A Study On Concomitant Polymorphism Of Prasugrel Hydrochloride And Conformational Polymorphism Of Tolfenamic Acid

Different polymorphs of the same compound behave differently in physicochemical properties due to their differences in structure. The diffences in melting point, solubility, stability, dissolution rate and bioavailability directly result in the differences of pharmaceutical behavior among polymorphs. Some of the polymorphic behavior such as concomitant polymorphism and the cause of its formation, polymorphic transformation and conformational polymorphism were studied in detail in this work. The study on polymorphic behavior of pharmaceutical products cannot only provide theoretical basis for the selection of optimal polymorphs but it can be also served a lot for the polymorphic control and optimazition of the products as a basic method and approach.Prasugrel hydrochloride is a platelet inhibitor and chosen in this work since it has at least two polymorphs and five solvates, which makes it a great model compound to investigate concomitant polymorphism, polymorphic transformation, the relationship between solvent and polymorph formation and other polymorphic behavior. Tolfenamic acid is a nonsteroidal anti-inflammatory drug and its molecule is of high degree of conformational flexibility, thus can be selected as the perfect model compound to study on the relationship between conformational flexibility and crystallization. In this work, the influence of each aspect during crystallization on the polymorph formation of the final product was validated from the viewpoint of reaction kinetics, crystallization thermodynamics and kinetics, and polymorphic transformation kinetics. In addition, the effects of interaction between solvent-solute molecules and the interplay between solute-solute molecules on the polymorph formation of prasugrel hydrochloride and tolfenamic acid were investigated in detail.1. The reactive crystallization of prasugrel hydrochloride was monitored in situ by Raman spectroscope and ATR-FTIR. The influence of reaction kinetics and polymorphisc transformation kinetics on the polymorph formation was determined. The reason of concomitant polymorphism of prasugrel hydrochloride in 2-propanol was discussed from the aspects of cryatllization thermodynamics and kinetics.2. The solubility of prosugrel hydrochloride form I was experimently determined using a gravimetrical method and that of form II in different solvents and temperatures was measured with the assistance of in situ Raman. The relative stability of the two forms, the thermodynamic driving force for polymorphic transformation and the effect of hydrogen bond donor ability, hydrogen bond acceptance ability and polarity/polarizability of solvent on solubility were derived from the viewpoint of thermodynamics.3. Solvent-mediated polymorphic transformation of prasugrel hydrochloride from form II to form I was monitored in situ using Raman spectroscope, from which the rate determining step during polymorphic transition was determined in conjuction with the data from a gravimetrical method. The effect of solvent, temperature, solid loadings and agitation rate on polymorphic transformation rate were studied in detail.4. The induction time of the primary heterogeneous nucleation of the stable form during polymorphic transformation was measured with in situ Raman. The effect of hydrogen bond donor ability, hydrogen bond acceptance ability and polarity/polarizability of solvent on the polymorph formation was investigated from the viewpoint of crystallization thermodynamics and kinetics as well as the tight association between solvent and polymorphs.5. The relative relationship between tofenamic acid form I and form II was determined through thermal analysis, solubility measurement and polymorphic transformation experiment. The effect of solvent, temperature and supersaturation on the formation of tolfenamic acid conformational polymorphism was investigated. In addition, the effect of molecular conformational flexibility on crystallization was validated through molecular simulation and calculation.