Isothermal Microcalorimetry To Investigate the Phase Separation for Amorphous Solid Dispersions of AMG 517 with HPMC-AS

Abstract

Understanding the crystallization kinetics of an amorphous drug is critical for the development of an amorphous solid dispersion (ASD) formulation. This paper examines the phase separation and crystallization of the drug AMG 517 in ASDs of varying drug load at various conditions of temperature and relative humidity using isothermal microcalorimetry. ASDs of AMG 517 in hydroxypropyl methylcellulose acetate succinate (HPMC-AS) were manufactured using a Buchi 290 mini spray dryer system. ASDs were characterized using modulated differential scanning calorimetry (mDSC) and scanning electron microscopy (SEM) prior to isothermal microcalorimetry evaluation, and crystallinity was measured using (19)F solid state nuclear magnetic resonance spectroscopy (SSNMR), before and after crystallization. The crystallization of ASDs of AMG 517 in HPMC-AS was significantly slowed by the presence of HPMC-AS polymer, indicating enhanced physical stability for the ASD formulations. A two-phase crystallization was observed by isothermal microcalorimetry at temperatures near the glass transition temperature (Tg), indicating a drug-rich phase and a miscible ASD phase. (19)F SSNMR showed that only partial crystallization of the drug occurred for the ASDs, suggesting a third phase which did not crystallize, possibly representing a thermodynamically stable, soluble component. Isothermal microcalorimetry provides important kinetic data for monitoring crystallization of the drug in the ASDs and, together with (19)F SSNMR, suggests a three-phase ASD system for AMG 517 in HPMC-AS.

Insights into Atomic-Level Interaction between Mefenamic Acid and Eudragit EPO in a Supersaturated Solution by High-Resolution Magic-Angle Spinning NMR Spectroscopy

“…Although several attempts have been made to investigate the interactions in a solid dispersion, 8, 16 there are still only few studies that investigate the intermolecular interactions in supersaturated solutions. Indeed, the intermolecular interaction site between MFA and EPO in the solid dispersion by infra-red spectroscopy, 13 C NMR and 13 C spin-lattice relaxation time ( 13 C T 1 ) NMR measurements was reported.…”

Structural Characterization of Amorphous Solid Dispersions

“…Depending upon the composition, a single mixed T g (T gm ) of a miscible binary ASD can normally be distinguished from that of the API or the polymer. However, strong drug-polymer intermolecular interactions such as ionic/polyelectrolytic interactions, salt formation, or others can increase the T gm to be higher than that of individual components (Weuts et al 2005) as recently shown for a hydrogen bonding (H-bonding) system (Calahan et al 2013). A single T gm is considered as an indicator of complete molecular mixing between drug and polymer.…”

Amorphous Solid Dispersions

“…Depending upon the composition, a single mixed T g (T gm ) of a miscible binary ASD can normally be distinguished from that of the API or the polymer. However, strong drug-polymer intermolecular interactions such as ionic/polyelectrolytic interactions, salt formation, or others can increase the T gm to be higher than that of individual components as recently shown for a hydrogen bonding (H-bonding) system (Calahan et al 2013). A single T gm is considered as an indicator of complete molecular mixing between drug and polymer.…”

“…The region-I represents crystallization from drug-rich phase, region-II represents that from miscible ASD portion and region-III represents the absence of crystallization signal due to the amorphous fraction retained below solid solubility. (Adapted from Calahan et al 2013) models described experimental data better compared to the Avrami, Tobin model. Calahan et al (2013) investigated the crystallization behavior of AMG 517, an investigational drug, from its ASD prepared in hydroxypropyl methyl cellulose-acetate succinate (HPMC-AS) using IMC at elevated temperature and RH.…”

“…(Adapted from Calahan et al 2013) models described experimental data better compared to the Avrami, Tobin model. Calahan et al (2013) investigated the crystallization behavior of AMG 517, an investigational drug, from its ASD prepared in hydroxypropyl methyl cellulose-acetate succinate (HPMC-AS) using IMC at elevated temperature and RH. TAM thermograms (Fig.…”