(W1130-07-38) Investigation of Physical Stability of Coamorphous Systems at Elevated Temperature and Humidity Conditions

Purpose: Coamorphous materials are a novel class of multi-component molecular solids and offer an alternative to polymer-based amorphous solid dispersions for improving the performance of poorly water-soluble drugs. Distinct from ASDs, coamorphous materials have access to variety of transformation pathways (physical mixtures or a variety of different stoichiometry (X:Y) cocrystals) and thus physical stability for this class of materials is uniquely challenged. The purpose of this study is to investigate the production and physical stability of coamorphous materials prepared with naringenin (NAR, a model low-solubility drug) and theophylline or theobromine (THY/THE, model coformers respectively). Many previous studies overestimate the physical stability of coamorphous materials by neglecting the impact of temperature and moisture or lose mechanistic insight by combining high temperature and high humidity stress conditions together; however, our approach independently assesses the impact of moisture and temperature on the physical stability of each new coamorphous material. Additionally, examination of the crystalline products formed following the stress helps identify how different coformers differentially affect physical stability for the same drug. This will be important for the development of new coamorphous materials as a formulation strategy for poorly water-soluble drugs.

Methods: Neat grinding, liquid assisted grinding (LAG) and water slurrying were selected to prepare multi-component materials with NAR and THY or THE. Neat grinding in a planetary ball mill generated two new coamorphous materials: ca-NAR:THY and ca-NAR:THE. LAG or water slurry did not produce a coamorphous material; however, each method yielded the same 1:1, NAR:THY cocrystal. For NAR and THE, LAG and slurry only resulted in physical mixtures. The physical stability of each coamorphous material was investigated under three distinct storage conditions: 65°C/ < 10%RH, 21°C/85% RH and room conditions (21°C/ < 10% RH). Differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD) were employed to monitor for any recrystallized products formed during the stability studies. Stoichiometry of the initial multi-component materials and any crystallization products from the stability assays were determined using ¹H-NMR. Insight into how the fundamental intermolecular interactions changed during the amorphous-to-crystalline transition for each material was obtained through analyzing FTIR spectra. Lastly, amorphous NAR was prepared using an in-situ, heat-cool-heat DSC method to assess its glassy properties (T_g, fragility, etc.) and help assist in understanding the formation and physical stability of coamorphous materials.

Results: Both ca-NAR:THY and ca-NAR:THE were physically stable up to four months under dry storage conditions (21°C/ < 10% RH) at ambient temperatures. Following a week of dry, high-temperature stress, ca-NAR:THY recrystallized into the 1:1 co-crystal, while ca-NAR:THE recrystallized into a physical mixture. Given the stress temperature is close to the materials’ measured T_g’s, sufficient molecular mobility was available to encourage relatively quick recrystallization. Exposure of ca-NAR:THY to high relative humidity (at room temperature) also resulted in recrystallization to the 1:1 co-crystal after 4 weeks, while ca-NAR:THE recrystallized into a physical mixture in only two weeks. FTIR analysis of specific molecular vibrational frequency shifts indicated that exposure to high temperature or high humidity facilitated THY dimer formation, leading to crystallization of the cocrystal (from ca-NAR:THY) or physical mixture (from ca-NAR:THE). Moreover, from the DSC studies, pure NAR was found to be strong glass, characterized by experimental and kinetic fragility, with good glass forming ability. Thus, stable coamorphous materials at dry conditions could be justified by stronger intermolecular interactions in CAMs along with good glass forming ability of NAR. Identifying good glass formers with strong hydrogen bonding potential may be a strategy for identifying new coamorphous materials.

Conclusion: This work highlights two novel coamorphous materials ca-NAR:THY and ca-NAR:THE, generated by neat grinding. Our study emphasizes that recrystallization and product formation is sensitive to storage condition (temperature and humidity) and the intermolecular interactions with the specific coformer. Moreover, investigating the nature of the product formed (co-crystal, physical mixture, etc.) under different stress conditions provides better insight into the transformation pathways, and in long term will assist research in improving the physical stability of coamorphous materials for formulating poorly water-soluble compounds.


Overlay of powder X-ray diffractograms of NAR:THY multi-component materials under room conditions, elevated temperature, and elevated humidity conditions. Coamorphous NAR:THY transformed to a 1:1 cocrystal following exposure to elevated temperature or elevated humidity. On the right is a schematic representation of possible intermolecular interactions in the NAR:THY amorphous (A) to co-crystal (B) conversion. Dashed line represents probable hydrogen bonding.