Quantifying the chameleonic properties of macrocycles and other high-molecular-weight drugs

Synthetic polymer single-chain nanoparticles (SCNPs) are an emerging new class of nanomaterials that possess similar folded structures as natural proteins. However, most SCNPs reported so far are p...

Lipophilicity is a physicochemical parameter well known as a decisive factor for predicting the successful development of a drug. Thus, a balance between potency and physicochemical properties during medicinal chemistry optimization is needed. In this study, the lipophilicity of isoindole-1,3(2H)-dione derivatives designed as phosphodiesterase 10A (PDE10A) inhibitors was determined by chromatographic [reversed-phase thin-layer chromatography (RP-TLC) and ultra-performance liquid chromatography/mass spectrometry (UPLC/MS)] and in silico methods. To assess the correlation between the obtained lipophilicity parameters, principal component analysis (PCA) was performed. logP values obtained by chromatographic (logPRP-TLC and logPUPLC/MS) and in silico methods were compared using the PCA method. The results of PCA revealed that logPUPLC/MS and in silico clogP provided by the ChemDraw program were highly correlated. Compounds’ drug likeness was screened, and the pharmacokinetic properties were predicted. All the investigated compounds displayed drug-likeness properties, and they met the criteria of Lipinski’s rule of five, which predicted the oral bioavailability of drug candidates. Analysis of the influence of physicochemical properties on the biological activity showed that the compounds with increased potency on PDE10A had significantly higher topological polar surface area (TPSA) values. The blood‒brain barrier permeability and the hemolytic activity of model compound 18 were examined. The model compound 18 displayed no toxicity effect on erythrocytes in the hemolytic assay and good parallel artificial membrane permeability. The results showed that phthalimide compounds with benzimidazole moiety are a source of compound-targeted inhibition of PDE10A with balanced physicochemical and drug-likeness properties.

P‐glycoprotein Influences the Brain Concentrations of Cetirizine (Zyrtec®), a Second‐Generation Non‐Sedating Antihistamine

Increasing the efficiency of hydrocarbon field development is an important issue. One of the methods for increasing oil recovery is the injection of aqueous solutions of polymers. Although this method has been known and used for quite some time, further systematic research is needed to further improve its effectiveness. In this work, systematic computational studies of the features of oil displacement by aqueous polymer solutions from a naturally fractured structure were carried out. Direct numerical modeling of a two-phase immiscible flow in the process of displacing oil from a natural fracture structure using solutions of anionic polymers based on polyacrylamide was carried out. Aqueous solutions of three different polymers were considered, the concentrations of which varied from 0 to 0.1%, and the molecular weights were from 10 to 20 mln c.u. The rheological properties of polymers and their wetting characteristics have been previously studied in laboratory experiments. A distinctive feature of the polymers considered was the non-Newtonian nature of their aqueous solutions even at low concentrations. To take these processes into account, the computational technique has been extended to the case of non-Newtonian rheology for immiscible two-phase flow in one of the media. During numerical simulations, the effect of the concentration of polymers, their molecular weight, and charging density on the flow regimes in a fractured reservoir have been investigated systematically at various crude oil viscosities. It has been shown that the use of a 0.1% aqueous solution of polyacrymalide can increase the oil-recovery factor by 1.8 times. It has been established that, with an increase in the molecular weight and surface charge density of the polymer, the efficiency of its use for enhancing oil recovery increases. With an increase in the viscosity of the displaced oil, the effect of using the injection of the considered polymers also increases. The data obtained in this work can be used to further improve polymer-flooding technologies for oil fields.

The extraction of phenylalanine, tyrosine and tryptophan from aqueous salt solutions by water soluble polymer - poly-N-vinylpyrrolidone having a molecular weight of 3,500 has been studied. Under identical conditions set quantitative characteristics extraction has been established, general scheme of analysis has been developed. Effect the volume ratio of aqueous and organic phases to the recovery of phenylalanine, tryptophan and tyrosine has been studied. The dependence of solution viscosity of the polymer and the speed of lamination systems the molecular weight and concentration of the extractant has been set. It was established that the most studied aromatic amino fully extracted solution of PVP-3500 at a concentration of 0,12 g/cm3, while the ratio of the equilibrium amounts of aqueous and organic phases 10:4. Optimized conditions for the almost complete extraction of phenylalanine, tyrosine and tryptophan from aqueous salt solutions. The technique of extraction-spectrophotometer determination of aromatic amino acids in aqueous solution. Based highs proposed scheme of interaction with PVP-3500 extractable substances. We have developed a technique characterized by express (analysis time 30 - 40 min), accuracy (relative error within 7%), ecology (and lack of toxic extragants "green extraction"). Learned extraction systems applicable to practically complete extraction of phenylalanine, tyrosine and tryptophan from aqueous solutions.

Mucoadhesive thiolated chitosans as platforms for oral controlled drug delivery: synthesis and in vitro evaluation

Quantitative analysis of excipients to the permeability of BCS class III drugs

Through ultrasonic assisted radical polymerization, hydrophobically associating polyacrylamide (U-HAPAM) was prepared by acrylamide (AM), 2-acrylamido -2- methyl propane sulfonic acid (AMPS), and long-aliphatic-chain hydrophobic monomer octadecyl acrylate (ODA). The effects of ultrasonic frequency power on total monomer conversion, relative molecular mass and the aqueous solution behavior were discussed. The results showed that, when the ultrasonic power was 120 W, there was a good thickening ability, total monomer conversion was 76.36 %, relative weight-average molecular mass was 72500, the critical association mass concentration (C*) was 0.27 wt% and there were good intermolecular hydrophobically associating interactions in the copolymer aqueous solution. U-HAPAM was pseudoplastic fluid; the associating behavior of the U-HAPAM had apparent effects on the dynamic moduli (G′and G″) and the apparent average aggregate size (d*). When mass concentration of copolymer (Cm) was 0.40 wt%, the apparent viscosity attained 453.6 mPa·s. The viscosity retention index (VRI) was 60.99 % as the temperature reached 80 °C. The apparent viscosity of U-HAPAM in mineralized water was increased towards 502.9 mPa·s as the degree of mineralization (M) was 19334 mg/L. Under the effect of ultrasounds, the ODA was effectively introduced into U-HAPAM without micromolecule emulsifier, which endowed the copolymer good solution properties.

Shape, molecular weight distribution and viscosity of amylopectin in dilute solution

PurposeThe purpose of this paper is to investigate in situ modification of cyclohexanone‐formaldehyde resins (CFR) by 4‐vinyl aniline (Van). The roles of the reaction temperature, the conductivity, thermal properties, and molecular weight of the product were investigated. CFR was in situ modified with VAn in the presence of sodium hydroxide. Ketonic resin‐bound 4‐vinyl aniline was synthesised with a one‐step method of in situ modification of ketonic resin. The roles of the reaction temperature and the conductivity of the product were investigated.Design/methodology/approachKetone, formalin (37% aqueous solution), vinyl aniline were mixed and then 20% aqueous NaOH solution was added to produce the resin. The solubility, molecular weight and thermal properties of the products were investigated.FindingsThe 4‐vinyl aniline modified cyclohexanone‐formaldehyde resins were found to have conductivity values of 10−4 and 10−2 S/cm and may be considered as conductive ketonic resin. Soluble and processable conductive ketonic resins were developed.Research limitations/implicationsThe reaction mixture of CFR must be stirred continuously at low temperature. Subsequently, 37% formalin was added dropwise in equal portions while refluxing. Temperature should be controlled to prevent the thermal polymerisation of vinyl group and higher branching of amino groups. The amount of vinyl aniline used in reaction mixture is limited since the formed resin may become insoluble in common organic solvents.Practical implicationsThis study provides technical information for the synthesis of conducting resins. The modified resins contain vinyl groups. The chemical redox or radical system can be used to polymerise these vinyl groups and resins with much higher molecular weight may be produced. The resins may also promote the adhesive strength of a coating and corrosion inhibition to metal surfaces of a coating.Originality/valueVinyl aniline modified cyclohexanone formaldehyde resins have been synthesised in the presence of a basice catalyst. These soluble and conductive resins may overcome difficulties in the applications of conducting polymers and open new application areas. Therefore, the vinyl aniline modified resin may find a number of new application areas, as well as existing conducting resin and polymer applications.

In 1997, the 'Rule of Five' (Ro5) suggested physicochemical limitations for orally administered drugs, based on the analysis of chemical libraries from the early 1990s. In this review, we report on the trends in oral drug product development by analyzing products launched between 1994 and 1997 and between 2013 and 2019. Our analysis confirmed that most new oral drugs are within the Ro5 descriptors; however, the number of new drug products of drugs with molecular weight (MW) and calculated partition coefficient (clogP) beyond the Ro5 has slightly increased. Analysis revealed that there is no single scientific or technological reason for this trend, but that it likely results from incremental advances are being made in molecular biology, target diversity, drug design, medicinal chemistry, predictive modeling, drug metabolism and pharmacokinetics, and drug delivery.

ABSTRACTThis work employed total internal reflectance fluorescence (TIRF) to examine the adsorption kinetics of polyethylene oxide (PEO) on silica from aqueous solution in controlled shearing flow. Studies with PEO, fluorescently labeled such that TIRF tracked the chain number on the surface, exhibited an overshoot in the early stages of adsorption. This overshoot was not seen with other polymers such as polyvinyl alcohol, and hydroxyethyl cellulose, possibly because these other polymers were labeled such that TIRF measured the interfacial mass. Indeed, reflectometry studies of PEO adsorption, sensitive to interfacial mass, showed no overshoot. This suggests that the overshoot results from the selectivity of the surface for high molecular weight populations within a polydisperse sample. Initially short chains adsorb because they diffuse to the surface quickly. At longer times, higher molecular weight chains reach the surface and replace the short chains. This evolution occurs as the mass coverage increases (according to reflectivity) but the number of adsorbed chains, and hence the TIRF signal decrease at long times. A study of the impact of the molecular weight distribution confirmed this hypothesis.Several complications to the molecular weight selectivity hypothesis, however, arose: First, the same PEO samples which overshot during adsorption on silica showed no overshoot on a polystyrene substrate. This suggested that the ability to overshoot was governed by the substratesegment interactions, even though the molecular weight distribution within the sample determined the overshoot shape. Further, the effect of transport conditions (wall shear rate, bulk polymer concentration) were not completely consistent with the molecular weight competition hypothesis, which was based on surface-solution equilibrium, taking into account transport-limited rates of adsorption. Finally certain runs, where the adsorption process was interrupted by solvent flow and later allowed to proceed, never reached the full coverage seen for uninterrupted runs. Hence, the surface coverage and possibly the chain configurations can depend on the history of the adsorption process, a feature which points to surface relaxations and non-equilibrium structures.

Aggregates of sodium hyaluronate with cationic and aminoxide surfactants in aqueous solution — light scattering study

Background: Diabetes mellitus is a major chronic health problem globally, so the patterns of drug utilization study of oral anti-hyperglycemic drugs are of chief concern to promote rational drug use in diabetics and make available the valuable information for the healthcare providers. Objective: This study was performed to determine the drug utilization pattern of oral anti-hyperglycemic drugs in Type-2 diabetes mellitus (T2DM) patients in a tertiary care teaching hospital in Eastern India. Materials and Methods: A prospective, observational, and noncomparative study was carried for 12 weeks in T2DM patients on oral anti-hyperglycemic drugs for at least 1 week. Results: Total 230 patients were enrolled with mean age of 54.66 ± 13.24 years and duration of diabetes was 8.71 ± 7.78 years. Among these, 78 (33.91%) were in the age group 51–60 years, 132 (57.39%) had a diabetic history of <10 years, and 168 (73.04%) had associated hypertension. Mean number of drugs prescribed were 7.01 ± 2.73. Total numbers of patients receiving more than five drugs were 162 (70.43%). The biguanide (85.21%) was the most commonly prescribed oral anti-hyperglycemic drugs followed by sulfonylureas (58.26%). The 97 (75.78%) female patients were shown good compliance as compared with 72 (70.58%) males. Conclusion: Metformin (Biguanide) was the most commonly prescribed oral anti-hyperglycemic drugs for Type-2 diabetes. This study indicates the clinical monitoring of the patient's compliance to the prescribed drug for achieving good glycemic control is also recommended, along with other comprehensive management such as life style changes, dietary modification, treatment of complications, and co-morbidities related to diabetes.

Drug permeability is often a limiting step in drug action, requiring chemical optimization of a drug candidate to improve this property. Such optimization is typically performed in the context of a congeneric series, where substituents are varied to optimize the target property. Motivated by this need the present work examines the influence of chemical substituents on passive permeability (log P pass) across parallel artificial membranes (PAMPA) undertaken for three congeneric series of compounds; benzoic acids, pyridines and quinolines. PAMPA showed pyridine and quinoline to have high permeability and chemical substituents to typically reduce the permeability. On the contrary, benzoic acid showed poor permeability and chemical substituents typically increased the permeability. To quantitate these effects with respect to physical properties, models were built to explain and predict the permeability of these classes of compounds based on computed molecular descriptors. Models for the benzoic acid series in the ionized state indicated the solvent accessible surface area, cavity dispersion and the free energy of solvation in hexane as well as in water to dominate permeability. However, when the acid group is treated as neutral, the free energy of solvation in water, the fraction polar surface area, the polar surface area and difference in the free energy of solvation between hexane and water were important; these terms, among others, were also important for the neutral pyridine-quinoline series. Considering that the permeability of the benzoic acid series is about 2 orders of magnitude lower than the pyridines and quinolines and that a shift of approximately two pH units in the p K a of the acid group of benzoic acid will allow for the neutral species of the molecule to dominate under experimental conditions (pH = 6.5), these results suggest that the additional energy barrier associated with permeation of the benzoic acid series is associated with the need to protonate the acidic group, thereby forming the neutral species which may then cross the hydrophobic region of the membrane.