Preparation and Characterization of Multicomponent Solids to Improve the Physical Properties of Active Pharmaceutical Ingredients

Abstract

The purpose of the present research work was to tailor the physicochemical properties of newlineAPIs by utilising the concept of crystal engineering technique. For the present research newlinework, the APIs selected were Pirfenidone (PFD) and Acetazolamide (ACZ). PFD is an newlineanti-fibrotic agent used for the treatment of Idiopathic Pulmonary Fibrosis (IPF). The newlinedaily recommended dose of PFD is very high (2403 mg/day) and must be mitigated by newlineadditives. Two cocrystals of PFD were obtained with FA and TA with reduced aqueous newlinesolubility in order to sustain the release rate from its dosage form. A sustained release newlinetablet formulation containing PFD-FA cocrystal was successfully prepared and evaluated newlinefor its in-vitro and in-vivo performances. Cocrystal formulation sustained the release up newlineto 12 h as indicated by in-vitro dissolution study, whereas 100% drug was released within newline45 min from reference formulation, PIRFENEX® newline. Further, a comparative oral newlinebioavailability study was conducted in healthy human volunteers which revealed that the newlinecocrystal formulation was bioequivalent to the reference formulation, PIRFENEX® newline. ACZ newlinesuffers from several poor physicochemical properties, including low solubility, low newlinepermeability, and poor flowability and tabletability. In the present work, a 1:1 cocrystal newlineof acetazolamide with p-aminobenzoic acid (ACZ-PABA) was prepared by liquid newlineassisted grinding and its solid-state and mechanical properties were thoroughly newlinecharacterized, based on which a tablet product was developed with superior newlinebiopharmaceutical performance in healthy human volunteers against the commercial newlinetablet, DIAMOX® newline. ACZ-PABA cocrystal exhibited significantly better pharmaceutically newlinerelevant properties, such as solubility, permeability, intrinsic dissolution rate, newlinehygroscopicity, flowability and tabletability, over pure ACZ. The simultaneous newlineimprovement in all these properties enabled the development of a tablet product of ACZ newlineby direct compression. The ACZ-PABA based tablet exhibits better in-vitro drug newlinedissol