Molecular Dynamics of Hydration Shells of Adsorbates in Entropy-Driven Adsorption (Hydrophobic Bonding) to Activated Carbon Surfaces.

Hydrophobic bonding is a phenomenon wherein the adsorption of solutes from aqueous solutions is driven largely by the desire of solvent molecules to interact with each other, thus squeezing out solute molecules onto the adsorbent surface. A novel computational analysis of hydration shell water dynamics was used to study the driving force for the hydrophobic bonding of five small drug molecules to activated carbon. It was demonstrated that the solvation of these drug molecules produced hydration shells of lower density and molecular mobility than bulk water, up to 10.5-14 Å distance. Excellent correlations were found between the simulated water-water hydrogen bonding lifetimes in the hydration shell and the experimental capacity constants of hydrophobic bonding (KHB) obtained from the Two-Mechanism Langmuir-Like Equation. KHB also correlated well with the solute-solvent vdW interaction energies in a manner that could allow future predictions of KHB values from simple simulations. Such correlations were not found with the capacity constant of the well-known enthalpy-driven adsorption. The driving force for hydrophobic bonding has entropic origins due to the elimination of water structuring in the hydration shells. However, unlike a typical entropy-driven process, hydrophobic bonding to activated carbon was also associated with a large exothermic enthalpy change when studied with isoperibol calorimetry.

Disagreements Between Calorimetric and Van't Hoff Enthalpies of Adsorption: A New Langmuir-like Model to Account for the Effect of Solvent Displacement Stoichiometry.

The reported inconsistencies between calorimetry and the van't Hoff equation hinder the utility of thermodynamics in pharmaceutical research. In ligand binding or adsorption assays, it is believed that the van't Hoff equation falls short because of the lack of stoichiometric treatment in the equilibrium constant. A new modified Langmuir-Like equation that accounts for the stoichiometry of solute adsorption and solvent displacement is proposed in this work. The performance of the model was evaluated by studying the adsorption of phenobarbital from aqueous solutions by commercial activated carbon. The amount of water occupying the adsorption sites was estimated by graphical analysis of the 'knee point' of water-vapor adsorption isotherms and was found to correlate well with the relative percentage of hydroxyl and carbonyl surface groups. It was found that one phenobarbital molecule displaces 2-6 water molecules from the adsorption site. It is shown that adsorption enthalpy was not affected by the adjustment for stoichiometry, supporting the notion that the van't Hoff enthalpy is intrinsic and is independent of the stoichiometry of solvent displacement in Langmuir-based binding. The widely reported disparities between the van't Hoff and calorimetric enthalpies are unlikely to be from a stoichiometric origin.

Disagreements Between Calorimetric and Van't Hoff Enthalpies of Adsorption II: Effect of pH and pH Buffers on Phenobarbital Adsorption to Activated Carbon.

The reported inconsistencies between the van't Hoff equation and calorimetry hinder the utility of thermodynamics in biochemical and pharmaceutical research. A novel thermodynamic approach is developed herein for ligand adsorption with a focus on the interpretation of calorimetric data in the presence of concurrent proton exchange reactions. Such exchange reactions typically result in a pH-dependence of calorimetric measurements that obscures intrinsic binding enthalpies. It is shown that for the adsorption of phenobarbital to activated carbon, the measured calorimetric enthalpy is a result of three linked acid/base equilibria. A model was established to predict the intrinsic binding enthalpy using 1) the adsorbate's pKa and 2) the adsorbate's enthalpy of protonation. The observed calorimetric enthalpy of binding exhibited both pH and buffer-dependence and was between -5 and -42 kJ/mol. Meanwhile, the predicted intrinsic enthalpy (-25.1 kJ/mol) of binding was in excellent agreement with the measured intrinsic enthalpy (-25.6 kJ/mol). Corrections to the observed calorimetric enthalpies allowed comparisons with enthalpies obtained from the van't Hoff method. It is shown that the predicted intrinsic calorimetric enthalpy agrees well with the van't Hoff enthalpies in instances where observed enthalpies significantly deviated. This treatment is general and is not specific to phenobarbital or activated carbon.

A study of Kollicoat® MAE100P film's structure and properties.

Generally, an organic-solvent-based film is denser and tougher than a corresponding aqueous-dispersion-based film. However, Kollicoat® MAE100P films prepared from aqueous dispersions had greater tensile strengths compared to the films cast from organic solutions. It was proposed that MAE100P polymer particles in aqueous media had a core-shell structure with a hydrophilic shell and a hydrophobic core. The hydrophilic shell was rich in ionized methacrylic acid (MAA) groups and the hydrophobic core primarily contained unionized MAA and ethyl acrylate (EA). As a result, ionized MAA formed a continuous phase which worked as a rigid frame and greatly improved the mechanical properties of aqueous-dispersion-based films. In order to prove this theory and investigate the effect of ionization level on this polymer system, the properties of pH, turbidity, zeta potential, and particle size of MAE100P dispersions were measured as a function of ionization level. The tensile strengths and thermal and mechanical properties of MAE100P films prepared from organic solution or aqueous dispersions of different ionization levels were investigated as well. FTIR was used to characterize the polymer films. Drug release in 0.1 N HCl from coated pellets was studied using the basket method. The experimental results showed that the original MAE100P polymer particles (if not specified, the ionization level is 6%) had a highly-charged surface. The properties of polymer aqueous dispersions were significantly changed by the ionization levels. Aqueous-dispersion-based MAE100P films or coats were stronger and comparable to or somewhat more effective in inhibiting drug diffusion than were organic-solvent-based coats. The tensile strength initially increased and then decreased with an increase of ionization level, while the water-uptake rate by the films continuously increased. Two endothermic peaks were observed in the DSC thermograms for cured MAE100P films. The high-Tg endothermic peak increased with an increase in ionization level, while the low-Tg peak didn't exhibit significant change except for the 18% ionization film. In the dynamic mechanical analysis, two relaxations in the storage modulus were observed in the aqueous-dispersion-based films. These data may suggest a two-phase structure in the form of a core-shell structure. The tensile-strength ratio for aqueous-dispersion-based films over organic-solvent-based films for MAE100P was close to that reported for films formed from polymer substances/particles with core-shell structures. In summary, the core-shell structure might result in a two-phase structure in the bulk MAE100P film prepared from aqueous dispersion. This special structure led to significantly-improved mechanical properties for aqueous-dispersion-based MAE100 films. The ionization levels had complicated effects on the polymer system by increasing the amount of ionic aggregates while also solubilizing the polymer and changing the mechanism of film formation.

Thermodynamic Evaluation of the Interaction Driven by Hydrophobic Bonding in the Aqueous Phase.

In the present study, the interaction between phenobarbital and activated carbons which is driven by hydrophobic bonding was evaluated. The Two-Mechanism Langmuir-Like Equation was proposed to describe the isotherms for phenobarbital adsorbing to activated carbons. The parameters in the Two-Mechanism Langmuir-Like Equation obtained from the nonlinear fitting of isotherms were used in the calculations of the differential Gibbs free energy for the hydrophobic bonding-driven interaction. Two thermodynamic models, the Modified Crisp Model and the van't Hoff Equation, were adopted to estimate the differential Gibbs free energy. And, comparing the differential Gibbs free energy obtained from the 2 thermodynamic relationships, it can be determined that an adsorbing phenobarbital molecule displaces 12 water molecules on the hydrocarbon surfaces of the activated carbons (hydrophobic bonding case). The difference between the estimates of the differential Gibbs free energy obtained by the Modified Crisp Model and by the van't Hoff Equation provides a new experimental method to calculate the number of solvent molecules displaced by an adsorbing solute molecule. This is a completely general technique for the hydrophobic bonding-driven interaction and is not limited to the systems studied. The calculated positive differential entropy confirmed that the adsorption process was entropy driven.

The Effects of Curing and Casting Methods on the Physicochemical Properties of Polymer Films.

Most film coatings in the pharmaceutical industry are prepared using organic solvents or aqueous solvents. Due to different film-formation mechanisms, their properties are significantly different from each other. Curing can alter the microstructure of films by improving the coalescence of polymer particles for aqueous dispersion-based films or accelerating macromolecule relaxation for organic solvent-based films. The aim of this study was to investigate the effects of preparation methods and curing on the physicochemical properties of Kollicoat® SR30D and Kollicoat® MAE100P films. The film's properties, including water diffusion coefficient, mechanical properties, plasticizer loss, swelling behavior, and contact angle, were measured for uncured or cured aqueous dispersion-based or organic solvent-based films. The results indicated that curing decreased water diffusivities in films and increased film's tensile strength. Curing resulted in plasticizer loss from SR30D films but not from MAE100P films due to strong interaction between plasticizer and MAE100P. The surface of organic solvent-based films was more hydrophobic than that of aqueous dispersion-based films. The contact angle of organic solvent-based films was increased after curing possibly because curing decreased roughness of the film surface. Organic solvent-based SR30D films had better mechanical properties than the corresponding aqueous dispersion-based films because of higher degree of polymer-polymer entanglement in the organic solvent-based films. However, contradictory phenomena were observed in MAE100P films possibly due to a "core-shell" structure reserved in the aqueous dispersion-based MAE100P films. In summary, casting methods and curing have significant impact on the film properties due to different film structures, coalescence, or film relaxation, and other concurrent effects including evaporation of residue solvent and plasticizers.

Thermodynamic Estimate of the Number of Solvent Molecules Displaced by a Solute Molecule for Enthalpy-Driven Adsorption: Phenobarbital and Activated Carbons as the Model System.

A Modified Crisp Equation, describing the differential Gibbs free energy of the adsorption process, is being proposed, which considers multiple sites available on the surface for adsorption and their relative fractions. The differential Gibbs free energy can be calculated by the van't Hoff Equation, which depends on the affinity constant in the Langmuir-like equation. To consider the number of solvent molecules displaced by a solute molecule in the adsorption process, a new derivative of the Langmuir-like equation is being proposed as well. By comparing the differential Gibbs free energies obtained from the 2 thermodynamic relationships, it can be determined that a phenobarbital molecule displaces 5 water molecules on the activated carbon surface for site-specific adsorption from solution. For the series of experimental conditions studied, including 4 activated carbons, pH effects, temperature effects, and solvent effects, the corrected differential Gibbs free energies using n1 = 5 for site-specific adsorption are quite consistent between the 2 thermodynamic relationships. The difference between the estimates of the differential Gibbs free energies by the Modified Crisp Equation and the van't Hoff Equation provides a new experimental method to calculate the number of solvent molecules displaced by an adsorbing solute molecule.

Quantitative Structure-Activity Relationship Analysis of the Effect of Metoclopramide and Related Compounds on the Surface Ionization of Fumed Silica.

Potentiometric titration curves were generated for fumed silica with various concentrations of dissolved metoclopramide. The effects of various benzamide analogs of metoclopramide, which are positively charged in the titration medium and differ solely by their aromatic substituents, as well as lidocaine, which is also structurally analogous but is mainly in the unionized form, were also studied. At sufficiently high pH, pH 7.0 and above, the silica surface charge was independent of the metoclopramide concentration. A reasonable linear relationship with a positive slope was found between the logarithmic octanol-water partition coefficient (log P) values of the compounds and the negative surface charge determined at pH 7.0 and 7.2. These results can be attributed to specific adsorbate-surface interactions rather than concentration effects. The carbonyl oxygens of the benzamide structures most likely form hydrogen bonds with the neutral silanols. The use of positively charged triethylamine and ephedrine resulted in surface charge values that were the least negative in the aforementioned quantitative structure-activity relationship analyses. These results are consistent with ionic interactions between the positively charged aliphatic amine groups and the negatively charged surface silanols occurring simultaneously with the nonionic interactions.

The influence of the adsorption of metoclopramide on the surface ionization of fumed silica.

The effect of adsorbed metoclopramide on the surface ionization of fumed silica was studied using potentiometric titration. Adsorption isotherms of metoclopramide to unionized and negatively-charged silica surfaces were generated and compared to the titration data. The adsorption of metoclopramide caused the silica surface charge to become more negative with increasing pH that was independent of ionic strength which suggested that specific adsorbate-surface interactions were occurring. Adsorption studies showed that metoclopramide adsorbs to the unionized silica surface. Ionization caused drug adsorption to increase which was consistent with at least two distinct surface adsorption sites. The ratio of the additional amount of metoclopramide adsorbed to the surface ionized group density determined from the titration curves was approximately unity which showed conclusively that the negatively-charged silanols constitute one of the surface adsorption sites. Potentiometric titration has been shown to be a useful technique for determining the number and types of adsorption sites on the silica surface.

Characterizing compaction-induced thermodynamic changes in a common pharmaceutical excipient.

Work, heat, and internal energy change values were measured during compression of a common pharmaceutical tablet excipient, anhydrous lactose, using a compression calorimeter. Heat of solution measurements were used independently to measure the energy change caused by compaction. Both the compression calorimeter and the heat of solution measurements showed an increase in anhydrous lactose's energy state as a result of the net compression and decompression process. Excellent agreement between the energy change measured by compression calorimetry (0.94 J/g) and the energy change measured by solution calorimetry (0.91 J/g) strongly supports the data and results generated by the compression calorimeter. Furthermore, specific volume and specific surface area measurements were used to investigate the nature of the measured energy increase. The results indicate that the vast majority of the stored energy is most likely associated with residual strain within the compacted particles.

Quantitative mineralogical properties (morphology-chemistry-structure) of pharmaceutical grade kaolinites and recommendations to regulatory agencies.

The physical and chemical characteristics of kaolinite (kaolin) may be variable, and minor amounts of other clay minerals, nonclay minerals, and other impurities may affect the properties of kaolinites. Thus specific technical properties of pharmaceutical grade kaolinites become very important because these clays are used in medical applications, e.g., as pharmaceutical excipients, and will be consumed by humans. Seven pharmaceutical grade kaolinite specimens were used in this study: K1004, KA105, 2242-01, K2-500, Acros, Acros-mono, and KX0007-1. In addition, two kaolinites from the Clay Minerals Society Source Clays, KGa-1b and KGa-2, were used for comparison purposes. The Acros-mono and 2242-01 kaolinites contained minor amounts of illite, which was demonstrated both compositionally and structurally by using inductively coupled plasma spectroscopy and powder X-ray diffraction. The KX0007-1 kaolinite powder was found to be heavily contaminated with quartz, cristobalite, and alunite. Crystal structure computations also showed excess Si in its tetrahedral site, and the mineral no longer has the typical kaolinite crystal structure. These widely-used industrial standards should be quantitatively characterized morphologically, compositionally, and structurally. Results of the mineralogical characteristics should be clearly labeled on the pharmaceutical grade kaolinites and reported to the relevant regulatory agencies.

Specific and non-specific interactions of procaine with activated carbon surfaces.

The adsorption of procaine on eight activated carbon surfaces from simulated intestinal fluid (SIF) was evaluated using a rotating bottle method and isoperibol calorimetry. The adsorption data were fit using the modified Langmuir-like equation to calculate the non-specific and specific adsorption capacities. The surface atomic compositions were determined by X-ray photoelectron spectroscopy (XPS). A linear relationship was found between the relative non-specific adsorption capacity and the unoxidized hydrocarbon content of the activated carbon surfaces, which indicated that the non-specific adsorption site for procaine is the bare carbon surface. The apparent area occupied per procaine molecule, calculated from the specific capacity, was linearly correlated to the sum of the relative percentages of the C-O and O-C=O functional states on the surfaces. This suggested that the primary adsorption sites for procaine on the activated carbon surfaces were the oxygen-containing functional states of C-O and O-C=O, where procaine was adsorbed via hydrogen bonding. The differential heats of displacement for procaine on the four activated carbon surfaces are approximately equal to each other, which indicated that the interactions between procaine and the functional states on all surfaces are energetically equivalent.

Using compression calorimetry to characterize powder compaction behavior of pharmaceutical materials.

The process by which pharmaceutical powders are compressed into cohesive compacts or tablets has been studied using a compression calorimeter. Relating the various thermodynamic results to relevant physical processes has been emphasized. Work, heat, and internal energy change values have been determined with the compression calorimeter for common pharmaceutical materials. A framework of equations has been proposed relating the physical processes of friction, reversible deformation, irreversible deformation, and inter-particle bonding to the compression calorimetry values. The results indicate that irreversible deformation dominated many of the thermodynamic values, especially the net internal energy change following the compression-decompression cycle. The relationships between the net work and the net heat from the complete cycle were very clear indicators of predominating deformation mechanisms. Likewise, the ratio of energy stored as internal energy to the initial work input distinguished the materials according to their brittle or plastic deformation tendencies.

Interpreting deformation behavior in pharmaceutical materials using multiple consolidation models and compaction energetics.

Tableting behavior is often characterized using qualitative analyses of compactibility and compressibility measurements. More quantitative methods use consolidation models to estimate parameters indicative of the predominating deformation mechanism exhibited by a material. It will be shown that a concerted approach, using multiple consolidation models and mechanical energy analysis, presents a more reliable way of evaluating the relative plasticity of pharmaceutical materials and identifying complicating behaviors. Force versus displacement data for compact formation, porosity versus pressure and tensile strength data for ejected compacts were collected with a single instrument. The porosity and tensile strength data were analyzed using two relatively new models and the results were compared to three more classical models. Additionally, the mechanical work measurements were used to interpret the consolidation model predictions. Although the individual models are susceptible to a number of errors, complications and invalid assumptions, confidence can be gained when diverse models provide similar predictions. Disagreement between the model predictions can be taken as a sign of atypical behavior that should be further investigated by looking at the material's mechanical energetics. Finally, the use of work energy associated with compression and decompression as an initial measure of plasticity is supported.

Influence of the polymer-micelle interaction on micelle-substrate binding.

In an attempt to investigate how a nonionic polymer, hydroxypropyl methylcellulose (HPMC), interacts with a cationic surfactant, hexadecyltrimethylammonium bromide (CTAB), a dialysis method was employed for directly measuring the HPMC-CTAB interaction. The result showed that an interaction existed between CTAB and HPMC, and the higher the HPMC concentration the greater the fraction of CTAB bound. The shift in the UV spectra represents the change in the microenvironment. UV spectroscopy was employed to indicate the location of substrates, alpha-NA, IBA, and oil red O, in the CTAB micelles. The study of solubility as a function of CTAB concentration was the method used for determining the binding constants of the substrates. The addition of HPMC decreased the binding constants of the substrates to the micelles. It implied that the HPMC-CTAB interaction influenced the substrate binding regions. The IBA binding constant was also determined using a potentiometric titration method. The results agreed well between the two methods.

Aerosol OT microemulsions as carriers for transdermal delivery of hydrophobic and hydrophilic local anesthetics.

The skin permeation enhancement of many kinds of drugs and cosmetic substances by microemulsions has been widely known; however, the correlations between microemulsion microstructures and the efficiency of skin permeation are not fully elucidated. Therefore, the aim of our study was to investigate the influence of microemulsion types on in vitro skin permeation of model hydrophobic drugs and their hydrophilic salts. The microemulsion systems were composed of isopropyl palmitate (IPP), water, a 2:1 w/w mixture of Aerosol OT (AOT) and 1-butanol, and a model drug. The concentrations of surfactant mixture and model drug were maintained at 45% and 1% w/w, respectively. The concentrations of IPP and water were 15% and 39% w/w, respectively, for oil-in-water (o/w) type and vice versa for water-in-oil (w/o) type. The samples were prepared by simple mixing and characterized by visual appearance, pH, refractive index, electrical conductivity, viscosity, and determination of the state of water and IPP in the formulations using differential scanning calorimetry. Transdermal flux of lidocaine, tetracaine, dibucaine, and their respective hydrochloride salts from the drug-loaded AOT-based microemulsions through heat-separated human epidermis was investigated in vitro using modified Franz diffusion cells. The o/w microemulsions resulted in the highest fluxes of the model drugs in base form as compared with the other formulations within the same group of drugs. Moreover, the skin permeation of drug from microemulsions depended on drug molecular structure and interaction between drug and surfactant.

Investigation of the drug release and surface morphological properties of film-coated pellets, and physical, thermal and mechanical properties of free films as a function of various curing conditions.

The purpose of the present investigation was to elucidate the influence of curing on different physical properties of Eudragit NE and RS coating systems. Increased curing times resulted in decreased drug release rates from Eudragit NE-coated beads. However, an increase in drug release rates was noticed at longer curing times and higher temperatures for the Eudragit RS coating system. The surface morphological changes of the film-coated beads revealed that there were no visible macroscopic changes as a result of curing. The absence of any ibuprofen melting peak in the DSC thermograms of cured NE and RS coated beads confirmed that there was no surface crystallization of ibuprofen. These results indicated that the increase in drug release rates from RS coated pellets, when subjected to long curing times, resulted from loss of plasticizer. Free films of Eudragit NE exhibited an increase in tensile strength with increased curing times, whereas Eudragit RS free films showed a decrease in tensile strength beyond 4 h of curing at 70 and 90 degrees C. The film thicknesses and weights of free films of Eudragit RS prepared with triethyl citrate plasticizer were found to change more dramatically with curing than did free films of Eudragit RS prepared with ibuprofen as the plasticizer. An increase in pore volume was also observed with increased curing times for Eudragit RS free films. Such changes with curing were shown to be due to the loss of plasticizer molecules, leading to the formation of molecular-scale voids and channels.

The effect of binary mixture composition and magnesium stearate concentration on the Hiestand Tableting Indices and other related mechanical properties.

Maltodextrins were chosen as model excipients because maltodextrins possess a series of molecular weights that showed systematically changing consolidation mechanisms. As maltodextrin molecular weight increases, the plasticity of the material increases. Three commercial grades of Maltrin (M040, M100, and M150) were used to prepare binary powder mixtures (M040-M150 and M040-M100). For each mixture, magnesium stearate was added at concentrations of 0%, 0.16%, 0.32%, 0.48%, and 0.64%. The Hiestand Tableting Indices and other related mechanical properties were used to quantify the effects of magnesium stearate addition on the compaction properties of the binary mixtures. Linear relationships were observed between the Hiestand Bonding Indices and the compositions of the compacts in the absence of magnesium stearate. However, the Hiestand Bonding Indices were related to compact compositions in polynomial fashion when magnesium stearate was present in the binary mixtures. The Hiestand Brittle Fracture Indices varied with compact compositions in polynomial fashion with and without magnesium stearate.