title: Factors affecting the formation of eutectic solid dispersions and their dissolution behavior.
abstract: The objective of this work was to obtain a fundamental understanding of the factors, specifically the properties of poorly water-soluble drugs and water-soluble carriers, which influence predominantly, the formation of eutectic or monotectic crystalline solid dispersion and their dissolution behavior. A theoretical model was applied on five poorly water-soluble drugs (fenofibrate, flurbiprofen, griseofulvin, naproxen, and ibuprofen) having diverse physicochemical properties and water-soluble carrier (polyethylene glycol (PEG) 8000) for the evaluation of these factors. Of these, two drugs, fenofibrate and flurbiprofen, and PEG of different molecular weights (3350, 8000, and 20000), were chosen as model drugs and carriers for further investigation. Experimental phase diagrams were constructed and dissolution testing was performed to assess the performance of the systems. The theoretical model predicted the formation of eutectic or monotectic solid dispersions of fenofibrate, griseofulvin, ibuprofen, and naproxen with PEG, holding the contribution of specific intermolecular interactions between compound and carrier to zero. In the case of the flurbiprofen-PEG eutectic system, intermolecular interactions between drug and polymer needed to be taken into consideration to predict the experimental phase diagram. The results of the current work suggest that the thermodynamic function of melting point and heat of fusion (as a measure of crystal energy of drug) plays a significant role in the formation of a eutectic system. Lipophilicity of the compound (as represented by cLog P) was also demonstrated to have an effect. Specific interactions between drug and carrier play a significant role in influencing the eutectic composition. Molar volume of the drug did not seem to have an impact on eutectic formation. The polymer molecular weight appeared to have an impact on the eutectic composition for flurbiprofen, which exhibits specific interactions with PEG, whereas no such impact of polymer molecular weight on eutectic composition was observed for fenofibrate, which does not exhibit specific interactions with PEG. The impact of polymer molecular weight on dissolution of systems where specific drug-polymer interactions are exhibited was also observed. The current work provides valuable insight into factors affecting formation and dissolution of eutectic systems, which can facilitate the rational selection of suitable water-soluble carriers.
authors.affiliation: Pharmaceutical and Analytical Development, Novartis Pharmaceutical Corporation, East Hanover, NJ 07936, USA. sudha.vippagunta@novartis.com
authors.forename: Sudha R
authors.initials: SR
authors.lastname: Vippagunta
authors.forename: Zeren
authors.initials: Z
authors.lastname: Wang
authors.forename: Stefanie
authors.initials: S
authors.lastname: Hornung
authors.forename: Steven L
authors.initials: SL
authors.lastname: Krill
mesh_terms: D004337:Drug Carriers; D011345:Fenofibrate / Q000737:chemistry*; D005480:Flurbiprofen / Q000737:chemistry*; D006118:Griseofulvin / Q000737:chemistry*; D007052:Ibuprofen / Q000737:chemistry*; D008956:Models, Chemical; D008970:Molecular Weight; D009288:Naproxen / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry*; D012967:Sodium Dodecyl Sulfate / Q000737:chemistry; D012995:Solubility; D044366:Transition Temperature; D014867:Water / Q000737:chemistry
chemical_list: D004337:Drug Carriers; D014867:Water; D006118:Griseofulvin; D012967:Sodium Dodecyl Sulfate; D011092:Polyethylene Glycols; D009288:Naproxen; D005480:Flurbiprofen; D011345:Fenofibrate; D007052:Ibuprofen