Solid dispersions of itraconazole and enteric polymers made by ultra-rapid freezing.
The primary objective of the study is to investigate the influence of composition parameters including drug:polymer ratio and polymer type, and particle structure of enteric solid dispersions on the release of ITZ under sink and supersaturated dissolution conditions. Modulated differential scanning calorimetry (MDSC) was utilized to define the level of ITZ miscibility with each polymer. The compositions were completely miscible at 60% ITZ for both polymers and as high as 70% in HP-55. High potency composition glass transition temperatures (T(g)) correlated with predicted T(g)'s from the Gordon-Taylor equation, however, recrystallization exotherms revealed pure amorphous regions indicating that phase separation occurred during particle formation. Furthermore, in vitro studies including X-ray powder diffraction (XRD), scanning electron microscopy (SEM), surface area analysis (BET), and dissolution were performed to determine differences between low potency (completely miscible) and high potency (partially miscible) compositions. Dissolution studies on low potency ITZ compositions revealed that miscibility plays an active role in ITZ release under sink conditions, and square root diffusion through the enteric polymer is observed. Supersaturated dissolution profiles revealed high potency compositions had maximum saturation levels (C/Ceq(max)) between 10.6- and 8-times equilibrium solubility, but had higher cumulative extents of supersaturation, compared to low potency compositions which had C/Ceq(max) values of 15-19.6. However, these low potency compositions rapidly precipitated leading to significantly lower AUCs (p<0.05). The change in the miscibility of the solid dispersion had a pronounced effect of drug release (sink) while differences in potency influenced supersaturated dissolution profiles.
Overhoff
Kirk A
KA
College of Pharmacy, University of Texas at Austin, Austin, TX 78712, USA.
Moreno
Alejandro
A
Miller
Dave A
DA
Johnston
Keith P
KP
Williams
Robert O
RO
D000180:Acrylic Resins / Q000737:chemistry*; D002152:Calorimetry, Differential Scanning; D003460:Crystallization; D004058:Diffusion; D005079:Excipients / Q000737:chemistry*; D005615:Freezing; D006863:Hydrogen-Ion Concentration; D017964:Itraconazole / Q000737:chemistry* / Q000493:pharmacokinetics; D007700:Kinetics; D008747:Methylcellulose / Q000031:analogs & derivatives* / Q000737:chemistry; D008855:Microscopy, Electron, Scanning; D053758:Nanoparticles / Q000737:chemistry; D011108:Polymers / Q000737:chemistry; D011208:Powders / Q000737:chemistry; D012995:Solubility; D013499:Surface Properties; D044366:Transition Temperature; D014961:X-Ray Diffraction
D000180:Acrylic Resins; C446821:Eudragit L100-55; D005079:Excipients; D011108:Polymers; D011208:Powders; D017964:Itraconazole; D008747:Methylcellulose; C053309:hydroxypropyl methylcellulose phthalate