title: Effects of Manufacturing Methods on Dissolution and Absorption of Ketoconazole in the Presence of Organic Acid as a pH Modifier.
abstract: Poorly water-soluble compounds have a potential risk of low and variable bioavailability caused by incomplete dissolution. Incorporation of organic acids as pH modifiers is effective method for solubility enhancement of basic compounds and requires no special technique and equipment. The purpose of this study was to evaluate the effect of manufacturing method on the extent of drug solubility enhancement. We successfully prepared the granules and tablets containing ketoconazole (KZ), which is weakly basic, as a model compound and citric acid as a pH modifier using conventional wet and dry granulations. KZ solubility under non-sink condition was enhanced with supersaturation using both wet and dry granulations. High-shear granulation was the most effective method in terms of KZ dissolution enhancement, because both an intimate contact and strong bonding between KZ and incorporated acid were achieved. KZ dissolved amount from the granules prepared by high-shear granulation was about eight times higher than that from the granules without the acid. The granulation involved to suppress a diffusion of acid dissolved, leading to the effectively maintained supersaturation state. The bioavailability of KZ after oral administration to rats was improved by applying high-shear granulation with citric acid independent of gastrointestinal pH. The granules prepared by high-shear granulation showed the bioavailability about 1.7-fold higher than that of the physical mixture in rats with and without neutralization of stomach. As a result, both the dissolution and absorption rates of KZ after oral administration were enhanced using conventional manufacturing technology.
authors.affiliation: Department of Biopharmaceutics, Kyoto Pharmaceutical University, 5, Misasagi-Nakauchicho, Yamashina-ku, Kyoto, 607-8414, Japan. adachim@kaw.boehringer-ingelheim.com.|Department of Chemistry, Manufacturing, and Control, Kobe Pharma Research Institute, Nippon Boehringer Ingelheim Co., Ltd., 6-7-5, Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo, 650-0047, Japan. adachim@kaw.boehringer-ingelheim.com.
authors.forename: Masashi
authors.initials: M
authors.lastname: Adachi
authors.affiliation: Department of Biopharmaceutics, Kyoto Pharmaceutical University, 5, Misasagi-Nakauchicho, Yamashina-ku, Kyoto, 607-8414, Japan.
authors.forename: Yuta
authors.initials: Y
authors.lastname: Hinatsu
authors.affiliation: Department of Biopharmaceutics, Kyoto Pharmaceutical University, 5, Misasagi-Nakauchicho, Yamashina-ku, Kyoto, 607-8414, Japan.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Kusamori
authors.affiliation: Department of Biopharmaceutics, Kyoto Pharmaceutical University, 5, Misasagi-Nakauchicho, Yamashina-ku, Kyoto, 607-8414, Japan.
authors.forename: Hidemasa
authors.initials: H
authors.lastname: Katsumi
authors.affiliation: Department of Pharmaceutical Technology, Kobe Pharmaceutical University, 4-19-1, Motoyama-kitamachi, Higashinada-ku, Kobe, 658-8558, Japan.
authors.forename: Toshiyasu
authors.initials: T
authors.lastname: Sakane
authors.affiliation: Department of Chemistry, Manufacturing, and Control, Kobe Pharma Research Institute, Nippon Boehringer Ingelheim Co., Ltd., 6-7-5, Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo, 650-0047, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Nakatani
authors.affiliation: Department of Chemistry, Manufacturing, and Control, Kobe Pharma Research Institute, Nippon Boehringer Ingelheim Co., Ltd., 6-7-5, Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo, 650-0047, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Wada
authors.affiliation: Department of Biopharmaceutics, Kyoto Pharmaceutical University, 5, Misasagi-Nakauchicho, Yamashina-ku, Kyoto, 607-8414, Japan. yamamoto@mb.kyoto-phu.ac.jp.
authors.forename: Akira
authors.initials: A
authors.lastname: Yamamoto
mesh_terms: D065567:Absorption, Physiological; D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical; D019343:Citric Acid / Q000737:chemistry; D006863:Hydrogen-Ion Concentration; D007654:Ketoconazole / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D051381:Rats; D012995:Solubility; D013607:Tablets / Q000737:chemistry; D014867:Water / Q000737:chemistry
chemical_list: D013607:Tablets; D014867:Water; D019343:Citric Acid; D007654:Ketoconazole
keywords: bioavailability; dissolution rate; granulation; solubility; supersaturation