title: Acid-Base Interactions of Polystyrene Sulfonic Acid in Amorphous Solid Dispersions Using a Combined UV/FTIR/XPS/ssNMR Study.
abstract: This study investigates the potential drug-excipient interactions of polystyrene sulfonic acid (PSSA) and two weakly basic anticancer drugs, lapatinib (LB) and gefitinib (GB), in amorphous solid dispersions. Based on the strong acidity of the sulfonic acid functional group, PSSA was hypothesized to exhibit specific intermolecular acid-base interactions with both model basic drugs. Ultraviolet (UV) spectroscopy identified red shifts, which correlated well with the color change observed in lapatinib-PSSA solutions. Fourier transform infrared (FTIR) spectra suggest the protonation of the quinazoline nitrogen atom in both model compounds, which agrees well with data from the crystalline ditosylate salt of lapatinib. X-ray photoelectron spectroscopy (XPS) detected increases in binding energy of the basic nitrogen atoms in both lapatinib and gefitinib, strongly indicating protonation of these nitrogen atoms. (15)N solid-state NMR spectroscopy provided direct spectroscopic evidence for protonation of the quinazoline nitrogen atoms in both LB and GB, as well as the secondary amine nitrogen atom in LB and the tertiary amine nitrogen atom in GB. The observed chemical shifts in the LB-PSSA (15)N spectrum also agree very well with the lapatinib ditosylate salt where proton transfer is known. Additionally, the dissolution and physical stability behaviors of both amorphous solid dispersions were examined. PSSA was found to significantly improve the dissolution of LB and GB and effectively inhibit the crystallization of LB and GB under accelerated storage conditions due to the beneficial strong intermolecular acid-base interaction between the sulfonic acid groups and basic nitrogen centers.
authors.affiliation: Department of Industrial and Physical Pharmacy, Purdue University , West Lafayette, Indiana 47907, United States.
authors.forename: Yang
authors.initials: Y
authors.lastname: Song
authors.affiliation: Birck Nanotechnology Center, Purdue University , West Lafayette, Indiana 47907, United States.
authors.forename: Dmitry
authors.initials: D
authors.lastname: Zemlyanov
authors.affiliation: GlaxoSmithKline , Collegeville, Pennsylvania 19426, United States.
authors.forename: Xin
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Industrial and Physical Pharmacy, Purdue University , West Lafayette, Indiana 47907, United States.
authors.forename: Haichen
authors.initials: H
authors.lastname: Nie
authors.affiliation: Center for Drug Evaluation and Research, Food and Drug Administration , Silver Spring, Maryland 20993, United States.
authors.forename: Ziyang
authors.initials: Z
authors.lastname: Su
authors.affiliation: Department of Industrial and Physical Pharmacy, Purdue University , West Lafayette, Indiana 47907, United States.
authors.forename: Ke
authors.initials: K
authors.lastname: Fang
authors.affiliation: College of Life Sciences, Nanjing Normal University , Nanjing 210046, P. R. China.
authors.forename: Xinghao
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Industrial and Physical Pharmacy, Purdue University , West Lafayette, Indiana 47907, United States.
authors.forename: Daniel
authors.initials: D
authors.lastname: Smith
authors.affiliation: Department of Industrial and Physical Pharmacy, Purdue University , West Lafayette, Indiana 47907, United States.
authors.forename: Stephen
authors.initials: S
authors.lastname: Byrn
authors.affiliation: Small Molecule Pharmaceutical Sciences, Genentech, Inc. , South San Francisco, California 94080, United States.
authors.forename: Joseph W
authors.initials: JW
authors.lastname: Lubach
mesh_terms: D000136:Acid-Base Equilibrium; D000970:Antineoplastic Agents / Q000737:chemistry*; D002152:Calorimetry, Differential Scanning; D003460:Crystallization; D004337:Drug Carriers; D004339:Drug Compounding; D004355:Drug Stability; D005079:Excipients; D000077156:Gefitinib; D000077341:Lapatinib; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D056951:Photoelectron Spectroscopy / Q000379:methods*; D011137:Polystyrenes / Q000737:chemistry*; D011799:Quinazolines / Q000737:chemistry; D012995:Solubility; D013056:Spectrophotometry, Ultraviolet / Q000379:methods*; D017550:Spectroscopy, Fourier Transform Infrared / Q000379:methods*
chemical_list: D000970:Antineoplastic Agents; D004337:Drug Carriers; D005079:Excipients; D011137:Polystyrenes; D011799:Quinazolines; D000077341:Lapatinib; C003321:polystyrene sulfonic acid; D000077156:Gefitinib
keywords: XPS; amorphous; dissolution rate; gefitinib; ionic interaction; lapatinib; physical stability; salt; solid dispersion; solid-state NMR