Interlaboratory Validation of Small-Scale Solubility and Dissolution Measurements of Poorly Water-Soluble Drugs.
The purpose of this study was to investigate the interlaboratory variability in determination of apparent solubility (Sapp) and intrinsic dissolution rate (IDR) using a miniaturized dissolution instrument. Three poorly water-soluble compounds were selected as reference compounds and measured at multiple laboratories using the same experimental protocol. Dissolution was studied in fasted-state simulated intestinal fluid and phosphate buffer (pH 6.5). An additional 6 compounds were used for the development of an IDR measurement guide, which was then validated with 5 compounds. The results clearly showed a need for a standardized protocol including both the experimental assay and the data analysis. Standardization at both these levels decreased the interlaboratory variability. The results also illustrated the difficulties in performing disc IDR on poorly water-soluble drugs because the concentrations reached are typically below the limit of detection. The following guidelines were established: for compounds with Sapp >1 mg/mL, the disc method is recommended. For compounds with Sapp <100 μg/mL, IDR is recommended to be performed using powder dissolution. Compounds in the interval 100 μg/mL to 1 mg/mL can be analyzed with either of these methods.
Department of Pharmacy, Uppsala University, Uppsala Biomedical Centre, Uppsala SE-751 23, Sweden.
Sara B E
SBE
Andersson
Department of Pharmacy, Uppsala University, Uppsala Biomedical Centre, Uppsala SE-751 23, Sweden.
Caroline
C
Alvebratt
Pharmaceutical Sciences, Janssen Pharmaceutica, Beerse 2340, Belgium.
Jan
J
Bevernage
Chemical and Pharmaceutical Analysis, Sanofi-Aventis Recherche Développement, 34184 Montpellier, France.
Damien
D
Bonneau
Drug Product Design, Pharmaceutical Sciences, Pfizer Ltd., Sandwich, Kent CT13 9NJ, UK.
Claudia
C
da Costa Mathews
Biopharmaceutics, Product Development, AstraZeneca, Macclesfield SK10 2NA, UK.
Rikesh
R
Dattani
Department of Pharmacy, Uppsala University, Uppsala Biomedical Centre, Uppsala SE-751 23, Sweden.
Khadijah
K
Edueng
Pre-Development Sciences, Sanofi, Waltham, Massachusetts 02451.
Yan
Y
He
Pharmaceutical Science and CMC Biologics, Valby DK-2500, Denmark; Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen DK-2100, Denmark.
René
R
Holm
Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen DK-2100, Denmark.
Cecilie
C
Madsen
Drug Product Development, AbbVie Deutschland GmbH & Co KG, Ludwigshafen 67061, Germany.
Thomas
T
Müller
Bayer Pharma AG, Chemical and Pharmaceutical Development, Research Center Aprath, Wuppertal 42096, Germany.
Uwe
U
Muenster
Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen DK-2100, Denmark.
Anette
A
Müllertz
Orion Pharma, P.O. Box 65, 02101 Espoo, Finland.
Krista
K
Ojala
Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen DK-2100, Denmark.
Thomas
T
Rades
Pharmaceutical Development, Boehringer Ingelheim, 55218 Ingelheim am Rhein, Germany.
Peter
P
Sieger
Department of Pharmacy, Uppsala University, Uppsala Biomedical Centre, Uppsala SE-751 23, Sweden. Electronic address: christel.bergstrom@farmaci.uu.se.
Christel A S
CAS
Bergström
D000465:Algorithms; D001826:Body Fluids / Q000737:chemistry; D002021:Buffers; D002626:Chemistry, Pharmaceutical / Q000379:methods* / Q000592:standards*; D002851:Chromatography, High Pressure Liquid; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D011208:Powders; D015203:Reproducibility of Results; D012995:Solubility; D014961:X-Ray Diffraction
D002021:Buffers; D011208:Powders
apparent solubility; dissolution; intrinsic dissolution rate; poorly water-soluble drug; preformulation; small scale