Johan Remmelgas

Fundamental Mechanisms for Tablet Dissolution: Simulation of Particle Deaggregation Via Brownian Dynamics

For disintegrating tablet formulations, deaggregation of small particles is sometimes one of the rate-limiting processes for drug release. Because the tablets contain particles that are in the colloidal size range, it may be assumed that the deaggregation process, at least qualitatively, is governed by Brownian motion and electrostatic and van der Waals interactions, where the latter two can be described by a Derjaguin-Landau-Verwey-Overbeek interaction potential. On the basis of this hypothesis, the present work investigates the applicability of Brownian dynamics (BD) simulations as a tool to understand the deaggregation mechanism on a fundamental level. BD simulations are therefore carried out to determine important deaggregation characteristics such as the so-called mean first passage time (MFPT) and first passage time distribution (FPTD) for various two-, three-, and four-particle aggregates. The BD algorithm is first validated and tuned by comparison with analytical expressions for the MFPT and FPTD in the two-particle case. It is then shown that the same algorithm can also be used for the three-particle case. Lastly, the simulations of three- and four-particle aggregates show that the initial shape of the aggregates may significantly affect the deaggregation time.

A mechanistic model for the prediction of in-use moisture uptake by packaged dosage forms

A mechanistic model for the prediction of in-use moisture uptake of solid dosage forms in bottles is developed. The model considers moisture transport into the bottle and moisture uptake by the dosage form both when the bottle is closed and when it is open. Experiments are carried out by placing tablets and desiccant canisters in bottles and monitoring their moisture content. Each bottle is opened once a day to remove one tablet or desiccant canister. Opening the bottle to remove a tablet or canister also causes some exchange of air between the bottle headspace and the environment. In order to ascertain how this air exchange might depend on the customer, tablets and desiccant canisters are removed from the bottles by either carefully removing only one or by pouring all of the tablets or desiccant canisters out of the bottle, removing one, and pouring the remaining ones back into the bottle. The predictions of the model are found to be in good agreement with experimental data for moisture sorption by desiccant canisters. Moreover, it is found experimentally that the manner in which the tablets or desiccant canisters were removed does not appreciably affect their moisture content.

On-off dissociation dynamics of colloidal doublets

First-passage time theory is used to analyze the dissociation behavior of doublets of colloidal particles. The first-passage time distribution for particles interacting via a DLVO potential is determined numerically. For strongly attractive particles the distribution becomes broad such that the mean first-passage time becomes a poor measure of the dynamics. In spite of this, use can be made of the mean in a matching condition, which allows for reproducing distributions for strongly attractive doublets by a semi-analytical solution for particles interacting only through surface adhesion. The smallest eigenvalue in the analytical solution, which governs the long-time asymptotic behavior of the first-passage time distribution, is identified analytically for strongly attractive pairs of particles. In addition, in this limit the distribution is shown to asymptote to an exponential distribution, which means that the dissociation process can be simply captured by an on-off model, without sacrificing the effect of the surface chemistry, with a constant probability for dissociation. This probability is simply related to the surface-adhesive parameter and the separation distance at which the pair of particles ceases to be considered a doublet.

A Qualitative Method for Prediction of Amine Oxidation in Methanol and Water

We have developed a predictive method, based on quantum chemical calculations, that qualitatively predicts N-oxidation by hydrogen peroxides in drug structures. The method uses linear correlations of two complementary approaches to estimate the activation barrier without calculating it explicitly. This method can therefore be automated as it avoids demanding transition state calculations. As such, it may be used by chemists without experience in molecular modeling and provide additional understanding to experimental findings. The predictive method gives relative rates for N,N-dimethylbenzylamine and N-methylmorpholine in good agreement with experiments. In water, the experimental rate constants show that N,N-dimethylbenzylamine is oxidized three times faster than N-methylmorpholine and in methanol it is two times faster. The method suggests it to be two and five times faster, respectively. The method was also used to correlate experimental with predicted activation barriers, linear free-energy relationships, for a test set of tertiary amines. A correlation coefficient R(2) = 0.74 was obtained, where internal diagnostics in the method itself allowed identification of outliers. The method was applied to four drugs: caffeine, azelastine, buspirone, and clomipramine, all possessing several nitrogens. Both overall susceptibility and selectivity of oxidation were predicted, and verified by experiments.

Experimental and Quantum Chemical Evaluations of Pyridine Oxidation Under Drug Development Stress Test Conditions.

The oxidation reaction of pyridine by hydrogen peroxides in water media was investigated by combining quantum chemical calculations and laboratory experiments. Pyridine was selected as a model system for aromatic amines that frequently occurs in drug molecules. Several different reaction conditions, commonly used in stress testing of drug molecules during drug development, were investigated to increase mechanistic insight to this class of oxidation reactions. Of special interest is to note that small amounts of acetonitrile, a regularly used cosolvent to keep poorly soluble drug molecules in water solution, could catalyze the oxidation reaction in the presence of hydrogen peroxide. Consequently, attention needs to be taken when comparing data from different stress test studies of amine oxidation by hydrogen peroxides at different pH, and with and without acetonitrile. In particular, they need to be controlled when identifying the proper intrinsic stability of the drug molecule.

Towards quantitative prediction of the performance of dry powder inhalers by multi-scale simulations and experiments

Graphical abstract Figure. No caption available. ABSTRACT This work demonstrates the use of multi‐scale simulations coupled with experiments to build a quantitative prediction tool for the performance of adhesive mixtures in a dry powder inhaler (DPI). Using discrete element model (DEM), the behaviour of fine‐carrier particle assemblies upon different mechanisms encountered during dose entrainment and dispersion can be described at the individual particle level. Combining these results with computational fluid dynamics (CFD) simulations, the complete dosing event from a DPI can be captured and key performance measures can be extracted. A concept of apparent surface energy, ASE, was introduced to overcome challenges associated with the complex particle properties, e.g. irregular particle shapes and surface roughness. This approach correctly predicts trends observed experimentally regarding API adhesivity, flow rate and device geometry. By incorporating the effects of drug load, critical adhesion and surface energy distributions to the simulation tool, the fine particle fraction could be predicted with good agreement to experiments for two different formulations in two different devices at two flow rates. It is concluded that multi‐scale simulations provide a useful tool to support device and formulation development, as well as to gain further insight into the physical mechanisms governing dispersion from DPIs.