Continuous production of itraconazole-based solid dispersions by hot melt extrusion: Preformulation, optimization and design space determination.

The purpose of this work was to increase the solubility and the dissolution rate of itraconazole, which was chosen as the model drug, by obtaining an amorphous solid dispersion by hot melt extrusion. Therefore, an initial preformulation study was conducted using differential scanning calorimetry, thermogravimetric analysis and Hansen's solubility parameters in order to find polymers which would have the ability to form amorphous solid dispersions with itraconazole. Afterwards, the four polymers namely Kollidon® VA64, Kollidon® 12PF, Affinisol® HPMC and Soluplus®, that met the set criteria were used in hot melt extrusion along with 25wt.% of itraconazole. Differential scanning confirmed that all four polymers were able to amorphize itraconazole. A stability study was then conducted in order to see which polymer would keep itraconazole amorphous as long as possible. Soluplus® was chosen and, the formulation was fine-tuned by adding some excipients (AcDiSol®, sodium bicarbonate and poloxamer) during the hot melt extrusion process in order to increase the release rate of itraconazole. In parallel, the range limits of the hot melt extrusion process parameters were determined. A design of experiment was performed within the previously defined ranges in order to optimize simultaneously the formulation and the process parameters. The optimal formulation was the one containing 2.5wt.% of AcDiSol® produced at 155°C and 100rpm. When tested with a biphasic dissolution test, more than 80% of itraconazole was released in the organic phase after 8h. Moreover, this formulation showed the desired thermoformability value. From these results, the design space around the optimum was determined. It corresponds to the limits within which the process would give the optimized product. It was observed that a temperature between 155 and 170°C allowed a high flexibility on the screw speed, from about 75 to 130rpm.

From near-infrared and Raman to surface-enhanced Raman spectroscopy: progress, limitations and perspectives in bioanalysis.

Over recent decades, spreading environmental concern entailed the expansion of green chemistry analytical tools. Vibrational spectroscopy, belonging to this class of analytical tool, is particularly interesting taking into account its numerous advantages such as fast data acquisition and no sample preparation. In this context, near-infrared, Raman and mainly surface-enhanced Raman spectroscopy (SERS) have thus gained interest in many fields including bioanalysis. The two former techniques only ensure the analysis of concentrated compounds in simple matrices, whereas the emergence of SERS improved the performances of vibrational spectroscopy to very sensitive and selective analyses. Complex SERS substrates were also developed enabling biomarker measurements, paving the way for SERS immunoassays. Therefore, in this paper, the strengths and weaknesses of these techniques will be highlighted with a focus on recent progress.

Active content determination of pharmaceutical tablets using near infrared spectroscopy as Process Analytical Technology tool.

The aim of this study was to develop Near infrared (NIR) methods to determine the active content of non-coated pharmaceutical tablets manufactured from a proportional tablet formulation. These NIR methods intend to be used for the monitoring of the active content of tablets during the tableting process. Firstly, methods were developed in transmission and reflection modes to quantify the API content of the lowest dosage strength. Secondly, these methods were fully validated for a concentration range of 70-130% of the target active content using the accuracy profile approach based on ß-expectation tolerance intervals. The model using the transmission mode showed a better ability to predict the right active content compared to the reflection one. However, the ability of the reflection mode to quantify the API content in the highest dosage strength was assessed. Furthermore, the NIR method based on the transmission mode was successfully used to monitor at-line the tablet active content during the tableting process, providing better insight of the API content during the process. This improvement of control of the product quality provided by this PAT method is thoroughly compliant with the Quality by Design (QbD) concept. Finally, the transfer of the transmission model from the off-line to an on-line spectrometer was efficiently investigated.

Optimization of a pharmaceutical tablet formulation based on a design space approach and using vibrational spectroscopy as PAT tool.

The aim of the present study was to optimize a tablet formulation using a quality by design approach. The selected methodology was based on the variation of the filler grade, taking into account the particle size distribution (PSD) of active pharmaceutical ingredient (API) in order to improve five critical quality attributes (CQAs). Thus, a mixture design of experiments (DoE) was performed at pilot scale. The blending step was monitored using near infrared (NIR) spectroscopy as process analytical technology tool enabling real-time qualitative process monitoring. Furthermore, some tablets were analyzed by Raman imaging to evaluate the API distribution within the samples. Based on the DoE results, design spaces were computed using a risk-based Bayesian predictive approach to provide for each point of the experimental domain the expected probability to get the five CQAs jointly within the specifications in the future. Finally, the optimal conditions of the identified design space were successfully validated. In conclusion, a design space approach supported by NIR and Raman spectroscopy was able to define a blend that complies with the target product profile with a quantified guarantee or risk.

Thorough characterization of a Self-Emulsifying Drug Delivery System with Raman hyperspectral imaging: a case study.

Newly developed drugs often have poor bioavailability due to their poor water solubility (BCS class 2 drugs). It is therefore necessary to develop new strategies to enhance their solubility and their activity, among which, Self-Emulsifying Drug Delivery System (SEDDS). The efficacy of the drugs contained in these preparations is mainly affected by the solid state and the particle size of the active pharmaceutical ingredient (API). However, it is quite complex, long and expensive to characterize these parameters with classical techniques such as X-ray powder diffraction, differential scanning calorimetry or hot stage microscopy. The present article presents, through a case study, the advantages of the Raman hyperspectral imaging in the characterization of such formulations. Indeed, Raman chemical imaging may fully characterize SEDDS with single equipment and operator in a non-destructive way allowing the follow-up of the formulation during stability studies. Raman imaging is therefore a tool of choice in the PAT framework since it increases the knowledge of the formulation and the process. A quantitative multivariate method using Raman hyperspectral imaging to assay the API in the lipid based formulation has been developed and fully validated following the "total error" approach.

A new criterion to assess distributional homogeneity in hyperspectral images of solid pharmaceutical dosage forms.

During galenic formulation development, homogeneity of distribution is a critical parameter to check since it may influence activity and safety of the drug. Raman hyperspectral imaging is a technique of choice for assessing the distributional homogeneity of compounds of interest. Indeed, the combination of both spectroscopic and spatial information provides a detailed knowledge of chemical composition and component distribution. Actually, most authors assess homogeneity using parameters of the histogram of intensities (e.g. mean, skewness and kurtosis). However, this approach does not take into account spatial information and loses the main advantage of imaging. To overcome this limitation, we propose a new criterion: Distributional Homogeneity Index (DHI). DHI has been tested on simulated maps and formulation development samples. The distribution maps of the samples were obtained without validated calibration model since different formulations were under investigation. The results obtained showed a linear relationship between content uniformity values and DHI values of distribution maps. Therefore, DHI methodology appears to be a suitable tool for the analysis of homogeneity of distribution maps even without calibration during formulation development.