Tonglei Li
Journal of Molecular Graphics and Modelling. 2007. DOI: 10.1016/j.jmgm.2007.08.001

[+]

[-] Density functional theory (DFT) provides a rigorous theoretical framework for analyzing and interpreting electronic structures of molecules and crystals. One electron density-based concept is the Fukui function, which describes the responding sensitivity of a molecular system to electronic perturbations. As a local property, the Fukui function is directly associated with local polarizability, so it may be capable of describing the intermolecular interaction in an organic crystal with regard to molecular packing. Herein, we demonstrate such an application to the aspirin single crystal and discuss potentials of the DFT-based concepts for studying electronic structures of organic crystals.

Clare Aubrey-Medendorp, Matthew J. Swadley, and Tonglei Li
Pharmaceutical Research, 2007. DOI:10.1007/s11095-007-9346-9

[+]

[-] Indomethacin exhibits conformational polymorphism. Crystal structures of two polymorphs have been solved bearing different molecular conformations. Herein, the conformational variance in the crystals was examined by density functional theory (DFT) calculations in order to understand the mutual influence between electronic structures and crystal packing. The polymorphism of indomethacin lies in various meta-stable conformations of the molecule that are results of different orientations between the two aromatic indole and phenyl rings. The analysis of electronic and nuclear Fukui functions permits the revelation of local energy barriers that determine the conformational diversity and, for the case of indomethacin, the conformational polymorphism.

Clare Aubrey-Medendorp, Sean Parkin, and Tonglei Li
Journal of Pharmaceutical Sciences, 2007. DOI:10.1002/jps.21055

[+]

[-] Much of the existing literature dealing with crystalline aspirin is vague or ambiguous with regard to indexing of the crystal faces. The inconsistency with which the indices of the dominant faces have been assigned leads to confusion in analysis of surface properties. To clarify this, we have conducted crystal growth experiments on aspirin, and indexed the crystal faces with X-ray diffraction, paying special attention to the placement of symmetry elements. The space group was confirmed as P21/c, and the dominant face was (100). Contact angle measurements made on the two major faces of aspirin indicate the (100) face to be more hydrophobic than the (001) face, likely due to the acetyloxy moiety, not the carboxyl, exposed on the (100).

Sihui Long, Maxime Siegler and Tonglei Li
Acta Crystallographica, E63:o3080, 2007

[+]

[-] In the crystal, all the hydrogen-bond donors and acceptors are involved in hydrogen bonds. The packing can be described as columns, two ion-pairs wide, propagating along the a axis. The columns are formed through N—H...Cl hydrogen bonds linking pairs of cations and anions around centers of symmetry and further connecting these pairs in the [100] direction. In addition, the aromatic rings on each side of the columns are stacked above each other, indicating pi-pi stacking.

Salin Gupta, Sihui Long and Tonglei Li
Acta Crystallographica, E63:o2784, 2007

[+]

[-] Four molecules, all adopting a planar conformation, are found in the asymmetric unit. The compound forms hydrogen-bonded sheets parallel to the [001] direction via intermolecular N— H...O and O—H...O hydrogen bonds. Each sheet consists of interconnected dimers; these sheets can be viewed as infinitely fused 32-membered hydrogen-bonded rings.

Sihui Long, Sean Parkin and Tonglei Li
Acta Crystallographica, E63:o906-o907, 2007

[+]

[-] In the title compound, C14H15N2O2.C2F3O2, the two aromatic rings of the cation are almost perpendicular to each other. The cations and anions are connected through hydrogen bonds into a one-dimensional network. There is an intramolecular N—H...O hydrogen bond between the secondary amine group and the carboxylic acid group.

Matthew Swadley and Tonglei Li
Journal of Chemical Theory and Computation, 3:505-513 2007

[+]

[-] 1,3,5-Trinitro-s-triazine, or cyclotrimethylene trinitramine, or RDX, is a sensitive, secondary explosive, which has been the subject of a number of studies regarding the sensitivity and mechanism of decomposition in energetic materials. Several initial mechanistic steps have been proposed for RDX decomposition, with no conclusive agreement upon any one as the definitive pathway. Our research utilizes density functional theory (DFT)-based calculations and concepts, particularly the nuclear Fukui function, to analyze the effects of additive/depletive electronic perturbation upon vapor conformers and crystal RDX structures. Since the nuclear Fukui function is a measure of the physical stress that a nucleus encounters upon a change in the electron population, it may provide useful information regarding the role of each atom in unimolecular decomposition. The results illustrate that both homolytic cleavage of N-N bonds and elimination of HONO from RDX exhibit favorability as initial steps in the decomposition of RDX in either phase. The nuclear Fukui function proved a valuable tool for gaining insight into the initial steps of unimolecular reactions.

Tonglei Li
Journal of Pharmaceutical Sciences, 96:755-760, 2007

[+]

[-] This report presents electronic calculations of two aspirin polymorphs in order to understand the origin of polymorphism in aspirin crystals. Analysis of the calculated electronic structures, particularly the nuclear Fukui functions, reveals a structural tension between the carboxylic and acetyloxy groups, which may play a key role in the formation of aspirin polymorphs. Calculations of the lattice energies of the two polymorphs indicate that aspirin crystals may be enantiotropic.

Sihui Long, Maxime Siegler and Tonglei Li
Acta Crystallographica, E63:o279-o281, 2006

[+]

[-] The title compound, C6H4ClNO2, forms centrosymmetric dimers via intermolecular hydrogen bonds between carboxylic groups. Weak Cl...Cl interactions further bridge these dimers, leading to infinite chains. In contrast, acid-to-pyridine hydrogen-bonded catemer motifs are observed in both nicotinic acid and 2-chloronicotinic acid. Only intramolecular halogen-bonded S(5) loops exist in 2-chloronicotinic acid.

Sihui Long, Maxime Siegler and Tonglei Li
Acta Crystallographica, E63:o5664-o5665, 2006

[+]

[-] The title compound, C6H5NO2, a tautomer of 2-hydroxynicotinic acid, adopts a planar conformation. An intramolecular O—H...O hydrogen bond of 2.504 (2) A is found. The compound forms one-dimensional hydrogen-bonded chains along the [101] direction via an intermolecular N— H...O hydrogen bond of 2.810 (2) A.

Tonglei Li
Crystal Growth and Design, 6:2000-2003, 2006

[+]

[-] Single-crystal neutron diffraction studies indicated that the terminal methyl groups of aspirin and acetaminophen crystals demonstrated large librational or torsional motions as compared to other atoms. Herein, we report a study using density functional theory for understanding the Hellmann-Feynman forces and how the nuclear Fukui function may provide the underlying cause for the large disorders of the methyl group.

Sihui Long, Maxime Siegler and Tonglei Li
Acta Crystallographica, E62:o4278-o4279, 2006

[+]

[-] The title compound, C13H11ClN2O2, contains two aromatic rings linked by an amide group, and adopts a near-planar conformation. There are intra- and intermolecular N—H...O hydrogen bonds, forming centrosymmetric dimers.

Tonglei Li and Shaoxin Feng
Pharmaceutical Research, 23:2326-2332, 2006

[+]

[-] Purpose. Lattice energies of drug crystals are closely associated with many important physicochemical properties including polymorphism of the crystals. Current quantum mechanical methods that can be applied to calculate the lattice energy of most drug crystals are not capable of fully considering the van der Waals interaction energy, a dominant component in the lattice energy. Herein, we report the results of using empirically augmented quantum mechanical methods for predicting the lattice energies of selected drug crystals.
Methods. Long-range van der Waals energies were evaluated by atomYatom pairwise C6Rj6 functions that were damped at short interatomic distance where interatomic interactions could be better evaluated by density functional theory (DFT). The atomic C6 coefficients were taken from literature, and three damping functions were tested. For the quantum mechanical calculations, different basis sets were tested with aspirin as the model system. Basis set superposition error (BSSE) was considered. In addition to aspirin, acetaminophen Form I and Form II, and s(+)- and (T)-ibuprofen were calculated and the results were compared to experimental values. Experimentally determined single crystal structures were optimized prior to both empirical and DFT energy calculations.
Results. Lattice energies calculated by the empirically augmented quantum mechanical methods are in very good agreement with experimental values, suggesting the approach is acceptable. The results also indicate that the long-range van der Waals or dispersion energy is a significant part of the lattice energy, which cannot be accurately estimated by the DFT methods alone.
Conclusions. Due to the empirical nature for estimating the dispersion energy, choosing the right empirical parameters is crucial. The methods and parameters tested seem to be able to produce reliable values of lattice energies of the drug crystals.

Sihui Long, Maxime Siegler and Tonglei Li
Acta Crystallographica, E62:o4211-o4213, 2006

[+]

[-] The asymmetric unit of the title compound, C15H16N2O2, contains two molecules and in each of the molecules, the two aromatic rings, lying in two different planes, are bridged by a secondary amino group. This might be due to steric hindrance caused by the isopropyl group. Intra- and intermolecular N— H...O hydrogen bonds link the molecules, forming an infinite one-dimensional tape structure; they may be effective in the stabilization of the crystal structure.

Shaoxin Feng and Tonglei Li
Journal of Chemical Theory and Computation, 2:149-156, 2006

[+]

[-] Calculation of the lattice energy of organic crystals is needed for predicting important structural and physicochemical properties such as polymorphism and growth morphology. Quantum mechanical methods that can be used for calculating typical organic crystals are unable to fully estimate van der Waals energies in a crystal. A method by augmenting the density functional theory with an analytical, nonelectronic approach for accounting for the dispersion energy was tested for selected organic crystals. The results illustrate the feasibility of this method for the prediction of the lattice energy of organic crystals. It is also shown that the dispersion energy is a dominant component of the lattice energy, particularly for those organic crystals that have no hydrogen bonds.

Jessika Colón Soto, Carlos Peroza Meza, Wanda Caraballo, Carlos Conde, Tonglei Li, Kenneth R. Morris, and Rodolfo J. Romañach
PAT (The Journal of Process Analytical Technology), 2:8-15, 2005

[+]

[-] The initial results in the development of an on-line system to determine the drug content of tablets as they come out of a tablet press are described. The system uses a specially designed conveyor belt to provide fast tablet presentation system to the spectrometer. Near infrared diffuse reflectance spectra were obtained with a diode array spectrometer at 50 and 110 tablets per minute, respectively. Calibration models were developed for the quantitative determination of the drug content of the tablets. The root mean square error of prediction (RMSEP) was 3.86 mg for 50 tablets per minute (tpm), and 4.36 mg at 110 tpm, for tablets with a drug content ranging from 63.7 to 121 mg per tablet. The bias or average error was 0.82 mg at 50 tpm and 1.42 mg at 110 tpm.

Tonglei Li and Shaoxin Feng
Pharmaceutical Research, 22:1964-1969, 2005

[+]

[-] Purpose. Solid-state reactions are highly anisotropic. Different polymorphs of the same compound may have remarkably different chemical reactivities. It was reported that two polymorphs of indomethacin single crystals, alpha- and gamma-forms, reacted with ammonia gas at dramatically different rates. In this study, the effect of crystal packing on their difference in chemical reactivity was investigated by examining the electronic structures and properties of the crystal forms.
Methods. Ab initio methods, including density functional theory, were used to calculate electronic structures of the a- and g-forms of indomethacin. In particular, nuclear Fukui functions were obtained to elucidate how a molecule in a crystal may respond to an electronic perturbation that can be caused by a chemical reaction.
Results. Different conformers in the two polymorphs showed different electronic structures. The carboxylic group of one symmetrically different molecule in the a-form had significantly larger nuclear Fukui functions than those of other molecules of either the a- or g-form, supporting the experimental observation that the a-form was much more reactive with ammonia than the g-form. In addition, the large nuclear Fukui functions associated with atoms other than those from the carboxylic group were attributed to the tension of two dislodged aromatic rings.
Conclusions. Electronic calculations were able to provide insightful glimpses into the effect of crystal packing on the solid-state reaction of indomethacin. The nuclear Fukui function, which characterizes the physical stress on an atom due to perturbation in electron density, may provide a powerful means of studying the solid-state reactions of organic crystals at the electronic level.

Shaoxin Feng and Tonglei Li
Journal of Physical Chemistry A, 109:7258-7263, 2005

[+]

[-] Solid-state reactions are commonly observed in organic crystals, including pharmaceutical and agricultural materials, fine chemicals, dyes, explosives, optics, and many other substances. The fact that these reactions are in general highly anisotropic with regard to the initiation and propagation in a crystal has led to this study for investigating the effect of crystal packing on the reaction mechanism and kinetics of organic crystals. We have used electron density-based concepts, including nuclear Fukui function, developed from density functional theory, for elucidating the effect of electronic structures of different polymorphs on the difference in their chemical reactivity. Two polymorphs of flufenamic acid were studied. The calculation results on major reacting faces of the two forms support their reactivity difference with ammonia gas. In addition, we calculated surface energies of reacting faces to discuss how the mechanical difference may affect the propagation of solid-state reaction.

Tonglei Li, Shubin Liu, Shaoxin Feng, and Clare E. Aubrey
Journal of the American Chemical Society, 127:1364-1365, 2005

[+]

[-] Wettability is one of the anisotropic surface properties of molecular crystals that exhibit the structural variance of chemical moieties on various growth faces. The divergence in liquid-solid interactions at different faces is thought to be related to the inherent responding capacity or sensitivity of a solid surface to the perturbation in electronic structures and atomic positions as a result of the contact by a liquid. Since the Fukui function, according to density functional theory (DFT), is a local function for describing such sensitivity to the structural perturbation and is directly related to local softness, it has been proposed and tested to use an integrated Fukui function over a crystallographic plane for describing the anisotropy of solid-liquid interactions. It is found that the contact angle of a polar solvent, such as water, on a crystal surface shows an intimate connection to the integrated Fukui functions of the surface, illustrating an extension of Pearson's HSAB (hard and soft acids and bases) to crystal systems. The concept of face-integrated Fukui function and the approach to apply the HSAB with the DFT-based concepts may provide a powerful means for describing anisotropic properties, including wettability of organic crystals.

Hong Wen, Tonglei Li, Kenneth R. Morris, and Kinam Park
Journal of Physical Chemistry B, 108:11219-11227, 2004

[+]

[-] The broad objective of this research is to better understand the dissolution processes of drug crystals in the molecular level, especially the interactions between solvent molecules and drug molecules at the interface. For aspirin and R-glycine crystals, the (100) face of aspirin and the (010) face of R-glycine were used for partial dissolution studies. The etching patterns for both aspirin and R-glycine reflect the directionality and strength of the attachment energies projected onto the faces of interest very well, and the predicted etching patterns match observed etching patterns well especially for solvents with weak and moderate solubilizing ability. These results further support our conclusions from earlier publications that surface diffusion, guided by the directional attachment energies, is the primary architect of etching pattern morphology. The solubilizing ability of solvents can significantly affect the surface diffusion time of the involved molecules. In the directions of the dominant attachment energies, the etching patterns in solvents with high solubilizing ability (e.g., pyridine, acetone) become less pronounced than the etching patterns in solvents with low ability (e.g., dichloroethane). Surface adsorption of the solvent also plays an important role in etching pattern formation. In R-glycine crystals, acetone may form hydrogen bonds with glycine and introduces certain anisotropy in the relatively deeper etched pits, i.e., oval etching patterns whose basic directionality is, however, still controlled by attachment energy network. Overall, the formation of etching patterns is mainly determined by attachment energies that are important in guiding surface diffusion, and is also affected by solvents with different solubilizing ability and surface adsorption potential.

Hong Wen, Tonglei Li, Kenneth R. Morris, and Kinam Park
Journal of Physical Chemistry B, 108:2270-2278, 2004

[+]

[-] The objective of this work was to further elucidate the dissolution process of acetaminophen crystals at the molecular level. The differences in the etching patterns from different solvents were used to study the interactions between solvent and acetaminophen molecules at the solid-liquid interface, such as solubilizing ability and potential solvent adsorption. The predicted etching patterns, based on the projections of attachment energies on the corresponding faces together with the solubilizing ability of the solvents, fit the observed etching patterns well. On the (001) face, the etching patterns were predominantly in the direction of the a-axis, which was also the direction of the dominant attachment energy. On the (110) face, the etching patterns were consistently in the direction of the c-axis irrespective of solvent used, and they were variable in other directions. These were well fit by the predicted etching patterns accounting for the different solubilizing ability of solvents. Both the most significant etching pattern deviations (on the (010) face) and the most significant morphology changes were observed with dichloroethane for acetaminophen. The morphology of acetaminophen crystals from different solvents showed that only the crystals from dichloroethane had significant elongation along the c-axis, which suggests the existence of stronger adsorption in the a-axis and b-axis directions than along the c-axis for dichloroethane. Overall, the current work suggests that the crystal interaction network, together with the interactions between solvent and acetaminophen, affects surface diffusion and plays an important role in the dissolution process.

Tonglei Li, Gerard Frunzi, Amy Donner, Candi Choi, and Kenneth R. Morris
Journal of Pharmaceutical Sciences, 92:1526-1530, 2003

[+]

[-] The advent of PAT, Process Analytical Technologies, offers the possibility of large scale monitoring of tablets as they come off the press. The most rapid techniques allowing the largest sample sizes are based on reflectance spectroscopy. As these techniques sample only a portion of the tablet, it is critical to prove that sampling a portion has a larger (and, therefore, more conservative) statistical variance than sampling the entire. Once demonstrated, a partial sampling technique, for example, a Near Infrared (NIR) sensor, should be able to provide a safe bracket for content uniformity evaluation. It is the purpose of this report to support the claim that the coefficient of variance (CV) from sampling a part of a dosage form cannot be smaller than the CV from sampling the whole dosage form. This hypothesis will be supported in this study by both a statistical proof and experimental data acquired from a model tablet system.

Jennifer J. Wang, Tonglei Li, Simon D Bateman, Rober Erck, and Kenneth R. Morris
Journal of Pharmaceutical Sciences, 92:798-814, 2003

[+]

[-] Adhesion problems during tablet manufacturing have been observed to be dependent on many formulation and process factors including the run time on the tablet press. Consequently, problems due to stickingmayonly become apparent towards the end of the development process when a prolonged run on the tablet press is attempted for the first time. It would be beneficial to predict in a relative sense if a formulation or new chemical entity has the potential for adhesion problems early in the development process. It was hypothesized that favorable intermolecular interaction between the drug molecules and the punch face is the first step or criterion in the adhesion process. Therefore, the rank order of adhesion during tablet compression should follow the rank order of these energies of interaction. The adhesion phenomenon was investigated using molecular simulations and contact mode atomic force microscopy (AFM). Three model compounds were chosen from a family of ‘‘profen’’ compounds. Silicon nitride AFM tips were modified by coating a 20-nm iron layer on the surfaces by sputter coating. Profen flat surfaces were made by melting and recrystallization. The modified AFM probe and each profen surface were immersed in the corresponding profen saturated water during force measurements using AFM. The work of adhesion between iron and ibuprofen, ketoprofen, and flurbiprofen in vacuum were determined to be -184.1, -2469.3, -17.3 mJ m^-2, respectively. The rank order of the work of adhesion between iron and profen compounds decreased in the order: ketoprofen>ibuprofen>flurbiprofen. The rank order of interaction between the drug molecules and the iron superlattice as predicted by molecular simulation using Cerius2 is in agreement with the AFM measurements. It has been demonstrated that Atomic Force Microscopy is a powerful tool in studying the adhesion phenomena between organic drug compounds and metal surface. The study has provided insight into the adhesion problems occurring during tablet compression and a direction for continued study.

Xiaoming Chen, Tonglei Li, Kenneth R. Morris, and Stephen R. Byrn
Molecular Crystals and Liquid Crystals, 381:121-131, 2002

[+]

[-] The objective of this study is to compare the reactivity of two polymorphs of flufenamic acid with ammonia and relate it to crystal packing. Forms I and III of flufenamic acid were exposed to dry ammonia vapor. Optical microscopy, microscopic Raman, and XRPD were used to characterize the possible changes. The different reactivity of Forms I and III was clearly observed under dry ammonia vapor from 12%; ammonium hydroxide. Single crystals of Form I gradually became opaque within 180 min, whereas single crystals of Form III retained transparent. FT-Raman analysis revealed that significant ammonium salt was formed at the major face of Form I, while the reaction of Form III was undetectable. So Form I is more reactive than Form III at ambient temperature, which agrees with their thermodynamic order. At 60°C, the thermodynamic order switches and Form I is the stable form. However, Form I is still more reactive with ammonia than Form III at 60°C. The reaction rate is likely to be determined more by kinetic factors. The good accessibility of reaction groups could be one of the reasons that Form I is more reactive.

Tonglei Li, Hong Wen, Kinam Park, and Ken Morris
Crystal Growth & Design, 2:185-189, 2002

[+]

[-] The growth of acetaminophen single crystals in the presence of the structurally similar or “tailormade” additive, 4-methylacetanilide, showed elongation along the c axis and reduction along the a axis when the additive’s concentration was increased from 1 to 6 mM. This may indicate preferred binding between the host and additive molecules along the a axis, but along the c axis there is little effect on the growth. In addition, at higher concentrations of 4-methylacetanilide (3 and 6 mM), new faces, {4h01}, appeared while the {2h01} were absent. The alignment of host molecules on the growth front is likely to be a coordinated result of the adsorption of additive molecules and the adsorption-induced relaxation of the host molecule conformation. Earlier etching studies provide support for this argument. The additive was chosen as a “surrogate” for a solvent with similar molecular structural properties as part of the ongoing effort to investigate the effect of solvent on crystal morphology.

Tonglei Li, Kenneth R. Morris, and Kinam Park
Crystal Growth & Design, 2:177-184, 2002

[+]

[-] Tailor-made additives of acetaminophen were shown to be very effective in changing the etching patterns on the cleaved surface of the single crystal (i.e., the (010) face in an aqueous environment). The shape of the etch pits was “mutated” from a parallelogram to a square shape when the concentration of additives was increased. Monte Carlo simulation was carried out to study the formation mechanism of the square-shaped etch pit. When the intermolecular interactions between acetaminophen on the surface were treated the same as in the bulk, including the adsorption of additive molecules alone failed to align the additive-terminated kink sites perpendicular to the c axis. Therefore, it has been hypothesized that an additive molecule can stabilize a “relaxed” state of molecules on the surface of the crystal that may form stronger interactions with its neighboring molecules along the [102] axis. Such a relaxed state is possible only if the two neighboring sites along the [102] direction are unoccupied by host molecules because of the extra space that would be required for the methyl group’s motion. Supporting evidence for the concept was found in the literature.

Tonglei Li, Kenneth R. Morris, and Kinam Park
Pharmaceutical Research, 18:398-402, 2001

[+]

[-] Etching patterns of (010) face of acetaminophen single crystals created by aqueous solutions of tailor-made additives, acetanilide and 4-methyl acetanilide, were examined by AFM. The data support the hypothesis that additive molecules were able to adsorb on the crystal surface, diffuse and occupy crystal lattices, disrupt the original supramolecular interaction network and thus, change the shape of etch pits from parallelogram to rectangular, square, or circular. Because tailor-made additives were used, the changes of etching patterns are very likely to be a result of the adsorption of additive molecules.

Tonglei Li and Kinam Park
Computational and Theoretical Polymer Science, 11:133-142, 2001

[+]

[-] Conformational changes of a simplified model of grafted poly(ethylene oxide) (PEO) chains were simulated using an off-lattice Monte Carlo model. A random-walk scheme was used in our simulations. The initial polymer structure was modeled with molecular mechanics and models of grafted polymer chains were built using programs developed in our laboratory. During the simulation, all bond angles and bond lengths were kept fixed while the dihedral angles of backbones were changed to search for energy-favorite conformations. Torsional energy, van der Waals interaction, and Coulombic interaction were considered. Periodic boundary conditions were implemented. In addition, the solvent quality was simulated implicitly by modifying the Lennard-Jones 12–6 van der Waals expression. Each PEO chain, 50-monomer long, was represented with a united-atom model. Eight series of simulations with varying solvent quality, simulation temperature, and Coulombic interaction were carried out. For each series, nine different initial grafting densities of grafted PEO chains were considered. Five different conformations were simulated at each grafting density. The calculated system energies, scaling properties, and atom density profiles were studied. Changes in solvent quality produced different structural behaviors. As the grafting density increased, there was a mushroom-to-brush transition, and the scaling property of average layer thickness was dependent on the grafting density.

Tonglei Li, Kenneth R. Morris, and Kinam Park
Journal of Physical Chemistry B, 104:2019-2032, 2000

[+]

[-] Understanding the evolution of surface morphology or surface texture of molecular crystals by dissolution/ etching may be useful in determining the dissolution mechanisms at the molecular level. In this study, partial dissolution tests were conducted on the (010) face of acetaminophen single crystals with selected solvents: water, dichloroethane, pyridine, acetone, ethyl acetate, and acetic anhydride. Surface textures and etching patterns were examined with an atomic force microscope (AFM). It was found that etching patterns were regular and their shape depended on the solvent used for the etching. The etching patterns observed were parallelogram (by water and acetic anhydride), slit (by dichloroethane), hexagonal (by pyridine), square (by acetone), or rectangular (by ethyl acetate). It seems that all etching patterns are related to the underlying crystal structure. The crystal structure was used in simulation of the dissolution process by a computer model. Two essential events were considered during the simulation, detachment of crystal molecules, and surface diffusion of the desorbed molecules. Simulation results indicated that surface diffusion played the key role in forming etching patterns. The surface diffusion was thought to be guided or confined by the underlying crystal structure, especially the supramolecular interaction network. The discrepancy in the etching patterns between the simulation results and some of the experimental observations was explained by adsorption of solvent molecules on the crystal surface. It was likely that the adsorption of solvent molecules changed or interrupted the original interaction network within the crystal structure, leading to the mutation of the etching pattern. Our study indicated that the etching pattern at the crystal surface was influenced not only by the solvent-solid interaction but also by the crystal structure and the mutual recognition between solvent molecules and crystal molecules.

Tonglei Li, and Kinam Park
Pharmaceutical Research, 15:1222-1232, 1998

[+]

[-] Purpose. Reliable methods are needed to characterize the surface roughness of pharmaceutical solid particles for quality control and for finding the correlation with other properties. In this study, we used fractal analysis to describe the surface roughness.
Method. Atomic force microscopy (AFM) was used to obtain three-dimensional surface profiles. The variation method was used to calculate fractal dimensions. We have measured fractal dimensions of four granule samples, four powders, and two freeze-dried powders.
Results. A computer program was written to implement the variation method. The implementation was verified using the model surfaces generated by fractional Brownian motion. The fractal dimensions of most particles and granules were between 2.1 and 2.2, and were independent of the scan size we measured. The freeze-dried samples, however, showed wide variation in the values of fractal dimension, which were dependent on the scan size. As scan size increased, the fractal dimension also increased up to 2.5.
Conclusions. Fractal analysis can be used to describe surface roughness of pharmaceutical particles. The variation method allows calculation of reliable fractal dimensions of surface profiles obtained by AFM. Careful analysis is required for the estimation of fractal dimension, since the estimates are dependent on the algorithm and the digitized model size (i.e., number of data points of the measured surface profile) used. The fractal dimension of pharmaceutical materials is also a function of the observation scale (i.e., the scan size) used in the profile measurement. The multi-fractal features and the scale-dependency of fractal dimension result from the artificial processes controlling the surface morphology.

Tonglei Li, Hai-Bang Lee, and Kinam Park
Journal of Biomaterials Science, Polymer Edition, 9:327-344, 1998

[+]

[-] There is a need for synthesizing glucose-sensitive molecules which can be used in glucose sensors and self-regulating insulin delivery devices. Currently, glucose sensitive proteins, such as glucose oxidase or concanavalin A (Con-A), are used for detecting glucose molecules. For long-term in vivo applications, it is necessary to synthesize non-proteineous glucose-sensitive molecules which are biocompatible, nontoxic, cost-effective, and independent on the environmental factors such as the pH, ionic strength, or the presence of divalent cations. The knowledge to design the artificial glucose-binding materials comes from the analysis of the binding sites of 4 types of natural glucose-binding proteins. They are human beta-Cell glucokinase, D-xylose isomerase, lectins (Lathyrus ochrus isolectin I and Con-A), and glucose/galactose binding protein. Analysis of the glucose-binding sites of their 3-dimensional crystal structures showed that the hydrogen bonds between the hydroxyl groups of glucose and a few types of amino acid residues of proteins provide the main attraction. Double fork-shaped hydrogen bondings have been observed. Hydrophobic interactions between the pyranose ring of glucose and aromatic rings of hydrophobic amino acid residues also play an important role in the glucose specificity. A sandwich geometry could be formed among the hydrophobic groups. Based on this stereochemical analysis, we are able to design what types of monomers needed in the synthesis with the consideration of the geometric and interacting aspects found in the glucose-binding proteins.

Tonglei Li, Dane O. Kildsig, and Kinam Park
Journal of Controlled Release, 48:57-66, 1997

[+]

[-] Diffusion of small molecules in amorphous polymers has been examined by computer simulation. Diffusion coefficients of small molecules with molecular weight ranging from 16.04 (methane) to 452.50 (fluocinolone acetonide) daltons in four amorphous polymers were calculated using the QUANTA, CHARMM and Cerius2 programs. The four amorphous polymers used in our calculation were polyethylene (PE), poly(dimethyl siloxane) (PDMS), poly(methyl methacrylate-co-hydroxyethyl methacrylate) (P(MMA-co-HEMA)), and ethyl and benzyl esters of hyaluronic acid (HA-E, HA-B). The calculated diffusion coefficients (Dc) were compared with the experimentally obtained values (De) found in the literature. The ratio of Dc/De varied from 0.04 to 24,000. In general, the close values of Dc to De were obtained when the system deals with hydrophobic molecules diffusing through hydrophobic polymers. The Dc/De ratio became either very high or very low when the experimental system included hydrophilic diffusants and/or hydrophilic polymeric systems. Our study suggests that the current computer simulation of molecular diffusion may be useful in obtaining relative values rather than absolute diffusion coefficient values.

Tonglei Li, Shaofan Lin, and Jinbei Zhang
Selected Papers of Engineering Chemistry and Metallurgy (Chinese), 173-178, 1993

Tonglei Li, and Shaofan Lin
Journal of Computers and Applied Chemistry (Chinese), 9:92-98, 1992