EFFECT OF PHYSICOCHEMICAL PROPERTIES OF EMULSIONS FORMED BY SELF-EMULSIFYING DRUG DELIVERY SYSTEMS (SEDDS) ON THE SOLUBILIZATION STATE OF DRUG: IN VITRO STUDY Original Article NASER M. Y. HASAN 1* * Received: 22 Jul 2018, Revised and Accepted: 19 Nov 2018 School of Pharmacy, Applied Science Private University, Jordan Email: n_hassan@asu.edu.jo ABSTRACT Objective: Parameters in the oil pre-concentrate which can affect the solvent capacity of the resultant dispersion such as, oil-cosurfactant ratio, type of surfactant used in the system, the inclusion of water soluble co-solvents and the solubilization capacity of native surfactants such as, bile salts and lecithin were studied in an attempt to circumvent crystallization of drug during its passage in the gut. Methods: Different types of self-emulsifying systems representing type II, IIIA and IIIB, were used to probe the influence of the various physicochemical properties of the resultant dispersions on the fate of dissolved model lipophilic drug. This was achieved by studying emulsification behavior of lipid systems in fed and fasted biological fluids, analyzing solubilization/drug crystallization kinetics and oil droplet diameter measurement. Results: Self-micro-emulsifying lipid systems lost solvent capacity on dispersion and were not able to keep the drug in solution at equilibrium. Miglyol 812/Imwitor ratio in the pre-concentrate mixture appeared to influence the kinetics of drug crystallization. Pre-microemulsion systems containing Tagat TO dispersions were found to hold more drugs in solution at equilibrium than in the case of systems containing Cremophor RH40. The inclusion of as little as 10-20% PEG in the lipid mixture accelerated drug precipitation. Bile salt-lecithin mixed micelles appears to some extent enhance the solubilization capacity of these systems after dispersion Conclusion: Solvency of emulsions formed by self-emulsifying drug delivery in various emulsification media is a crucial parameter influencing the fate of dissolved drug after the dispersion of the formulations. Keywords: SEDDS, SMEDDS, Lipid formulations, Medium chain mono-and glycerides, Poorly water-soluble compounds © 2019 The Authors. Published by Innovare Academic Sciences Pvt Ltd. This is an open-access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/) DOI: http://dx.doi.org/10.22159/ijap.2019v11i1.28664 INTRODUCTION Lipid-based drug delivery systems (LBDDS) including self- emulsifying drug delivery systems (SEDDS) or self-micro- emulsifying drug delivery system (SMEDDS) are isotropic mixtures of oils and non-ionic surfactants which upon gentle agitation in water produce (o/w) dispersions of droplets<5 µm [1] or between 5 and 140 nm [2], respectively. Due to high hydrophilic content of SMEDDS which include materials such as; polar oils including mixed mono and/or di-medium chain glycerides, high HLB nonionic surfactants (>12), and hydrophilic co-solvents, these oil vehicles are considered more hydrophilic than SEDDS. Oil-based systems were classified into type I, II, IIIA, IIIB and IV, based on various physicochemical factors such as; the hydrophilicity of the oil mixture, the particle size of the resultant dispersion and the formulation digestibility [3-4]. Type IV formulations do not contain natural lipids and represent the most hydrophilic formulations. Hydrophilicity of the lipid mixture increases by moving from type 1 lipid class system to type 4. The reformulation of cyclosporine A as Neoral® is an archetypal example of a Type III system [5]. The HIV protease inhibitor amprenavir (Agenerase®) which contains TPGS as a surfactant and PEG 400 and propylene glycol as co-solvents [6] is an example of Type IV formulations which do not contain natural lipids and thus represent the most hydrophilic formulations. Amprenavir (Agenerase®) was succeeded though by a pro-drug, fosamprenavir [7]. These lipid formulations are thoroughly characterized and studied, and hence represent one of quintessential approach for the bioavailability enhancement poorly- water-soluble compounds; especially class II drugs. The past nearly 4 decades from 1975 through 2013 have shown rampant growth in utilizing solubilization techniques, accounting on average for around 6% of all new molecular entities (NMEs) approved [8]. Furthermore, the same study has shown that LBDDS are the most widely used solubilization platform. It is estimated that LBDDS oral drug products account for 2–4% of all commercially available drug products according to a study by Strickley in 2007 [9]. According to various drug databases and reviews, there are more than 36 different oral LBDDS on the market of 27 unique drug molecules that were FDA approved by FDA [10-12]. Some of the most recent LBDDS products include; Isotretinoin (Absorica®, by Cipher pharmaceuticals a reformulation of isotretinoin (Accutane); New drug application year NDA; 2012) [13], Enzalutamide (Xtandi®, NDA; 2012) [14], Nintedanib (Ofev®, NDA; 2014) [15] and Calcifediol (Rayaldee™, NDA; 2016) [16]. In the design of successful lipid formulations with maximize the bioavailability; key elements in the lipid composite have to be optimized [17-18]. Nonetheless, crystallization of the drug in the lumen of the gut depends on the hydrophilicity of oil system; log P of the drug and the solubilization capacity of native surfactants (bile salt-lecithin mixed micelles) to maintain the drug in solution during digestion. The medium into which the drug must dissolve has a great influence on its solubility hence; suitable media which satisfactorily simulate the physiological conditions are needed. In the GI tract, the solubility of the drug is a function of aqueous solubility, crystallinity, drug lipophilicity, pKa MATERIALS AND METHODS in relation to the pH profile of GI tract, solubilization by native surfactants (such as bile salts and lecithin) and ingested food components. Four suitable media have been suggested to simulate the composition of proximal GI tract [19]: SGF plus surfactant for fasted state stomach; long-life milk (3.5% fat) for fed state stomach; FaSSIF and FeSSIF for fasted and fed state small intestine. Physicochemical properties of emulsions formed by various types of lipid systems which can influence drug solubilization were studied here in an attempt to probe the fate of dissolved drug after dispersion. Materials Miglyol 812 (medium chain triglyceride) and Imwitor 988 (C 8/C 10 mono/diglycerides) were supplied by Condea Chemie GmbH. Tagat TO (PEG-(25)-glyceryl trioleate) was supplied by Goldschmidt AG, International Journal of Applied Pharmaceutics ISSN- 0975-7058 Vol 11, Issue 1, 2019