Design of a Stable Coamorphous System Using Lactose as an Antiplasticizing Agent for Diphenhydramine Hydrochloride with a Low Glass Transition Temperature.

Abstract

Coamorphous systems comprising small molecules are emerging as counterparts to polymeric solid dispersions. However, the glass transition temperatures (Tgs) of coamorphous materials are relatively low because of the lack of polymeric carriers with higher Tgs. This study aimed to investigate the applicability of lactose (LAC) as an antiplasticizing coformer to a coamorphous system. Diphenhydramine hydrochloride (DPH) was selected as a model drug (Tg = 16 °C). Differential scanning calorimetry showed a comelting point in addition to a decrease in the neat melting points depending on the composition of the physical mixtures, suggesting that the mixture of DPH-LAC was eutectic. The melting point of the eutectic mixture was calculated according to the Schröder-van Laar equation. The heat of fusion of the eutectic mixture was maximized at a 70:30 molar ratio of DPH to LAC; at this point, the melting peaks of the pure components disappeared. The heat flow profiles following the melting and cooling of DPH-LAC physical mixtures at the ratios from 10:90 to 90:10 showed a single Tg, suggesting the formation of a coamorphous system. Lactose showed a Tg of over 100 °C, and the Tg of DPH increased with the molar ratio of LAC; it was 84 °C at a 10:90 molar ratio of DPH to LAC. The Raman image indicated the formation of a homogeneous dispersion of DPH and LAC in the coamorphous system. Peak shifts in the infrared spectra indicated the presence of intermolecular interactions between the amino group of DPH and the hydroxyl group of LAC. Principal component analysis of the infrared spectra revealed a significant change at the 70:30 molar ratio of DPH to LAC, which was in agreement with the results of the thermal analysis. A stability test at 40 °C revealed rapid crystallization of the supercooled liquid DPH. The coamorphous samples containing 10-50% of LAC remained in an amorphous state for 21 days, and no crystallization was observed for the samples containing >60% of LAC for 28 days. The relatively lower Tg (less than 40 °C) of the coamorphous system containing 10-50% of LAC might have caused crystallization during storage. These findings indicate that LAC, which is a safe and widely used pharmaceutical excipient, can be applied to coamorphous systems as an antiplasticizing coformer.