View with images and charts Formulation and In-Vitro Evaluation of Ternary Solid Dispersion of Aceclofenac by 3 2 Factorial Design INTRODUCTION 1.1 HISTORICAL BACKGROUND OF SOLID DISPERSION TECHNOLOGY [1] The effect of the particle size of the drugs on their dissolution rates and biological availability was reviewed comprehensively by Fincher. For drugs whose gastrointestinal absorption is rate limited by dissolution, reduction of the particle size generally increases the rate of absorption and or total bioavailability. This commonly occurs for drugs with poor watersolubility. For example, the therapeutic dose of griseofulvin was reduced to 50% by micronization and it also produced a more constant and reliable blood level. The commercial dose of spironolactone was also decreased to half by just a slight reduction of particle size. Such enhancement of drug absorption could further be increased several fold if a micronized product was used. In 1961, a unique approach of solid dispersion to reduce the particle size and increase rates of dissolution and absorption was first demonstrated by Sekiguchi and Obi. They proposed the formation of a eutectic mixture of a poorly soluble drug such as sulfathiazole with a physiologically inert, easily soluble carrier such as urea. The eutectic mixture was prepared by melting the physical mixture of the drug and the carrier, followed by a rapid solidification process. Upon exposure to aqueous fluids, the active drug was expected to be released into the fluids as fine, dispersed particles because of the fine dispersion of the drug in the solid eutectic mixture and the rapid dissolution of the soluble matrix. Chiou and Riegelman recently advocated the application of glass solution to increase dissolution rates. They used PEG 6000 as a dispersion carrier. It is believed that this relatively new field of pharmaceutical technique and principles will play an important role in increasing dissolution, absorption and therapeutic efficacy of drugs in future dosage forms. Therefore, a thorough understanding of its fast release principles, methods of preparation, selection of suitable carriers, determination of physical properties, limitations and disadvantages will be essential in the practical and effective application of this approach. In addition to absorption enhancement, the solid dispersion technique may have numerous pharmaceutical applications which remain to be further explored. It is possible that such a technique can be used to obtain a homogeneous distribution of a small amount of drug at solid state, to stabilize unstable drugs, to dispense liquid or gaseous compounds, to formulate a fast release priming dose in a sustained release dosage form, and to formulate sustained release regimens of soluble drugs by using poorly soluble or insoluble carriers. 1.2 INTRODUCTION TO SOLID DISPERSION TECHNOLOGY [2]: The enhancement of oral bioavailability of poorly water soluble drugs remains one of the most challenging aspects of drug development. Although salt formation, solubilization and particle size reduction have commonly been used to increase dissolution rate and thereby oral absorption and bioavailability of such drugs, there are practical limitations of these techniques. The salt formation is not feasible for neutral compounds and the synthesis of appropriate salt forms of drugs that are weakly acidic or weakly basic may often not be practical. Even when salts can be prepared, an increased dissolution rate in the GIT may not be achieved in many cases because of the reconversion of salts into aggregates of their respective acid or base forms. The solubilization of drugs in organic solvents or in aqueous media by the use of surfactants and cosolvents leads to liquid formulations that are usually undesirable from the viewpoints of patient acceptability and commercialization. Although particle size reduction is commonly
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