Multi-component forms of the 2nd generation H1 receptor antagonist drug, Bilastine and its enhanced physicochemical characteristics.

Bilastine (BIL) is a novel 2nd generation antihistamine medication is used to treat symptoms of chronic urticaria and allergic rhinitis. However, its poor solubility limits its therapeutic efficacy. In order to enhance the physicochemical characteristics of BIL, various molecular adducts of BIL (Salt, hydrate and co-crystal) were discovered in this study using two distinct salt-formers: Terephthalic acid (TA), 2,4-Dihydroxybenzoic acid (2,4-DHBA), and three nutraceuticals (Vanillic Acid (VA), Hydroquinone (HQN) and Hippuric acid (HA)). Various analytical methods were used to examine the synthesised adducts, including Powder X-Ray Diffraction (PXRD), Single Crystal X-ray Diffraction (SCXRD), and thermal analysis (Thermogravimetric analysis (TGA) and Differential Scanning Calorimetry (DSC)). Single-crystal X-ray diffraction (SCXRD) studies avowed that the architectures of the molecular adducts are maintained in the solid state by an array of strong (N+H⋯O-, NH⋯O, OH⋯O) and weak (CH⋯O) hydrogen bonds. Additionally, a solubility test was performed to establish the in vitro release characteristics of newly synthesised BIL adducts and it observed that most of the molecular adducts exhibit higher rates of dissolution in comparison to pure BIL; in particular, BIL.TA.HYD showed the highest solubility and the fastest rate of dissolution. Moreover, experiments on flux permeability and diffusion demonstrated that the BIL.TA.HYD and BIL.VA salts had strong permeability and a high diffusion rate. In addition, the synthesized adduct's stability was assessed at 25 °C and 90 % ± 5 % relative humidity, and it was found that all the molecular salts were stable and did not undergo any phase changes or dissociation. The foregoing result leads us to believe that the newly synthesized molecular adducts' increased permeability and solubility will be advantageous for the creation of novel BIL formulations.

Construction and application of H1R ligand screening materials based on SMA stabilization and his-tag covalent immobilization of membrane proteins.

The histamine H1 receptor (H1R) plays a pivotal role in allergy initiation and undergoes the necessity of devising a high-throughput screening approach centered on H1R to screen novel ligands effectively. This study suggests a method employing styrene maleic acid (SMA) extraction and His-tag covalent bonding to immobilize H1R membrane proteins, minimizing the interference of nonspecific proteins interference while preserving native protein structure and maximizing target exposure. This approach was utilized to develop a novel material for high-throughput ligand screening and implemented in cell membrane chromatography (CMC). An H1R-His-SMALPs/CMC model was established and its chromatographic performance (selectivity, specificity and lifespan) validated, demonstrating a significant enhancement in lifespan compared to previous CMC models. Subsequently, this model facilitated high-throughput screening of H1R ligands in the compound library and preliminary activity verification of potential H1R antagonists. Identification of a novel H1R antagonist laid the foundation for further development in this area.

Molecular mechanism of antihistamines recognition and regulation of the histamine H1 receptor.

Histamine receptors are a group of G protein-coupled receptors (GPCRs) that play important roles in various physiological and pathophysiological conditions. Antihistamines that target the histamine H1 receptor (H1R) have been widely used to relieve the symptoms of allergy and inflammation. Here, to uncover the details of the regulation of H1R by the known second-generation antihistamines, thereby providing clues for the rational design of newer antihistamines, we determine the cryo-EM structure of H1R in the apo form and bound to different antihistamines. In addition to the deep hydrophobic cavity, we identify a secondary ligand-binding site in H1R, which potentially may support the introduction of new derivative groups to generate newer antihistamines. Furthermore, these structures show that antihistamines exert inverse regulation by utilizing a shared phenyl group that inserts into the deep cavity and block the movement of the toggle switch residue W4286.48. Together, these results enrich our understanding of GPCR modulation and facilitate the structure-based design of novel antihistamines.

Formulation and assessment of hydroxyzine HCL solid lipid nanoparticles by dual emulsification technique for transdermal delivery.

Hydroxyzine HCL (HHCL) is an antihistamine, used for the treatment of allergic skin conditions. The purpose of this study was to achieve a dual phase drug delivery rate across the intact skin, to enhance HHCL permeation through the stratum corneum, to assess the peripheral H1-antihistaminic activity and the extent to which HHCL was systemically absorbed from transdermal gel loaded with solid lipid nanoparticles (SLNs), as well as to avoid its extreme bitterness. According to 23 factorial design, eight formulations of HHCL-SLNs were prepared by the double emulsification method. Lipid type (XA), surfactant concentration (XB) and co-surfactant concentration (XC) were the independent variables. All formulations were characterized for their surface morphology, particle size, entrapment efficiency and in-vitro drug release study. The optimized formula that provides greater desirability was then incorporated into the transdermal gel. In addition, the efficacy of the developed gel was tested in-vivo using 2,4-Dinitrochlorobenzene induced atopic dermatitis as lesion model in mice. F4 showed an average diameter 111 nm ± 0.03, zeta potential - 30 MV ± 2.4 and EE 75.2% ± 4.4. TEM images showed spherical, smooth morphology with uniform particles distribution. In-vivo study demonstrated potent antipruritic efficacy of transdermal gel in atopic dermatitis such as induced lesions compared to HHCL gel. Hence, HHCL solid lipid nanoparticles transdermal gel may be considered as potential for delivery of HHCL and alternatively to traditional oral use.

The Role of Alcohol Dehydrogenase in Drug Metabolism: Beyond Ethanol Oxidation.

Alcohol dehydrogenases (ADHs) are most known for their roles in oxidation and elimination of ethanol. Although less known, ADHs also play a critical role in the metabolism of a number of drugs and metabolites that contain alcohol functional groups, such as abacavir (HIV/AIDS), hydroxyzine (antihistamine), and ethambutol (antituberculosis). ADHs consist of 7 gene family numbers and several genetic polymorphic forms. ADHs are cytosolic enzymes that are most abundantly found in the liver, although also present in other tissues including gastrointestinal tract and adipose. Marked species differences exist for ADHs including genes, proteins, enzymatic activity, and tissue distribution. The active site of ADHs is relatively small and cylindrical in shape. This results in somewhat narrow substrate specificity. Secondary alcohols are generally poor substrates for ADHs. In vitro-in vivo correlations for ADHs have not been established, partly due to insufficient clinical data. Fomepizole (4-methylpyrazole) is a nonspecific ADH inhibitor currently being used as an antidote for the treatment of methanol and ethylene glycol poisoning. Fomepizole also has the potential to treat intoxication of other substances of abuse by inhibiting ADHs to prevent formation of toxic metabolites. ADHs are inducible through farnesoid X receptor (FXR) and other transcription factors. Drug-drug interactions have been observed in the clinic for ADHs between ethanol and therapeutic drugs, and between fomepizole and ADH substrates. Future research in this area will provide additional insights about this class of complex, yet fascinating enzymes.

Roles of Lys191 and Lys179 in regulating thermodynamic binding forces of ligands to determine their binding affinity for human histamine H1 receptors.

Docking simulations based on the crystal structure of human histamine H1 receptors have predicted crucial roles of Lys1915.39 and Lys179ECL2, which exist at the entrance of the ligand-binding pocket, in increasing the H1-receptor selectivity for carboxylated second-generation antihistamines via electrostatic interaction. In this study, we evaluated the roles of Lys1915.39 and Lys179ECL2 in regulating the thermodynamic binding forces of non-carboxylated and carboxylated antihistamines that determine their binding affinity for human H1 receptors. The binding enthalpy and entropy of the 3 sets of non-carboxylated and corresponding carboxylated antihistamines (doxepin and olopatadine, desloratadine and loratadine, and terfenadine and fexofenadine, respectively) were estimated using the van't Hoff equation with the dissociation constants obtained from the displacement curves of the non-carboxylated and carboxylated antihistamines against the binding of [3H]mepyramine to the membrane preparations of Chinese hamster ovary cells expressing human H1 receptors at various temperatures, ranging from 4 °C to 37 °C. We found that the affinity for carboxylated antihistamines was lower than that for the corresponding non-carboxylated compounds due to lower enthalpy-dependent electrostatic binding forces and/or entropy-dependent hydrophobic binding forces. Mutations of Lys1915.39 and/or Lys179ECL2 to alanine mostly increased the binding affinity for antihistamines due to a variety of changes in both enthalpy- and entropy-dependent binding forces. These results suggest that Lys1915.39 and Lys179ECL2 may not contribute to selectively increasing the binding affinity for carboxylated antihistamines via electrostatic interaction, but that they can negatively modulate the binding affinity for non-carboxylated and carboxylated antihistamines non-selectively by affecting their electrostatic as well as hydrophobic binding forces.

Hydroxypropyl ß-cyclodextrin nanohybrid monoliths for use in capillary electrochromatography with UV detection: application to the enantiomeric separation of adrenergic drugs, anticholinergic drugs, antidepressants, azoles, and antihistamine.

Two kinds of hydroxypropyl ß-cyclodextrin nanohybrid monoliths were synthesized and applied in capillary electrochromatography with UV detection. One column was fabricated by concurrently using glycidyl methacrylate-bonded hydroxypropyl ß-cyclodextrin (GMA-HP-ß-CD), sodium 3-mercaptopropanesulphonate, and alkoxysilanes in the "one-pot" process. The other was prepared by free radical polymerization of GMA-HP-ß-CD, vinylmethylcyclosiloxane, ethylene dimethacrylate, and 2-acrylamido-2-methyl propane sulfonic acid. Compared to the former hybrid monolith, the latter one displayed improved enantiomeric separation. For ten adrenergic drugs, six anticholinergic drugs, two antidepressants, six azoles, and one antihistamine enantiomeric separation was obtained on the monolith synthesized by free radical polymerization. Twelve out of twenty-five drugs were baseline-separated. Especially, anisodamine with two chiral centers was successfully separated with resolution values of 3.06, 2.11, and 2.17. The nanohybrid monoliths were characterized by optical microscopy, scanning electron microscopy, FT-IR, nitrogen adsorption analysis, and thermogravimetric analysis. Relative standard deviation values less than 5% were obtained through run-to-run, day-to-day, and column-to-column investigations (n = 3). Graphical abstract Schematic representation of two kinds of hydroxypropyl ß-cyclodextrin nanohybrid monoliths based on "one-pot" approach (route I) and free radical polymerization approach (route II), respectively.

Cell-based, animal and H1 receptor binding studies relative to the sedative effects of ketotifen and norketotifen atropisomers.

OBJECTIVES: Ketotifen (K) and its active metabolite norketotifen (N) exist as optically active atropisomers. They both have antihistaminic and anti-inflammatory properties but the S-atropisomer of N (SN) causes less sedation than K and RN in rodents. This study investigated whether this could be related to a lower concentration of SN in brain or a lower affinity of SN for rat brain H1 receptors. METHODS: Ketotifen and norketotifen atropisomers were quantified using a validated chiral HPLC assay. RBE4 and Caco-2 cell monolayers were used in uptake and permeability studies, respectively. Free and total brain-to-plasma (B/P) ratios were determined after injecting racemic K and N into rat tail veins. Affinity for rat brain H1 receptors (KI ) was determined using the [3 H]mepyramine binding assay. KEY FINDINGS: Uptake and permeation studies indicate no stereoselective transport for K or N. B/P ratios reveal the brain concentration of N is lower than K with no stereoselective transport into brain. Finally, the [3 H]mepyramine binding assay shows SN has the lowest affinity for rat brain H1 receptors. CONCLUSION: The lower sedative effect of SN in rodents is probably due to a combination of a lower uptake of N than K into the brain and less affinity of SN for CNS H1 receptors.

Enantiomeric Separation of Meclizine Hydrochloride in Pharmaceutical Dosage Form by HPLC Method.

OBJECTIVE: A basic, powerful and isocratic chiral fluid chromatographic technique was created and approved for the enantiomeric partition of meclizine hydrochloride in pharmaceutical dose structure. METHODS: The chromatographic partition was accomplished on Phenomenex® Lux Cellulose 1 (250 mm x 4.6 mm i.d, 5 µm molecule size) section utilizing portable stage framework containing acetonitrile: 25mM ammonium bicarbonate (75:25%v /v). The versatile stage was siphoned on the segment at the stream pace of 1.0 mL/min, and UV recognition was done at 230 nm. RESULT: The breaking points of recognition and measurement were observed to be 0.25 µg/mL and 1.00 µg/mL individually, for 20µL infusion volume. The alignment bend demonstrated phenomenal linearity over the focus scope of 1-5 µg/mL for (±) meclizine enantiomers with a relationship coefficient (r2 = 0.999). The recuperation investigation of meclizine from tablet plan was observed to be 97.33% and 98.81% separately. Meclizine standard arrangement and versatile stage were observed to be steady for in any event 32h. The meclizine enantiomers were very much settled with mean maintenance times of about (+) Meclizine at 13.14 min and (-) Meclizine at 14.33 min individually. CONCLUSION: The created technique was broadly approved and demonstrated to be hearty, exact, exact and appropriate for the examination of meclizine enantiomers in tablet measurement structure and security investigations of meclizine.

Facile electrochemical preparation of overoxidizedpolypyrrole/RGO composite for ds-DNA immobilization: a novel signal amplified sensing platform for electrochemical determination of chlorpheniramine.

BACKGROUND: Chlorpheniramine (CPA), thanks to its relatively lower side effects, is a widely prescribed medicine for alleviating allergic symptoms as well as some medical emergencies. Owning to this extensive use, many efforts have been directed to measure chlorpheniramine both in vivo and in vitro. High performance liquid chromatography (HPLC), both normal and reverse phase, as well as spectrochemical and electrochemical methods are analytical approaches which have been extensively exploited for determination of CPA. Among them, electrochemical techniques have found elegant place for analysis of CPA due to simplicity, sensitivity and ease of instrumentation. METHODS: Herein, we have reported the preparation and characterization of a biosensor by immobilization of double-stranded DNA on the surface of overoxidizedpolypyrrole-reduced graphene oxide modified pencil graphite electrode (ds-DNA-PPyox/RGO/PGE) as well as its novel usability in measurement of chlorpheniramine (CPA). Scanning electron microscopy (SEM), electrochemical impedance spectroscopy (EIS), UV-Vis spectroscopy and differential pulse voltammetry (DPV) were exploited in order to characterize and evaluate the performance of the proposed biosensor. RESULTS: Final results showed that proposed strategy for modification of PGE introduces an ultra-sensitive biosensor for CPA which offers the best detection limitamong all previously reported electrochemical sensors for CPA. Taking advantage of this biosensor for determination of CPA, a wide linear dynamic range from 0.05 to 200 µM, and a low limit of detection 0.023 µM were obtained by using DPV method. Usability of this biosensor was also confirmed by determination of CPA in tablet and spiked urine samples. CONCLUSIONS: Overoxidized polypyrrole-reduced graphene oxide offered a suitable substrate for immobilization of ds-DNA by which a new biosensor for determination of CPA was fabricated. Proposed biosensor can successfully be used for determination of CPA in urine samples taking advantage of electroanalytical methods. Graphical abstract.

Improvement of solubility and dissolution of ebastine by fabricating phosphatidylcholine/ bile salt bilosomes.

Although ebastine (EBT) can impede histamine-induced skin allergic reaction and persuade long acting selective H1 receptor antagonistic effects but its poor water solubility circumscribed its clinical application. The main objective of this research work was to improve the aqueous solubility and oral bioavailability of EBT by preparing EBT-loaded bilosomes (EBT-PC-SDC-BS). A thin film hydration method was used to prepare ebastine loaded bilosomes. The prepared-formulations were optimized considering size, morphology and entrapment efficiency. The SEM images revealed regular and spherical shape of bilosomes. Average size of the prepared EBT-PC-SDC-BS was 665.8 nm and zeta potential was around-32.9 mV with 89.05 % average entrapment efficiency (EE).Importantly, the solubility of EBT in water was amplified up to 17.9 µg/ml compared to pure drug (2 µg/mL) reflecting a highest solubility increase of 751 %. In vitro drug release results of prepared EBT-PC-SDC-BS exhibited improved release behavior. Finally, it is established from the results that the EBT-PC-SDC-BS could function as a favorable nano-carrier system to improve the solubility as well as dissolution of EBT.

Design, synthesis and biological activity of a novel ethylenediamine derivatives as H1 receptor antagonists.

In this study, a series of novel ethylenediamine compounds were obtained by structural modification of the lead compounds with thonzylamine, and using the principle of modifying by bioisostere formation and modification with alkyl groups. In vitro assay, the biological activities showed that the target compounds have good properties in inhibiting mast cell degranulation and releasing histamine and ß-aminohexidase, such as the compounds 5c, 5g, 5k, 5l and 5o, especially of compound 5k to mast cell degranulation is IC50 = 0.0106 ±â€¯0.001 µmol⋅L-1, histamine release was IC50 = 0.0192 ±â€¯0.005 µmol⋅L-1 and ß-hexosaminidase release was IC50 = 0.0455 ±â€¯0.002 µmol⋅L-1in vitro. At the same time, in vivo biological activities assay results showed that have a good Histamie induce bronchospasm effect with relatively long duration and good protective effect in vivo, among which the protective effect of compound 5k was 79.74 ±â€¯0.30%, compounds 5c, 5g, 5k, 5l and 5o could inhibit the capillary permeability of increasing which were caused by histamine.

Route to Prolonged Residence Time at the Histamine H1 Receptor: Growing from Desloratadine to Rupatadine.

Drug-target binding kinetics are an important predictor of in vivo drug efficacy, yet the relationship between ligand structures and their binding kinetics is often poorly understood. We show that both rupatadine (1) and desloratadine (2) have a long residence time at the histamine H1 receptor (H1R). Through development of a [3H]levocetirizine radiolabel, we find that the residence time of 1 exceeds that of 2 more than 10-fold. This was further explored with 22 synthesized rupatadine and desloratadine analogues. Methylene-linked cycloaliphatic or ß-branched substitutions of desloratadine increase the residence time at the H1R, conveying a longer duration of receptor antagonism. However, cycloaliphatic substituents directly attached to the piperidine amine (i.e., lacking the spacer) have decreased binding affinity and residence time compared to their methylene-linked structural analogues. Guided by docking studies, steric constraints within the binding pocket are hypothesized to explain the observed differences in affinity and binding kinetics between analogues.

Probe dependency in the determination of ligand binding kinetics at a prototypical G protein-coupled receptor.

Drug-target binding kinetics are suggested to be important parameters for the prediction of in vivo drug-efficacy. For G protein-coupled receptors (GPCRs), the binding kinetics of ligands are typically determined using association binding experiments in competition with radiolabelled probes, followed by analysis with the widely used competitive binding kinetics theory developed by Motulsky and Mahan. Despite this, the influence of the radioligand binding kinetics on the kinetic parameters derived for the ligands tested is often overlooked. To address this, binding rate constants for a series of histamine H1 receptor (H1R) antagonists were determined using radioligands with either slow (low koff) or fast (high koff) dissociation characteristics. A correlation was observed between the probe-specific datasets for the kinetic binding affinities, association rate constants and dissociation rate constants. However, the magnitude and accuracy of the binding rate constant-values was highly dependent on the used radioligand probe. Further analysis using recently developed fluorescent binding methods corroborates the finding that the Motulsky-Mahan methodology is limited by the employed assay conditions. The presented data suggest that kinetic parameters of GPCR ligands depend largely on the characteristics of the probe used and results should therefore be viewed within the experimental context and limitations of the applied methodology.

Fabrication of Hierarchical Polymeric Thin Films by Spin Coating Toward Production of Amorphous Solid Dispersion for Buccal Drug Delivery System: Preparation, Characterization, and In Vitro Release Investigations.

The landscape of thin films is continuously evolving as an attractive self-administration mean to drive patient compliance. This work reports incorporation of drugs into various polymeric compositions using spin coating technology to screen amorphous solid dispersion film formation for buccal applications. Polarized light microscopy and differential scanning calorimetry were used for characterization. Physical stability was assessed after films storage at 0% RH/25°C for 6 months. Chlorpheniramine maleate, theophylline, and famotidine were used as model drugs and mixed with Opadry amb II® or Kollicoat IR®. Acryl-EZE II® or Zein was also used as surface (design I) or surface and base polymers (design II). Of all the drug-Opadry combinations, only chlorpheniramine was amorphously dispersed up to 25% (w/w). In contrast, Kollicoat IR® resulted in amorphous dispersions of all the tested drugs, suggesting that it has a better solubilization capacity. Drugs prepared in design II achieved higher in vitro release compared to respective design I, indicating that lower content of Acryl-EZE II® or Zein can decrease drug release over 3 h. It has been also revealed that Zein could improve physical stability of the aged theophylline solid-dispersed films. Release kinetics of model drugs were satisfactory when described by first-order kinetics, facilitated through anomalous transport of both diffusion and polymer swelling.

Multi-Layer Self-Nanoemulsifying Pellets: an Innovative Drug Delivery System for the Poorly Water-Soluble Drug Cinnarizine.

Beside their solubility limitations, some poorly water-soluble drugs undergo extensive degradation in aqueous and/or lipid-based formulations. Multi-layer self-nanoemulsifying pellets (ML-SNEP) introduce an innovative delivery system based on isolating the drug from the self-nanoemulsifying layer to enhance drug aqueous solubility and minimize degradation. In the current study, various batches of cinnarizine (CN) ML-SNEP were prepared using fluid bed coating and involved a drug-free self-nanoemulsifying layer, protective layer, drug layer, moisture-sealing layer, and/or an anti-adherent layer. Each layer was optimized based on coating outcomes such as coating recovery and mono-pellets%. The optimized ML-SNEP were characterized using scanning electron microscopy (SEM), differential scanning calorimetry (DSC), X-ray diffraction (XRD), in vitro dissolution, and stability studies. The optimized ML-SNEP were free-flowing, well separated with high coating recovery. SEM showed multiple well-defined coating layers. The acidic polyvinylpyrrolidone:CN (4:1) solution presented excellent drug-layering outcomes. DSC and XRD confirmed CN transformation into amorphous state within the drug layer. The isolation between CN and self-nanoemulsifying layer did not adversely affect drug dissolution. CN was able to spontaneously migrate into the micelles arising from the drug-free self-nanoemulsifying layer. ML-SNEP showed superior dissolution compared to Stugeron® tablets at pH 1.2 and 6.8. Particularly, on shifting to pH 6.8, ML-SNEP maintained > 84% CN in solution while Stugeron® tablets showed significant CN precipitation leaving only 7% CN in solution. Furthermore, ML-SNEP (comprising Kollicoat® Smartseal 30D) showed robust stability and maintained > 97% intact CN within the accelerated storage conditions. Accordingly, ML-SNEP offer a novel delivery system that combines both enhanced solubilization and stabilization of unstable poorly soluble drugs.

Formulation Development and Evaluation of Diphenhydramine Nasal Nano-Emulgel.

The aim of present study is to formulate diphenhydramine nasal nano-emulgels, having lipophilic nano-sized interior droplets, with better penetration for targeted controlled delivery to mucous membrane. Different diphenhydramine (DPH) nasal nano-emulgels were developed having propylene glycol and olive oil (as permeation enhancers) by using RSM for optimization and then evaluated for physico-chemical characteristics and thermal stability. In-vitro drug release through cellophane membrane was conducted and results were analyzed statistically. Further, gelation, mucoadhesive stress, and ex-vivo and histopathological studies were performed on optimized formulation by using goat nasal membrane. Among all formulations, E2 showed maximum DPH release at higher concentration olive oil (4%) and lower concentration propylene glycol (PG) (25%) within 4 h. All formulations have followed first-order kinetics and drug release mechanism was Fickian diffusion. Analysis of variance (ANOVA) and multiple linear regression analysis (MLRA) were used to compare results among formulations and 3D surface plots were constructed also. Optimized formulation showed immediate prolong gelation in artificial nasal mucosa and excellent mucoadhesive property (72.5 ± 1.5 dynes/cm2). Approximately 97.1% optimized formulation was permeated through membrane within 4 h, having a high flux rate (33.19 ± 0.897 µg/cm2/min) with diffusion coefficient (0.000786 ± 4.56 × 10-5 cm2/min) while drug contents remained on mucosal membrane for 24 h. Histopathologically, change on intra-mucosal surface of excised membrane was observed due to passage of drug through it. In summary, combination of PG and olive oil in nasal DPH nano-emulgel can be utilized successfully for targeted controlled delivery. The optimized formulation has excellent permeability and prolonged residence time on mucosal surface, which prove its good anti-histaminic activity in case of allergic rhinitis.

Practical and Sustainable Synthesis of Optically Pure Levocabastine, a H1 Receptor Antagonist.

A practical and sustainable method for the synthesis of levocabastine hydrochloride (1), a H1 receptor antagonist for the treatment of allergic conjunctivitis, that can be applied to the industrial production of the compound has been developed. Substantial improvements over the previously reported procedure are achieved via efficient preparation of an optically active key intermediate (5) without chiral resolution and with a more effective detosylation, which complements the previous procedure. Notably, our process requires no chromatographic purification and provides levocabastine hydrochloride in greater than 99.5% purity in a 14.2% overall yield.

Study of Sedative Tea Phytocomplex within the Framework of Studies Aimed at Creation of a Rectal Dosage Form with Antihistaminic Effect.

We designed a new complex drug with antiallergic effect containing, in addition to the main component loratadine, a phytocomplex for an extra therapeutic effect. A collection of plants with sedative activity is chosen and the optimal agent for extraction of bioactive compounds (40% ethanol) and optimal degree of plant fragmentation are determined. Chemical composition of the sedative tea is evaluated by reverse phase HPLC. The marker components of the species are detected: xanthohumol and isoxanthohumol - Humulus lupulus cone components, Mentha piperita rosmarinic acid, and scutellareine, Menyanthes trifolia element - quercetin-3-rutinoside, and caffeic acid. Standardization of the species by the absolute graduation method in conversion to quercetin-3-rutinoside is suggested.

Simultaneous optimization of pH and binary organic composition by grid form modeling of the retention behavior in reversed-phase ultra high-performance liquid chromatography.

A novel computer-assisted methodology for the simultaneous optimization of aqueous pH and binary organic eluent composition through a broad range of analytical conditions of reversed-phase ultra high-performance liquid chromatography is proposed. Two of nonlinear prediction models were employed to fit into the retention time (tR) on a linear gradient elution with a predefined slope. One model was derived from Bernoulli-type probability distribution to predict the value of tR against the pH value of the aqueous eluent. This sigmoid-shaped model was successfully fitted for tR value shift in the presence of three levels of organic eluent compositions (volumetric mixing of acetonitrile/methanol ratios 1:0, 1:1, and 0:1). The resultant pH versus tR value models were subsequently combined into grid form by quadratic multiple regression models based on the solubility parameter theory and their binary organic composition axes. The predicted tR values afforded from grid models were highly accurate for 13 different acidic non-steroidal anti-inflammatory drugs [root mean square error (RMSE) ≤0.030] and 16 basic histamine H1-receptor blockers (RMSE ≤0.067) in a pH ranging from 2.5 to 9.0 and an acetonitrile/methanol volumetric mixing ratio ranging from 1:0 to 0:1. Each compatibility score was defined as the indicator of the peak separation. Scores were calculated for all combinations of aqueous pH values and binary organic compositions via the predicted tR values. A colored map generated from the calculated scores was greatly effective in determining optimal combinations of both mobile phase conditions. By employing this predictive data, all analytes in both acidic and basic sample mixtures were finally separated at their respective optimized conditions.