Abstract
Amorphous solid dispersions (ASDs) have been proven to increase the bioavailability of poorly soluble drugs. It is desirable that the ASD provide a rapid dissolution rate and a sufficient stabilization of the generated supersaturation. In many cases, one polymer alone is not able to provide both features, which raises a need for reasonable polymer combinations. In this study we aimed to generate a rapidly dissolving ASD using the hydrophilic polymer polyvinyl alcohol (PVA) combined with a suitable precipitation inhibitor. Initially, PVA and hydroxypropylmethylcellulose acetate succinate (HPMCAS) were screened for their precipitation inhibitory potential for celecoxib in solution. The generated supersaturation in presence of PVA or HPMCAS was further characterized using dynamic light scattering. Binary ASDs of either PVA or HPMCAS (at 10% and 20% drug load) were prepared by hot-melt extrusion and solid-state analytics were conducted using differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD) and fourier-transformed infrared spectroscopy (FT-IR). The non-sink dissolution studies of the binary ASDs revealed a high dissolution rate for the PVA ASDs with subsequent precipitation and for the HPMCAS ASDs a suppressed dissolution. In order to utilize the unexploited potential of the binary ASDs, the PVA ASDs were combined with HPMCAS either predissolved or added as powder and also formulated as ternary ASD. We successfully generated a solid formulation consisting of the powdered PVA ASD and HPMCAS powder, which was superior in monophasic non-sink dissolution and biorelevant biphasic dissolution studies compared to the binary and ternary ASDs.
Highlights
Amorphous solid dispersions (ASDs) represent a promising formulation approach in order to increase the bioavailability of poorly soluble drugs of the BCS class II [1,2,3,4]
The subsequently prepared binary CXB ASDs with either hydroxypropylmethylcellulose acetate succinate (HPMCAS) or polyvinyl alcohol (PVA) as matrix polymer were of amorphous nature
The PVA ASDs exhibited a high dissolution rate facilitated by the hydrophilic nature of the polymer and stronger hydrogen bonds with CXB within the solid phase, but with a subsequent precipitation over time
Summary
Amorphous solid dispersions (ASDs) represent a promising formulation approach in order to increase the bioavailability of poorly soluble drugs of the BCS class II [1,2,3,4]. The generation of supersaturation in a decent amount of time upon dissolution i.e., dissolution rate [6] and second the ability to maintain supersaturation for a sufficient duration i.e., precipitation inhibition [7] In many cases, these features cannot be accomplished by one single polymer. During AAPS the molecularly dispersed, single phased ASD separates into a drug-rich and a polymer-rich domain within the solid-state. This phenomenon is facilitated in presence of water (from adsorbed moisture or upon contact with the dissolution medium) as a result of enhanced molecular mobility due to the plasticization effect of water [11]. A few studies investigated ternary ASDs with a combination of hydrophilic and hydrophobic polymers and showed a benefit compared to the respective binary ASD formulation, by achieving optimized dissolution rate and supersaturation maintenance [17,18]
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