Purpose: Sufficient tablet mechanical strength is a prerequisite for successful tableting and the shelf-life of the finished dosage form. Tablet mechanical strength can be assessed by tensile strength, elastic modulus, and indentation hardness (H). The latter two can be obtained from three-point bending and macroindentation of tablets. The macroindentation H signifies the resistance to the permanent deformation of tablet, which provides a measure of material plasticity. However, the macroindentation H could not be determined for materials that forms weak tablets or when the tablet surface is not smooth, such as for tablets that have punch sticking problem. The goal of this work was to develop an approach to predict the H of such a compound from its binary mixture with a good tablet forming excipient.
Methods: Binary mixture formulations of ten standard model powders included different proportions of tablet excipients (mannitol, lactose and dicalcium phosphate dihydrate), organic acid (succinic acid), and drug (theophylline anhydrate) with microcrystalline cellulose (MCC) were prepared. Tablets were prepared over a 25-300 MPa compression pressure on a compaction simulator (Presster) at 100 ms dwell time and were subsequently indented using a spherical indenter (3.175 mm in diameter, attached to a texture analyzer) for 3 min. The indent force was varied from 12-30 N depending on tablet porosity and mixture. The indent area was determined using a calibrated digital microscope assisted with rubbing contrast enhancing graphite on tablet surface. Nanoindentation was conducted, using a Berkovich tip on the single crystal of selected test compounds, by displacement-controlled method with holding time of 10 sec. The H of the binary mixtures of standard compounds was predicted from the individual components by applying linear, harmonic and power mixture rules. Heckel analysis was used for determining compressibility of the standard and test compounds. Once a suitable mixing rule was identified, test compounds comprised of either sticking sensitive or poor tablet forming compounds, such as acetaminophen, ibuprofen, carbamazepine, acesulfame free acid and potassium salt, piroxicam, griseofulvin, were used to determine their H using the mixture model. The influence of particle size on the predicted H was also assessed on different size fractions of sodium chloride, sucrose and mefenamic acid.
Results: The power mixing rule, using either volume fraction or weight fraction, yielded H of standard model powder that correlated linearly with that experimentally determined (Fig.1). The H values of problematic test compounds, obtained using the power mixing rule, followed an acceptable correlation with H values of single crystals determined using the micro or nanoindentation H (with few outliers). The H showed an inverse correlation with particle size particularly for non-plastic compounds, which is consistent with the expected effect of particle size on material plasticity. The predicted H of the test compounds also overlapped globally with the in-die yield pressure as that observed for the standard compounds, again implying the reasonable accuracy of the prediction method.
Conclusion: The study shows the validity of determining macroindentation H of problematic compounds from their mixtures with MCC. This method may find broad application in characterizing mechanical properties of drugs that do not form tablets for experimental determination of H.