The objectives of this study were (i) to develop a computational model based on molecular dynamics technique to predict the miscibility of indomethacin in carriers (polyethylene oxide, glucose, and sucrose) and (ii) to experimentally verify the in silico predictions by characterizing the drug-carrier mixtures using thermoanalytical techniques. Molecular dynamics (MD) simulations were performed using the COMPASS force field, and the cohesive energy density and the solubility parameters were determined for the model compounds. The magnitude of difference in the solubility parameters of drug and carrier is indicative of their miscibility. The MD simulations predicted indomethacin to be miscible with polyethylene oxide and to be borderline miscible with sucrose and immiscible with glucose. The solubility parameter values obtained using the MD simulations values were in reasonable agreement with those calculated using group contribution methods. Differential scanning calorimetry showed melting point depression of polyethylene oxide with increasing levels of indomethacin accompanied by peak broadening, confirming miscibility. In contrast, thermal analysis of blends of indomethacin with sucrose and glucose verified general immiscibility. The findings demonstrate that molecular modeling is a powerful technique for determining the solubility parameters and predicting miscibility of pharmaceutical compounds.
Purpose. The aim of this study was to develop a highly sensitive powder X-ray diffraction (XRD) technique for quantification of crystallinity in substantially amorphous pharmaceuticals, utilizing synchrotron radiation and a 2-D area detector. Methods. Diffraction data were acquired at the European Synchrotron Radiation Facility (France) using a 2-D charge-coupled device detector. The crystallization of amorphous sucrose was monitored in situ, isothermally at several temperatures in the range of 90 to 160-C. An algorithm was developed for separation of the crystalline and amorphous intensities from the total diffraction pattern. Results. The synchrotron XRD technique allowed powder diffraction patterns to be recorded with a time resolution of 40 ms. The gradual crystallization of sucrose is analogous to a series of physical mixtures with increasing content of the crystalline component. The in situ crystallization approach circumvented the problem of inhomogeneity in mixingVa potentially serious issue at extreme mixture compositions. The estimated limit of detection of crystalline sucrose in an amorphous matrix was 0.2% w/w, a considerable improvement over the reported value of õ1% w/w with a conventional XRD. Conclusion. High-intensity XRD can discern subtle changes in the lattice order of materials. The first evidence of crystallization can serve as an indicator of the potential physical instability of the product.
The objectives of this study were as follows: (i) To develop an in silico technique, based on molecular dynamics (MD) simulations, to predict glass transition temperatures (Tg) of amorphous pharmaceuticals. (ii) To computationally study the effect of plasticizer on Tg. (iii) To investigate the intermolecular interactions using radial distribution function (RDF). Amorphous sucrose and water were selected as the model compound and plasticizer, respectively. MD simulations were performed using COMPASS force field and isothermal-isobaric ensembles. The specific volumes of amorphous cells were computed in the temperature range of 440-265 K. The characteristic "kink" observed in volume-temperature curves, in conjunction with regression analysis, defined the Tg. The MD computed Tg values were 367 K, 352 K and 343 K for amorphous sucrose containing 0%, 3% and 5% w/w water, respectively. The MD technique thus effectively simulated the plasticization effect of water; and the corresponding Tg values were in reasonable agreement with theoretical models and literature reports. The RDF measurements revealed strong hydrogen bond interactions between sucrose hydroxyl oxygens and water oxygen. Steric effects led to weak interactions between sucrose acetal oxygens and water oxygen. MD is thus a powerful predictive tool for probing temperature and water effects on the stability of amorphous systems during drug development.
Two dimensional powder X-ray diffractometry, using a high intensity source, is a powerful technique to study kinetics of rapid solid-state reactions. The inhibitory effect of excipients can have profound effect on phases formed during pharmaceutical processing.
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