Towards better process understanding: chemometrics and multivariate measurements in manufacturing of solid dosage forms.

The manufacturing of tablets involves many unit operations that possess multivariate and complex characteristics. The interactions between the material characteristics and process related variation are presently not comprehensively analyzed due to univariate detection methods. As a consequence, current best practice to control a typical process is to not allow process-related factors to vary i.e. lock the production parameters. The problem related to the lack of sufficient process understanding is still there: the variation within process and material properties is an intrinsic feature and cannot be compensated for with constant process parameters. Instead, a more comprehensive approach based on the use of multivariate tools for investigating processes should be applied. In the pharmaceutical field these methods are referred to as Process Analytical Technology (PAT) tools that aim to achieve a thorough understanding and control over the production process. PAT includes the frames for measurement as well as data analyzes and controlling for in-depth understanding, leading to more consistent and safer drug products with less batch rejections. In the optimal situation, by applying these techniques, destructive end-product testing could be avoided. In this paper the most prominent multivariate data analysis measuring tools within tablet manufacturing and basic research on operations are reviewed.

In-line monitoring of the drug content of powder mixtures and tablets by near-infrared spectroscopy during the continuous direct compression tableting process.

Continuous manufacturing methods offer economic and quality advantages when compared with batch manufacturing methods. In continuous manufacturing, one requires real time assurance of quality of product via the implementation of PAT tools. This study focuses on an in-line near-infrared (NIR) spectroscopic method for determining the drug content of powder mixtures and tablets during a continuous tableting process. Tablets consisting of acetaminophen (20-30%), lactose (69.07-78.93%) and magnesium stearate (0.93-1.07%) were prepared in a continuous direct compression line that consisted of two loss-in-weight feeders, one for acetaminophen and one for premixed lactose and magnesium stearate, and a continuous mixer followed by a rotary tablet press. NIR spectroscopy was applied to the continuous mixer and tablet press to perform a 100% product check at full tableting speed. The UV-spectrophotometric method was used as an off-line reference method to determine the acetaminophen content in the samples. The powder mixture and tablet samples were taken during the process for the calibration of continuous mixer and tablet press, respectively. For the continuous mixer, model creation with the PLS method yielded R-Square and RMSEC (root mean square error of calibration) values of 0.975% and 0.56%, respectively. For the tablet press, the corresponding R-Square and RMSEC values were 0.943% and 0.75%, respectively. A test run demonstrated good predictability in the estimation of the API content in the powder mixtures and tablets during the continuous tableting process. For the continuous mixer and tablet press, the RMSEP (root mean square error of prediction) values were 0.96% and 1.37%, respectively. This study demonstrates that an NIR instrument capable of fast spectra acquisition can be a valuable tool for the in-line monitoring of the continuous mixing and tableting processes.

X-ray microtomography analysis of intragranular drug migration during fluidized bed and oven tray drying.

During the drying process of a wet granulate, water-soluble compounds can migrate to the outer layers of the granule with the evaporating solvent. This migration can affect structural and mechanical characteristics of the granules as the solute accumulates on the granule's outer crust. The objective of this study was to compare the effect of the fluidized bed and oven tray at different drying temperatures on the characteristics of intragranular migration. The extent of migration and the migration effect on granule structure and granule strength were investigated using light microscopy and computerized X-ray microtomography, in both qualitative and quantitative terms. In addition, a mechanical tester was used to assess granule strength and granule failure type. Multivariate analysis of variance with a follow-up discriminant analysis was conducted to investigate the effect of the drying method and the drying temperature on the granule structure. There were significant differences in the intragranular distribution of water-soluble compound as well as in the granule structures and mechanical properties between the drying methods, where drying temperature had only a marginal effect.

Evolution of granule structure and drug content during fluidized bed granulation by X-ray microtomography and confocal Raman spectroscopy.

The distribution of the drug in the granular end product is a critical quality attribute in fluidized bed spray granulation of pharmaceuticals. The evolution of drug content inhomogeneity in a case study was examined as a function of granulation time. Intragranular structure was also investigated using confocal Raman spectroscopy and computerized X-ray microtomography. A principal component analysis was conducted on the results to investigate granule structure-drug content relationships. Inhomogeneity increased at the beginning of the process but later it was found to decrease. Changes in the homogeneity were accompanied by significant changes in the intragranular structure. It was concluded that segregation of the primary components explained the observed inhomogeneity at low saturation levels when the granules grow by layering, but at elevated moisture levels, granule growth is mediated by the coalescence of agglomerates, which promotes homogeneous distribution of the drug particles.

2(S)-(Cycloalk-1-enecarbonyl)-1-(4-phenyl-butanoyl)pyrrolidines and 2(S)-(aroyl)-1-(4-phenylbutanoyl)pyrrolidines as prolyl oligopeptidase inhibitors.

In order to replace the P2-P1 amide group, different 1-cycloalkenyls and 2-aryls were studied in the place of the P1 pyrrolidine group of a 4-phenylbutanoyl-L-Pro-pyrrolidine structure, which is a well-known prolyl oligopeptidase inhibitor SUAM-1221. The 1-cyclopentenyl and the 2-thienyl groups gave novel compounds, which were equipotent with the corresponding pyrrolidine-analog SUAM-1221. It was shown that the P2-P1 amide group of POP inhibitors can be replaced by an alpha,beta-unsaturated carbonyl group or the aryl conjugated carbonyl group.