Commercial scale transfer of a twin-screw melt granulation process for high drug load fevipiprant tablets.

OBJECTIVE: This work summarizes select methodology of twin-screw melt granulation (TSMG) and process analytical technology that were used in the successful scaling-up and commercial transfer of high drug load (80.5% w/w) immediate release fevipiprant tablets. SIGNIFICANCE: The unique and compelling learnings from this industry work are (1) insights into Novartis AG's commercial scale transfer using TSMG and (2) rapid, nondestructive NIR methodology as a PAT tool for RTR testing. No prior literature combines these two aspects at the level of detail we present/disclose. METHODS: Scaling up of TSMG was guided by specific energy values obtained for the 27 mm (pilot scale) and 50 mm (commercial scale) twin-screw extruders (TSE). Proven acceptable ranges (PARs) were confirmed by varying the critical process parameters (CPPs) for granulation (screw speed) and tableting (dwell time and crushing strength) at three process levels (upper, target, and lower). An at-line NIR method was developed and validated for real-time release testing (RTRT). RESULTS: The combination of CPPs were selected to have the same effect on critical quality attributes (CQAs), that is, lower (-) and upper (+) process level challenged tablet aspect/appearance and dissolution, respectively. TSMG was performed using a 50 mm extruder at constant feed rate. Compression of the six final blends (∼300 kg) showed no impact of varied granulation and compression process conditions on both CQAs. A near-infrared spectroscopy method was validated to determine content uniformity, assay, identity, and to predict CQAs on uncoated tablets in preparation for a real RTRT of future batches.

An analytical method for lubricant quality control by NIR spectroscopy.

The excellent compatibility of polyol esters (POEs) with general fluids coolants such as CO(2) and non-chlorinated coolants (e.g. hydrofluorocarbons, HFCs) in terms of solubility, miscibility and chemical stability has fostered their use as lubricants by the refrigeration industry. The most widely used POEs bases consist of esters of polyalcohols - such as pentaerythritol, dipentaerythritol and neopentylglycol - with mixtures of carboxylic acids of 4-10 carbon atoms. Their thermophysical properties (viscosity mainly) are crucial with a view to producing efficient lubricants for specific applications. Usually, POE formulations, which usually contain several bases, are characterized in terms of global indices. In this work, we developed a methodology based on NIR spectroscopy for the characterization and analysis of lubricant formulations. The products, including lubricant bases and lubricant formulations, are characterized by reference to two spectral libraries that are used to identify as the starting lubricant bases as well as the lubricant formulations. It has been proposed to build libraries in cascade for the differentiation of lubricant formulations without and with low content in additives. Once the identification of the formulation is applied PLS multivariate models are used to determine the components of a lubricant formulation and its viscosity.

On-line monitoring of a granulation process by NIR spectroscopy.

Near infrared (NIR) spectroscopy has been used in a noninvasively mode to develop qualitative and quantitative methods for the monitoring of a wet granulation process. The formulation contained API (10%w/w) and microcrystalline cellulose and maize starch as main excipients. NIR spectra have been acquired through the glass window of the fluidizer in reflectance mode without causing interference to neither the process nor the formulation. The spectral data has been used to develop a qualitative multivariate model based on principal component analysis (PCA). This qualitative model allows the monitoring of different steps during the granulation process only using the spectral data. Also, a quantitative calibration model based on partial least squares (PLS) methodology has been obtained to predict relevant parameters of the process, such as the moisture content, particle size distribution, and bulk density. The methodology for data acquisition, calibration modeling and method application is relatively low-cost and can be easily performed on most of the pharmaceutical sites. Based on the results, the proposed strategy provides excellent results for the monitoring of granulation processes in the pharmaceutical industry.

Nir-chemical imaging study of acetylsalicylic acid in commercial tablets.

Near Infrared Chemical Imaging (NIR-CI) is demonstrating an increasing interest in pharmaceutical research since it meets the challenging analytical needs of pharmaceutical quality and may serve as a versatile adjunct to conventional NIR spectroscopy in many fields. The direct analysis of samples by using hyperspectral imaging techniques, which provide a NIR spectrum in each pixel of the image, generates a big amount of information from one sample. Focusing the interest in pharmaceutical research, several chemometric algorithms are demonstrating their usefulness extracting the relevant information (i.e. quantitative determination of the component in one sample) in tablets with only one sample and without damaging it. In this work, a quantitative method to analyze different commercial Acetylsalicylic acid tablets is proposed by using Multivariate Curve Resolution-Alternating Least Squares (MCR-ALS) method to the hyperspectral image and without any previous calibration model. For this purpose, a large concentration range of active pharmaceutical ingredient (ASA, Acetylsalicylic acid in this work), between 82% and 12%, was covered depending on the manufacturer. MCR-ALS allowed obtaining a concentration maps for acetylsalicylic acid and therefore, consequent analysis of the ASA distribution in the tablet was developed by using the histograms of the distribution of concentration. Results certified the good distribution of ASA despite the different origins of the tablets. Moreover, the obtained values of concentration showed a very good concordance with the nominal value of ASA. As a matter of fact, the quality of the results demonstrated the useful of encompassing NIR-CI techniques with MCR-ALS and, consequently, the well development on the production of Acetylsalicylic acid tablets.