Monitoring Polymorphic Phase Transitions in Flufenamic Acid Amorphous Solid Dispersions Using Hyphenated X-ray Diffraction-Differential Scanning Calorimetry

Flufenamic acid (FFA) is a highly polymorphic drug molecule with nine crystalstructures reported in the Cambridge Structural Database. This study explores the use ofsynchrotron X-ray powder diffraction combined with differential scanning calorimetry to studycrystallization and polymorphic phase transitions upon heating FFA-polymer amorphous soliddispersions (ASDs). Ethyl cellulose (EC, 4 cp) and hydroxypropylmethylcellulose (HPMC)grades with different viscosities and substitution patterns were used to prepare dispersions withFFA at 5:1, 2:1, 1:1, and 1:5 w/w drug/polymer ratios by quench cooling. We employed a 6 cpHPMC 2910 material and two HPMC 2208 samples at 4000 and 100 000 cp. Hyphenated X-ray diffraction (XRD)-differential scanning calorimetry (DSC) studies show that the 6 and100 000 cp HPMCs and 4 cp EC polymers can stabilize FFA form IV by inhibiting thetransition to form I during heating. It appears that the polymers stabilize FFA in bothamorphous and metastable forms via a combination of intermolecular interactions and viscosityeffects. Increasing the polymer content of the ASD also inhibits polymorphic transitions, withdrug/polymer ratios of 1:5 w/w resulting in FFA remaining amorphous during heating. The comparison of FFA ASDs prepared withdifferent samples of HPMCs and ECs suggests that the chemical substitution of the polymer (HPMC 2208 has 19-24% methoxygroups and 4-12% hydroxypropyl groups, while HPMC 2910 has 28-30% methoxy groups and 7-12% hydroxypropyl groups)plays a more significant role in directing polymorphic transitions than the viscosity. A previously unreported polymorph of FFA was also noted during heating but its structure could not be determined.

Automated summary

This study investigates the crystallization and polymorphic phase transitions of FFA-polymer amorphous solid dispersions using synchrotron X-ray powder diffraction and differential scanning calorimetry. The results show that polymers can stabilize the crystalline form of FFA by inhibiting the transition process. Increasing the polymer content further inhibits polymorphic transitions.