factors influencing the preparation of micro/nanoparticles? (a) the application of aggregation inhibitors. (b) the active agent-excipient ratio (c) the type and quantity of the solvent (d) the temperature and humidity of the environment.
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Poorly water-soluble drug candidates are becoming more prevalent. It has been estimated that approximately 60–70% of the drug molecules are insufficiently soluble in aqueous media and/or have very low permeability to allow for their adequate and reproducible absorption from the gastrointestinal tract (GIT) following oral administration. Formulation scientists have to adopt various strategies to enhance their absorption. Lipidic formulations are found to be a promising approach to combat the challenges. In this review article, potential advantages and drawbacks of various conventional techniques and the newer approaches specifically the self-emulsifying systems are discussed. Various components of the self-emulsifying systems and their selection criteria are critically reviewed. The attempts of various scientists to transform the liquid self-emulsifying drug delivery systems (SEDDS) to solid-SEDDS by adsorption, spray drying, lyophilization, melt granulation, extrusion, and so forth to formulate various dosage forms like self emulsifying capsules, tablets, controlled release pellets, beads, microspheres, nanoparticles, suppositories, implants, and so forth have also been included. Formulation of SEDDS is a potential strategy to deliver new drug molecules with enhanced bioavailability mostly exhibiting poor aqueous solubility. The self-emulsifying system offers various advantages over other drug delivery systems having potential to solve various problems associated with drugs of all the classes of biopharmaceutical classification system (BCS).
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1. Introduction
Various strategies have been widely investigated to enhance the bioavailability of poorly absorbed drugs in order to increase their clinical efficacy when administered orally. It is estimated that between 40% and 70% of all new chemical entities identified in drug discovery programs are insufficiently soluble in aqueous media [1, 2]. The increase in the proportion of poorly soluble candidates is frequently attributed to improvements in synthesis technology, which has enabled the design of very complicated compounds, and a change in discovery strategy from a so-called phenotypic approach to a target-based approach [3]. Various physicochemical properties which contribute to the poor solubility of various drugs include their complex structure, size, high molecular weight, high lipophilicity, compound H-bonding to solvent, intramolecular H-bonding, intermolecular H-bonding (crystal packing), crystallinity, polymorphic forms, ionic charge status, pH, and salt form [4].
Lipinski's rule of five has been widely proposed as a qualitative predictive model for the assessment of absorption of poorly absorbed compounds. In the discovery setting “the rule of 5” predicts that poor absorption or permeation is more likely when there are more than 5 H-bond donors, 10 H-bond acceptors, the molecular weight is greater than 500, and the calculated Log P is greater than 5. The rule of five only holds for compounds that are not substrates for active transporters and efflux mechanisms [5]. Thus, in vivo assessment of new drug candidates in animal model is performed to assess the absorption of drug. Poorly absorbed drugs pose a challenge to the formulation scientists to develop suitable dosage form which can enhance their bioavailability.
Broadly, poorly soluble drugs can be formulated in three different forms to overcome the challenge of poor absorption—crystalline solid formulations, amorphous formulations, and lipid formulations [6].
1.1. Crystalline Solid Formulations
Modification of the physicochemical properties such as salt formation and micronization of the crystalline compound to increase the surface area and thus dissolution may be one approach to improve the dissolution rate of the drug. Particle size of about 2–5 μm can be achieved by micronization using air-jet mill. The nanocrystal technology can reduce the crystalline particle size to 100–250 nm using ball-milling [7], dense gas technologies [8], and so forth. However, these methods have their own limitations. For instance, salt formation of neutral compounds is not feasible. Particle size reduction may not be desirable in situations where poor wettability and handling difficulties are experienced for very fine powders [9].
1.2. Amorphous Formulations
Amorphous formulations include “solid solutions” which can be formed using a variety of technologies including spray drying and melt extrusion [9–11]. Amorphous formulations may include surfactants and polymers providing surface activity during dispersion.
Other formulation strategies which are most popularly adopted to enhance the bioavailability of such drugs include the complexation with cyclodextrins [12], formulation of polymeric conjugates [13], nanoparticles, solid lipid nanoparticles (SLN) [14], use of permeation enhancers, and surfactants [15]