Effect of Various Operational Parameters on Drug Release from a 1% Hydrocortisone Semisolid Dosage Form Using the Vertical Diffusion Cell Apparatus

Abstract

The purpose of this study was to identify operational parameters of the vertical diffusion cell (VDC) apparatus that have an influence on results of drug release testing from semisolid dosage forms, which are one of three types of topically applied products (see USP General Chapter Topical and Transdermal Drug Products—Product Quality Tests ). The VDC apparatus operates using a static diffusion cell, a synthetic membrane, and an appropriate receptor medium. A cream formulation containing 1% hydrocortisone was used for the current study. The operational parameters investigated were stirring rate, mixing helix, stirring while sampling, medium degassing, membrane wetting with Ethomeen (a surfactant), and membrane wetting time. Stat-Ease design of experiment software was used to create partial factorial experimental designs to evaluate these parameters. The effects of the operational parameters were evaluated using mean drug release rate (slope, μg/cm2/min1⁄2) and the standard deviation (SD) of six individual release rates for each experimental setup. Results of the study indicate that one parameter, the presence of Ethomeen for wetting the membrane, had a large and significant effect on both drug release rates and SD. Two parameters, stirring while sampling and mixing helix, had a significant impact on the drug release rate when Ethomeen was not used. Two parameters, medium degassing and stirring while sampling, had significant effects on the variability of the results (SD). Additionally, instrument-specific parameters (e.g., mixing helix) also contributed significantly to the variability of drug release rates. INTRODUCTION Topically applied drug products include ophthalmic, semisolid, and transdermal dosage forms (1). Drug products topically administered via the skin fall into two general categories, those applied for local action (e.g., semisolid dosage forms) and those intended for systemic effects (e.g., transdermal drug products). The drug substance in either category must be released from the carrier before it can contact the epidermal surface and be available for penetration into the stratum corneum and lower layers of the skin. A performance test for topical drug products therefore should be able to measure drug release from the dosage form. Although it is not an indicator of bioavailability, the drug release test should be capable of detecting changes in the finished product drug release characteristics that have the potential to alter the biological performance of the drug in the dosage form. The drug release test for semisolid dosage forms should be reproducible and reliable. The vertical diffusion cell (VDC) apparatus, which uses a static diffusion cell, a synthetic membrane, and an appropriate receptor medium, has emerged as one of the most widely used apparatus for testing the in vitro release of topical dosage forms (2, 3). The VDC apparatus is simple to operate and generally yields reliable and reproducible results when employed by properly trained laboratory personnel (4). The objective of the present study was to evaluate the influence of some operational parameters on the release of the drug from the semisolid dosage form. The authors evaluated individual or combined effects of stirring rate, mixing helix, membrane wetting with Ethomeen, membrane wetting time, stirring while sampling, and medium degassing on the release rate of a 1% hydrocortisone cream formulation using two VDC apparatus, each from a different vendor. The study evaluated the release rate (steady-state flux) and between-cell standard deviation (SD) of release rates of 1% hydrocortisone cream. MATERIALS AND METHODS Materials and Reagents Reagents used were a current and valid lot of USP Hydrocortisone Reference Standard, Milli-Q water, acetonitrile HPLC grade (Fisher Scientific, Waltham, MA), water HPLC grade, ethanol (Warner Graham, Cockeysville, MD), isopropyl myristate (IPM) (Alfa Aesar, Ward Hill, MA), Ethomeen-12 (AkzoNobel), and Tuffryn 0.45-μm mem*Corresponding author. e-mail: ess@usp.org dx.doi.org/10.14227/DT190312P6