers such as polyethylene glycol (PEG) and hydroxypropyl cellulose (HPC) could induce hydrate transformation at lower relative humidity (75%), whereas PVP could avoid hydrate conversions at 93% RH. PEG, when physically mixed with olanzapine, showed to accelerate hydrate conversion, especially when the materials were subjected to a tableting process before storage. This study showed an interesting interplay between the polymer’s choice, load and chemistry that could further be used to maintain the stability of olanzapine in solid-dosage products. Transformations of olanzapine during processing, namely during the rapid expansion of supercritical solutions (RESS) and rapid expansion of supercritical solutions into aqueous solutions (RESSAS) processes were also taken into consideration. These technologies enabled the production of nanoparticles and nanosuspensions of olanzapine, respectively. During the RESSAS process the selection of the right excipients was imperative to produce stable nanosuspensions before and after freeze drying the products. Microcrystalline cellulose and polymers (PEG, PVP and HPC) were used in the process of extrusion and spheronisation of olanzapine. The transformations which occur during processing (wet environments are involved) and during dissolution of the pellets were taken into consideration. During the extrusion process olanzapine showed to hydrate into a mixture of different hydrates when extruded in the presence of microcrystalline cellulose. The addition of polymers such as PVP and HPC to the formulation allowed olanzapine to remain anhydrous during processing and dissolution, which showed to significantly influence the dissolution of the drug. PEG, on the other hand, could not avoid the hydrate formation of olanzapine, having this transformation an impact on the physical and mechanical characteristics of the pellets, as well as an impact on the drug performance. The impact of the polymer content and molecular weight into olanzapine stabilization during wetting were also taken into consideration. In conclusion, the research carried out contributed to a better understanding of the complex characterization of solid state olanzapine and formulated products prepared by different technologies. In detail, it showed the impact of polymorphic/pseudopolymorphic changes on OLZ’s technological performance and dissolution, which highlighted the importance of this study during preformulation and formulation studies.

2016Tese de doutoramento

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Fundação para a Ciência e a Tecnologia

Número da atribuição

SFRH/BD/90118/2012