Applicability of Raman and near-infrared spectroscopy in the monitoring of freeze-drying injectable ibuprofen.

The freeze-drying process is an expensive, time-consuming and rather complex process. Therefore, process analytical technology (PAT) tools have been introduced to develop an optimized process and control critical process parameters, which affect the final product quality. The aim of the present work was to study the applicability of at-line near-infrared (NIR) and Raman spectroscopy approach in the monitoring of the freeze-drying process. Freeze-dried powders, which were developed previously, were manufactured as a multi-component system, containing ibuprofen (IBP). The NIR proved to be a useful tool for the monitoring of the freeze-drying process, since it was able to determine residual moisture content (RMC) and hence predict its values by using the partial least square (PLS) model. In addition, the evaluation of the correlation between the NIR and off-line HPLC IBP content results showed that NIR spectra were consistent with the HPLC measurements, even though overlapping absorption bands in multi-component system were observed. This research also studied the ability of using the at-line Raman measurements for the evaluation of the crystallinity and polymorphic transformations during the process, such as IBP ionization and mannitol polymorphism. The results were in correlation with XRPD results, but parameters of PLS models were not optimal. Nevertheless, this approach still assured better process understanding. To conclude, high applicability of the at-line NIR in the monitoring of the freeze-dried powder production was successfully demonstrated, suggesting that it can be used as a single tool to monitor RMC and IBP content as well as process deviations during the freeze-drying process.

Solubilization of ibuprofen for freeze dried parenteral dosage forms.

Ibuprofen, a weakly acidic non-steroidal anti-inflammatory drug having poor aqueous solubility, is a challenging drug for the development of pharmaceutical formulations, resulting in numerous research attempts focusing on improvement of its solubility and consequently bioavailability. Most studies have been done for solid dosage forms, with very little attention paid to parenterals. Hence, the main purpose of the present study was to enhance ibuprofen solubility as a result of formulation composition and the freeze drying process. Moreover, the purpose was to prepare a freeze dried dosage form with improved ibuprofen solubility that could, after simple reconstitution with water for injection, result in an isotonic parenteral solution. Solubility of ibuprofen was modified by various excipients suitable for parenteral application. Drug interactions with selected excipients in the final product/lyophilisate were studied by a combined use of XRPD, DSC, Raman and ss-NMR. Analyses of lyophilized samples showed solubility enhancement of ibuprofen and in situ formation of an ibuprofen salt with the alkaline excipients used.

Characterization of agglomerated carvedilol by hot-melt processes in a fluid bed and high shear granulator.

The purpose of this study was to prepare and characterize granulated carvedilol by melt-in and spray-on melt granulation in a fluid bed and a high shear granulator. Granulates having comparable particle size distribution and good flow properties were obtained with proper adjustment of process parameters for each binder (poloxamer 188, polyethylene glycol 4000, and gliceryl monosterate), procedure (spray-on and melt-in) and equipment (fluid bed and high shear granulator). In-line probes for particle size measurements proved to be a useful tool for determining the end point of melt granulation. The product temperature during melt granulation was found to be the critical process parameter for achieving appropriate granulate particle size distribution. The results showed that melt granulation using hydrophilic binders is an effective method to improve the dissolution rate of carvedilol. The method of binder addition to the powders (melt-in or spray-on procedure) was found to strongly influence the dissolution rate of carvedilol. The highest dissolution rates were obtained when the spray-on procedure is used, independently from the type of granulator used. The results also suggest that the most probable explanation for the increase in the dissolution rate of granulated carvedilol is improvement of the wettability through intimate contact between hydrophilic binder and hydrophobic drug.