title: The Precipitation Behavior of Poorly Water-Soluble Drugs with an Emphasis on the Digestion of Lipid Based Formulations.
abstract: An increasing number of newly discovered drugs are poorly water-soluble and the use of natural and synthetic lipids to improve the oral bioavailability of these drugs by utilizing the digestion pathway in-vivo has proved an effective formulation strategy. The mechanisms responsible for lipid digestion and drug solubilisation during gastrointestinal transit have been explored in detail, but the implications of drug precipitation beyond the potential adverse effect on bioavailability have received attention only in recent years. Specifically, these implications are that different solid forms of drug on precipitation may affect the total amount of drug absorbed in-vivo through their different physico-chemical properties, and the possibility that the dynamic environment of the small intestine may afford re-dissolution of precipitated drug if present in a high-energy form. This review describes the events that lead to drug precipitation during the dispersion and digestion of lipid based formulations, common methods used to inhibit precipitation, as well as conventional and newly emerging characterization techniques for studying the solid state form of the precipitated drug. Moreover, selected case studies are discussed where drug precipitation has ensued from the digestion of lipid based formulations, as well as the apparent link between drug ionisability and altered solid forms on precipitation, culminating in a discussion about the importance of the solid form on precipitation with relevance to the total drug absorbed.
authors.affiliation: Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, 3052, Australia.
authors.forename: Jamal
authors.initials: J
authors.lastname: Khan
authors.affiliation: Department of Pharmacy, Pharmaceutical Design and Drug Delivery, University of Copenhagen, Studiestræde 6, København K, Denmark.
authors.forename: Thomas
authors.initials: T
authors.lastname: Rades
authors.affiliation: Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, 3052, Australia. ben.boyd@monash.edu.|ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus), 381 Royal Parade, Parkville, VIC, 3052, Australia. ben.boyd@monash.edu.
authors.forename: Ben
authors.initials: B
authors.lastname: Boyd
mesh_terms: D001682:Biological Availability; D002626:Chemistry, Pharmaceutical / Q000379:methods; D004063:Digestion; D006801:Humans; D007421:Intestine, Small / Q000378:metabolism; D008055:Lipids / Q000737:chemistry*; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D012995:Solubility; D014867:Water / Q000737:chemistry*
chemical_list: D008055:Lipids; D004364:Pharmaceutical Preparations; D014867:Water
keywords: Digestion; Lipids; Lipolysis; Poorly water-soluble drugs; Precipitation; Solid state