Benoxaprofen crystal forms: estimation of thermodynamic relationship with the aid of energy/temperature diagram

A novel crystal form of Benoxaprofen (BPN) was identified and compared with the physicochemical properties of other three crystal forms. This study utilized the physicochemical characterization data to establish the polymorphic identity of each crystal form as well as to derive a thermodynamic relationship between the crystal forms. The relative crystal energetics of crystal form I and form II were studied from the competitive and concomitant polymorphic melt crystallization. The thermodynamic relationship/stability, among the four crystal forms, was demonstrated with an aid of a semi-quantitative energy/temperature (E/T) diagram. The polymorphic transformation of crystal form I and form II is monotropically related to crystal form III, whereas crystal form III and form IV follow an enantiotropic relationship. Crystal form I and form II are thermodynamically stable from absolute zero to their melting temperature. Crystal form III is not stable at absolute zero/ambient conditions; however, it is thermodynamically stable at temperature above 25 °C. The relative crystal energy inferred from concomitant melt crystallization as well as the real-time stability data of the crystal forms was corroborated with the thermodynamic stability determined from E/T diagrams. This study result provides the unequivocal identification and characterization of all the four crystal forms as well as the estimation of their thermodynamic and physical properties to aid the selection of the right polymorphic crystal form during the drug substance and drug product development.