Solid-state and particle size control of pharmaceutical cocrystals using atomization-based techniques

The increasing prevalence of poor solubility and thus bioavailability in the pharmaceutical industry is a major concern, with approximately 90% of new chemical entities effected. While many strategies have been successful in overcoming this shortfall, the work presented in this thesis aims to further explore the cocrystallization route, with an emphasis on further probing the versatility of supercritical fluid (SCF) based approaches. The ultimate aim of the work presented in this thesis is to demonstrate control over the resulting solid-state of both polymorphic and non-polymorphic cocrystalline systems, as well as control of particle size, and to compare and contrast the screening capability of various methodologies, specifically the supercritical enhanced atomization (SEA) method.

Chapter 1 provides an overview of the key concepts of this research area, such as solid-state of pharmaceutical compounds, crystallization, pharmaceutical cocrystals and recent trends of such, and top-down and bottom-up particle production processes, applicable to pharmaceutical cocrystals. This chapter also contains a description of the primary active pharmaceutical ingredients (APIs) that are focused on throughout the project.

Chapter 2 focuses on the production of the most recently FDA approved cocrystal, Seglentis®, composed of celecoxib (CEL) and tramadol hydrochloride (TRA), using a supercritical fluid technique; SEA. Specifically, the aim of this study is to investigate the ability of this SEA method to accurately and reproducibly control both particle size and solid-state of the produced celecoxib-tramadol hydrochloride particles (non-polymorphic system). Furthermore, the amorphous and crystalline samples produced, which display a particle size ranging from 0.12 to 1.16 µm, were incorporated in tablets and assessed on the basis of tabletability, compactability and compressibility.

Chapter 3 delves further into the ability of this SEA method to control cocrystal solid-state, and compared to another atomization-based method, electrospraying. Specifically, the objective of this study is to investigate the solid-state control aspect with regards to polymorphic cocrystal systems. Three pharmaceutical cocrystals were processed, which exhibit polymorphism, isonicotinamide-citric acid (IsoCa), ethenzamide-saccharin (EthSac) and ethenzamide-gentisic acid (EthGa). The electrospraying process produced the stable form of EthSac and EthGa, while producing both stable and metastable forms of IsoCa. The SEA method however showed more control over polymorphic outcome for IsoCa, producing pure α and β forms, and of EthSac, producing form II and mixtures of form I and II, showing an improvement over all other techniques, as well as allowing for easier product isolation in compared to electrospraying.

Chapter 4 employs a computational coformer screening method, investigating molecular complementarity (MC) and hydrogen bond propensity (HBP) of a list of coformers against the API celecoxib. The shortened list of coformers were experimentally screened with CEL using a variety of methods for the purposes of method comparison; liquid assisted grinding (LAG), solvent evaporation (SE), gas antisolvent crystallization (GAS) and SEA. While GAS displayed a limitation in screening liquid coformers, one liquid coformer, n-ethylacetamide, was found to produce a new form with CEL. This new solid form was confirmed by powder x-ray diffraction (PXRD). The new form was analysed by a variety of different characterization methods and determined to be a 1:2 solvate, which exhibits an improved dissolution profile in comparison to the as-received CEL.

Chapter 5 includes concluding remarks on the previously discussed chapters in this thesis, with future perspectives and directions summarized in chapter 6.