title: Thermodynamic Stability Analysis of Tolbutamide Polymorphs and Solubility in Organic Solvents.
abstract: Melting temperatures and enthalpies of fusion have been determined by differential scanning calorimetry (DSC) for 2 polymorphs of the drug tolbutamide: FI(H) and FV. Heat capacities have been determined by temperature-modulated DSC for 4 polymorphs: FI(L), FI(H), FII, FV, and for the supercooled melt. The enthalpy of fusion of FII at its melting point has been estimated from the enthalpy of transition of FII into FI(H) through a thermodynamic cycle. Calorimetric data have been used to derive a quantitative polymorphic stability relationship between these 4 polymorphs, showing that FII is the stable polymorph below approximately 333 K, above which temperature FI(H) is the stable form up to its melting point. The relative stability of FV is well below the other polymorphs. The previously reported kinetic reversibility of the transformation between FI(L) and FI(H) has been verified using in situ Raman spectroscopy. The solid-liquid solubility of FII has been gravimetrically determined in 5 pure organic solvents (methanol, 1-propanol, ethyl acetate, acetonitrile, and toluene) over the temperature range 278 to 323 K. The ideal solubility has been estimated from calorimetric data, and solution activity coefficients at saturation in the 5 solvents determined. All solutions show positive deviation from Raoult's law, and all van't Hoff plots of solubility data are nonlinear. The solubility in toluene is well below that observed in the other investigated solvents. Solubility data have been correlated and extrapolated to the melting point using a semiempirical regression model.
authors.affiliation: Department of Chemical and Environmental Science, Synthesis and Solid State Pharmaceutical Centre, Materials and Surface Science Institute, University of Limerick, Limerick, Ireland; Department of Chemical Engineering and Technology, KTH Royal Institute of Technology, Stockholm, Sweden. Electronic address: micsva@kth.se.
authors.forename: Michael
authors.initials: M
authors.lastname: Svärd
authors.affiliation: Department of Chemical and Environmental Science, Synthesis and Solid State Pharmaceutical Centre, Materials and Surface Science Institute, University of Limerick, Limerick, Ireland.
authors.forename: Masood
authors.initials: M
authors.lastname: Valavi
authors.affiliation: Department of Chemical and Environmental Science, Synthesis and Solid State Pharmaceutical Centre, Materials and Surface Science Institute, University of Limerick, Limerick, Ireland.
authors.forename: Dikshitkumar
authors.initials: D
authors.lastname: Khamar
authors.affiliation: Department of Chemical and Environmental Science, Synthesis and Solid State Pharmaceutical Centre, Materials and Surface Science Institute, University of Limerick, Limerick, Ireland.
authors.forename: Manuel
authors.initials: M
authors.lastname: Kuhs
authors.affiliation: Department of Chemical and Environmental Science, Synthesis and Solid State Pharmaceutical Centre, Materials and Surface Science Institute, University of Limerick, Limerick, Ireland; Department of Chemical Engineering and Technology, KTH Royal Institute of Technology, Stockholm, Sweden.
authors.forename: Åke C
authors.initials: ÅC
authors.lastname: Rasmuson
mesh_terms: D002152:Calorimetry, Differential Scanning / Q000379:methods; D004355:Drug Stability; D007004:Hypoglycemic Agents / Q000032:analysis / Q000737:chemistry; D009930:Organic Chemicals / Q000032:analysis / Q000737:chemistry; D012995:Solubility; D012997:Solvents / Q000032:analysis* / Q000737:chemistry*; D013816:Thermodynamics; D014044:Tolbutamide / Q000032:analysis* / Q000737:chemistry*; D014961:X-Ray Diffraction / Q000379:methods
chemical_list: D007004:Hypoglycemic Agents; D009930:Organic Chemicals; D012997:Solvents; D014044:Tolbutamide
keywords: FTIR; Raman spectroscopy; activity coefficient; calorimetry (DSC); crystal polymorphism; polymorph; solubility; thermodynamics; transformation