On 27 August at 15 Andres Lust will defend his PhD thesis titled „Water mediated solid state transformations of a polymorphic drug – effect on pharmaceutical product performance“ in the Faculty of Medicine in the University of Tartu.
Thesis supervisors: Senior Researcher Karin Kogermann, PhD, University of Tartu, Estonia
Professor Peep Veski, Dr. Pharm, University of Tartu, Estonia
Opponent: Professor Guy Van Den Mooter, PhD, Catholic University of Leuven, Belgium
Many drugs can exist in different solid-state forms (e.g., crystalline, amorphous, hydrates/solvates, co-crystals). As given forms differentiate from each other by the arrangement of molecules towards each other in three-dimensional space, they have different physicochemical properties such as dissolution rate, solubility and physical stability. The main goal of the present study was to investigate the properties of the solid state forms of a poorly water-soluble model drug piroxicam (PRX). Emphasis was given on the water-mediated solid state transformations that may occur during pharmaceutical processing and storage. Also the biopharmaceutical relevance of these solid state transformations was revealed.
The model drug exhibits a clear solid-state dependent dissolution. Amorphous PRX (in solid dispersion, SD) was shown to have an improved dissolution rate compared to its crystalline counterparts (PRX anhydrate form I, AH and monohydrate, MH). It was also discovered that MH remained stable in a dissolution medium while AH and SD recrystallized as MH within 220 and 10 minutes, respectively. Amorphous PRX (in SD) was shown to have an improved oral bioavailability in rats compared to its crystalline counterparts AH and MH). The present SDs were physically stable in powder form under low humidity (0% RH) and low to room temperature (6 °C and 25 °C) conditions for at least six months. Aging at higher humidity (40% and 75% RH) and at room temperature (25 °C) caused amorphous PRX (in SDs) to recrystallize as a AH or MH within one month and two to three months, respectively. Water-mediated solid- state process-induced transformations (PITs) of amorphous PRX can occur during aqueous-based drug-layer coating of pellets, and solid-state change can be verified using Raman spectroscopy. AH and MH were stable during drug-layer coating, but amorphous PRX in solid dispersion (SD) crystallized as MH already after 10 minutes of coating.