6 FEBRUARY 2020 www.dissolutiontech.com In Vitro Release Testing (IVRT) of Topical Hydrocortisone Acetate Creams: A Novel Approach Using Positive and Negative Controls Nyengeterai Amanda Mudyahoto 1 , Seeprarani Rath 1 , Ashmita Ramanah 1 , and Isadore Kanfer 1,2* 1 Division of Pharmaceutcs, Faculty of Pharmacy, Rhodes University, Grahamstown, South Africa. 2 Leslie Dan Faculty, University of Toronto, Toronto, ON, Canada. ABSTRACT The objectve was to develop and validate an in vitro release testng (IVRT) method to assess the release of hydrocortsone acetate (HCA) from fve topical formulatons. A marketed generic cream containing 1% HCA was used as the reference product. Vertcal difusion cells (VDCs) were used to assess and compare the release rates of HCA from cream formulatons containing 0.5%, 1%, and 1.5% HCA. The study describes a novel approach to test the discriminatory power by including both positve and negatve controls to declare pharmaceutcal equivalence or inequivalence. The validated method was found to be sensitve, linear, precise, reproducible, robust, and selectve for the analysis of HCA from topical cream products. Equivalence or inequivalence was established based on SUPAC-SS acceptance criteria using a 90% CI with limits of 75–133.33%. The IVRT method was shown to have discriminatory ability to appropriately measure signifcant diferences in drug release from various cream formulatons. This approach also provides useful informaton for the future development of acceptable IVRT methods to assess topical dosage forms for local acton containing diferent drugs. INTRODUCTION S ince an in vitro release rate can refect numerous and combined efects of several physical and chemical parameters, including solubility, partcle size of the actve pharmaceutcal ingredient (API) and rheological propertes of the dosage form, in vitro release testng (IVRT) has been recommended by the United States Food and Drug Administraton (US FDA) as a test to assess pharmaceutcal equivalence/inequivalence between pre- and post-approval product changes ( 1, 2). The utlity of IVRT was extended in 2012 when the US FDA published a draf guidance for assessing bioequivalence (BE) of acyclovir topical ointment, which was the frst such publicaton recommending IVRT for use as a waiver of BE studies for a locally actng topical product ( 3). This partcular guidance provided useful and promising informaton for the future applicaton of IVRT as a method for assessment of the sameness of topical formulatons intended for local acton. Subsequently, the US FDA has published several draf guidances using in vitro methods for biowaivers for topical products ( 3– 8). In additon, a recent draf guideline published by the European Medicines Agency (EMA) also makes provision to use IVRT for the approval of generic products ( 9). However, a comprehensive validaton of the IVRT method is imperatve to ensure that the resultng method has the requisite atributes of sensitvity, precision, selectvity, and reproducibility necessary to detect diferences relatng to qualitatve (Q1) and quanttatve (Q2) propertes and the microstructure and arrangement of mater (Q3) between products ( 10, 11 ). In light of the above, an IVRT method was developed and validated to assess creams containing 1% hydrocortsone acetate (HCA). Two marketed products containing 1% HCA and three additonal creams specifcally manufactured to contain 0.5%, 1%, and 1.5% HCA were studied. A positve control was included to ensure that the method had the necessary capability to confrm sameness, and negatve controls ensured the method had the requisite discriminatory power to detect signifcant diferences. MATERIALS AND METHODS Chemicals and Formulations Hydrocortsone acetate (HCA) was obtained from Sigma- Aldrich (St. Louis, MO, USA). High-performance liquid chromatography (HPLC) grade acetonitrile was obtained from Romil Ltd (200 UV ROMIL-SpS Super Purity Solvent, Waterbeach, Cambridge, UK) and ethanol (95%) was purchased from Merck Laboratories (Wadeville, Gauteng, South Africa). The water used for chromatography was dx.doi.org/10.14227/DT270120P6 e-mail: I.Kanfer@ru.ac.za * Corresponding author.