Search

Flufenamic acid (FFA) is a highly polymorphic drug molecule with nine crystal structures reported in the Cambridge Structural Database. This study explores the use of synchrotron X-ray powder diffraction combined with differential scanning calorimetry to study crystallization and polymorphic phase transitions upon heating FFA-polymer amorphous solid dispersions (ASDs). Ethyl cellulose (EC, 4 cp) and hydroxypropylmethylcellulose (HPMC) grades with different viscosities and substitution patterns were used to prepare dispersions with FFA at 5:1, 2:1, 1:1, and 1:5 w/w drug/polymer ratios by quench cooling. We employed a 6 cp HPMC 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 and 100 000 cp HPMCs and 4 cp EC polymers can stabilize FFA form IV by inhibiting the transition to form I during heating. It appears that the polymers stabilize FFA in both amorphous and metastable forms via a combination of intermolecular interactions and viscosity effects. Increasing the polymer content of the ASD also inhibits polymorphic transitions, with drug/polymer ratios of 1:5 w/w resulting in FFA remaining amorphous during heating. The comparison of FFA ASDs prepared with different samples of HPMCs and ECs suggests that the chemical substitution of the polymer (HPMC 2208 has 19-24% methoxy groups 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.

In this study, the polymorphic transitions of mefenamic acid (MA) were studied by synchrotron X-ray powder diffraction combined with differential scanning calorimetry (XRD-DSC). The initial material was found to be phase-pure form I which, when heated, produces two endotherms that can be observed by DSC at 162.72 and 219.55°C. The former was found to correspond to a solid–solid enantiotropic transition from form I to a mixture of forms II and III. The latter is the melting point of form II. As form I is heated, significantly greater unit-cell expansion is seen in the a direction than in b and c, which can be explained by the stronger intermolecular interactions in the bc plane. Refinements of the reported MA structures against the patterns collected during heating revealed that at 175°C there exists a mixture of forms I, II and III, whereas only forms II and III remain at 205°C. However, reflections are observed at both temperatures which cannot be fitted with the known forms of MA. It is hypothesized that a new form of MA is produced upon heating. The stability of MA after the enantiotropic transition temperature is II > III > I, which differs from the previously reported II > I > III.

Co‐crystallisation is widely explored as a route to improve the physical properties of pharmaceutical active ingredients, but little is known about the fundamental mechanisms of the process. Herein, we apply a hyphenated differential scanning calorimetry—X‐ray diffraction technique to mimic the commercial hot melt extrusion process, and explore the heat‐induced synthesis of a series of new co‐crystals containing isonicotinamide. These comprise a 1:1 co‐crystal with 4‐hydroxybenzoic acid, 2:1 and 1:2 systems with 4‐hydroxyphenylacetic acid and a 1:1 crystal with 3,4‐dihydroxyphenylactic acid. The formation of co‐crystals during heating is complex mechanistically. In addition to co‐crystallisation, conversions between polymorphs of the co‐former starting materials and co‐crystal products are also observed. A subsequent study exploring the use of inkjet printing and milling to generate co‐crystals revealed that the synthetic approach has a major effect on the co‐crystal species and polymorphs produced., Co‐crystallisation is widely explored as a route to improve the physical properties of pharmaceutical active ingredients, but little is known about the fundamental mechanisms of the process. In this study, X‐ray diffraction was used to provide an unprecedented insight into pharmaceutical co‐crystallisation processes (see figure).