title: Impact of polymer type on bioperformance and physical stability of hot melt extruded formulations of a poorly water soluble drug.
abstract: Amorphous solid dispersion formulations have been widely used to enhance bioavailability of poorly soluble drugs. In these formulations, polymer is included to physically stabilize the amorphous drug by dispersing it in the polymeric carrier and thus forming a solid solution. The polymer can also maintain supersaturation and promote speciation during dissolution, thus enabling better absorption as compared to crystalline drug substance. In this paper, we report the use of hot melt extrusion (HME) to develop amorphous formulations of a poorly soluble compound (FaSSIF solubility=1μg/mL). The poor solubility of the compound and high dose (300mg) necessitated the use of amorphous formulation to achieve adequate bioperformance. The effect of using three different polymers (HPMCAS-HF, HPMCAS-LF and copovidone), on the dissolution, physical stability, and bioperformance of the formulations was demonstrated. In this particular case, HPMCAS-HF containing HME provided the highest bioavailability and also had better physical stability as compared to extrudates using HPMCAS-LF and copovidone. The data demonstrated that the polymer type can have significant impact on the formulation bioperformance and physical stability. Thus a thorough understanding of the polymer choice is imperative when designing an amorphous solid dispersion formulation, such that the formulation provides robust bioperformance and has adequate shelf life.
authors.affiliation: Biopharmaceutics, Pharmaceutical Sciences and Clinical Supply, Merck & Co. Inc., West Point, PA 19486, United States. Electronic address: amitava_mitra@merck.com.
authors.forename: Amitava
authors.initials: A
authors.lastname: Mitra
authors.affiliation: Analytical Sciences, Pharmaceutical Sciences and Clinical Supply, Merck & Co. Inc., West Point, PA 19486, United States.
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.affiliation: Preformulation, Pharmaceutical Sciences and Clinical Supply, Merck & Co. Inc., West Point, PA 19486, United States; College of Pharmacy, University of Kentucky, United States.
authors.forename: Patrick
authors.initials: P
authors.lastname: Marsac
authors.affiliation: Analytical Sciences, Pharmaceutical Sciences and Clinical Supply, Merck & Co. Inc., West Point, PA 19486, United States.
authors.forename: Brian
authors.initials: B
authors.lastname: Marks
authors.affiliation: Preformulation, Pharmaceutical Sciences and Clinical Supply, Merck & Co. Inc., West Point, PA 19486, United States.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Formulation Sciences, Pharmaceutical Sciences and Clinical Supply, Merck & Co. Inc., West Point, PA 19486, United States.
authors.forename: Chad
authors.initials: C
authors.lastname: Brown
mesh_terms: D000818:Animals; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical / Q000379:methods; D004285:Dogs; D004337:Drug Carriers / Q000737:chemistry*; D004339:Drug Compounding / Q000379:methods; D004355:Drug Stability; D008297:Male; D008747:Methylcellulose / Q000031:analogs & derivatives* / Q000737:chemistry; D004364:Pharmaceutical Preparations / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism; D011108:Polymers / Q000737:chemistry*; D011759:Pyrrolidines / Q000737:chemistry; D012995:Solubility; D014753:Vinyl Compounds / Q000737:chemistry; D014867:Water / Q000737:chemistry
chemical_list: D004337:Drug Carriers; D004364:Pharmaceutical Preparations; D011108:Polymers; D011759:Pyrrolidines; D014753:Vinyl Compounds; C402301:poly(vinylpyrrolidone-co-vinyl-acetate); D014867:Water; C048331:hydroxypropylmethylcellulose acetate succinate; D008747:Methylcellulose
keywords: Anti-nucleation; Dissolution; Hot melt extrusion; Pharmacokinetics; Solid dispersion; Stability