Effects of Manufacturing Conditions on Pharmaceutical Properties of Petrolatum Ointment-Distribution of Hydrocarbon.

Petrolatum ointment, which is an oleaginous ointment, is generally produced through manufacturing processes such as melting, mixing, and cooling. In this type of semisolid formulation, the manufacturing conditions of each process are empirically known to affect the quality of the resultant preparation; however, in many cases, the details of the factors are unclear. To clearly investigate the influence of the pharmaceutical properties of petrolatum ointments, we manufactured several ointments while changing the conditions of the mixing and cooling process after melting white petrolatum. As a result, the temperature at the termination was determined to influence the pharmaceutical properties of the final product. To investigate these phenomena, each petrolatum ointment sample was examined via digital microscopy and laser Raman analysis, and the distribution of the liquid-solid parts of samples was investigated. The internal structure of the ointment sample manufactured at a mixing-stop temperature of 40 °C, the needle crystals and the spherical aggregates surrounding them appropriately coexisted, while the structure exhibited a state wherein the two were linked in a semisolid phase. Meanwhile, for the ointment sample manufactured under the lowest mixing-stop temperature of 25 °C, the liquid part and the spherical aggregates were clearly separated, indicating that the liquid part was easily separated from ointments. In addition, the distribution of the hydrocarbons among the samples was measured via GC-MS; no significant difference in chemical structure was observed. In conclusion, the internal structure of the petrolatum ointment was changed by the manufacturing conditions, and this affected the pharmaceutical properties.

Determination of Density Distribution of Tablets Using Synchrotron X-ray Computed Tomography.

The purpose of this study was to determine the density distribution of scored and round-faced tablets using synchrotron X-ray computed tomography. The tablets were made by direct compression of standard formulations. The density distribution of scored flat-faced tablets was uniform in the whole cross-sectional image. However, the tablet formulated using microcrystalline cellulose (MCC) was very dense at the tip of the score only. It is caused by the poor fluidity of MCC particles. In the case of round-faced tablets, the density in the central section of the tablet was relatively low, compared with those of peripheral areas. These observations correlated well with the results obtained by the finite element method simulation using appropriate material models.

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.

Effect of process variables on the Drucker-Prager cap model and residual stress distribution of tablets estimated by the finite element method.

A multivariate statistical technique was applied to clarify the causal correlation between variables in the manufacturing process and the residual stress distribution of tablets. Theophylline tablets were prepared according to a Box-Behnken design using the wet granulation method. Water amounts (X1), kneading time (X2), lubricant-mixing time (X3), and compression force (X4) were selected as design variables. The Drucker-Prager cap (DPC) model was selected as the method for modeling the mechanical behavior of pharmaceutical powders. Simulation parameters, such as Young's modulus, Poisson rate, internal friction angle, plastic deformation parameters, and initial density of the powder, were measured. Multiple regression analysis demonstrated that the simulation parameters were significantly affected by process variables. The constructed DPC models were fed into the analysis using the finite element method (FEM), and the mechanical behavior of pharmaceutical powders during the tableting process was analyzed using the FEM. The results of this analysis revealed that the residual stress distribution of tablets increased with increasing X4. Moreover, an interaction between X2 and X3 also had an effect on shear and the x-axial residual stress of tablets. Bayesian network analysis revealed causal relationships between the process variables, simulation parameters, residual stress distribution, and pharmaceutical responses of tablets. These results demonstrated the potential of the FEM as a tool to help improve our understanding of the residual stress of tablets and to optimize process variables, which not only affect tablet characteristics, but also are risks of causing tableting problems.