Latent structure analysis in the pharmaceutical process of tablets prepared by wet granulation.

BACKGROUND: Granule characteristics are some of the important intermediate qualities that determine tablet properties. However, the relationships between granule and tablet characteristics are poorly understood. The aim of this study was to elucidate relationships among formulation factors, granule characteristics, and tablet properties using a non-linear response surface method (RSM) incorporating a thin-plate spline interpolation (RSM-S) and a Bayesian network (BN). METHOD: Tablets containing lactose (Lac), cornstarch (CS), and microcrystalline cellulose (MCC) were prepared by wet granulation. Ten formulations were prepared by an extreme vertices design. The angle of repose (Y1), compressibility (Y2), cohesion force (Y3), internal friction angle (Y4), and mean particle size (Y5) were measured as granule characteristics. Tensile strength (TS) and disintegration time (DT) were measured as tablet properties. RESULTS: RSM-S results showed that TS increased with increasing amounts of MCC and Lac. DT decreased with increasing amounts of MCC and CS. The optimal BN models were predicted using four evaluation indices -Y3 was shown to be the most important factor for TS, whereas Y2, Y3, and Y4 were relatively important for predicting DT. Moreover, tablets with excellent tablet properties (i.e. high TS and low DT) were produced by relatively high Y1, low Y2, high Y3, high Y4, and middle Y5 values, and resulted from the middle of MCC, middle-to-low CS, low Lac, and middle-to-low magnesium stearate (Mg-St) amounts. CONCLUSION: The RSM-S and BN techniques are useful for revealing complex relationships among formulation factors, granule characteristics, and tablet properties.

Numerical Investigation of the Residual Stress Distribution of Flat-Faced and Convexly Curved Tablets Using the Finite Element Method.

The stress distribution of tablets after compression was simulated using a finite element method, where the powder was defined by the Drucker-Prager cap model. The effect of tablet shape, identified by the surface curvature, on the residual stress distribution was investigated. In flat-faced tablets, weak positive shear stress remained from the top and bottom die walls toward the center of the tablet. In the case of the convexly curved tablet, strong positive shear stress remained on the upper side and in the intermediate part between the die wall and the center of the tablet. In the case of x-axial stress, negative values were observed for all tablets, suggesting that the x-axial force always acts from the die wall toward the center of the tablet. In the flat tablet, negative x-axial stress remained from the upper edge to the center bottom. The x-axial stress distribution differed between the flat and convexly curved tablets. Weak stress remained in the y-axial direction of the flat tablet, whereas an upward force remained at the center of the convexly curved tablet. By employing multiple linear regression analysis, the mechanical properties of the tablets were predicted accurately as functions of their residual stress distribution. However, the multiple linear regression prediction of the dissolution parameters of acetaminophen, used here as a model drug, was limited, suggesting that the dissolution of active ingredients is not a simple process; further investigation is needed to enable accurate predictions of dissolution parameters.