The application of Near-Infrared Spatially Resolved Spectroscopy in scope of achieving continuous real-time quality monitoring and control of tablets with challenging dimensions.

In scope of achieving real-time release of tablets, quality attributes need to be monitored and controlled through Process Analytical Technology tools such as near-infrared spectroscopy (NIRS). The authors evaluated the suitability of NIR-Spatially Resolved Spectroscopy (NIR-SRS) for continuous real-time monitoring and control of content uniformity, hardness and homogeneity of tablets with challenging dimensions. A novel user-friendly research and development inspection unit was used as standalone equipment for the analysis of small oblong tablets with deep-cut break lines. A total of 66 tablets varying in hardness and Active Pharmaceutical Ingredient (API) content were inspected, with each tablet being analysed five times and measurements repeated on three different days. Partial Least Squares (PLS) models were developed to assess content uniformity and hardness, of which the former showed higher accuracy. The authors attempted to visualize tablet homogeneity through NIR-SRS spectra by regressing all spectra obtained during a single measurement using a content uniformity PLS model. The NIR-SRS probe demonstrated its potential towards real-time release testing through its ability to quickly monitor content uniformity, hardness and visualize homogeneity, even for tablets with challenging dimensions.

Raw material variability of an active pharmaceutical ingredient and its relevance for processability in secondary continuous pharmaceutical manufacturing.

Active Pharmaceutical Ingredients (API) raw material variability is not always thoroughly considered during pharmaceutical process development, mainly due to low quantities of drug substance available. However, synthesis, crystallization routes and production sites evolve during product development and product life cycle leading to changes in physical material attributes which can potentially affect their processability. Recent literature highlights the need for a global approach to understand the link between material synthesis, material variability, process and product quality. The study described in this article aims at explaining the raw material variability of an API using extensive material characterization on a restricted number of representative batches using multivariate data analysis. It is part of a larger investigation trying to link the API drug substance manufacturing process, the resulting physical API raw material attributes and the drug product continuous manufacturing process. Eight API batches produced using different synthetic routes, crystallization, drying, delumping processes and processing equipment were characterized, extensively. Seventeen properties from seven characterization techniques were retained for further analysis using Principal Component Analysis (PCA). Three principal components (PCs) were sufficient to explain 92.9% of the API raw material variability. The first PC was related to crystal length, agglomerate size and fraction, flowability and electrostatic charging. The second PC was driven by the span of the particle size distribution and the agglomerates strength. The third PC was related to surface energy. Additionally, the PCA allowed to summarize the API batch-to-batch variability in only three PCs which can be used in future drug product development studies to quantitatively evaluate the impact of the API raw material variability upon the drug product process. The approach described in this article could be applied to any other compound which is prone to batch-to-batch variability.

A simple approach for ultrasensitive detection of bisphenols by multiplexed surface-enhanced Raman scattering.

Bisphenol A (BPA) is well known for its use in plastic manufacture and thermal paper production despite its risk of health toxicity as an endocrine disruptor in humans. Since the publication of new legislation regarding the use of BPA, manufacturers have begun to replace BPA with other phenolic molecules such as bisphenol F (BPF) and bisphenol B (BPB), but there are no guarantees regarding the health safety of these compounds at this time. In this context, a very simple, cheap and fast surface-enhanced Raman scattering (SERS) method was developed for the sensitive detection of these molecules in spiked tap water solutions. Silver nanoparticles were used as SERS substrates. An original strategy was employed to circumvent the issue of the affinity of bisphenols for metallic surfaces and the silver nanoparticles surface was functionalized using pyridine in order to improve again the sensitivity of the detection. Semi-quantitative detections were performed in tap water solutions at a concentrations range from 0.25 to 20 µg L(-1) for BPA and BPB and from 5 to 100 µg L(-1) for BPF. Moreover, a feasibility study for performing a multiplex-SERS detection of these molecules was also performed before successfully implementing the developed SERS method on real samples.

Vibrational spectroscopy and microspectroscopy analyzing qualitatively and quantitatively pharmaceutical hot melt extrudates.

Since the last decade, more and more Active Pharmaceutical Ingredient (API) candidates have poor water solubility inducing low bioavailability. These molecules belong to the Biopharmaceutical Classification System (BCS) classes II and IV. Thanks to Hot-Melt Extrusion (HME), it is possible to incorporate these candidates in pharmaceutical solid forms. Indeed, HME increases the solubility and the bioavailability of these drugs by encompassing them in a polymeric carrier and by forming solid dispersions. Moreover, in 2004, the FDA's guidance initiative promoted the usefulness of Process Analytical Technology (PAT) tools when developing a manufacturing process. Indeed, the main objective when developing a new pharmaceutical process is the product quality throughout the production chain. The trend is to follow this parameter in real-time in order to react immediately when there is a bias. Vibrational spectroscopic techniques, NIR and Raman, are useful to analyze processes in-line. Moreover, off-line Raman microspectroscopy is more and more used when developing new pharmaceutical processes or when analyzing optimized ones by combining the advantages of Raman spectroscopy and imaging. It is an interesting tool for homogeneity and spatial distribution studies. This review treats about spectroscopic techniques analyzing a HME process, as well off-line as in-line, presenting their advantages and their complementarities.

Data processing of vibrational chemical imaging for pharmaceutical applications.

Vibrational spectroscopy (MIR, NIR and Raman) based hyperspectral imaging is one of the most powerful tools to analyze pharmaceutical preparation. Indeed, it combines the advantages of vibrational spectroscopy to imaging techniques and allows therefore the visualization of distribution of compounds or crystallization processes. However, these techniques provide a huge amount of data that must be processed to extract the relevant information. This review presents fundamental concepts of hyperspectral imaging, the basic theory of the most used chemometric tools used to pre-process, process and post-process the generated data. The last part of the present paper focuses on pharmaceutical applications of hyperspectral imaging and highlights the data processing approaches to enable the reader making the best choice among the different tools available.

Development of a quantitative approach using surface-enhanced Raman chemical imaging: first step for the determination of an impurity in a pharmaceutical model.

This publication reports, for the first time, the development of a quantitative approach using surface-enhanced Raman chemical imaging (SER-CI). A pharmaceutical model presented as tablets based on paracetamol, which is the most sold drug around the world, was used to develop this approach. 4-Aminophenol is the main impurity of paracetamol and is actively researched in pharmaceutical formulations because of its toxicity. As its concentration is generally very low (<0.1%, w/w), conventional Raman chemical imaging cannot be used. In this context, a SER-CI method was developed to quantify 4-aminophenol assessing a limit of quantification below its limit of specification of 1000 ppm. Citrate-reduced silver nanoparticles were used as SERS substrate and these nanoparticles were functionalized using 1-butanethiol. Different ways to cover the tablets surface by butanethiol-functionalized silver nanoparticles were tested and a homogeneity study of the silver nanoparticles covering was realized. This homogeneity study was performed in order to choose the best way to cover the surface of tablets by silver colloid. Afterwards, the optimization of the SER-CI approach was necessary and different spectral intensity normalizations were tested. Finally, a quantitative approach using SER-CI was developed enabling to quantify 4-aminophenol from 0.025% to 0.2% in paracetamol tablets. This quantitative approach was tested on two different series of tablets using different batches of silver nanoparticles.

Determination of 4-aminophenol in a pharmaceutical formulation using surface enhanced Raman scattering: from development to method validation.

A surface enhanced Raman scattering (SERS) method able to quantify 4-aminophenol in a pharmaceutical formulation based on acetaminophen, also called paracetamol, was developed and, for the first time, successfully validated. In this context, silver nanoparticles were synthesized according to the method described by Lee-Meisel and used as SERS substrate. The repeatability of the silver colloid synthesis was tested using different methods to characterize the size and the zeta potential of silver nanoparticles freshly synthesized. To optimize the SERS samples preparation, a design of experiments implicating concentrations of citrate-reduced silver nanoparticles and aggregating agent was performed in order to maximize the Raman signal enhancement. Finally, an approach based on tolerance intervals and accuracy profiles was applied in order to thoroughly validate the method in a range of concentrations comprised from 3 to 15 µg mL(-1) using normalized band intensities. The standard addition method was selected as method calibration. Therefore, measurements were carried out on 4-aminophenol spiked solutions of the pharmaceutical formulation. Despite the well-known stability and reproducibility problems of SERS, the validation was performed using two operators and five batches of nanoparticles, one for each validation day.

Critical review of near-infrared spectroscopic methods validations in pharmaceutical applications.

Based on the large number of publications reported over the past five years, near-infrared spectroscopy (NIRS) is more and more considered an attractive and promising analytical tool regarding Process Analytical Technology and Green Chemistry. From the reviewed literature, few of these publications present a thoroughly validated NIRS method even if some guidelines have been published by different groups and regulatory authorities. However, as any analytical method, the validation of NIRS method is a mandatory step at the end of the development in order to give enough guarantees that each of the future results during routine use will be close enough to the true value. Besides the introduction of PAT concepts in the revised document of the European Pharmacopoeia (2.2.40) dealing with near-infrared spectroscopy recently published in Pharmeuropa, it agrees very well with this mandatory step. Indeed, the latter suggests to use similar analytical performance characteristics than those required for any analytical procedure based on acceptance criteria consistent with the intended use of the method. In this context, this review gives a comprehensive and critical overview of the methodologies applied to assess the validity of quantitative NIRS methods used in pharmaceutical applications.