title: Development of In Vitro-In Vivo Correlation for Amorphous Solid Dispersion Immediate-Release Suvorexant Tablets and Application to Clinically Relevant Dissolution Specifications and In-Process Controls.
abstract: Although in vitro-in vivo correlations (IVIVCs) are commonly pursued for modified-release products, there are limited reports of successful IVIVCs for immediate-release (IR) formulations. This manuscript details the development of a Multiple Level C IVIVC for the amorphous solid dispersion formulation of suvorexant, a BCS class II compound, and its application to establishing dissolution specifications and in-process controls. Four different 40 mg batches were manufactured at different tablet hardnesses to produce distinct dissolution profiles. These batches were evaluated in a relative bioavailability clinical study in healthy volunteers. Although no differences were observed for the total exposure (AUC) of the different batches, a clear relationship between dissolution and Cmax was observed. A validated Multiple Level C IVIVC against Cmax was developed for the 10, 15, 20, 30, and 45 min dissolution time points and the tablet disintegration time. The relationship established between tablet tensile strength and dissolution was subsequently used to inform suitable tablet hardness ranges within acceptable Cmax limits. This is the first published report for a validated Multiple Level C IVIVC for an IR solid dispersion formulation demonstrating how this approach can facilitate Quality by Design in formulation development and help toward clinically relevant specifications and in-process controls.
authors.affiliation: Biopharmaceutics, Pharmaceutical Sciences and Clinical Supply, Merck Research Laboratories, West Point, Pennsylvania.
authors.forename: Filippos
authors.initials: F
authors.lastname: Kesisoglou
authors.affiliation: Analytical Chemistry in Development and Supply, Merck Manufacturing Division, West Point, Pennsylvania.
authors.forename: Andre
authors.initials: A
authors.lastname: Hermans
authors.affiliation: Global Pharmaceutical Commercialization, Merck Manufacturing Division, West Point, Pennsylvania.
authors.forename: Colleen
authors.initials: C
authors.lastname: Neu
authors.affiliation: Quantitative Pharmacology and Pharmacometrics, PPDM, Merck Research Laboratories, West Point, Pennsylvania.
authors.forename: Ka Lai
authors.initials: KL
authors.lastname: Yee
authors.affiliation: Biostatistics and Research Decision Sciences, Merck Research Laboratories, North Wales, Pennsylvania.
authors.forename: John
authors.initials: J
authors.lastname: Palcza
authors.affiliation: Global Pharmaceutical Commercialization, Merck Manufacturing Division, West Point, Pennsylvania.
authors.forename: Jessica
authors.initials: J
authors.lastname: Miller
mesh_terms: D019540:Area Under Curve; D001381:Azepines / Q000737:chemistry* / Q000493:pharmacokinetics*; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical / Q000379:methods; D018592:Cross-Over Studies; D006244:Hardness; D064368:Healthy Volunteers; D006801:Humans; D012995:Solubility; D013607:Tablets / Q000737:chemistry* / Q000493:pharmacokinetics*; D014230:Triazoles / Q000737:chemistry* / Q000493:pharmacokinetics*
chemical_list: D001381:Azepines; D013607:Tablets; D014230:Triazoles; C551624:suvorexant
keywords: Quality by Design (QbD); bioavailability; dissolution; hardness; in vitro/in vivo correlations (IVIVC); mathematical model; pharmacokinetics; solid dispersion; tablet