Salt screening and characterization for poorly soluble, weak basic compounds: case study albendazole.
In preclinical development, salt forms are often screened to assess their ability to improve drug candidate properties. In this study albendazole was used as a model for poorly soluble, weak basic compounds typical of current drug discovery programs. Four salts, the hydrochloride, mesylate, sulfate und tosylate, were prepared and characterized with respect to their physicochemical properties. Identity was confirmed by 1H NMR spectroscopy, ion chromatography and vibrational spectroscopy. The solid state forms of the albendazole salts were examined by scanning electron microscopy (SEM), X-ray powder diffraction (XRPD), laser diffraction measurement of particle size distribution (PSD), B.E.T. measurement of the specific surface area and 13C solid state NMR spectroscopy. Thermal behaviour and hygroscopicity were assessed by thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), dynamic vapour sorption (DVS), Karl Fischer titration (KFT) and by variable temperature XRPD. Additionally, solubility and dissolution experiments were carried out in water and buffers. The different salt forms show pronounced differences in their physicochemical behaviour, especially with respect to hygroscopicity (sulfate > hydrochloride > tosylate > mesylate) and dissolution (rank order is pH dependent, all better than the free base). A salt form with highly improved physicochemical properties, the mesylate, was identified. The results demonstrate that extensive physicochemical characterization is needed to select the salt form most appropriate for further pharmaceutical development.
Ciba Vision/Alcon, Gross-Wallstadt, Germany.
G S
GS
Paulekuhn
J B
JB
Dressman
C
C
Saal
D000327:Adsorption; D015766:Albendazole / Q000737:chemistry*; D000468:Alkalies; D000871:Anthelmintics / Q000737:chemistry*; D002712:Chlorides; D006863:Hydrogen-Ion Concentration; D009682:Magnetic Resonance Spectroscopy; D008698:Mesylates; D008855:Microscopy, Electron, Scanning; D010316:Particle Size; D012492:Salts; D012995:Solubility; D017550:Spectroscopy, Fourier Transform Infrared; D013059:Spectrum Analysis, Raman; D013431:Sulfates; D013499:Surface Properties; D013818:Thermogravimetry; D014961:X-Ray Diffraction
D000468:Alkalies; D000871:Anthelmintics; D002712:Chlorides; D008698:Mesylates; D012492:Salts; D013431:Sulfates; D015766:Albendazole