Blend uniformity end-point determination using near-infrared spectroscopy and multivariate calibration.

A multivariate calibration approach using near-infrared (NIR) spectroscopy for determining blend uniformity end-point of a pharmaceutical solid dosage form containing 29.4% (w/w) drug load with three major excipients (crospovidone, lactose, and microcrystalline cellulose) is presented. A set of 21 off-line, static calibration samples were used to develop a multivariate partial least-squares (PLS) calibration model for on-line predictions of the API content during the blending process. The concentrations of the API and the three major excipients were varied randomly to minimize correlations between the components. A micro-electrical-mechanical-system (MEMS) based NIR spectrometer was used for this study. To minimize spectral differences between the static and dynamic measurement modes, the acquired NIR spectra were preprocessed using standard normal variate (SNV) followed by second derivative Savitsky-Golay using 21 points. The performance of the off-line PLS calibration model were evaluated in real-time on 67 production scale (750L bin size) blend experiments conducted over 3 years. The real-time API-NIR (%) predictions of all batches ranged from 93.7% to 104.8% with standard deviation ranging from 0.5% to 1.8%. These results showed the attainment of blend homogeneity and were confirmed with content uniformity by HPLC of respective manufactured tablets values ranging from 95.4% to 101.3% with standard deviation ranging from 0.5% to 2.1%. Furthermore, the performance of the PLS calibration model was evaluated against off-target batches manufactured with high and low amounts of water during the granulation phase of production. This approach affects the particle size and hence blending. All the off-target batches exhibited API-NIR (%) predictions of 94.6% to 103.5% with standard deviation ranging from 0.7% to 1.9%. Using off-target data, a systematic approach was developed to determine blend uniformity end-point. This was confirmed with 3 production scale batches whereby the blend uniformity end-point was determined using the PLS calibration model. Subsequently, the uniformity was also ascertained with conventional thief sampling followed by HPLC analysis and content uniformity by HPLC of the manufactured tablets.

Development of robust quantitative methods by near-infrared spectroscopy for rapid pharmaceutical determination of content uniformity in complex tablet matrix.

Robust NIR transmission spectroscopic methods have been developed for determination of content uniformity (CU) of pharmaceutical products with a complex tablet matrix. The tablets of interest, formulated with eight components with active drug load of approximately 30% (w/w), are non-film coated, embossed, and round with thickness values of 3.6 and 5.6 mm, for the 125 and 500 mg dosage strength, respectively. The calibration data set contained seven laboratory scale batches of tablets with concentration range of active pharmaceutical ingredients (API) varying from 85 to 115% relative to label claim (LC) as well as four full scale production batches of tablets that included the natural physical variability of tablets. The reference concentration values were established by a high performance liquid chromatographic method. Partial least-squares (PLS) regression method was used to generate the calibration models. The root mean squared error of calibration for 125 and 500 mg was 1.6 and 1.5% in LC, respectively. The calibration models were validated in terms of measurement accuracy, repeatability, precision, robustness and transferability. Robustness assessment involved challenging the model with tablets incorporating variations in hardness, excipient vendors, excipient content and excipient particle size. The methods exhibited excellent measurement accuracy based on 87 batches (ten tablets for each batch) evaluated. The transferability of the developed NIR methods was demonstrated by comparing the NIR CU results associated with the same set of tablets scanned at the development site with those scanned at the production site. The result indicates that the NIR method can be used as a suitable alternative to the HPLC method for rapid tablet CU release test in pharmaceuticals.