title: Evaluating drug delivery with salt formation: Drug disproportionation studied in situ by ATR-FTIR imaging and Raman mapping.
abstract: Two different vibrational spectroscopic approaches, ATR-FTIR spectroscopic imaging and Raman mapping, were used to investigate the components within a tablet containing an ionised drug during dissolution experiments. Delivering certain drugs in their salt form is a method that can be used to improve the bioavailability and dissolution of the poorly aqueous soluble materials. However, these ionised species have a propensity to covert back to their thermodynamically favourable free acid or base forms. Dissolution experiments of the ionised drug in different aqueous media resulted in conversion to the more poorly soluble free acid form, which is detrimental for controlled drug release. This study investigates the chemical changes occurring to formulations containing a development ionised drug (37% by weight), in different aqueous pH environments. Firstly, dissolution in a neutral medium was studied, showing that there was clear release of ionised monosodium form of the drug from the tablet as it swelled in the aqueous medium. There was no presence of any drug in the monohydrate free acid form detected in these experiments. Dissolution in an acidic (0.1M HCl) solution showed disproportionation forming the free acid form. Disproportionation occurred rapidly upon contact with the acidic solution, initially resulting in a shell of the monohydrate free acid form around the tablet edges. This slowed ingress of the solution into the tablet before full conversion of the ionised form to the free acid form was characterised in the spectroscopic data.
authors.affiliation: Department of Chemical Engineering, Imperial College London, London SW7 2AZ, United Kingdom.
authors.forename: Andrew V
authors.initials: AV
authors.lastname: Ewing
authors.affiliation: Bristol-Myers Squibb, Reeds Lane, Moreton, Wirral, Merseyside CH46 1QW, United Kingdom.
authors.forename: Patrick S
authors.initials: PS
authors.lastname: Wray
authors.affiliation: Bristol-Myers Squibb, Reeds Lane, Moreton, Wirral, Merseyside CH46 1QW, United Kingdom.
authors.forename: Graham S
authors.initials: GS
authors.lastname: Clarke
authors.affiliation: Department of Chemical Engineering, Imperial College London, London SW7 2AZ, United Kingdom. Electronic address: s.kazarian@imperial.ac.uk.
authors.forename: Sergei G
authors.initials: SG
authors.lastname: Kazarian
mesh_terms: D001682:Biological Availability; D002626:Chemistry, Pharmaceutical / Q000379:methods; D016503:Drug Delivery Systems / Q000379:methods; D006863:Hydrogen-Ion Concentration; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D012965:Sodium Chloride / Q000737:chemistry*; D012995:Solubility; D017550:Spectroscopy, Fourier Transform Infrared / Q000379:methods; D013059:Spectrum Analysis, Raman / Q000379:methods; D013607:Tablets / Q000737:chemistry
chemical_list: D004364:Pharmaceutical Preparations; D013607:Tablets; D012965:Sodium Chloride
keywords: Chemical imaging; Dissolution; FT-IR spectroscopy; Raman spectroscopy; Salt formation