Critical Tools in Tableting Research: Using Compaction Simulator and Quality by Design (QbD) to Evaluate Lubricants' Effect in Direct Compressible Formulation.

As commonly known, the product development stage is quite complex, requires intensive knowledge, and is time-consuming. The selection of the excipients with the proper functionality and their corresponding levels is critical to drug product performance. The objective of this study was to apply quality by design (QbD) principles for formulation development and to define the desired product quality profile (QTPP) and critical quality attributes (CQA) of a product. QbD is a risk- and science-based holistic approach for upgraded pharmaceutical development. In this study, Ibuprofen DC 85W was used as a model drug, Cellactose® 80 along with MicroceLac® 100 as a filler, and magnesium stearate, stearic acid, and sodium stearyl fumarate as lubricants. By applying different formulation parameters to the filler and lubricants, the QbD approach furthers the understanding of the effect of critical formulation and process parameters on CQAs and the contribution to the overall quality of the drug product. An experimental design study was conducted to determine the changes of the obtained outputs of the formulations, which were evaluated using the Modde Pro 12.1 statistical computer program that enables optimization by modeling complex relationships. The results of the optimum formulation revealed that MicroceLac® 100 was the superior filler, while magnesium stearate at 1% was the optimum lubricant. A design space that indicates the safety operation limits for the process and formulation variables was also created. This study enriches the understanding of the effect of excipients in formulation and assists in enhancing formulation design using experimental design and mathematical modeling methods in the frame of the QbD approach.

Elucidating the Variability of Magnesium Stearate and the Correlations With Its Spectroscopic Features.

The objective of this study is to investigate the variability in physiochemical and spectral properties of commercially available vegetable-grade magnesium stearate (MgSt) samples and to assess the correlation between physiochemical properties and near-infrared and Raman spectroscopic features to determine if fast spectral measurements could be used for physical and chemical evaluation. Thirteen MgSt samples of 9 manufacturer grades were obtained from 3 suppliers. The chemical composition was examined using gas chromatography and loss on drying. The physical characteristics were examined on 3 levels: solid state, particle, and bulk level. Comparing the largest to the smallest test values of 13 samples, the variation of the properties ranged from 7% to 335%, with majority of them varying by more than 100% of the smallest value. The samples could be categorized into 4 groups based on solid state properties (1) monohydrate, (2) dihydrate, (3) mixture of monohydrate and dihydrate, and (4) anhydrous form. Scanning electron microscopy images revealed 2 morphological types: thin, flat, and plate-like crystal habit versus irregular crystal habit. The overall variability was mapped using Principal Component Analysis. The greatest variation was due to different manufacturers and perhaps manufacturing methods and starting materials. Based on correlations to physiochemical properties of MgSt, near-infrared and Raman spectra showed potential as a rapid technique for evaluating the differences in excipient properties.

Influence of process parameters on content uniformity of a low dose active pharmaceutical ingredient in a tablet formulation according to GMP.

The article describes the development and production of tablets using direct compression of powder mixtures. The aim was to describe the impact of filler particle size and the time of lubricant addition during mixing on content uniformity according to the Good Manufacturing Practice (GMP) process validation requirements. Processes are regulated by complex directives, forcing the producers to validate, using sophisticated methods, the content uniformity of intermediates as well as final products. Cutting down of production time and material, shortening of analyses, and fast and reliable statistic evaluation of results can reduce the final price without affecting product quality. The manufacturing process of directly compressed tablets containing the low dose active pharmaceutical ingredient (API) warfarin, with content uniformity passing validation criteria, is used as a model example. Statistic methods have proved that the manufacturing process is reproducible. Methods suitable for elucidation of various properties of the final blend, e.g., measurement of electrostatic charge by Faraday pail and evaluation of mutual influences of researched variables by partial least square (PLS) regression, were used. Using these methods, it was proved that the filler with higher particle size increased the content uniformity of both blends and the ensuing tablets. Addition of the lubricant, magnesium stearate, during the blending process improved the content uniformity of blends containing the filler with larger particles. This seems to be caused by reduced sampling error due to the suppression of electrostatic charge.

Validation of an in-line Raman spectroscopic method for continuous active pharmaceutical ingredient quantification during pharmaceutical hot-melt extrusion.

A calibration model for in-line API determination was developed based on Raman spectra collected during hot-melt extrusion. This predictive model was validated by calculating the accuracy profile based on the analysis results of validation experiments. Furthermore, based on the data of the accuracy profile, the measurement uncertainty was determined. Finally, the robustness of the model was evaluated. A Raman probe was implemented in the die of a twin-screw extruder, to monitor the drug concentration during extrusion of physical mixtures containing 15, 20, 25, 30 and 35% (w/w) metoprolol tartrate (MPT) in Eudragit(®) RS PO, an amorphous copolymer of acrylic and methacrylic acid esters with a low content of quaternary ammonium groups, which are present as salts. Several different calibration models for the prediction of the MPT content were developed, based on the use of single spectra or averaged spectra, and using partial least squares (PLS) regression or multivariate curve resolution (MCR). These predictive models were validated by extruding and monitoring mixtures containing 17.5, 22.5, 25.0, 27.5 and 32.5% (w/w) MPT. Each validated concentration was monitored on three different days, by two different operators. The ß-expectation tolerance intervals were calculated for each model and for each of the validated MPT concentration levels (ß was set at 95%), and acceptance limits were set at 10% (relative bias), indicating that at least 95% of future measurements should not deviate more than 10% from the true value. The only model where these acceptance limits were not exceeded was the MCR model based on averaged Raman spectra. The uncertainty measurements for this model showed that the unknown true value can be found at a maximum of ±7.00% around the measured result, with a confidence level of 95%. The robustness of this model was evaluated via an experimental design varying throughput, screw speed and barrel temperature. The robustness designs showed no significant influence of any of the process settings on the predicted concentration values. Raman spectroscopy proved to be a fast, non-destructive and reliable method for the quantification of MPT during hot-melt extrusion. From the accuracy profile of the MCR model based on averaged spectra, it was concluded that for each MPT concentration in the validated concentration range, 95 out 100 future routine measurements will be included within the acceptance limits (10%).

Pitfalls in drying oils identification in art objects by gas chromatography.

Drying oils identification in art objects is an important step in the scientific investigation of the artifact which provides conservators and art historians with valuable information concerning materials used and painting techniques applied. The present communication is devoted to pitfalls and troubleshooting in drying oils identification by means of GC-MS analysis of fatty acids composition in a microsample of an art object. We demonstrate that in the case of nonlinear instrument response the ratios of palmitic to stearic (P/S), distinctive for each oil type and used for drying oil identification, depend on sample dilution so that different dilutions of the same sample can give different P/S ratios. This phenomenon can hinder drying oil identification and lead to erroneous interpretations. This is an important observation as nowadays very often the P/S ratio is calculated from the corresponding peak area ratios or by the use of one-point calibration method. In these approaches, the linearity of the instrument response is not controlled and ensured. In the case analyzed, the nonlinear instrument response was attributed to incomplete sample evaporation in the injector. Packing of the glass liner with deactivated glass wool improved the sample evaporation and ensured the linearity of the instrument response and independence of the P/S ratio from sample dilution.