title: Improved human bioavailability of vemurafenib, a practically insoluble drug, using an amorphous polymer-stabilized solid dispersion prepared by a solvent-controlled coprecipitation process.
abstract: The present work deals with improving the solubility of vemurafenib, a practically insoluble drug, by converting it into an amorphous-solid dispersion using a solvent-controlled precipitation process. The dispersion containing vemurafenib and hypromellose acetate succinate (HPMCAS), an enteric polymer, is termed microprecipitated bulk powder (MBP), in which the drug is uniformly dispersed within the polymeric substrate. HPMCAS was found to be the most suitable polymer for vemurafenib MBP, among a series of enteric polymers based on superior physical stability and drug-release characteristics of the MBP. The MBP provided a greater rate and extent of dissolution than crystalline drug, reaching an apparent drug concentration of 28-35 µg/mL, almost 30-fold higher than solubility of crystalline drug at 1 µg/mL. The supersaturation was also maintained for more than 4 h. Upon exposure to high temperature and humidity, the MBP was destabilized, resulting in crystallization and lower dissolution rate. The control of moisture and temperature is essential to maintain the stability of the MBP. In a relative human bioavailability study, vemurafenib MBP provided a four- to fivefold increase in exposure compared with crystalline drug. Improving solubility with an amorphous-solid dispersion is a viable strategy for the development of practically insoluble compounds.
authors.affiliation: Pharmaceutical and Analytical R&D, Hoffmann-La Roche Inc., Nutley, New Jersey 07110, USA.
authors.forename: Navnit
authors.initials: N
authors.lastname: Shah
authors.forename: Raman M
authors.initials: RM
authors.lastname: Iyer
authors.forename: Hans-Juergen
authors.initials: HJ
authors.lastname: Mair
authors.forename: Duk Soon
authors.initials: DS
authors.lastname: Choi
authors.forename: Hung
authors.initials: H
authors.lastname: Tian
authors.forename: Ralph
authors.initials: R
authors.lastname: Diodone
authors.forename: Karsten
authors.initials: K
authors.lastname: Fähnrich
authors.forename: Anni
authors.initials: A
authors.lastname: Pabst-Ravot
authors.forename: Kin
authors.initials: K
authors.lastname: Tang
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Scheubel
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Grippo
authors.forename: Sebastian A
authors.initials: SA
authors.lastname: Moreira
authors.forename: Zenaida
authors.initials: Z
authors.lastname: Go
authors.forename: James
authors.initials: J
authors.lastname: Mouskountakis
authors.forename: Theresa
authors.initials: T
authors.lastname: Louie
authors.forename: Prabha N
authors.initials: PN
authors.lastname: Ibrahim
authors.forename: Harpreet
authors.initials: H
authors.lastname: Sandhu
authors.forename: Linda
authors.initials: L
authors.lastname: Rubia
authors.forename: Hitesh
authors.initials: H
authors.lastname: Chokshi
authors.forename: Dharmendra
authors.initials: D
authors.lastname: Singhal
authors.forename: Waseem
authors.initials: W
authors.lastname: Malick
mesh_terms: D000085:Acetates / Q000737:chemistry; D000293:Adolescent; D000328:Adult; D000368:Aged; D001682:Biological Availability; D011232:Chemical Precipitation; D003460:Crystallization; D004337:Drug Carriers / Q000737:chemistry*; D004355:Drug Stability; D006801:Humans; D006813:Humidity; D065347:Hypromellose Derivatives; D007211:Indoles / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics*; D008297:Male; D008747:Methylcellulose / Q000031:analogs & derivatives* / Q000737:chemistry; D008875:Middle Aged; D012995:Solubility; D012997:Solvents; D013386:Succinates / Q000737:chemistry*; D013449:Sulfonamides / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics*; D044366:Transition Temperature; D000077484:Vemurafenib; D014961:X-Ray Diffraction; D055815:Young Adult
chemical_list: D000085:Acetates; D004337:Drug Carriers; D007211:Indoles; D012997:Solvents; D013386:Succinates; D013449:Sulfonamides; D000077484:Vemurafenib; D065347:Hypromellose Derivatives; D008747:Methylcellulose