Study of the Seismoelectric Effect of the Second Kind Using Molecular Sensors.

The article is devoted to the study of the potential possibilities of using molecular-electronic sensors of seismic waves for field work using the seismoelectric method to explore the hydrocarbon deposits. The introduction provides an analytical review of the current state of research based on data from science magazines and patents. It is shown that at present, seismoelectric effects are at the stage of experimental implementation into the practice of field work for oil and gas geophysical prospecting. Further in the article, theoretical estimates and results of mathematical modeling of the manifestation of seismoelectric (SE) phenomena in the regions of hydrocarbon anomalies are presented, numerical estimates of the values of the seismic and secondary electromagnetic fields are given. The analysis of the results (on a tank and real gas condensate field) showed that the use of molecular-electronic geophones, which have a higher sensitivity and operate in a wider frequency range (up to 0.1 Hz), allows one to obtain higher signal-to-noise ratio. Thus, it has been experimentally established that the use of molecular sensors for recording seismic electric effects when searching for deposits is more preferable when carrying out field work.

Frequency Response Stabilization and Comparative Studies of MET Hydrophone at Marine Seismic Exploration Systems.

Low frequency hydrophone with a frequency range of 1-300 Hz for marine seismic exploration systems has been developed. The operation principle of the hydrophone bases on the molecular electronic transfer that allows high sensitivity and low level self-noise at low frequencies (<10 Hz) to be achieved. The paper presents a stabilization method of the frequency response within the frequency range at a depth up to 30 m. Laboratory and marine tests confirmed the stated characteristics as well as the possibility of using this sensor in bottom marine seismic systems. An experimental sample of the hydrophone successfully passed a comparative marine test at Gelendzhik Bay (Black Sea) with the technical support of Joint-Stock Company (JSC) "Yuzhmorgeologiya". One of the main results is the possibility of obtaining high-quality information in the field of low frequencies, which was demonstrated in the course of field tests.

Parenteral delivery of HPßCD: effects on drug-HSA binding.

It is thought that cyclodextrins, such as 2-hydroxypropyl-ß-cyclodextrin (HPßCD), will at high concentration affect pharmacokinetics of drugs through competitive binding with plasma proteins. Albumin is the major component of plasma proteins responsible for plasma protein binding. The purpose of this study was to evaluate in vitro the competitive binding of drugs between human serum albumin (HSA) and HPßCD in isotonic pH 7.4 phosphate buffer saline solution (PBS) at ambient temperature. Eight model drugs were selected based on their physicochemical properties and ability to form complexes with HSA and HPßCD. The drug/HPßCD stability constants (K(1:1)) were determined by the phase-solubility method and HSA/HPßCD competitive binding determined by an equilibrium dialysis method. Protein binding of drugs that are both strongly protein bound and have high affinity to HPßCD (i.e., have high K(1:1) value) is most likely to be affected by parenterally administered HPßCD. However, this in vitro study indicates that even for those drugs single parenteral dose of HPßCD has to be as high as 70 g to have detectable effect on their protein binding. Weakly protein bound drugs and drugs with low affinity towards HPßCD are insensitive to the cyclodextrin presence regardless their lipophilic properties.

Thermodynamic studies of Fenbufen, Diflunisal, and Flurbiprofen: sublimation, solution and solvation of biphenyl substituted drugs.

Temperature dependency of saturated vapour pressure for Fenbufen (FBF) was obtained. Heat capacities for Fenbufen, Diflunisal (DIF), and Flurbiprofen (FBP) were measured, and standard thermodynamic functions of sublimation were calculated (FBF: DeltaGsub298=74.0 kJ mol(-1); DeltaHsub298=155.0+/-0.8 kJ mol(-1); DeltaSsub298=272+/-3 J mol(-1)K(-1); DIF: DeltaGsub298=57.6 kJ mol(-1); DeltaHsub298=120.1+/-0.6 kJ mol(-1); DeltaSsub298=210+/-2 J mol(-1)K(-1); FBP: DeltaGsub298=53.3 kJ mol(-1); DeltaHsub298=110.2+/-0.5 kJ mol(-1); DeltaSsub298=191+/-2 J mol(-1)K(-1)). Thermochemical parameters of fusion process for FBF were obtained, and evaporation enthalpy was estimated from fusion and sublimation enthalpies. Temperature dependencies of the solubility in buffer solutions (pHs 2.0 and 7.4), n-Octanol, and n-Hexane were measured, and solution and solvation thermodynamic functions were calculated. The transfer thermodynamic functions from n-Hexane to solvents used (imitating specific "drug-solvent" interaction), and from buffer solutions to n-Octanol (imitating partitioning/distribution processes) were analyzed. Specific/non-specific "drug-solvent" interaction ratios in terms of solvation enthalpies were estimated. All studied solutions are characterized by prevalence of non-specific "drug-solvent" interactions. A difference exists between mechanisms of partitioning and distribution of studied drugs.

The difference between partitioning and distribution from a thermodynamic point of view: NSAIDs as an example.

Solubility and solvation of some NSAIDs were studied in their non-ionic (aqueous buffers of pH 2.0) and ionic molecular form (pH 7.4) over a wide temperature interval. Absolute scale values for the thermodynamic terms (Gibbs energy, enthalpy and entropy) were obtained. Thermodynamic parameters of the transfer of the molecules from one buffer to the other (representing protonation/deprotonation) were derived. It has been found that the thermodynamic characteristics of solvation (hydration) of (+)- and (+/-)-IBP in the buffers show a difference, which is larger than the experimental error. This may be explained by differences in the association states of the molecules in solution. For the other NSAIDs studied, a correlation between the Gibbs energy of transfer, deltaG(tr) (pH 7.4-->pH 2.0) and the pK(a)-value, and a compensation effect between the enthalpic and entropic terms have been revealed. Thermodynamic aspects of the transfer process from the buffers to n-octanol were analysed. The two types of the transfer processes (non-dissociated molecule to octanol (partitioning), and dissociated form to octanol (distribution)) have essentially different driving forces: partitioning is enthalpy driven, whereas the transfer of the ionic form is entropy driven. The following points are discussed: (a) significance of using water-octanol systems (logP as a measure of drug lipophilicity) to describe biological membranes (lipid systems); (b) differences in thermodynamic aspects of the partitioning/distribution processes of these systems; (c) advantages of the present transfer method approach in comparison with temperature dependencies of logP to analyse the driving forces of partitioning/distribution.

Self-Assembly of Cyclodextrins and Their Complexes in Aqueous Solutions.

Cyclodextrins (CDs) are enabling pharmaceutical excipients that can be found in numerous pharmaceutical products worldwide. Because of their favorable toxicologic profiles, CDs are often used in toxicologic and phase I assessments of new drug candidates. However, at relatively high concentrations, CDs can spontaneously self-assemble to form visible microparticles in aqueous mediums and formation of such visible particles may cause product rejections. Formation of subvisible CD aggregates are also known to affect analytical results during product development. How and why these CD aggregates form is largely unknown, and factors contributing to their formation are still not elucidated. The physiochemical properties of CDs are very different from simple amphiphiles and lipophilic molecules that are known to self-assemble and form aggregates in aqueous solutions but very similar to those of linear oligosaccharides. In general, negligible amounts of aggregates are formed in pure CD solutions, but the aggregate formation is greatly enhanced on inclusion complex formation, and the extent of aggregation increases with increasing CD concentration. The diameter of the aggregates formed is frequently less than about 300 nm, but visible aggregates can also be formed under certain conditions.

Thermodynamics of solutions III: comparison of the solvation of (+)-naproxen with other NSAIDs.

Naproxen was studied by classical thermoanalytical methods, namely sublimation calorimetry, solution calorimetry and the solubility method. Temperature dependence of a saturated vapor pressure was obtained and the sublimation enthalpy, deltaHsub(0) and entropy, deltaSsub(0) and their relative fraction of the total process were calculated. These parameters yielded for naproxen were compared to the respective data of other naphthalene derivatives. The crystal lattice energy of naproxen was calculated by two force fields (Gavezzotti et al. and Mayo et al.) and compared to the experimental data. Contributions of different motifs of the naproxen molecule to the total packing energy were analyzed. The Gibbs energy of solvation as well as enthalpic and entropic terms thereof in aliphatic alcohols have been studied for naproxen, and compared to model substances and other non-steroid anti-inflammatory drugs (benzoic acid, diflunisal and flurbiprofen). The major driving force of the solvation process is the enthalpy. The respective contributions of the specific and the non-specific solvation interactions in terms of absolute and relative values have been investigated.

Thermodynamics of sublimation, crystal lattice energies, and crystal structures of racemates and enantiomers: (+)- and (+/-)-ibuprofen.

Thermodynamic differences between ibuprofen (IBP) racemate and the (+)-enantiomer were studied by X-ray diffraction, thermoanalysis, and crystal energy calculations. The thermodynamic functions of sublimation (as a measure of crystal lattice energy) were obtained by the transpiration method. The sublimation enthalpies (DeltaH(sub)) of (+/-)-IBP and (+)-IBP are 115.8 +/- 0.6 and 107.4 +/- 0.5 kJ. mol(-1), respectively. Using the temperature dependency of the saturated vapor pressure, the relative fractions of enthalpy and entropy of the sublimation process were calculated, and the sublimation process for both the racemate and the enantiomer was found to be enthalpy driven (62%). Two different force fields, Mayo et al. (M) and Gavezzotti (G), were used for comparative analysis of crystal lattice energies. Both force fields revealed that the van der Waals term contributes more to the packing energy in (+)-IBP than in (+/-)-IBP. The hydrogen bonding energy, however, contributes at 29.7 and 32.3% to the total crystal lattice energy in (+)-IBP and (+/-)-IBP (M), respectively. Furthermore, different structure fragments of the IBP molecule were analyzed with respect to their contribution to nonbonded van der Waals interactions. The effect of the C-H distance on the van der Waals term of the crystal lattice energy was also studied.

Thermodynamics of solutions IV: Solvation of ketoprofen in comparison with other NSAIDs.

The present work discusses the characteristics of solvation (Gibbs energy, enthalpic and entropic terms of Gibbs energy) for ketoprofen together with other nonsteroidal antiinflammatory drugs (NSAIDs) in aliphatic alcohols. Ketoprofen was studied by classical thermoanalytical methods of sublimation calorimetry, solution calorimetry, and solubility. Temperature dependence of the saturated vapor pressure was determined, and the sublimation enthalpy, delta H(sub) (0) and sublimation entropy, delta S(sub)(0), as well as their respective relative fractions in the total process were calculated. The parameters yielded for ketoprofen were compared with the respective literature data of other benzophenone derivatives. The Gibbs energy of solvation as well as enthalpic and entropic terms thereof in aliphatic alcohols were also studied for ketoprofen and compared with the properties of model substances and other NSAIDs (benzoic acid, diflunisal, flurbiprofen, and naproxen). In all cases, the major driving force of the solvation process is enthalpy. Correlations were derived between Gibbs energy of solvation in octanol, delta G(solv)(oct), and the transfer Gibbs energy from water to octanol, delta G(tr)(0).

Thermodynamics of solutions. II. Flurbiprofen and diflunisal as models for studying solvation of drug substances.

Three independent methods (sublimation, solubility and solution calorimetry) were used to study the dissolution and solvation processes of diflunisal (DIF) and flurbiprofen (FBP). Thermodynamic functions for the sublimation of DIF and FBP were obtained. Concentrations of saturated solutions and standard solution enthalpies of DIF and FBP in aliphatic alcohols and individual organic solvents were measured. Correlation analysis between: (a) the thermodynamic functions for a substance in various solvents, and (b) the same functions for different compounds was carried out. The investigated substances can be arranged with increasing Gibbs energy of solvation as follows: benzoic acid

Solvation and hydration characteristics of ibuprofen and acetylsalicylic acid.

Ibuprofen and acetylsalicylic acid were studied by thermoanalytical methods: sublimation calorimetry, solution calorimetry, and with respect to solubility. Upon measuring the temperature dependences of the saturated vapor pressure, enthalpies of sublimation, DeltaH(0) (sub), as well as the entropies of sublimation, DeltaS(0) (sub), and their respective relative fractions in the total process were calculated. The Gibbs energy of solvation in aliphatic alcohols as well as the enthalpic and entropic fractions thereof were also studied and compared with the respective properties of model substances and other nonsteroidal antiinflammatory drugs (benzoic acid, diflunisal, flurbiprofen, ketoprofen, and naproxen). In all cases, enthalpy was found to be the driving force of the solvation process. Correlations were derived between Gibbs energy of solvation in octanol, DeltaG(Oct) (solv), and the transfer Gibbs energy from water to octanol, DeltaG(0) (tr). Influence of mutual octanol and water solubilities on the driving force of partitioning is discussed. An enthalpy-entropy-compensation effect in octanol was observed, and consequences of deviation from the general trend are also discussed.

γ-Cyclodextrin nanoparticle eye drops with dorzolamide: effect on intraocular pressure in man.

PURPOSE: To test a new drug delivery platform with dorzolamide γ-cyclodextrin (γCD) nanoparticle eye drops for intraocular pressure (IOP) control and safety and compare with Trusopt.(®) METHODS: Self-aggregating γCD nanoparticle eye drops containing 3% dorzolamide were given once a day (QD) and compared with Trusopt given three times a day (TID) in a prospective randomized single masked crossover trial over 24 h. Seventeen subjects with IOP over 18 mmHg were recruited. IOP was measured with an Icare Tonometer Pro.(®) RESULTS: There was no statistically significant difference in the IOP lowering effect of dorzolamide nanoparticle eye drops QD and Trusopt TID. At peak (4 h), the IOP reduction from baseline was 3.8±2.6 mmHg (18%, P<0.05) in the nanoparticle eye drop group and 3.1±3.7 mmHg in the Trusopt group (14%, P<0.05, P=0.97 between groups). At trough (24 h), the IOP reduction was 1.4±2.8 mmHg (6%, P>0.05) in nanoparticle eye drop group and 1.5±2.0 mmHg (7%, P>0.05) in the Trusopt group (P=0.23 between groups). Burning sensation measured on the visual analogue scale (1-100) was less from the nanoparticle eye drops (12±15) than from the Trusopt (37±30), (P=0.0038). Visual acuity and conjunctival hyperemia did not differ between the two groups. CONCLUSIONS: Dorzolamide cyclodextrin nanoparticle eye drops QD lower IOP and the effect seems comparable to Trusopt given TID. The nanoparticle eye drops are well tolerated and seem to have a better safety profile than Trusopt.

Cyclodextrins.

Although cyclodextrins (CDs) have been studied for over 100 years and can be found in at least 35 pharmaceutical products, they are still regarded as novel pharmaceutical excipients. CDs are oligosaccharides that possess biological properties that are similar to their linear counterparts, but some of their physicochemical properties differ. CDs are able to form water-soluble inclusion complexes with many poorly soluble lipophilic drugs. Thus, CDs are used to enhance the aqueous solubility of drugs and to improve drug bioavailability after, for example, oral administration. Through CD complexation, poorly soluble drugs can be formulated as aqueous parenteral solutions, nasal sprays and eye drop solutions. These oligosaccharides are being recognized as non-toxic and pharmacologically inactive excipients for both drug and food products. Recently, it has been observed that CDs and CD complexes in particular self-assemble to form nanoparticles and that, under certain conditions, these nanoparticles can self-assemble to form microparticles. These properties have changed the way we perform CD research and have given rise to new CD formulation opportunities. Here, the pharmaceutical applications of CDs are reviewed with an emphasis on their solubilizing properties, their tendency to self-assemble to form aggregates, CD ternary complexes, and their metabolism and pharmacokinetics.

Encapsulation of drug molecules into calix[n]arene nanobaskets. role of aminocalix[n]arenes in biopharmaceutical field.

Calix[n]arenes (CAs) are supramolecular compounds able to form guest-host inclusion complexes with metal ions, small organic molecules, and small moieties of larger molecules. Although the CA literature is extensive, relatively few publications deal with water-soluble CAs, especially those containing nitrogen-based functionality. These CAs possess antibacterial and antifungal activity. Because of their molecular structure, they are surface active and also able to form water-soluble drug complexes, giving additional potential as enabling pharmaceutical excipients. This article provides an overview of the published data regarding synthesis, physicochemical properties, and pharmaceutical application of water-soluble CAs with emphasis on those that contain nitrogen-based substituents in their structure, particularly aminoCAs. In particular, it describes state-of-the-art in complexation of water-soluble CAs with pharmaceutically relevant ions and organic molecules up to amino acids, DNA, and proteins.

Cationic quaternized aminocalix[4]arenes: cytotoxicity, haemolytic and antibacterial activities.

This study reports the characterization of three cationic amphiphillic aminocalix[4]arenes as potential antimicrobial agents in vitro. In cytotoxicity tests on mouse macrophage RAW 264.7 cells aminocalix[4]arenes 1 and 3 showed no toxicity up to 200 and 100 µM concentrations, respectively, while 2 was non-toxic only up to 50 µM. With regard to the haemolytic activity on rabbit red blood cells, 1 was not active at concentrations up to 100 µM in contrast to the other two studied macrocycles. Compounds showed negligible ability to protect either mouse macrophage RAW 264.7 cells from anthrax lethal toxin of Bacillus anthracis (B. anthracis) or rabbit red blood cells from α-haemolysin of Staphylococcus aureus (S. aureus) in comparison to amino-ß-cyclodextrins. However, all aminocalix[4]arenes showed potential as antimicrobials. Their minimum inhibitory concentrations (MIC) against Escherichia coli (E. coli) and S. aureus were in the 16-32 µg/ml concentration range, while minimum lethal concentrations (MLC) varied from 16 to 256 µg/ml depending on the bacteria and aminocalix[4]arene considered. Macrocycle 1 showed partial synergism against S. aureus in tandem with a model antibacterial drug, fusidic acid, at certain concentration combinations.

The effect of parenterally administered cyclodextrins on the pharmacokinetics of coadministered drugs.

Cyclodextrins are used increasingly to formulate otherwise poorly soluble molecules for clinical use. Cyclodextrins, such as 2-hydroxypropyl-ß-cyclodextrin (HPßCD) and sulfobutylether ß-cyclodextrin (SBEßCD), are found in marketed parenteral drug formulations. Depending upon the relative affinities of a coadministered medication for cyclodextrin and plasma proteins, complexation with HPßCD or SBEßCD may alter its pharmacokinetics (PK). To explore this possibility, we applied a previously developed model for competitive binding of drugs with HPßCD and human serum albumin to a variety of commonly administered medications. We modeled this potential interaction in medications chosen on the basis of a hypothetical detrimental effect of HPßCD complexation with their therapeutic action (e.g., antibiotics), supplemented by a composite listing of concurrent medications. Stability constant (K(1:1)) values for drug-HPßCD 1:1 inclusion complexes were extracted from our own data and the literature. The K(1:1) values for the drugs tested ranged from 2 to 40,000 M(-1) and the plasma protein binding from about 20% to over 99%. None of the 63 drugs examined in the present study had a sufficiently high K(1:1) value for HPßCD complexation to affect plasma protein binding to a degree that would be expected to alter their PK substantively, for example, to require increased doses.

Self-assembly of cyclodextrins: the effect of the guest molecule.

The principle action by which cyclodextrins solubilize compounds is via inclusion complex formation. However, data suggest that cyclodextrins and their complexes also aggregate in solution and this aggregation contributes to their ability to solubilize poorly water-soluble materials. The current effort aims at better understanding the role of guest molecule nature (i.e. its structural and functional peculiarities) in cyclodextrin complex aggregation as well as in the aggregate stability assessed using a cellophane membrane permeability assay. A test set of 11 acidic, basic and neutral drugs and antibacterial agents (i.e. guests) were examined with regard to their interaction with hydroxypropyl-ß-cyclodextrin (HPßCD) and the resulting ability of the formed aggregates to move through a semi-permeable membrane of various molecular weight cut-off values. The data suggested that the interaction of HPßCD with certain guests resulted in the formation of structure large enough to poorly penetrate semi-permeable membrane. The aggregates appeared to be highly dynamic in that there were no qualitative differences between systems that were diluted immediately prior to permeation experiments and those allowed to equilibrate. Pharmaceutical polymers which have been shown to enhance solubilizing efficiency of cyclodextrins had little or no effect on the stability of the aggregates using the permeability paradigm as an endpoint with the exception of carboxymethylcellulose.

Self-assembly of cyclodextrin complexes: aggregation of hydrocortisone/cyclodextrin complexes.

Cyclodextrins (CDs) are well known functional excipients for solubilization and stabilization of drugs in aqueous formulations as well as enabling adjuncts for increasing the oral bioavailability of solid dosage forms. More recently a number of the valuable properties of these CDs have been ascribed to nanoparticulate aggregation in addition to its ability to form molecular inclusion complexes. The purpose of this study is to identify and characterize the aggregation of CD inclusion complexes with a model drug, hydrocortisone, in saturated solutions which are more relevant to drug formulation than highly dilute systems. Penetration studies of complexes through membranes and phase solubility relationships were assessed for saturated hydrocortisone solutions with the parent CDs, namely αCD, ßCD, γCD or with various water-soluble derivatives, i.e., 2-hydroxypropyl-ßCD (HPßCD), 2-hydroxypropyl-γCD (HPγCD) or sulfobutyl ether-ß-CD (SBEßCD). The data indicate that ßCD and γCD form micro-aggregates with hydrocortisone resulting in non-linear phase-solubility relationships. By contract, the other studies of CDs or CD derivatives were found to form nanoaggregates with hydrocortisone resulting in linear solubilization relationships. Permeability profiles were evaluated for the systems formed and are described in three sections specifically a section (section I) where flux is linear (Fickian) as a function of CD concentration, a section (section II) where flux deviates in a negative fashion from linearity but still increases as the CD concentration increases and a section (section III) where flux is independent of the cyclodextrin concentration. Diminished values of flux can be interpreted based on the formation of nanoaggregates of hydrocortisone/CD complexes. Extrapolation of section I data made it possible to obtain theoretical flux values which could be used to estimate the fraction of complexes and drug which participate in aggregation. The CDs which appeared to demonstrate the lowest tendency to form complex aggregates were αCD and SBEßCD, due to their low complexation efficacy and repulsive forces, respectively. Complex aggregates with these CDs are also smaller with maximum size between 50 and 100 kDa. HPßCD and HPγCD complex aggregates manifested a maximum size above 100 kDa and the fraction of drug which participates in complex aggregation with these species is higher than for the other materials assessed. In the case of 90 mM HPγCD solution, data suggest that 87% of all hydrocortisone is tied up in the form of aggregates. These high concentrations were confirmed by TEM which found most particles in the 3-5 nm range but rarely particles as large as 10 and 20 nm. Speculation on the mechanism of the aggregation processes and equilibrium constants are provided but these tend to punctuate our limited understanding of these potentially important processes.

Self-assembly of cyclodextrin complexes: effect of temperature, agitation and media composition on aggregation.

Recently it has been shown that aggregation of drug/cyclodextrin inclusion complexes is strongly influenced by the drug molecule in addition to self-assembling tendencies of the cyclodextrin itself in aqueous media. Whereas the mechanistic basis of cyclodextrin self-assembly is known, the driving forces for complex aggregation are still unknown. In the present study, the influence of temperature on hydrocortisone/2-hydroxypropyl-ß-cyclodextrin complex aggregation is investigated as are influences associated with the addition of ethanol or water soluble polymers to the aqueous systems. Furthermore the effect of stirring on the aggregation is assessed. Size exclusion permeability studies were conducted to estimate complex aggregation tendencies. The results indicate that self-assembled complex aggregates are metastable and notably become smaller with increasing temperature and the addition of ethanol. Water soluble polymers also reduce the size of the complex aggregates. Specifically, hexadimethrine bromide had the greatest impact, since addition of this compound eliminated aggregates from the systems or reduced their size below the molecular weight cut-off of the sizing membrane (8 kDa). Similar observations are made when aqueous solutions of hydrocortisone and 2-hydroxypropyl-ß-cyclodextrin are equilibrated by stirred.

Evaluation of sugammadex self-association.

Sugammadex, a thiolated γCD derivative used as an antagonist of steroidal blockers, was studied with regard to its tendency to self-associate in aqueous solution. Three independent methods - permeation through semi-permeable cellophane membranes, dynamic light scattering, and sedimentation equilibrium analytical ultracentrifugation - were used for this purpose. The results were in agreement with each other and showed no evidence of self-association in a wide sugammadex concentration range from 0.25 to 100mg/ml.