A framework for developing optimal tensile strength relationships based on characterization tools with focus on: particle size, lubricant sensitivity, and tablet shape
Creators: name: Modarres Razavi, Sonia
Publisher: name: No Publisher Supplied
Year: 2017

description: This work is a collection of problems all focused on mechanical strength of pharmaceutical tablets. The first problem focuses on relating material strength to the breaking force of non-flat faced tablets. We propose a general framework for determining optimal relationships for tensile strength of doubly convex tablets under diametrical compression. This approach is based on the observation that tensile strength is directly proportional to the breaking force and inversely proportional to a non-linear function of geometric parameters and materials properties. This generalization reduces to the analytical expression commonly used for at faced tablets, i.e., Hertz solution, and to the empirical relationship currently used in the pharmaceutical industry for convex-faced tablets, i.e., Pitt's equation. Under proper parameterization, optimal tensile strength relationship can be determined from experimental results by minimizing a figure of merit of choice.  This optimization is performed under the first-order approximation that a flat faced tablet and a doubly curved tablet have the same tensile strength if they have the same relative density and are made of the same powder, under equivalent manufacturing conditions. Furthermore, we provide a set of recommendations and best practices for assessing the performance of optimal tensile strength relationships in general. Based on these guidelines, we identify two new models, namely the general and mechanistic models, which are effective and predictive alternatives to the tensile strength relationship currently used in the pharmaceutical industry.  The second problem targets the utilization of a non-destructive technique to assess tablet strength. An ultrasound measurement system was employed as a non-destructive method to evaluate its reliability in predicting the tensile strength of tablets and investigate the benefits of incorporating it in a continuous line, manufacturing solid dosage forms. Tablets containing lactose, acetaminophen, and magnesium stearate were manufactured continuously and in batches. The effect of two processing parameters, compaction force and level of shear strain were examined. Elastic modulus and tensile strength of tablets were obtained by ultrasound and diametrical mechanical testing, respectively. It was found that as the blend was exposed to increasing levels of shear strain, the speed of sound in the tablets decreased and the tablets became both softer and mechanically weaker. Moreover, the results indicate that two separate tablet material properties (e.g., relative density and elastic modulus) are necessary in order to predict tensile strength. A strategy for tensile strength prediction is proposed that uses the existing models for elastic modulus and tensile strength of porous materials.  Ultrasound testing was found to be very sensitive in differentiating tablets with similar formulation but produced under different processing conditions (e.g., different level of shear strain), thus, providing a fast and non-destructive method for hardness prediction that could be incorporated to a continuous manufacturing process.  The third problem aims to adopt a Quality by Design paradigm to better control the mechanical strength of tablets as a critical quality attribute by understanding the effects of critical process parameters and critical material attributes. To this end, the effect of particle size distribution, lubricant concentration, and mixing time on the tensile strength and stiffness of tablets were studied. Two grades of lactose, lactose α-monohydrate and spray-dried lactose, were selected. Tablets were compressed to different relative densities ranging from 0.8 to 0.94 using an instrumented compactor simulator, and compaction curves showing the force-displacement profiles during compaction were obtained. The total work input during the compaction process is found to be higher for spray-dried lactose compared to lactose monohydrate. We propose a general model, which predicts the elastic modulus and tensile strength envelope that a specific powder can obtain based on its lubrication sensitivity for different particle size distributions. This was possible by introducing a new parameter in the existing tensile strength and elastic modulus models. A wide range of lubrication conditions was explored and the model exhibited a good predictability. The mechanical properties of lactose monohydrate tablets were noticeably dependent on particle size, unlike spray-dried lactose where little to almost no sensitivity to initial particle size was observed. The model is designed in a general fashion that can capture all the possible mechanical integrity behaviors in response to different lubrication conditions and initial particle size. Our model can be extended to all the powders that undergo different deformation mechanisms and is applicable for more complex pharmaceutical formulations.