Charlotte De Bleye

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.

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 β-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.

From Near-Infrared and Raman to Surface-Enhanced Raman Spectroscopy: Progress, Limitations, 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.

Towards a spray-coating method for the detection of low-dose compounds in pharmaceutical tablets using surface-enhanced Raman chemical imaging (SER-CI)

Surface-enhanced Raman chemical imaging (SER-CI) is a highly sensitive analytical tool recently used in the pharmaceutical field owing to the possibility to obtain high sensitivity along with spatial information. However, the covering method of the pharmaceutical samples such as tablets with metallic nanoparticles is a major issue for SER-CI analyses due to the difficulty to obtain a homogeneous covering of tablet surface with the SERS substrates. In this context, a spray-coating method was proposed in order to fully exploit the potential of SER-CI. A homemade apparatus has been developed from an electrospray ionization (ESI) probe in order to cover the pharmaceutical tablets with the colloidal suspension in a homogeneous way. The silver substrate was pulled through the airbrush by a syringe pump which was then nebulized into small droplets due to the contact of the solution with the gas flow turbulence. A robust optimization of the process was carried out by adjusting experimental parameters such as the liquid flow rate and the spraying time. Besides, the performances of this spraying technique were compared with two others covering methods found in the literature which are drop casting and absorption coating. A homogeneity study, conducted by SER-CI and matrix assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) applied to the different covering techniques was performed. The influence of the metallic nanoparticles deposit on soluble compounds was also investigated in order to highlight the advantages of using this new spray coating approach.