Format

Send to

Choose Destination
Eur J Pharm Biopharm. 2019 Jul;140:141-148. doi: 10.1016/j.ejpb.2019.04.017. Epub 2019 Apr 30.

Biorelevant dissolution testing of a weak base: Interlaboratory reproducibility and investigation of parameters controlling in vitro precipitation.

Author information

1
Drug Delivery and Disposition, KU Leuven, Leuven, Belgium.
2
Pharmaceutical Technology & Development, AstraZeneca, Macclesfield, United Kingdom.
3
Technical Research and Development, Novartis Pharma AG, Basel, Switzerland.
4
Pharmaceutical Sciences, Janssen Pharmaceutica, Johnson & Johnson, Beerse, Belgium.
5
Research & Development, Sanofi-Aventis, Vitry-sur-Seine, France.
6
GlaxoSmithKline R&D, Pharmaceutical Development & Supply, Ware, UK.
7
Institute of Pharmaceutical Technology, Goethe University, Frankfurt am Main, Germany.
8
Pharmaceutical Development, Boehringer Ingelheim Pharma GmbH, Biberach an der Riß, Germany.
9
Drug Product Science and Technology, Bristol-Myers Squibb, Moreton, UK.
10
Chemical and Pharmaceutical Development, Bayer AG, Wuppertal, Germany.
11
Pharmaceutical Sciences, Analytical Development, Orion Pharma, Turku, Finland.
12
Analytical Sciences, MRL, Merck & Co., Inc., Kenilworth, NJ, USA.
13
Drug Product Development, AbbVie Deutschland GmbH & Co. KG, Ludwigshafen, Germany.
14
Analytical Research and Development, Pfizer Ltd., Sandwich, UK.
15
Drug Delivery and Disposition, KU Leuven, Leuven, Belgium. Electronic address: Patrick.augustijns@kuleuven.be.

Abstract

Following a previous study which aimed to determine the interlaboratory reproducibility of biorelevant dissolution testing in the USP 2 apparatus for commercial formulations of two weak acids (ibuprofen and zafirlukast), this study attempts to determine the interlaboratory reproducibility using a similar protocol for a commercially available formulation of a weak base, indinavir. Fourteen partners including twelve industrial and two academic partners participated in this study. To ensure uniformity, all partners were provided with a standardized protocol to perform (i) a single medium dissolution test in fasted state simulated gastric and intestinal fluids (FaSSGF and FaSSIF, respectively) and (ii) a two-stage dissolution experiment simulating gastrointestinal transfer. Optionally, partners could run a single-stage dissolution test in fed state simulated intestinal fluid (FeSSIF). For each dissolution test, one Crixivan® capsule (containing 400 mg indinavir as its sulfate salt) was added as dose of interest. For the single medium dissolution test in FaSSIF, all partners observed rapid release of indinavir resulting in supersaturated concentrations, followed by precipitation to equilibrium solubility. The degree and period of supersaturation varied among the participating laboratories. Average dissolution profiles in FeSSIF appeared to be highly reproducible with dissolved concentrations remaining lower than the thermodynamic solubility of indinavir in FeSSIF. For the two-stage dissolution test, most partners observed supersaturated concentrations in the intestinal compartment; two partners observed no supersaturation due to immediate precipitation. Given the fact that a high interlaboratory but low intralaboratory variability was observed when supersaturation/precipitation occurred, an undefined factor was hypothesized as a potential cause of the variability in precipitation. Hence, the impact of several experimental factors on the supersaturation and precipitation behavior of indinavir was investigated in a next step. The investigation indicated that variability is likely attributable to a combination of factors, especially, the time elapsed between sampling and dilution of the sample with the mobile phase. Therefore, when designing a test in which supersaturation and precipitation is anticipated, stringent control of the test methodology, especially regarding sampling and dilution, is needed.

KEYWORDS:

Dissolution testing; Indinavir sulfate; Interlaboratory reproducibility; OrBiTo; Supersaturation/precipitation; USP 2 apparatus

PMID:
31051249
DOI:
10.1016/j.ejpb.2019.04.017

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center