title: Development of Tablet Formulation of Amorphous Solid Dispersions Prepared by Hot Melt Extrusion Using Quality by Design Approach.
abstract: The objective of the study was to identify the extragranular component requirements (level and type of excipients) to develop an immediate release tablet of solid dispersions prepared by hot melt extrusion (HME) process using commonly used HME polymers. Solid dispersions of compound X were prepared using polyvinyl pyrrolidone co-vinyl acetate 64 (PVP VA64), Soluplus, and hypromellose acetate succinate (HPMCAS-LF) polymers in 1:2 ratio by HME through 18 mm extruder. A mixture design was employed to study effect of type of polymer, filler (microcrystalline cellulose (MCC), lactose, and dicalcium phosphate anhydrous (DCPA)), and disintegrant (Crospovidone, croscarmellose sodium, and sodium starch glycolate (SSG)) as well as level of extrudates, filler, and disintegrant on tablet properties such as disintegration time (DT), tensile strength (TS), compactibility, and dissolution. Higher extrudate level resulted in longer DT and lower TS so 60-70% was the maximum amount of acceptable extrudate level in tablets. Fast disintegration was achieved with HPMCAS-containing tablets, whereas Soluplus- and PVP VA64-containing tablets had higher TS. Crospovidone and croscarmellose sodium were more suitable disintegrant than SSG to achieve short DT, and MCC was a suitable filler to prepare tablets with acceptable TS for each studied HME polymer. The influence of extragranular components on dissolution from tablets should be carefully evaluated while finalizing tablet composition, as it varies for each HME polymer. The developed statistical models identified suitable level of fillers and disintegrants for each studied HME polymer to achieve tablets with rapid DT (<15 min) and acceptable TS (≥1 MPa at 10-15% tablet porosity), and their predictivity was confirmed by conducting internal and external validation studies.
authors.affiliation: Boehringer Ingelheim Pharmaceuticals Inc., 900 Ridgebury Road, Ridgefield, Connecticut, 06877, USA. anjali_50@yahoo.com.
authors.forename: Anjali
authors.initials: A
authors.lastname: Agrawal
authors.affiliation: Boehringer Ingelheim Pharmaceuticals Inc., 900 Ridgebury Road, Ridgefield, Connecticut, 06877, USA.
authors.forename: Mayur
authors.initials: M
authors.lastname: Dudhedia
authors.affiliation: Evonik Corporation, 750 Lakeshore Parkway, Birmingham, Alabama, 35211, USA.
authors.forename: Weibin
authors.initials: W
authors.lastname: Deng
authors.affiliation: Boehringer Ingelheim Pharmaceuticals Inc., 900 Ridgebury Road, Ridgefield, Connecticut, 06877, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Shepard
authors.affiliation: Boehringer Ingelheim Pharmaceuticals Inc., 900 Ridgebury Road, Ridgefield, Connecticut, 06877, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Zhong
authors.affiliation: Boehringer Ingelheim Pharmaceuticals Inc., 900 Ridgebury Road, Ridgefield, Connecticut, 06877, USA.
authors.forename: Edward
authors.initials: E
authors.lastname: Povilaitis
authors.affiliation: Boehringer Ingelheim Pharmaceuticals Inc., 900 Ridgebury Road, Ridgefield, Connecticut, 06877, USA.
authors.forename: Ewa
authors.initials: E
authors.lastname: Zimny
mesh_terms: D002266:Carboxymethylcellulose Sodium / Q000737:chemistry; D002482:Cellulose / Q000737:chemistry; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D004339:Drug Compounding / Q000379:methods*; D005079:Excipients / Q000737:chemistry; D007785:Lactose / Q000737:chemistry; D008747:Methylcellulose / Q000031:analogs & derivatives / Q000737:chemistry; D010795:Phthalic Acids / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D011108:Polymers / Q000737:chemistry; D011145:Polyvinyls / Q000737:chemistry; D011205:Povidone / Q000737:chemistry; D011759:Pyrrolidines / Q000737:chemistry; D012995:Solubility; D013213:Starch / Q000031:analogs & derivatives / Q000737:chemistry; D013607:Tablets / Q000737:chemistry*; D013718:Tensile Strength; D014753:Vinyl Compounds / Q000737:chemistry
chemical_list: D005079:Excipients; D010795:Phthalic Acids; D011108:Polymers; D011145:Polyvinyls; D011759:Pyrrolidines; D013607:Tablets; D014753:Vinyl Compounds; C402301:poly(vinylpyrrolidone-co-vinyl-acetate); C572167:polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer; C007220:dimethyl 2,3,5,6-tetrachloroterephthalate; D011092:Polyethylene Glycols; C048331:hydroxypropylmethylcellulose acetate succinate; D002482:Cellulose; D008747:Methylcellulose; D013213:Starch; C048390:sodium starch glycolate; D011205:Povidone; D007785:Lactose; D002266:Carboxymethylcellulose Sodium; C109691:microcrystalline cellulose
keywords: amorphous; disintegrant; filler; hot melt extrusion; solid dispersion; tablet