Towards a real-time release of blends and tablets using NIR and Raman spectroscopy at commercial scales.

Near Infrared and Raman spectroscopy-based Process Analytical Technology tools were used for monitoring blend uniformity (BU) and content uniformity (CU) for solid oral formulations. A quantitative Partial Least Square model was developed to monitor BU as real-time release testing at a commercial scale. The model having the R2, and root mean square error of 0.9724 and 2.2047, respectively can predict the target concentration of 100% with a 95% confidence interval of 101.85-102.68% even after one year. The tablets from the same blends were investigated for CU using NIR and Raman techniques both in reflection and transmission mode. Raman reflection technique was found to be the best and the PLS model was developed using tablets compressed at different concentrations, hardness, and speed. The model with R2 and RMSE of 0.9766 and 1.9259, respectively was used for the quantification of CU. Both the BU and CU models were validated for accuracy, precision, specificity, linearity, and robustness. The accuracy was proved against the HPLC method with a relative standard deviation of less than 3%. The equivalency for BU by NIR and CU by Raman was evaluated using Schuirmann's Two One-sided tests and found equivalent to HPLC within a 2% acceptable limit.

Development of Inline Near-Infrared Spectroscopy Method for Real-Time Monitoring of Blend Uniformity of Direct Compression and Granulation-Based Products at Commercial Scales.

Blending is a critical intermediate unit operation for all solid oral formulations. For blend uniformity testing, API content in the blend must be quantified precisely. A detailed study was conducted to demonstrate the suitability of inline NIR (near-infrared) spectroscopy for blend uniformity testing of two solid oral formulations: existing direct compression (DC) product with a multistep blending process and granulation-based product with API granules. Both qualitative and quantitative methods were developed at a laboratory scale using statistical moving block standard deviation (MBSD) and multivariate data analysis such as principal component analysis (PCA) and partial least squares (PLS) regression. The qualitative MBSD method demonstrated that there was no need for multiple steps for the existing DC product. Hence, a simplified single-step process was developed for blending. Quantitative PLS models for blending processes of both the products were developed, validated, and successfully implemented at a commercial scale for the real-time release of blends. Results obtained from the validated model were in good agreement with the current method of sampling and chromatography.

Application of Quality by Design: Development to Manufacturing of Diclofenac Sodium Topical Gel.

The objective of the present study was to develop and optimize generic topical gel formulation of diclofenac sodium through quality by design approaches. The quality target product profile was set for the critical quality attributes of the gel. The key material variables like hydrophilic gelling agent carbopol and penetration enhancer kolliphor were optimized using design of experiments. A central composite design was used considering viscosity and cumulative percent diffusion of the drug after 0.5, 1, 2, 4 and 6 h as responses. The p values for all models generated for different responses were statistically significant (<0.5). Design space was established and verified at the laboratory scale. The predicted and observed values were in close agreement. The robustness of the formula was tested at a higher scale (10X and 200X). The capability index was calculated followed by Monte Carlo simulation and the Cpk values for all the responses were more than 1.33.