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theses

It takes a tremendous amount of research and development in order to put a new drug on the market or to make an existing medicine cheaper and therefore more affordable to many people around the world. This is mainly due to the complexity of the whole process itself (discovery, safety studies, drug substance development, drug product development, clinical trials, scale-up and manufacture), the ever increasing requirements from regulatory agencies (regarding drug quality, safety and efficacy) and the growing demand for cheaper, more affordable drugs. Drug product development (or drug formulation) is one of the main stages of pharmaceutical development, where the final dosage form is set and optimized. There are many requirements imposed on the final dosage form, including (but not limited to) the following: route of administration, size, taste, stability, drug substance uniformity, dissolution kinetics, cost, scalability, etc. Those requirements are set by the pharmacokinetics/pharmacodynamics of the drug or its physical properties, safety requirements, market projections, customer preference and agency guidance. In an effort to satisfy all requirements, the formulation methods are becoming more complex, often including several unit operations and many additives and excipients. The pharma industry is constantly on the search of more efficient and cheaper formulation methods. This work presents and studies a new manufacturing method for solid dosage forms using fluidized bed (FB) impregnation, which could eliminate many of the challenges during solid dosage manufacturing. The main difference between impregnation and dry blending is the placement of the active pharmaceutical ingredient (API) inside a porous carrier. This makes the final material flow properties independent of the physical properties of the API. The method consists of spraying an API solution in appropriate solvent onto a carefully chosen porous excipient in a fluidized state. The solution penetrates the porous carrier due to capillary forces and the solvent is evaporated soon after that. Impregnation and drying occur simultaneously, which could potentially make this impregnation method suitable for continuous implementation. Carefully choosing the operating conditions allows impregnation to occur without introducing spray drying or spray coating of the API. This work looks closely into the main requirements for successful API impregnation, establishes methodology for equipment and materials selection and identifies appropriate excipients suitable for impregnation. A toolbox of analytical methods for the full characterization of the impregnated product was developed and presented. Fluidized bed impregnation proof-of-concept was demonstrated using preliminary experiments. A case study with a model drug provided a more complete look into fluidized bed impregnation and established its benefits over conventional methods. It was demonstrated that FB impregnation can significantly improve the blend uniformity of the final formulation, independent on the drug load. The application of the impregnation technique was expanded to other drugs and excipients to demonstrate its robustness as a formulation method. It was found that FB impregnation can significantly improve dissolution kinetics of poorly soluble APIs by carefully choosing the excipient. Co-impregnation with additives led to further improvements in the dissolution profiles. Particle imaging using energy dispersive X-ray spectroscopy was used to characterize the internal distributions of the impregnated APIs within the porous matrix. Finally, a multi-scale mathematical modeling approach was developed that allows the calculation of some important process parameters. An impregnation simulation on a single-particle demonstrated the effect of several material properties on the API distribution inside the excipient.

ETD_8685

Ph.D.

Includes bibliographical references

by Plamen I. Grigorov

doi:10.7282/T3ZP49J3

ETD doctoral

The author owns the copyright to this work.