title: Manufacture and performance evaluation of a stable amorphous complex of an acidic drug molecule and Neusilin.
abstract: In this paper, we explore the use of Neusilin, an inorganic magnesium aluminometasilicate, to stabilize the amorphous form of an acidic drug Sulindac. Both cryomilling and ball milling of the drug with Neusilin were found to produce the amorphous phase. However, the ball-milled (BM) material exhibited superior physical stability when compared with the cryomilled material at 40°C/75% relative humidity. (13) C solid-state nuclear magnetic resonance investigation of the BM material revealed an acid-base reaction between Sulindac and Neusilin. Optimal milling conditions and the kinetics of salt formation were also established. As benchtop milling is a laboratory-scale process, a scalable process was developed to make Sulindac-Neusilin amorphous drug complex using hot-melt extrusion (HME). The dissolution properties of the resulting HME material was found to have been improved over the material made by benchtop milling while maintaining similar physical stability. The HME material was used to make tablets using a direct compression method. The HME tablets were found to have better dissolution properties than tablets made from crystalline Sulindac. For the broad class of acidic drugs containing the carboxyl moiety, inorganic silicates such as Neusilin would offer a better choice than organic polymers to stabilize the amorphous phase.
authors.affiliation: Small Molecule Process and Product Development, Amgen, Thousand Oaks, California 91320.
authors.forename: Jenifer
authors.initials: J
authors.lastname: Maclean
authors.affiliation: Small Molecule Process and Product Development, Amgen, Thousand Oaks, California 91320.
authors.forename: Cesar
authors.initials: C
authors.lastname: Medina
authors.affiliation: Small Molecule Process and Product Development, Amgen, Thousand Oaks, California 91320.
authors.forename: Dominick
authors.initials: D
authors.lastname: Daurio
authors.affiliation: Small Molecule Process and Product Development, Amgen, Thousand Oaks, California 91320.
authors.forename: Fernando
authors.initials: F
authors.lastname: Alvarez-Nunez
authors.affiliation: Small Molecule Process and Product Development, Amgen, Thousand Oaks, California 91320.
authors.forename: Janan
authors.initials: J
authors.lastname: Jona
authors.affiliation: College of Pharmacy, University of Kentucky, Lexington, Kentucky 40536.
authors.forename: Eric
authors.initials: E
authors.lastname: Munson
authors.affiliation: Small Molecule Process and Product Development, Amgen, Thousand Oaks, California 91320. Electronic address: karthikn@amgen.com.
authors.forename: Karthik
authors.initials: K
authors.lastname: Nagapudi
mesh_terms: D000143:Acids; D017607:Aluminum Compounds; D000538:Aluminum Silicates / Q000737:chemistry*; D019245:Compressive Strength; D004355:Drug Stability; D008274:Magnesium / Q000737:chemistry*; D017616:Magnesium Compounds; D015394:Molecular Structure; D044367:Phase Transition; D012492:Salts; D017640:Silicates; D012995:Solubility; D013467:Sulindac / Q000737:chemistry*; D013678:Technology, Pharmaceutical / Q000379:methods*; D044366:Transition Temperature
chemical_list: D000143:Acids; D017607:Aluminum Compounds; D000538:Aluminum Silicates; D017616:Magnesium Compounds; D012492:Salts; D017640:Silicates; D013467:Sulindac; C033065:aluminum magnesium silicate; D008274:Magnesium