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Abstract  

The effect of grinding on the physical properties and pharmaceutical performance of solid dispersions made of poly(ethylene) glycol 6000 (PEG6000) and temazepam or diazepam was studied using differential scanning calorimetry (DSC), X-ray powder diffraction and dissolution experiments. DSC-analysis of flash-cooled dispersions revealed that amorphous PEG present immediately after grinding crystallised upon aging mainly into the twice folded modification and to a small extent into the extended form. DSC-analysis of dispersions kept in the slab form for 1 month and subsequently ground, revealed that in the abscence of the grinding impulse crystallisation of PEG6000 takes place in the same way as in dispersions ground immediately after preparation and then aged for 1 month. Grinding solid dispersions immediately after preparation resulted in superior dissolution properties compared with solid dispersions kept in the monolith-slab form and subsequently ground. This difference in dissolution properties was found to be attributed to the drug and not to the polymer, more precisely, it was suggested that the drug particle size in ground dispersions was smaller than in dispersions kept in the slab form and subsequently ground. These findings suggest that grinding of solid dispersions immediately after preparation is the preparation method of choice instead of liquid filling of hard gelatin capsules resulting in monoliths.

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Abstract  

Differential scanning calorimetry (DSC) data showed that the crystallinity of poly(ethylene glycol) 6000 in solid dispersions containing and diazepam or temazepam only slightly increased upon aging and that the twice folded modification of the polymer unfolded into the once folded modification during aging, while the once folded modification did not unfold. This unfolding was found to be time and temperature dependent. X-ray powder diffraction data revealed that the drug crystallinity in the solid dispersions slightly increased upon aging. The dissolution profiles of aged and non-aged solid dispersions were comparable. It was concluded that polymer unfolding did not have an impact on the pharmaceutical performance of the investigated dispersions.

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Abstract  

Thermal analysis was performed on the anti-HIV agent loviride in order to test its suitability to be processed using hot-melt extrusion. Temperature characteristic parameters of crystallization were determined to quantify the stability of amorphous loviride. The present study has shown that cooling and heating loviride at different rates influenced its thermal stability. At high cooling rates melted loviride did not crystallize during cooling, and formed a glass that recrystallized during reheating. Very low cooling rates resulted in significant decomposition of the drug. The glass transition temperature was found to increase as a function of increasing heating rates and the activation energy for the transition from the glassy to the super-cooled liquid state was relatively high, indicating good stability of the glass.

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Abstract  

In the present study, we report on the thermal properties of a series of benzodiazepines. The heat of fusion varied between approximately 25 and 40 kJ mol–1, except for oxazepam and lorazepam where dimerization in the solid state increased the heat of fusion to 78.54(±0.37) and 77.03 (±0.84)kJ mol–1, respectively. Heating alprazolam at a low rate (0.5 K min–1) showed that polymorphs I and II are an enantiotropic pair with a solid-solid transition at 481.4 K It was shown that all benzodiazepines could be transformed to the glassy state by cooling fused samples, irrespective of the cooling rate. The size of the relaxation endotherm accompanying the glass transition increased by heating the glassy drugs at a higher rate through T g or by cooling the fused samples at a slower rate. The time dependence of the glass to liquid transition can be described to a good approximation as a first order transformation. The Gordon-Taylor equation was used to predict T g of a binary mixture of temazepam, diazepam or prazepam with polyHEMA. It was shown that the predictability was acceptable as long as the drug concentration was below 10%w/w; at higher concentration, specific drug-polymer interactions causing changes in free volume of the system could not be ignored.

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Journal of Thermal Analysis and Calorimetry
Authors: K. Six, Ch. Leuner, J. Dressman, G. Verreck, J. Peeters, N. Blaton, P. Augustijns, R. Kinget, and G. Van den Mooter
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