Phillip Choi

Application of Molecular Dynamics Simulation To Predict the Compatability between Water-Insoluble Drugs and Self-Associating Poly(ethylene oxide)-b-poly(ε-caprolactone) Block Copolymers

In the present work, molecular dynamics (MD) simulation was applied to study the solubility of two water-insoluble drugs, fenofibrate and nimodipine, in a series of micelle-forming PEO-b-PCL block copolymers with combinations of blocks having different molecular weights. The solubility predictions based on the MD results were then compared with those obtained from solubility experiments and by the commonly used group contribution method (GCM). The results showed that Flory-Huggins interaction parameters computed by the MD simulations are consistent with the solubility data of the drug/PEO-b-PCL systems, whereas those calculated by the GCM significantly deviate from the experimental observation. We have also accounted for the possibility of drug solubilization in the PEO block of PEO-b-PCL.

A molecular dynamics study of the effects of branching characteristics of LDPE on its miscibility with HDPE

Abstract The effects of branching characteristics of low-density polyethylene (LDPE) on its melt miscibility with high-density polyethylene (HDPE) were studied using molecular simulation. In particular, molecular dynamics (MD) was applied to compute Hildebrand solubility parameters ( δ ) of models of HDPE and LDPE with different branch contents at five temperatures that are well above their melting temperatures. Values computed for δ agreed very well with experiment. The Flory–Huggins interaction parameters ( χ ) for blends of HDPE and different LDPE models were then calculated using the computed δ values. The level of branch content for LDPE above which the blends are immiscible and segregate in the melt was found to be around 30 branches/1000 long chain carbons at the chosen simulation temperatures. This value is significantly lower than that of butene-based linear low-density polyethylene (LLDPE) (40 branches/1000 carbons) in the blends with HDPE computed by one of the authors (polymer 2000; 41:8741). The major difference between LDPE and LLDPE models is that each modeled LDPE molecule has three long chains while each modeled LLDPE molecule had only one long chain. The present results together with those of the LLDPE/HDPE blends suggest that the long chain branching may have significant influence on the miscibility of polyethylene blends at elevated temperatures.

Self-Associating Poly(ethylene oxide)-b-poly(α-cholesteryl carboxylate-ε-caprolactone) Block Copolymer for the Solubilization of STAT-3 Inhibitor Cucurbitacin I

An increase in the degree of chemical compatibility between drug and polymeric structure in the core has been shown to raise the encapsulation efficiency and lower the rate of drug release from polymeric micelles. In this study, to achieve an optimized polymeric micellar delivery system for the solubilization and controlled delivery of cucurbitacin I (CuI), the Flory-Huggins interaction parameter (chi(sc)) between CuI and poly(epsilon-caprolactone) (PCL), poly(alpha-benzylcarboxylate-epsilon-caprolactone) (PBCL) and poly(alpha-cholesteryl carboxylate-epsilon-caprolactone) (PChCL) structures was calculated by group contribution method (GCM) as an indication for the degree of chemical compatibility between different micellar core structures and CuI. The results pointed to a better compatibility between CuI and PChCL core rationalizing the synthesis of self-associating methoxy poly(ethylene oxide)-b-poly(alpha-cholesteryl carboxylate-epsilon-caprolactone) block copolymer (MePEO-b-PChCL). Novel block copolymer of MePEO-b-PChCL was synthesized through, first, preparation of substituted monomer, that is, alpha-cholesteryl carboxylate-epsilon-caprolactone, and further ring opening polymerization of this monomer by methoxy PEO (5000 g mol(-1)) using stannous octoate as catalyst. Synthesized block copolymers were characterized for their molecular weight and polydispersity by (1)H NMR and gel permeation chromatography. Self-assembled MePEO-b-PChCL micelles were characterized for their size, morphology, critical micellar concentration (CMC), capacity for the physical encapsulation of CuI, and mode of CuI release in comparison to MePEO-b-PCL and MePEO-b-PBCL micelles. Overall, the experimental order for the level of CuI encapsulation in different polymeric micellar formulations was consistent with what was predicted by the Flory-Huggins interaction parameter. Although MePEO-b-PChCL micelles exhibited the highest level of CuI loading, this structure did not show any significant superiority over MePEO-b-PCL in controlling CuI release. The most efficient control over the rate of CuI release was achieved by MePEO-b-PBCL micelles that had more viscous cores than that of MePEO-b-PChCL, instead. The results point to a potential for MePEO-b-PChCL micelles for the solubilization of cholesterol compatible drugs. It also highlights the inadequacy of the Flory-Huggins interaction parameter calculated by GCM in predicting the order of drug release from different polymeric micellar structures.

Molecular dynamics studies of the thermodynamics of HDPE/butene-based LLDPE blends

Abstract Hildebrand solubility parameters (δ) at elevated temperatures were computed for models of high-density polyethylene (HDPE) and a series of butene-based linear low-density polyethylene (b-LLDPE) with different branch contents using molecular dynamics simulation. And the δ values were then used to calculate the corresponding Flory–Huggins interaction parameter (χ) between HDPE and various b-LLDPE models. The results indicate that the level of branch content of b-LLDPE that is required to phase separate the blends in the liquid state is about 40 branches/1000 backbone carbons, regardless of temperature. This is consistent with the recent small angle neutron scattering (SANS) findings of Alamo et al. [Macromolecules 1997;30:561–566].

Determination of solvent-independent polymer-polymer interaction parameter by an improved inverse gas chromatographic approach

Abstract The solvent-dependence problem generally observed in the determination of polymer–polymer interaction parameters from inverse gas chromatography (IGC) measurements has been examined and resolved. The problem is mainly attributed to the use of different reference volumes in the calculations of χ12, χ13, and χ1(23) from the raw IGC data for different solvents. Upon selection of a common reference volume for all the solvents used, IGC data were found to be well described by the ternary version of the Flory–Huggins lattice theory; unique solvent-independent χ23 values were obtained. Our data on blends of high-density polyethylene (HDPE) and low-density polyethylene (LDPE) have also confirmed the validity of the zero Δχ criterion suggested by Su and Patterson twenty odd years ago (Macromolecules, 10 (1977) 708) so long as a common reference volume is used in the data analysis. If the latter criterion is not satisfied, measured χ23 values still vary with the solvent used. However, it is uncertain whether the present approach can be applied to the situation in which the solvents used do not meet the zero Δχ criterion. The χ23 values obtained in the present work suggest that HDPE/LDPE blends may exhibit a closed-loop phase behavior.

Molecular dynamics study of the encapsulation capability of a PCL–PEO based block copolymer for hydrophobic drugs with different spatial distributions of hydrogen bond donors and acceptors

Molecular dynamics simulation was used to study the potential of using a block copolymer containing three poly(epsilon-caprolactone) (PCL) blocks of equal length connected to one end of a poly(ethylene oxide) (PEO) block, designated as PEO-b-3PCL, to encapsulate two classes of hydrophobic drugs with distinctively different molecular structures. In particular, the first class of drugs consisted of two cucurbitacin drugs (CuB and CuI) that contain multiple hydrogen bond donors and acceptors evenly distributed on their molecules while the other class of drugs (fenofibrate and nimodipine) contain essentially only clustered hydrogen bond acceptors. In the case of cucurbitacin drugs, the results showed that PEO-b-3PCL lowered the Flory-Huggins interaction parameters (chi) considerably (i.e., increased the drug solubility) compared to the linear di-block copolymer PEO-b-PCL with the same PCL/PEO (w/w) ratio of 1.0. However, the opposite effect was observed for fenofibrate and nimodipine. Analysis of the intermolecular interactions indicates that the number of hydrogen bonds formed between the three PCL blocks and cucurbitacin drugs is significantly higher than that of the linear di-block copolymer. On the other hand, owing to the absence of hydrogen bond donors and the clustering of the hydrogen bond acceptors on the fenofibrate and nimodipine molecules, this significantly reduces the number of hydrogen bonds formed in the multi-PCL block environment, leading to unfavourable chi values. The findings of the present work suggest that multi-hydrophobic block architecture could potentially increase the drug loading for hydrophobic drugs with structures containing evenly distributed multiple hydrogen bond donors and acceptors.

Roles of Nonpolar and Polar Intermolecular Interactions in the Improvement of the Drug Loading Capacity of PEO-b-PCL with Increasing PCL Content for Two Hydrophobic Cucurbitacin Drugs

Molecular dynamics (MD) simulation was used to study the roles of nonpolar and polar intermolecular interactions in the improvement of the drug loading capacity of poly(ethylene oxide)-b-poly(epsilon-caprolactone) (PEO-b-PCL) with increasing PCL content for two water insoluble anticancer drugs: Cucurbitacin B (CuB) and Cucurbitacin I (CuI). In particular, random binary mixture models containing 10-12 wt % drug and remaining PEO-b-PCL with three different PCL/PEO (w/w) ratios (0.5, 1, and 2) were used to calculate their Flory-Huggins interaction parameters (chi). The MD simulation results show that, for both CuB and CuI, the computed chi decreases (i.e., affinity increases) with increasing PCL/PEO ratio. Such results are consistent with our experimental observation that increasing the PCL/PEO (w/w) ratio from 1 to 4.8 significantly increases the drug loading capacity of micelles formed by PEO-b-PCL for both drugs. Analysis of the energy data shows that increasing affinity (loading) at higher PCL/PEO ratio is attributed to the increase in favorable polar interactions and to the formation of additional hydrogen bonds (H-bonds) between the drugs and the PCL block rather than to the increase in the hydrophobic characteristics of the diblock copolymer as one would normally expect. In fact, the nonpolar intermolecular interactions became more unfavorable at higher PCL/PEO ratio. Analysis of the radial distribution functions of the model mixtures indicates that at high PCL/PEO ratio, multiple H-bond sites on the PCL block interacted with single H-bond sites on the drug molecules. However, at low PCL/PEO ratio, only single H-bonds formed between various H-bond sites on the drug molecules and those of the PCL and PEO blocks. It seems that formation of H-bonds between multiple H-bond sites on the PCL block and single H-bond sites on the drug molecules is responsible for inducing drug/PEO-b-PCL affinity. The finding also explains the experimental observation that release rates of both drugs decrease with increasing PCL/PEO ratio and that the decrease in the release rate of CuB is more pronounced than that of CuI. Our simulation results show that the number of H-bonds formed between CuB and the PCL block is much higher than that of CuI at high PCL/PEO ratio.

Molecular dynamics simulation of a pressure-driven liquid transport process in a cylindrical nanopore using two self-adjusting plates

Fluid transport through a nanopore in a membrane was investigated by using a novel molecular dynamics approach proposed in this study. The advantages of this method, relative to dual-control-volume grand-canonical molecular dynamics method, are that it eliminates disruptions to the system dynamics that are normally created by inserting or deleting particles from control volumes, and that it functions well for dense systems due to the number of particles being fixed in the system. Using the proposed method, we examined liquid argon transport through a nanopore by performing nonequilibrium molecular dynamics (NEMD) simulations under different back pressures. Validation of the code was performed by comparing simulation results to published experimental data obtained under equilibrium conditions. NEMD results show that constant pressure difference across the membrane was readily achieved.

Prediction of the solubility of cucurbitacin drugs in self-associating poly(ethylene oxide)-b-poly(α-benzyl carboxylate ɛ-caprolactone) block copolymer with different tacticities using molecular dynamics simulation

Molecular dynamics (MD) simulation was used to investigate the solubility of two hydrophobic drugs Cucurbitacin B (CuB) and Cucurbitacin I (CuI) in poly(ethylene oxide)-b-poly(alpha-benzyl carboxylate epsilon-caprolactone) (PEO-b-PBCL) block copolymers with different tacticities. In particular, di-block copolymer with three different tacticities viz. PEO-b-iPBCL, PEO-b-sPBCL, and PEO-b-aPBCL were used. The solubility was quantified by calculating the corresponding Flory-Huggins interaction parameters (chi) using random binary mixture models with 10wt% of drug. The tacticity of the di-block copolymer was found to influence significantly the solubility of two drugs in it. In particular, based on MD simulation results, only PEO-b-sPBCL exhibited solubility while the other two did not. Given the fact that the drugs were shown to be soluble in PEO-b-PBCL experimentally, it is predicted that the tacticity of the di-block copolymer synthesized in experiment is syndiotactic. This predication matches well with the dominant ring opening polymerization of cyclic lactones to syndiotactic polymers by stannous octoate as catalyst used to prepare PEO-b-PBCL block copolymers in our previous experiments. The simulation results showed that the solubility of the drugs in PEO-b-sPBCL is attributed to the favorable intra-molecular interaction of the di-block copolymer and favorable intermolecular interaction between the di-block copolymer and the drugs. Radial distribution function analysis provides useful insights into the nature and type of the intermolecular interactions.

Comparative study between continuum and atomistic approaches of liquid flow through a finite length cylindrical nanopore

Steady state pressure driven flow of liquid argon through a finite length cylindrical nanopore was investigated numerically by classical Navier-Stokes (NS) hydrodynamic models and nonequilibrium molecular dynamics (MD) simulations. In both approaches, the nanopore was nominally 2.2 nm in diameter and 6 nm long. For the MD simulations, the intermolecular properties of the walls were specified independently from the liquid. Comparisons between the approaches were made in terms of the gross feature of total flow rate through the nanopore, as well as the more refined considerations of the spatial distributions of pressure, density, and velocity. The results showed that for the NS equations to predict the same trends in total flow rate with increasing pressure difference as the MD simulation, submodels for variations in density and viscosity with pressure are needed to be included. The classical NS boundary conditions quantitatively agreed with the flow rate predictions from MD simulations only under the condition of having a neutral-like solid-liquid interaction. Under these conditions, the NS and MD models also agreed well in streamwise distributions of pressure, density, and velocity, but not in the radial direction.