From microstructures of tablets and granules to their dissolution behaviour

Introduction Dissolution testing is now an established and standardised method for measuring the performance of drug products (1). It allows results for different batches of the same product,similar products from different suppliers, or tests from different labs to be compared. It is, therefore,a useful tool for quality control and for formulation development,so much so that the FDA has made it a regulatory requirement for approval of new drugs. However,being an empirical method, it does have some drawbacks for formulation development. For example,existing empirical data or formula may be of little help for every new formulation,and a new series of tests may have to be performed. For every dissolution test,the sample product must have already been physically made. Both significantly add to the time and cost of taking a new drug to market. A theoretical model,on the other hand,can help to explain experimental observations and to predict the likely outcome of a new formulation at the design stage,thereby reducing the number of physical tests that have to be conducted and the total cost and time of drug development. This article introduces to the dissolution testing community a new computer modelling approach and demonstrates its capability and potential to fulfil the above role through hypothetical yet illustrative examples. It is called DigiPacTM Applications Suite*,based on a patented digital approach. It differs from existing models in two important ways. First, it is a mesoscale digital approach. In comparison, most existing models take a macroscopic vector-based approach. Secondly,and more importantly, it handles with ease real particle shapes,rather than some idealised geometrical models. Being a particle-level,or mesoscale,numerical model, it predicts the influence of particle size and shape distributions on the microstructure of granules and of tablets,and from the microstructure,the dissolution behaviour. The software implementation of the DigiPac approach includes modules for particle packing,flow calculation,and dissolution simulation. For tabletting,DigiPac links fundamental properties of excipient and incipient particles,through the initial packing and ultimately compaction,to the structure of the tablets. For dissolution,the starting point is a digitised microstructure of mixed components. The digital structure is either a simulated one using DigiPac packing module or a real one obtained using X-ray microtomography (XMT). Diffusion-convection equation is solved for each component using a finite difference scheme with the classic NoyesWhitney equation acting as the boundary condition at solid-liquid interfaces. The flow field,which is another input for dissolution simulations, is either calculated using a numerical technique called Lattice Boltzmann Method (LBM) or measured experimentally (e.g., in a dissolution test apparatus). Since DigiPac,XMT,and LBM are integral parts of the dissolution model and each is a relatively new technique (none being commercially available for more than five years), they are briefly described first,before the dissolution model itself is introduced and demonstrated.