title: Comparison of HPMC based polymers performance as carriers for manufacture of solid dispersions using the melt extruder.
abstract: Preparation of amorphous solid dispersions using hot-melt extrusion process for poorly water soluble compounds which degrade on melting remains a challenge due to exposure to high temperatures. The aim of this study was to develop a physically and chemically stable amorphous solid dispersion of a poorly water-soluble compound, NVS981, which is highly thermal sensitive and degrades upon melting at 165 °C. Hydroxypropyl Methyl Cellulose (HPMC) based polymers; HPMC 3cps, HPMC phthalate (HPMCP) and HPMC acetyl succinate (HPMCAS) were selected as carriers to prepare solid dispersions using hot melt extrusion because of their relatively low glass transition temperatures. The solid dispersions were compared for their ease of manufacturing, physical stability such as recrystallization potential, phase separation, molecular mobility and enhancement of drug dissolution. Two different drug loads of 20 and 50% (w/w) were studied in each polymer system. It was interesting to note that solid dispersions with 50% (w/w) drug load were easier to process in the melt extruder compared to 20% (w/w) drug load in all three carriers, which was attributed to the plasticizing behavior of the drug substance. Upon storage at accelerated stability conditions, no phase separation was observed in HPMC 3cps and HPMCAS solid dispersions at the lower and higher drug load, whereas for HPMCP, phase separation was observed at higher drug load after 3 months. The pharmaceutical performance of these solid dispersions was evaluated by studying drug dissolution in pH 6.8 phosphate buffer. Drug release from solid dispersion prepared from polymers used for enteric coating, i.e. HPMCP and HPMCAS was faster compared with the water soluble polymer HPMC 3cps. In conclusion, of the 3 polymers studied for preparing solid dispersions of thermally sensitive compound using hot melt extrusion, HPMCAS was found to be the most promising as it was easily processible and provided stable solid dispersions with enhanced dissolution.
authors.affiliation: Pharmaceutical and Analytical Development, Novartis Pharmaceuticals Corporation, One Health Plaza, East Hanover, NJ 07936, USA.
authors.forename: Indrajit
authors.initials: I
authors.lastname: Ghosh
authors.forename: Jennifer
authors.initials: J
authors.lastname: Snyder
authors.forename: Radha
authors.initials: R
authors.lastname: Vippagunta
authors.forename: Marilyn
authors.initials: M
authors.lastname: Alvine
authors.forename: Ronak
authors.initials: R
authors.lastname: Vakil
authors.forename: Wei-Qin
authors.initials: WQ
authors.lastname: Tong
authors.forename: Sudha
authors.initials: S
authors.lastname: Vippagunta
mesh_terms: D003460:Crystallization; D004337:Drug Carriers / Q000737:chemistry*; D004355:Drug Stability; D004356:Drug Storage; D006863:Hydrogen-Ion Concentration; D065347:Hypromellose Derivatives; D008747:Methylcellulose / Q000031:analogs & derivatives* / Q000737:chemistry; D012995:Solubility; D013997:Time Factors; D044366:Transition Temperature
chemical_list: D004337:Drug Carriers; D065347:Hypromellose Derivatives; C048331:hydroxypropylmethylcellulose acetate succinate; D008747:Methylcellulose; C053309:hydroxypropyl methylcellulose phthalate