Drug Release from Inert Spherical Matrix Systems Using Monte Carlo Simulations.

BACKGROUND: Computational approaches for predicting release properties from matrix devices have recently been purposed as an approach to better understand and predict such systems. The objective of this research is to study the behavior of drug delivery from inert spherical matrix systems of different size by means of computer simulation. METHODS: To simulate the matrix medium, a simple cubic lattice was used, which was sectioned to make a spherical macroscopic system. The sites within the system were randomly occupied by drug-particles or excipient-particles in accordance with chosen drug/excipient ratios. Then, the drug was released from the matrix system simulating a diffusion process. RESULTS: When the released fraction was processed until 90% release, the Weibull equation suitably expressed the release profiles. On the basis of the analysis of release equations, it was found that close to the percolation threshold an anomalous released occurs, while in the systems with an initial drug load greater than 0.45, the released was Fickian type. It was also possible to determine the amount of drug trapped in the matrix, which was found to be a function of the initial drug load. The relationship between the two mentioned variables was adequately described by a model that involves the error function. Based on the these results and by means of a non-linear regression to the previous model, it was possible to determine the drug percolation threshold in these matrix devices. CONCLUSION: It was found that the percolation threshold is consistent with the value predicted by the percolation theory.

Correlation between compactibility values and excipient cluster size using an in silico approach.

BACKGROUND: In silico simulation and percolation theory are important tools in the study of physical and mechanical behavior of pharmaceutical compacts. The aim was to generate a new in silico simulation program that describes the mechanical structure of binary compacts formed from an excipient with excellent compactibility and a drug with null compactibility. MATERIALS AND METHODS: Paracetamol and microcrystalline cellulose powders were compressed under different pressures. Values for the indentation hardness and tensile strength were measured and fitted to the Leuenberger's model. On the other hand, compacts with different composition were in silico simulated. In each system, the biggest excipient cluster was identified and quantified using the Hoshen-Kopelman algorithm. Then, the size of the biggest in silico cluster was correlated with experimental compactibility values. RESULTS AND DISCUSSION: The Leuenberger's model resulted in good fit to the experimental data for all formulations over 40% of excipient load. Formulations with high drug load (≥0.8) had reduced range for forming compacts and gave low compactibility values. The excipient percolation threshold for the simulated system was 0.3395, indicating that over this excipient fraction, a compact with defined mechanical properties will be formed. The compactibility values presented a change in the range of 0.3-0.4 of excipient fraction load, just where the in silico excipient percolation threshold was found. CONCLUSION: Physical measurements of the binary compacts showed good agreement with computational measurements. Subsequently, this in silico approach may be used for the optimization of pharmaceutical powder formulations used in tablet compression.

Parameters affecting drug release from inert matrices. 1: Monte Carlo simulation.

This study investigates the use of Monte Carlo simulation for the determination of release properties from cubic inert matrices. Specifically, the study has focused on factors including porosity, surface area and tortuosity. The release platform was formed by simulating matrices with different ratios of drug and excipient, which undergo drug release in a uni-directional (two-face) or omni-directional (six-face) process. Upon completion of each simulation the matrix 'carcass' was examined and porosity and tortuosity of the medium evaluated. The tortuosity of the medium was evaluated directly by a blind random walk algorithm. These parameters as well as the release profile were then studied with respect to common mathematical models describing drug diffusion (the square-root, power and Weibull models). It was found that, depending on their composition, the matrices systems were either homogeneous or heterogeneous in nature. Furthermore, it was found that the physical parameters could be successfully fitted to the a and b constants of the Weibull model. This approach allows the prediction of drug release from an inert matrix system with the knowledge of a few physical parameters.