Mechanism of drug release from polymethacrylate-based extrudates and milled strands prepared by hot-melt extrusion

• Published in: European journal of pharmaceutics and biopharmaceutics Vol. 71; no. 2; pp. 387 - 394
• Main Authors: Albers, Jessica, Alles, Rainer, Matthée, Karin, Knop, Klaus, Nahrup, Julia Schulze, Kleinebudde, Peter
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 01.02.2009; Elsevier
• Subjects: Biological and medical sciences; Calorimetry, Differential Scanning; Celecoxib; Chemistry, Pharmaceutical; Crystallization; Cyclooxygenase Inhibitors - chemistry; Dissolution; Drug Carriers - chemistry; Drug Stability; Drug Storage; Excipients - chemistry; General pharmacology; Hot-melt extrusion; Hypromellose Derivatives; Intrinsic dissolution; Medical sciences; Methylcellulose - analogs & derivatives; Methylcellulose - chemistry; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Polymethacrylate; Polymethacrylic Acids - chemistry; Pyrazoles - chemistry; Recrystallization inhibition; Solid dispersion; Solubility; Stability; Sulfonamides - chemistry; Temperature; Transition Temperature; X-Ray Diffraction; Hot-melt extrusion; Stability; Solid dispersion; Intrinsic dissolution; Celecoxib; Recrystallization inhibition; Dissolution; Polymethacrylate; Drug; Prostaglandin-endoperoxide synthase; Hot melt; Pharmaceutical technology; Enzyme; Enzyme inhibitor; Cyclooxygenase 2 inhibitor; Non steroidal antiinflammatory agent; Acrylate polymer; Extrusion; Oxidoreductases; Mechanism of action; Physicochemical properties; Release
• ISSN: 0939-6411; 1873-3441
• DOI: 10.1016/j.ejpb.2008.10.002

The aim of the study was the formulation of solid dispersions of the poorly water-soluble drug celecoxib and a polymethacrylate carrier by hot-melt extrusion. The objectives were to elucidate the mechanism of drug release from obtained extrudates and milled strands addicted to the solid-state properties of the solid dispersions and to examine and eliminate stability problems occurring under storage, exposure of mechanical stress, and in vitro dissolution. Transparent extrudates containing up to 60% drug could be prepared with a temperature setting below the melting point of celecoxib. XRPD and DSC measurements indicated the formation of a glassy solid solution, where the drug is molecularly dispersed in the carrier. The amorphous state of the glassy solid solution could be maintained during the exposure of mechanical stress in a milling process, and was stable under storage for at least 6 months. Solid-state properties and SEM images of extrudates after dissolution indicated a carrier-controlled dissolution, whereby the drug is molecularly dispersed within the concentrated carrier layer. The glassy solid solution showed a 58-fold supersaturation in 0.1 N HCl within the first 10 min, which was followed by a recrystallization process. Recrystallization could be inhibited by an external addition of HPMC.