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Monitoring polymorphic phase transitions in flufenamic acid amorphous solid dispersions using hyphenated X-ray diffraction–differential scanning calorimetry

DOI: 10.1021/acs.molpharmaceut.2c00016 DOI Help

Authors: Yuying Pang (University College London) , Asma Buanz (University College London) , Simon Gaisford (University College London) , Oxana V. Magdysyuk (Diamond Light Source) , Gareth R. Williams (University College London)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Molecular Pharmaceutics , VOL 3

State: Published (Approved)
Published: March 2022
Diamond Proposal Number(s): 18720 , 21819

Abstract: 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.

Journal Keywords: amorphous solid dispersion hydroxypropylmethylcellulose ethyl cellulose flufenamic acid X-ray diffraction differential scanning

Subject Areas: Materials, Chemistry, Medicine

Instruments: I12-JEEP: Joint Engineering, Environmental and Processing

Added On: 29/03/2022 15:31

Discipline Tags:

Drug Delivery Health & Wellbeing Chemistry Materials Science Polymer Science Life Sciences & Biotech

Technical Tags:

Diffraction X-ray Powder Diffraction