title: Investigation of griseofulvin and hydroxypropylmethyl cellulose acetate succinate miscibility in ball milled solid dispersions.
abstract: Solid dispersions of varying weight ratios compositions of the nonionic drug, griseofulvin and the hydrophilic, anionic polymer, hydroxylpropylmethyl cellulose acetate succinate, have been prepared by ball milling and the resulting samples characterized using a combination of Fourier transform infra-red spectroscopy, X-ray powder diffraction and differential scanning calorimetry. The results suggest that griseofulvin forms hydrogen bonds with the hydroxylpropylmethyl cellulose acetate succinate polymer when prepared in the form of a solid dispersion but not when prepared in a physical mixture of the same composition. As anticipated, the actual measured glass transition temperature of the solid dispersions displayed a linear relationship between that predicted using the Gordon-Taylor and Fox equations assuming ideal mixing, but interestingly only at griseofulvin contents less than 50 wt%. At griseofulvin concentrations greater than this, the measured glass transition temperature of the solid dispersions was almost constant. Furthermore, the crystalline content of the solid dispersions, as determined by differential scanning calorimetry and X-ray powder diffraction followed a similar trend in that the crystalline content significantly decreased at ratios less than 50 wt% of griseofulvin. When the physical mixtures of griseofulvin and the hydroxylpropylmethyl cellulose acetate succinate polymer were analyzed using the Flory-Huggins model, a negative free energy of mixing with an interaction parameter of -0.23 were obtained. Taken together these results suggest that anionic hydrophilic hydroxylpropylmethyl cellulose acetate succinate polymer is a good solvent for crystalline nonionic griseofulvin with the solubility of griseofulvin in the solid dispersion being was estimated to be within the range 40-50 wt%. Below this solubility limit, the amorphous drug exists as amorphous glassy solution while above these values the system is supersaturated and glassy suspension and solution may coexist.
authors.affiliation: Institute of Pharmaceutical Science, King's College London, Franklin Wilkins Building, 150 Stamford Street, London SE1 9NH, United Kingdom. hisham.al-obaidi@kcl.ac.uk
authors.forename: Hisham
authors.initials: H
authors.lastname: Al-Obaidi
authors.forename: M Jayne
authors.initials: MJ
authors.lastname: Lawrence
authors.forename: Noor
authors.initials: N
authors.lastname: Al-Saden
authors.forename: Peng
authors.initials: P
authors.lastname: Ke
mesh_terms: D002152:Calorimetry, Differential Scanning; D003460:Crystallization; D004339:Drug Compounding / Q000295:instrumentation / Q000379:methods*; D005079:Excipients / Q000737:chemistry*; D006118:Griseofulvin / Q000737:chemistry*; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D008747:Methylcellulose / Q000031:analogs & derivatives* / Q000737:chemistry; D015394:Molecular Structure; D044367:Phase Transition; D012995:Solubility; D017550:Spectroscopy, Fourier Transform Infrared; D014961:X-Ray Diffraction
chemical_list: D005079:Excipients; D006118:Griseofulvin; C048331:hydroxypropylmethylcellulose acetate succinate; D008747:Methylcellulose