Solid amorphous formulations for enhancing solubility and inhibiting Erlotinib crystallization during gastric-to-intestinal transfer.

The objective of this study was to improve the solubility and inhibit the crystallisation during the gastric-to-intestinal transfer of Erlotinib (ERL), a small molecule kinase inhibitor (smKI) compound class, which is classified as class II drug in the Biopharmaceutical Classification System (BCS). A screening approach combining different parameters (solubility in aqueous media, inhibitory effect of drug crystallisation from supersaturated drug solutions) was applied to selected polymers for the development of solid amorphous dispersions of ERL. ERL solid amorphous dispersions formulations were then prepared with 3 different polymers (Soluplus®, HPMC-AS-L, HPMC-AS-H) at a fixed drug: polymer ratio (1:4) by two different production methods (spray drying and hot melt extrusion). The spray-dried particles and cryo-milled extrudates were characterized by thermal properties, shape and particle size, solubility and dissolution behavior in aqueous media. The influence of the manufacturing process on these solid characteristics was also identified during this study. Based on the obtained results, it is concluded that the cryo-milled extrudates of HPMC-AS-L displayed better performance (enhanced solubility, reduced ERL crystallization during the simulated gastric-to-intestinal transfer) and represents a promising amorphous solid dispersion formulation for oral administration of ERL.

Dielectric study of the molecular mobility and the isothermal crystallization kinetics of an amorphous pharmaceutical drug substance.

During the development of new pharmaceutical products based on drug substances in their amorphous form, the molecular mobility of an amorphous active ingredient was characterized in detail within a very broad time-temperature range. The relation between the isothermal crystallization kinetics and the dynamics of this amorphous substance was investigated. First, dynamic dielectric spectroscopy (DDS) and the thermostimulated current (TSC) techniques were used to analyze the molecular mobility of the amorphous drug substance over a wide frequency and temperature range (the drug substance is referred to as SSR in this text and was chosen as a model glass-forming system). Two relaxation processes, corresponding to different molecular motions, were identified. The beta(a)-relaxation process, associated with intramolecular oscillation of small dipolar groups, followed Arrhenius temperature behavior over the entire time-temperature domain that was studied. However, the main alpha(a)-relaxation process, assigned to the dielectric manifestation of the dynamic glass transition of the amorphous phase, was described by Vogel-Fulcher-Tammann (VFT) and Arrhenius behavior above and below the glass transition temperature (T(g)) respectively. The physical meaning of these complex dynamics is explained in the context of the Adam and Gibbs (AG) model, by the temperature dependence of the size of cooperatively rearranging regions (CRR) that govern the time scale of delocalized molecular motions. The distinction between the molecular mobility and the structural relaxation of amorphous systems below T(g) is discussed. This work shows that the complementary nature of both DDS and TSC techniques is essential to directly analyze the intramolecular and molecular motions of disordered phases over a wide time-temperature range above and below the T(g). Second, real-time dielectric measurements were carried out to determine the isothermal crystallization kinetics of the SSR amorphous drug. Whatever the crystalline form obtained over time in the crystallization process, the decrease of the dielectric response of amorphous phase, which is characteristic of the isothermal crystallization, was studied to monitor the time dependence of the degree of crystallinity. The characteristic crystallization time, derived from Kohlrausch-Williams-Watt (KWW)-Avrami analyses performed at different temperatures, followed an Arrhenius temperature dependence. Behaviors specific to the molecular mobility of the amorphous drug substance were compared with the characteristic crystallization time. It was concluded that the crystal growth process of the SSR drug seems to be controlled by the intramolecular motions involving the beta(a)-relaxation mode and not by the molecular motions responsible for the alpha(a)-relaxation mode in the range of temperatures >T(g). Subsequent studies will focus on the crystallization process of the SSR drug in the glassy state (T < T(g)).