Jan Westergren

In silico predictions of gastrointestinal drug absorption in pharmaceutical product development : Application of the mechanistic absorption model GI-Sim

Oral drug delivery is the predominant administration route for a major part of the pharmaceutical products used worldwide. Further understanding and improvement of gastrointestinal drug absorption predictions is currently a highly prioritized area of research within the pharmaceutical industry. The fraction absorbed (fabs) of an oral dose after administration of a solid dosage form is a key parameter in the estimation of the in vivo performance of an orally administrated drug formulation. This study discloses an evaluation of the predictive performance of the mechanistic physiologically based absorption model GI-Sim. GI-Sim deploys a compartmental gastrointestinal absorption and transit model as well as algorithms describing permeability, dissolution rate, salt effects, partitioning into micelles, particle and micelle drifting in the aqueous boundary layer, particle growth and amorphous or crystalline precipitation. Twelve APIs with reported or expected absorption limitations in humans, due to permeability, dissolution and/or solubility, were investigated. Predictions of the intestinal absorption for different doses and formulations were performed based on physicochemical and biopharmaceutical properties, such as solubility in buffer and simulated intestinal fluid, molecular weight, pK(a), diffusivity and molecule density, measured or estimated human effective permeability and particle size distribution. The performance of GI-Sim was evaluated by comparing predicted plasma concentration-time profiles along with oral pharmacokinetic parameters originating from clinical studies in healthy individuals. The capability of GI-Sim to correctly predict impact of dose and particle size as well as the in vivo performance of nanoformulations was also investigated. The overall predictive performance of GI-Sim was good as >95% of the predicted pharmacokinetic parameters (C(max) and AUC) were within a 2-fold deviation from the clinical observations and the predicted plasma AUC was within one standard deviation of the observed mean plasma AUC in 74% of the simulations. GI-Sim was also able to correctly capture the trends in dose- and particle size dependent absorption for the study drugs with solubility and dissolution limited absorption, respectively. In addition, GI-Sim was also shown to be able to predict the increase in absorption and plasma exposure achieved with nanoformulations. Based on the results, the performance of GI-Sim was shown to be suitable for early risk assessment as well as to guide decision making in pharmaceutical formulation development.

Noble gas temperature control of metal clusters: A molecular dynamics study

We use classical molecular dynamics simulations to investigate temperature control of unsupported clusters using a noble gas atmosphere. The simulations are performed using a many-body interaction scheme for the intra-cluster potential, while a pairwise Lennard-Jones potential is used to model the interaction between the noble gas and the clusters. In order to isolate different parameters determining the energy exchange efficiency, we have studied the energy transfer with respect to (i) impact parameter, (ii) cluster temperature, (iii) noble gas temperature, (iv) gas–metal interaction strength, (v) metal potential, and (vi) noble gas mass. With these results, we are able to estimate the number of collisions needed to equilibrate a cluster at a given gas temperature. Our estimates are confirmed by simulations of cluster cooling in a noble gas atmosphere.

Statistical theory of cluster cooling in rare gas. I. Energy transfer analysis for palladium clusters in helium

The cooling and heating of palladium clusters Pd13 and Pd55 by binary collisions with atoms of a surrounding helium gas are studied by means of molecular dynamics simulation. The efficiency of the collisional energy transfer is determined as a function of cluster and gas temperature and of cluster phase, the cluster being in either a solid or a liquid phase. A simple statistical analysis is presented for the energy transfer between a cluster and a rare gas atom. The analysis is based on an ergodic collision assumption of microcanonical relaxation in each collision. The deviation from this limiting law is collected in a collision efficiency factor which reflects incomplete energy redistribution during the lifetime of the collision complex. The thermal energy and change in heat capacity observed for the clusters at the freezing (melting) transition is accounted for by a parametrized density of states reflecting separate contributions from a solid and a molten structure. The same density of states is then us...

In silico prediction of drug solubility: 4. Will simple potentials suffice?

In view of the extreme importance of reliable computational prediction of aqueous drug solubility, we have established a Monte Carlo simulation procedure which appears, in principle, to yield reliable solubilities even for complex drug molecules. A theory based on judicious application of linear response and mean field approximations has been found to reproduce the computationally demanding free energy determinations by simulation while at the same time offering mechanistic insight. The focus here is on the suitability of the model of both drug and solvent, i.e., the force fields. The optimized potentials for liquid simulations all atom (OPLS‐AA) force field, either intact or combined with partial charges determined either by semiempirical AM1/CM1A calculations or taken from the condensed‐phase optimized molecular potentials for atomistic simulation studies (COMPASS) force field has been used. The results illustrate the crucial role of the force field in determining drug solubilities. The errors in interaction energies obtained by the simple force fields tested here are still found to be too large for our purpose but if a component of this error is systematic and readily removed by empirical adjustment the results are significantly improved. In fact, consistent use of the OPLS‐AA Lennard‐Jones force field parameters with partial charges from the COMPASS force field will in this way produce good predictions of amorphous drug solubility within 1 day on a standard desktop PC. This is shown here by the results of extensive new simulations for a total of 47 drug molecules which were also improved by increasing the water box in the hydration simulations from 500 to 2000 water molecules.

Melting of palladium clusters—Canonical and microcanonical Monte Carlo simulation

We present Monte Carlo simulations of single palladium clusters of 13, 34, 54, 55, 147 and 309 atoms. The clusters are modeled by a many-body potential and they have been simulated at constant temperature or constant total energy. The caloric curves of the clusters, with the exception of Pd34, exhibit an S-bend at melting which is typical for a finite system. We have also observed the typical coexistence region of solid and molten clusters both in the canonical and the microcanonical ensembles. Pd34, in contrast, melts without an accompanying peak in heat capacity and at melting the atoms become mobile without any significant change in geometric structure. For the larger clusters a free energy barrier inhibits phase switching. In some cases of phase change from molten to solid structure the barrier is of purely entropic character. By a conversion of the results in the microcanonical simulations into temperature-dependent data, the simulations at fixed temperature and fixed total energy have been compared. The agreement is in most cases good. The results are furthermore compared to earlier molecular dynamics simulations with the Nose–Hoover thermostat. These results are in good agreement with the Monte Carlo simulations as well.

In vivo mechanisms of intestinal drug absorption from aprepitant nanoformulations

Over recent decades there has been an increase in the proportion of BCS class II and IV drug candidates in industrial drug development. To overcome the biopharmaceutical challenges associated with the less favorable properties of solubility and/or intestinal permeation of these substances, the development of formulations containing nanosuspensions of the drugs has been suggested. The intestinal absorption of aprepitant from two nanosuspensions (20 μM and 200 μM total concentrations) in phosphate buffer, one nanosuspension (200 μM) in fasted-state simulated intestinal fluid (FaSSIF), and one solution (20 μM) in FaSSIF was investigated in the rat single-pass intestinal perfusion model. The disappearance flux from the lumen (Jdisapp) was faster for formulations containing a total concentration of aprepitant of 200 μM than for those containing 20 μM, but was unaffected by the presence of vesicles. The flux into the systemic circulation (Japp) and, subsequently, the effective diffusion constant (Deff) were calculated using the plasma concentrations. Japp was, like Jdisapp, faster for the formulations containing higher total concentrations of aprepitant, but was also faster for those containing vesicles (ratios of 2 and 1.5). This suggests that aprepitant is retained in the lumen when presented as nanoparticles in the absence of vesicles. In conclusion, increased numbers of nanoparticles and the presence of vesicles increased the rate of transport and availability of aprepitant in plasma. This effect can be attributed to an increased rate of mass transport through the aqueous boundary layer (ABL) adjacent to the gut wall.

Molecular dynamics simulation of metal cluster cooling and heating in noble gas atmosphere

Abstract Metal cluster properties such as ionisation potential and reactivity strongly depend on the temperature of the cluster. Using molecular dynamics simulation we have investigated how much energy is transferred from noble gas atoms to unsupported Pd,3 clusters in collisions. Furthermore we propose a two-term density of states for Pd13 which leads to excellent prediction of the caloric equation of state obtained in simulations. Knowing the heat capacity of the cluster, the energy transfer can be converted into change of cluster temperature per collision at constant gas temperature and the cooling and heating of the cluster can be predicted. The predictions were in good agreement with cooling and heating simulations. Approximately 2000 collisions are required to cool Pd13 from 1500 K to 100 K in a helium gas at 100 K.

Melting of palladium clusters: density of states determination by Monte Carlo simulation

Abstract The density of states (DOS) has been calculated for the metal clusters Pd 13 , Pd 55 and Pd 147 using the recently proposed reference system equilibration (RSE) method. The interaction within the clusters was described by a many-body alloy potential. Using this DOS, the caloric curve of Pd 13 has been calculated and excellent agreement with canonical Monte Carlo simulations is obtained. For Pd 55 and Pd 147 , the solid and one molten isomers have been isolated in order to calculate the DOS for the isomers separately. The melting of the clusters occurs when the DOS for the solid and the molten isomers are equal. Comparison with previous microcanonical Monte Carlo simulations shows that the number of statistically equivalent molten isomers are 1.1×10 18 for Pd 55 and 4.1×10 41 for Pd 147 .

Statistical theory of cluster cooling in rare gas

The collisional energy transfer between a palladium cluster and a rarified inert gas medium has been studied by molecular dynamics simulation and interpreted by statistical theory. The cluster is Pd13 and the inert gas may be composed of helium, neon, argon or krypton. The cluster–inert gas collision cross section and the average energy transferred per collision are determined by following the collisions by classical trajectory calculations. Special attention is placed on the development of rigorous sampling techniques such that the average energy transfer vanishes when cluster and gas are at the same initial temperature. The dependence of the energy transfer on impact parameter is found to display an inner region of prevalent excitation and an outer region of prevalent deexcitation of the cluster. The energy transfer efficiencies observed fall a factor of between 0.05 and 0.4 below the ergodic collision limit with the heaviest gas atoms most efficient. The PEMET model explains the observed efficiencies in terms of an increased number of atom–atom encounters with increasing strength of attraction between atom and cluster and with lower temperature.

On the Role of Density Fluctuations in the Equation of State of a Simple Fluid

Abstract We address the wellknown problems intorduced into the theory of fluids by density fluctuations in the form of van der Waals loops and nonclassical critical phenomena. A clean separation of long and short range density fluctuations is achieved by use of cell-constrained models which display well-defined van der Waals loops and classical behaviour around the critical point. For a pure Lennard-Jones fluid with occupancy restricted to 1 or 8 particles per cell, the phase diagram is determined by Monte Carlo simulation. By considering the deviations from the normal simulations without cell constraint, the effects of longer range density fluctuations are exposed. The system size dependence of the van der Waals loops present in all simulations of fluids is analyzed in terms of the GvdW free energy density functional theory, which is formuiated on the basis of the cell concept. The loops are found to gradually disappear either with greater cel occupancy or increasing total particle number in the simulation box.