title: An Insight into Different Stabilization Mechanisms of Phenytoin Derivatives Supersaturation by HPMC and PVP.
abstract: In this study, we examined the stabilization mechanism of drug supersaturation by hypromellose (HPMC) and polyvinylpirrolidone (PVP). The poorly water-soluble drugs, phenytoin (diphenylhydantoin, DPH), and its synthesized derivatives monomethylphenytoin (MDPH) and dimethylphenytoin (DMDPH) were used. DPH supersaturation was efficiently maintained by both HPMC and PVP. HPMC maintained the supersaturation of MDPH and DMDPH in a similar manner to that of DPH, whereas the ability of PVP to maintain drug supersaturation increased as follows: DPH > MDPH > DMDPH. Caco-2 permeation studies and nuclear magnetic resonance measurements revealed that the permeability and molecular state of the drug in a HPMC solution barely changed. In fact, the solubilization of the drug into PVP changed its apparent permeability and molecular state. The drug solubilization efficiency by PVP was higher and followed the order: DPH > MDPH > DMDPH. The different drug solubilization efficiencies most likely result from the different strengths in the intermolecular interaction between the DPH derivatives and PVP. The difference in the stabilization mechanism of drug supersaturation by HPMC and PVP could determine whether the efficient maintenance of the drug supersaturation was dependent on the drug species.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Chiba University, Chuo-ku, Chiba, 260-8675, Japan.
authors.forename: Naoya
authors.initials: N
authors.lastname: Otsuka
authors.affiliation: Graduate School of Pharmaceutical Sciences, Chiba University, Chuo-ku, Chiba, 260-8675, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Ueda
authors.affiliation: Graduate School of Pharmaceutical Sciences, Chiba University, Chuo-ku, Chiba, 260-8675, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Ohyagi
authors.affiliation: Department of Synthetic Organic Chemistry, Research Institute of Pharmaceutical Sciences, Musashino University, Nishitokyo, Tokyo, 202-8585, Japan.
authors.forename: Kozue
authors.initials: K
authors.lastname: Shimizu
authors.affiliation: Department of Synthetic Organic Chemistry, Research Institute of Pharmaceutical Sciences, Musashino University, Nishitokyo, Tokyo, 202-8585, Japan.
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Katakawa
authors.affiliation: Department of Synthetic Organic Chemistry, Research Institute of Pharmaceutical Sciences, Musashino University, Nishitokyo, Tokyo, 202-8585, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Kumamoto
authors.affiliation: Graduate School of Pharmaceutical Sciences, Chiba University, Chuo-ku, Chiba, 260-8675, Japan.
authors.forename: Kenjirou
authors.initials: K
authors.lastname: Higashi
authors.affiliation: Graduate School of Pharmaceutical Sciences, Chiba University, Chuo-ku, Chiba, 260-8675, Japan.
authors.forename: Keiji
authors.initials: K
authors.lastname: Yamamoto
authors.affiliation: Graduate School of Pharmaceutical Sciences, Chiba University, Chuo-ku, Chiba, 260-8675, Japan.
authors.forename: Kunikazu
authors.initials: K
authors.lastname: Moribe
mesh_terms: D000927:Anticonvulsants / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability / Q000187:drug effects; D004339:Drug Compounding; D004355:Drug Stability; D020895:Enterocytes / Q000187:drug effects / Q000378:metabolism; D005079:Excipients / Q000737:chemistry*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D065347:Hypromellose Derivatives / Q000737:chemistry*; D007408:Intestinal Absorption / Q000187:drug effects; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008745:Methylation; D008956:Models, Chemical; D015394:Molecular Structure; D010672:Phenytoin / Q000031:analogs & derivatives / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D011205:Povidone / Q000737:chemistry*; D012995:Solubility; D012996:Solutions
chemical_list: D000927:Anticonvulsants; D005079:Excipients; D012996:Solutions; D065347:Hypromellose Derivatives; D010672:Phenytoin; D011205:Povidone
keywords: NMR spectroscopy; crystallization; drug derivative; permeability; polymers; solubilization; supersaturation