Comparison of the Solubility and Dissolution of Drugs in FastedState Biorelevant Media (FaSSIF and FaSSIF-V2)

Abstract

The equilibrium solubility values and dissolution profiles in each of the media (FaSSIF or FaSSIF-V2) produced using methylene chloride and the corresponding SIF Powder are equivalent for the drugs tested representing acid, basic, and neutral compounds. Therefore, it is practical to switch from the more labor-intensive solvent-evaporation method to the use of standardized instant powders for preparing biorelevant media without affecting the solubility and dissolution results. Testing in the two versions of FaSSIF media with different bile salt/lecithin ratios will give an indication on how the drug and formulation could be affected in vivo by the variations in bile salt/lecithin ratio within the range found in human small intestinal fluids. INTRODUCTION Biorelevant media are artificial in vitro media designed to share physicochemical properties with their corresponding fluids found in vivo in terms of osmolarity, pH, buffer capacity, and surfactant content, for example. Specifically, intestinal biorelevant media are widely used to mimic the properties of gastrointestinal fluids for in vitro solubility and dissolution studies. These media can also be used to simulate gastrointestinal stability and to perform permeability studies (1). Biorelevant media simulate the gastrointestinal fluids by containing the physiological surfactants, bile salt and lecithin. These media are particularly important for the development of poorly soluble drugs, because these surfactants significantly increase solubility. Biorelevant intestinal media were first proposed by Dressman et al. (2) at the University of Frankfurt in collaboration with Reppas from the University of Athens who identified the deficiencies of standard pharmacopeial media. These two groups also demonstrated the clear advantage of biorelevant media over standard conventional media for studying the solubility and dissolution of poorly soluble compounds. Biorelevant intestinal media simulate intestinal fluids secreted under fasted(FaSSIF) or fed-state conditions (FeSSIF). Food intake alters the physiochemical properties and composition of intestinal fluids for digestion. That is why separate intestinal media are defined for fastedand fed-state conditions. The two states of media enable formulation scientists to obtain solubility values and dissolution profiles of drugs and their formulations in vitro under both fasted and fed states. This can help detect food effects and optimize formulation performance using standard pharmacopeial dissolution test apparatus (e.g., USP Apparatus 2 and 4). There are biorelevant media representing fluids found along all regions in the gastrointestinal tract. However, simulated upper small intestinal media are the most commonly used, particularly for immediate-release drugs, because they simulate the fluids in the intestinal region from which most drugs are absorbed. FaSSIF and FaSSIF-V2 are the two most frequently used compositions for biorelevant intestinal media reflecting fasted-state conditions. The main difference between FaSSIF and FaSSIF-V2 is the reduced amount of lecithin in FaSSIF-V2 (Table 1) as compared with FaSSIF. The level of lecithin in both versions falls within the range typically found in aspirates sampled from healthy human volunteers. The purpose of this study was to evaluate the equilibrium solubility of four poorly water soluble drug substances (danazol, dipyridamole, ketoconazole, miconazole) and the drug dissolution from five drug products containing drugs with various pKa values under fasted-state conditions (i.e., without food interference) using the FaSSIF and FaSSIF-V2 media. The drug products contained acidic (mefenamic acid), basic (ketoconozole), or neutral (danazol, metoprolol, paracetamol) compounds. In addition, the solubility and drug dissolution behaviors were compared in media made from commercially available instant powders (SIF Powder Original and SIF Powder FaSSIF-V2 from biorelevant.com, UK) and prepared from methylene chloride as described by Marques (3). MATERIALS AND METHODS Materials Drugs Used for Solubility Testing Danazol was purchased from Jai Radhe (Ahmedabad, India). Dipyridamole was from Sigma Aldrich Chemie GmbH *Corresponding author. Contact: www.biorelevant.com/contact dx.doi.org/10.14227/DT200313P44