F. Damian

Physicochemical characterization of solid dispersions of the antiviral agent UC-781 with polyethylene glycol 6000 and Gelucire 44/14

The purpose of this study was to prepare and characterize solid dispersions of the antiviral thiocarboxanilide UC-781 with PEG 6000 and Gelucire 44/14 with the intention of improving its dissolution properties. The solid dispersions were prepared by the fusion method. Evaluation of the properties of the dispersions was performed using dissolution studies, differential scanning calorimetry, Fourier-transform infrared spectroscopy and X-ray powder diffraction. To investigate the possible formation of solid solutions of the drug in the carriers, the lattice spacings [d] of PEG 6000 and Gelucire 44/14 were determined in different concentrations of UC-781. The results obtained showed that the rate of dissolution of UC-781 was considerably improved when formulated in solid dispersions with PEG 6000 and Gelucire 44/14 as compared to pure UC-781. From the phase diagrams of PEG 6000 and Gelucire 44/14 it could be noted that up to approximately 25% w/w of the drug was dissolved in the liquid phase in the case of PEG 6000 and Gelucire 44/14. The data from the X-ray diffraction showed that the drug was still detectable in the solid state below a concentration of 5% w/w in the presence of PEG 6000 and Gelucire 44/14, while no significant changes in the lattice spacings of PEG 6000 or Gelucire 44/14 were observed. Therefore, the possibility of UC-781 to form solid solutions with the carriers under investigation was ruled out. The results from infrared spectroscopy together with those from X-ray diffraction and differential scanning calorimetry showed the absence of well-defined drug-polymer interactions.

Physical stability of solid dispersions of the antiviral agent UC-781 with PEG 6000, Gelucire 44/14 and PVP K30.

This paper describes the physical stability of solid dispersions of UC-781 with PEG 6000, Gelucire 44/14 and PVP K30 prepared by the solvent and melting methods. The concentration of the drug in the solid dispersions ranged from 5 to 80% w/w. The solid dispersions were stored at 4-8 and 25 degrees C (25% RH), then their physicochemical properties were analysed by differential scanning calorimetry (DSC), X-ray powder diffraction and dissolution studies as a function of storage time. The DSC curves of solid dispersions of UC-781 with PVP K30 did not show any melting peaks corresponding to UC-781 after storage, indicating no recrystallization of the drug. The DSC data obtained from PEG 6000 and Gelucire 44/14 showed some variations in melting peak temperatures and enthalpy of fusion of the carriers. It was shown that the enthalpy of fusion of PEG 6000 in the dispersions increased after storage; it was more pronounced for samples stored at 25 degrees C compared to those at 4-8 degrees C indicating the reorganization of the crystalline domains of the polymer. Similarly, the enthalpy of fusion of Gelucire 44/14 in the solid dispersions increased as a function of time. Dissolution of UC-781 from all solid dispersions decreased as a function of storage time. While these observations concurred with the DSC data for all solid dispersions, they were not reflected by X-ray powder diffraction data. It was concluded that it is the change of the physical state of the carriers and not that of the drug, which is responsible for the decreased dissolution properties of the solid dispersions investigated.

In vitro biodegradation study of acetyl and methyl inulins by Bifidobacteria and inulinase

The purpose of this study was to investigate if acetylated and methylated inulins can be degraded by inulinase from Aspergillus niger and by Bifidobacteria, in order to determine their potential in colonic drug delivery. Methyl and acetyl inulins were synthesized by the reaction of inulin (Raftiline HP) with methyl sulfate and acetic anhydride, respectively. The degree of substitution (DS) and the structure of the reaction products were confirmed by 13C-NMR. Degradation by inulinase was investigated in a citrate buffer (0.05 M, pH 4) or with a mixture of citrate buffer and DMSO at 37 degrees C. Biodegradation by Bifidobacteria was investigated under anaerobic conditions using an in-house prepared broth at 37 degrees C for 2 days. The resulting products were analyzed chromatographically; the formation of short chain fatty acids was followed by measuring the pH of the incubation media. The results obtained suggest that acetylated and methylated inulins are not biodegradable, since no degradation product could be detected after incubation; a decrease in pH was clearly observed in control samples (pure fructose and inulin), but not in the derivatized inulin samples. The results can probably be explained by a change in conformation of inulin due to derivatization.

Solid state properties of pure UC-781 and solid dispersions with polyvinylpyrrolidone (PVP K30).

The purpose of this study was to elucidate the physical structure of solid dispersions of the antiviral agent UC‐781 (N‐[4‐chloro‐3‐(3‐methyl‐2‐butenyloxy)phenyl]‐2‐methyl‐3‐furancarbo‐thioamide) with polyvinylpyrrolidone (PVP K30). Solid dispersions were prepared by co‐evaporating UC‐781 with PVP K30 from dichloromethane. The physicochemical properties of the dispersions were evaluated in comparison with the physical mixtures by differential scanning calorimetry (DSC), X‐ray powder diffraction, and FT‐IR spectroscopy. We investigated the single crystal structure of pure UC‐781. The data from single crystal analysis showed that UC‐781 crystallized with orthorhombic symmetry in the space group Pcab. Its cell parameters were found to be; a = 8.1556(7) Å, b = 17.658(2) Å and c = 23.609(2) Å; the unit cell was made up of eight molecules of UC‐781. The molecules formed intermolecular hydrogen bonds between NH and thio groups, and were packed in a herringbone‐like structure. The data from X‐ray powder diffraction showed that crystalline UC‐781 was changed into the amorphous state by co‐evaporating it with PVP K30. From differential scanning calorimetry analysis, UC‐781 peaks were observed in the DSC curves of all physical mixtures, while no peaks corresponding to the drug could be observed in the solid dispersions with the same drug composition up to the concentration of 50% w/w. The data from FT‐IR spectroscopy showed the distortions and disappearance of some bands from the drug, while other bands were too broad or significantly less intense compared with the physical mixtures of the crystalline drug in PVP K30. Furthermore, the results from IR spectroscopy demonstrated that UC‐781 interacted with PVP K30 in solid dispersions through intermolecular H‐bonding.