Cocrystallization for modulating physicochemical properties and its pharmaceutical implications

Abstract

Cocrystallization has gained considerable attention as a promising and versatile strategy for modulating the physicochemical properties and bioavailabilities of active pharmaceutical ingredients (API). Cocrystallization makes it possible to construct crystal structures with favourable physicochemical properties that have a wide range of applications and considerable flexibility. The present thesis was aimed at utilizing cocrystallization to modulate the physicochemical properties of some APIs and elucidate their pharmaceutical implications. This thesis was separated into three tasks: (1) Explore whether cocrystallization could modify the dissolution profile of a water-soluble drug to an extended release pattern: An isoniazid-curcumin (INH-CUR) cocrystal was prepared by rotary evaporation when the evaporation rate is above a threshold value, while slow evaporation failed to produce the cocrystal. Extended release profiles of INH with different release patterns were shown in the pH 1.2 and 6.8 phosphate buffers. At pH 1.2, plenty of CUR form III recrystallized on the powder surface of undissolved cocrystals, therefore, dramatically suppressing the release of INH to extend to at least 48 h. At pH 6.8, a great number of CUR form III with larger sizes recrystallized in the solution without affecting the INH release, and 24 hours later, the full release of INH was accomplished. (2) Elucidate how cocrystal solution-state stability would impact the cocrystal transformation and resulting dissolution pattern: To further study the finding that recrystallization of metastable CUR form III rather than the stable form I during INH-CUR dissolution study, this section aimed to study the effect of cocrystal solution-state stability on the polymorphic formation of APIs. Three CUR cocrystals, namely curcumin-resorcinol, curcumin-hydroquinone, and curcumin-phloroglucinol, were formed with structurally similar coformers and employed for dissolution studies with different buffers. At pH 1.2, all the CUR cocrystals obtained > 94% of metastable CUR form III with a negligible amount of CUR form I, by contrast, the purity of CUR form III obtained from ethanol mixed buffers was decreased substantially. When compared to two metastable cocrystals, a higher supersaturation level was required for the stable cocrystal to recrystallize pure CUR form III, which was confirmed by the difference in intermolecular interactions discovered through 1H NMR. (3) Study how the structurally-related coformers could affect the cocrystallization outcomes and physicochemical properties of resulting cocrystals. In order to further explore how the structurally similar coformers affect the resulting cocrystals, Three cocrystals of poorly water-soluble flufenamic acid (FFA) were synthesized by rapid solvent removal, including reported flufenamic acid-nicotinamide (FFA-NIC) 1:1 cocrystal, new flufenamic acid-isonicotinamide (FFA-IST) 1:1 cocrystal, and new flufenamic acid-picolinamide (FFA-PIC) 1:1 cocrystal. The resulting solid samples and parent components were collected and characterized by various characterization menthods. These cocrystals were placed in liquid paraffin to test their stability for potential topical formulations. The first study characterized a new INH-CUR cocrystal and elucidated the mechanism of its extended release profile. The second study elucidated the mechanism of phase transformation of CUR cocrystals, and the third one prepared three FFA cocrystals for further structural elucidation and property tests to explore structure-property correlation and formulation performances.