Amorphous formulations for dissolution and bioavailability enhancement of poorly soluble APIs

Poor water solubility of current active pharmaceutical ingredients (APIs) and new chemical entities (NCEs) is a major hurdle in the development of pharmaceutical dosage forms. More (APIs) and new chemical entities (NCEs) are a major hurdle in the development of pharmaceutical dosage forms. More than 40% of NCEs fall into Biopharmaceutical Classification System (BCS) class II category having a dissolution rate limited bioavailability. A 50%-attrition rate among drugs in development has been reported to result from poor biopharmaceutical properties, including water insolubility. From the perspective of medical professionals and patients, this means missing out on new potential and efficacious treatments to combat diseases and illnesses. For the pharmaceutical industry, this translates into a loss in potential revenue due to longer developmental time to formulate new products and a delay in transitioning them to the market. Among strategies to enhance bioavailability, amorphization by destroying or preventing long-range crystalline molecular order in solid-state drug compounds has been seen as a potentially universal method that can be applied to many APIs. It is not unusual to observe an increase in dissolution rate by several orders of magnitude. Since the amorphous form is meta-stable, it suffers from the drawback of returning to the crystalline state over time and thereby losing out on the enhancement in bioavailability. Stabilization of the amorphous form for an acceptable shelf-life remains a formidable technical challenge. Through bio-enhancement, the new amorphous formulations are expected to improve the efficacy of the solid dosage form and reduce the dosage of API required to produce a therapeutic effect at the required site of action. In terms of manufacturing and environmental considerations, there is a reduction in the material and energy consumption in the API production process by minimizing the wastage of drugs that is currently needed to ensure adequate exposure for a therapeutic benefit. In this review paper, we discuss the need for APIs in the amorphous state, use of several techniques to amorphize APIs and enhance the stability of the amorphous form under stress test conditions. Hot melt extrusion, coprecipitation using supercritical anti-solvent process and using functionalized excipients are a few methods of amorphous form stabilization that are discussed. The pivotal role of various pharmaceutically acceptable excipients that are used for stability enhancement and the mechanism therein are also discussed. (C) 2015 Elsevier B.V. All rights reserved.