| dc.description.abstract | A brief introduction to the pharmaceutical industry including regulation, batch/continuous manufacturing processes, and common dosage forms in pharmaceuticals was presented. Chemical engineering plays a crucial role in the pharmaceutical industry, especially for drug manufacturing. From active pharmaceutical ingredient (API) manufacturing to the downstream formulation, various unit operations are highly related to chemical engineering disciplines. For example, all of the manufacturing processed such as chemical synthesis, fermentation, purification, separation, and formulation would influence significantly the quality of the final drug product.
Powder properties such as particle size, shape, density, flowability, and compressibility are of importance in manufacturability, processibility, and bioavailability of drug products. Traditionally, powders obtained from API manufacturing (i.e. crystallization) may have adverse quality, size reduction (i.e. milling) or size enlargement (i.e. granulation) processes would be carried out to improve powder properties. However, crystallization and milling/granulation of APIs can be intensified to spherical crystallization. Spherical crystallization is a novel process intensification strategy related to powder manufacturing, and that can improve many properties produced by crystallization, such as size distribution, and downstream process efficiency.
In this dissertation, the spherical agglomeration processes for preparing granules of API drug including three-in-one intensified process of reaction, crystallization and spherical agglomeration, and mixing effect on spherical agglomeration.
Pure, isomorphic, round and free-flowing dimethyl fumarate granules were successfully produced directly from esterification through the three-in-one intensified process of three distinctive steps of reaction, crystallization and spherical agglomeration in a 0.5 L-sized jacketed glass stirred tank. Dimethyl fumarate was prepared by sulfuric acid-catalyzed esterification of fumaric acid with methanol. The mechanical properties such as density, porosity Carr’s index, friability and fracture force of round dimethyl fumarate granules were thoroughly studied and compared. The concept of scale-up for three-in-one intensified process was also verified in 10 L-sized jacketed glass stirred tank. Powder manufacturability such as flowability, blend uniformity and compressibility had been substantially enhanced by spherical agglomeration.
The spherical agglomerates of dimethyl fumarate have been successfully prepared in both 2 L-sized and 10 L-sized stirred vessels equipped with Maxblend impeller as well. Maxblend impeller create good mixing performance to increase the collision probability between particles. No significant difference on agglomerate size distribution was observed in comparison of 2 L-sized and 10 L-sized scales. | en_US |