title: Enhanced kinetic solubility profiles of indomethacin amorphous solid dispersions in poly(2-hydroxyethyl methacrylate) hydrogels.
abstract: The feasibility of forming solid molecular dispersions of poorly water-soluble drugs in crosslinked poly(2-hydroethyl methacrylate) (PHEMA) hydrogel has recently been reported by our group. The purpose of the present study is to investigate the extent of enhancement of kinetic solubility of amorphous solid dispersions (ASDs) of indomethacin (IND) in crosslinked PHEMA hydrogels as compared with those based on conventional water-soluble polymer carriers. Our results show that under non-sink conditions, the initial solubility enhancement is higher for ASDs based on polyvinylpyrrolidone (PVP) and hydroxypropylmethylcellulose acetate succinate (HMPCAS), but the ability to maintain this solubility enhancement at longer times is better for ASDs based on PHEMA over a period of 24h with the extent of solubility enhancement of IND ASDs in PHEMA falling between those in PVP and HPMCAS at 10.0% IND loading after 6h and outperforming those in PVP and HPMCAS at 32.9% IND loading after 8h. The observed kinetic solubility profiles reflect the fact that the amorphous IND is released from PHEMA by a different mechanism than those from water-soluble polymer carriers. In this case, the dissolution of IND ASD from water-soluble PVP and HPMCAS is almost instantaneous, resulting in an initial surge of IND concentration followed by a sharp decline due to the nucleation and crystallization events triggered by the rapid build-up of drug supersaturation. On the other hand, the dissolution of IND ASD from insoluble crosslinked PHEMA hydrogel beads is less rapid as it is regulated by a feedback-controlled diffusion mechanism, thus avoiding a sudden surge of supersaturation in the dissolution medium. The absence of an apparent decline in drug concentration during dissolution from IND-PHEMA ASD further reflects the diminished nucleation and crystallization events during IND dissolution from hydrogel-based solid molecular dispersions. Based on the XRD analyses, a threshold IND loading level of about 34% in PHEMA has been identified, above which amorphous to crystalline transition tends to occur. Also, by selecting the appropriate particle sizes, immediate to controlled release of IND from IND-PHEMA ASD can be readily achieved as the release rate increases with decreasing PHEMA bead size. Furthermore, a robust physical stability has been demonstrated in IND-PHEMA ASD with no drug precipitation for up to 8 months at IND loadings below 16.7% under direct open cup exposure to accelerated stability conditions (40°C/75% RH).
authors.affiliation: Department of Pharmaceutical Sciences, University of Toronto, 144 College St., Toronto, Ontario, Canada.
authors.forename: Dajun D
authors.initials: DD
authors.lastname: Sun
authors.forename: Tzu-chi Rob
authors.initials: TC
authors.lastname: Ju
authors.forename: Ping I
authors.initials: PI
authors.lastname: Lee
mesh_terms: D003432:Cross-Linking Reagents / Q000737:chemistry; D003460:Crystallization; D003692:Delayed-Action Preparations; D004337:Drug Carriers / Q000737:chemistry*; D004355:Drug Stability; D004356:Drug Storage; D005240:Feasibility Studies; D006813:Humidity; D020100:Hydrogels; D007213:Indomethacin / Q000008:administration & dosage / Q000737:chemistry*; D007700:Kinetics; D008747:Methylcellulose / Q000031:analogs & derivatives / Q000737:chemistry; D010316:Particle Size; D044367:Phase Transition; D011102:Polyhydroxyethyl Methacrylate / Q000737:chemistry*; D011205:Povidone / Q000737:chemistry; D012995:Solubility; D013997:Time Factors; D014961:X-Ray Diffraction
chemical_list: D003432:Cross-Linking Reagents; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D020100:Hydrogels; D011102:Polyhydroxyethyl Methacrylate; C048331:hydroxypropylmethylcellulose acetate succinate; D008747:Methylcellulose; D011205:Povidone; D007213:Indomethacin