Hydrogen Sulfate Salt Research Articles

Exploring Salts of Memantine with Inorganic Anions: From Polymorphism and Solid-State Transitions to Potential for Drug Formulations.

This study examines pharmaceutically acceptable inorganic salts of memantine, specifically focusing on hydrogen sulfate, sulfate, and dihydrogen phosphate salts, with the aim of finding alternatives to the commonly used chloride salt in the treatment of Alzheimer's disease. Through comprehensive solid-state characterization, including powder X-ray diffraction, thermal analysis, and solubility testing, we unveil complex polymorphic behaviors, reversible solid-state transitions, and significant differences in solubility and stability among the salts. Notably, the hydrogen sulfate salt emerges as a promising candidate for drug formulations, offering improved solubility, nonhygroscopic nature, and favorable morphological characteristics compared to the existing chloride salt. This work establishes a foundation for further investigation into memantine salts as potential therapeutics with improved efficacy.

Physiologically Based Biopharmaceutics Model for Selumetinib Food Effect Investigation and Capsule Dissolution Safe Space - Part I: Adults.

A physiologically based biopharmaceutics model (PBBM) was developed to mechanistically investigate the effect of formulation and food on selumetinib pharmacokinetics. Selumetinib is presented as a hydrogen sulfate salt, and in vitro and in vivo data were used to verify the precipitation rate to apply to simulations. Dissolution profiles observed for capsules and granules were used to derive product-particle size distributions for model input. The PBBM incorporated gut efflux and first-pass gut metabolism, based on intravenous and oral pharmacokinetic data, alongside in vitro data for the main enzyme isoform and P-glycoprotein efflux. The PBBM was validated across eight clinical scenarios. The quality-control dissolution method for selumetinib capsules was found to be clinically relevant through PBBM validation. A safe space for capsule dissolution was established using a virtual batch. The effect of food (low fat vs high fat) on capsules and granules was elucidated by the PBBM. For capsules, a lower amount was dissolved in the fed state due to a pH increase in the stomach followed by higher precipitation in the small intestine. First-pass gut extraction is higher for capsules in the fed state due to drug dilution in the stomach chyme and reduced concentration in the lumen. The enteric-coated granules dissolve more slowly than capsules after stomach emptying, attenuating the difference in first-pass gut extraction between prandial states. The PBBM was instrumental in understanding and explaining the different behaviors of the selumetinib formulations. The model can be used to predict the impact of food in humans.

Synthesis and absolute structure of (R)-2-(benzyl-selan-yl)-1-phenyl-ethanaminium hydrogen sulfate monohydrate: crystal structure and Hirshfeld surface analyses.

A hydrogen sulfate salt, C15H18NSe+·HSO4 -·H2O or [BnSeCH2CH(Ph)NH3 +](HSO4 -), of a chiral selenated amine (R)-2-(benzyl-selan-yl)-1-phenyl-ethan-amine (BnSeCH2CH(Ph)NH2) has been synthesized and characterized by elemental analysis,1H and 13C{1H} NMR, FT-IR analysis, and single-crystal X-ray diffraction studies. The title salt crystallizes in the monohydrate form in the non-centrosymmetric monoclinic P21 space group. The cation is somewhat W shaped with the dihedral angle between the two aromatic rings being 60.9 (4)°. The carbon atom attached to the amine nitro-gen atom is chiral and in the R configuration, and, the -C-C- bond of the -CH2-CH- fragment has a staggered conformation. In the crystal structure, two HSO4 - anions and two water mol-ecules form an R 4 4(12) tetra-meric type of assembly comprised of alternating HSO4 - anions and water mol-ecules via discrete D(2) O-H⋯O hydrogen bonds. This tetra-meric assembly aggregates along the b-axis direction as an infinite one-dimensional tape. Adjacent tapes are inter-connected via discrete D(2) N-H⋯O hydrogen bonds between the three amino hydrogen atoms of the cation sandwiched between the two tapes and the three HSO4 - anions of the nearest asymmetric units, resulting in a complex two-dimensional sheet along the ab plane. The pendant arrangement of the cations is stabilized by C-H⋯π inter-actions between adjacent cations running as chains down the [010] axis. Secondary Se⋯O [3.1474 (4) Å] inter-actions are also observed in the crystal structure. A Hirshfeld surface analysis, including d norm, shape-index and fingerprint plots of the cation, anion and solvent mol-ecule, was carried out to confirm the presence of various inter-actions in the crystal structure.

Catalytic Chemoselective O-Phosphorylation of Alcohols

Phosphorylation of alcohols is a fundamentally important reaction in both life science and physical science. Product phosphate monoesters play key roles in living organisms, natural products, pharmaceuticals, and organic materials. Most of the chemical methods to date for synthesizing phosphate monoesters, however, require multistep sequences or are limited to specific types of substrates possibly due to harsh conditions. An alternative way to enable the simple production of phosphate monoesters from highly functionalized precursor alcohols is, thus, highly desired. We report herein a catalytic phosphorylation of alcohols with high functional group tolerance using tetrabutylammonium hydrogen sulfate (TBAHS) and phosphoenolpyruvic acid monopotassium salt (PEP-K) as the catalyst and phosphoryl donor, respectively. This method enables the direct introduction of a nonprotected phosphate group to the hydroxy group of a diverse menu of alcohol substrates, including functionalized small molecules, carbohydrates, and unprotected peptides. Nuclear magnetic resonance, mass spectrometric, and density functional theory analyses suggest that an unprecedented mixed anhydride species, generated from PEP-K and TBAHS, acts as an active phosphoryl donor in this reaction. This operationally simple and chemoselective catalytic phosphorylation allows for the efficient production of densely functionalized O-phosphorylated compounds, which are useful in diverse fields including biology and medicine.

Hydrolysis of rapeseed oil to fatty acids using pyrrolidonium ionic liquids as catalysts

ABSTRACTThis study aimed to evaluate the hydrolysis of rapeseed oil using pyrrolidonium ionic liquids as catalysts under atmospheric pressure. The process parameters were optimized using a sequence of experimental protocols to evaluate the effects of ionic liquid loading, dosage of emulsifier, weight ratios of substrates, temperature and time. The results demonstrated that the ranking of catalytic activity of ionic liquids is N-methyl-2-pyrrolidonium hydrogen sulfate salt ([HNMP]HSO4)>1-(3-sulfonic acid) propyl-2-pyrrolidonium hydrogen sulfate salt ([C3SO3Hnhp]HSO4)>2-pyrrolidonium hydrogen sulfate salt ([Hnhp]HSO4). In a batch reactor, the hydrolysis reaction conditions in the presence of [HNMP]HSO4 were investigated and optimized as follows: catalyst loading of 20% (based on the weight of oil), oil/water weight ratio of 1:2, emulsifier loading dosage of 4 wt % (based on the weight of oil), hydrolysis temperature of 100°C, and hydrolysis time of 30 h. The catalytic performance of this ionic liquid remained excellent even after reuse five times.

A case study where pharmaceutical salts were used to address the issue of low in vivo exposure

The present active pharmaceutical ingredient (API) is a lipophilic compound with a significant risk of not achieving therapeutic plasma concentrations due to solubility-limited absorption. The aim of the presented studies was to investigate whether three novel salts of a new selected candidate in the cardiovascular therapy area could be applied to improve intestinal absorption and the subsequent in vivo exposure. Three salts (chloride, hydrogen sulfate, and hemi-1.5-naphtalenedisulphonate) of the compound were manufactured and investigated regarding solubility, dissolution rate, and in vivo exposure in rats. The chemical and physical stability of the salt forms (and the crystalline parent compound) were followed in solid state, when dissolved and when formulated as microsuspensions. All salts showed improved solubility in investigated media, increased dissolution rate, and elevated in vivo exposures compared to a nanocrystal formulation (top-down) of the parent free base of the compound. The chloride- and the hydrogen sulfate salts of the API showed similar patterns regarding the chemical stability in solid state as the crystalline free base, while the salt formed of the hemi-1.5-naphtalenedisulphonic acid showed significantly improved stability. In conclusion, this study showed that three salts of a new selected candidate drug could be used to improve solubility, increase dissolution rate, and enhance oral absorption compared with a more commonly used nanocrystal formulation of the API. However, the identity of the counter ion appeared to be of less importance. On the other hand, only the salt of the hemi-1.5-naphtalenedisulphonic acid seemed to improve chemical stability compared with the API.

Optimization of Epoxidized Methyl Acetoricinoleate Synthesis by Response Surface Methodology

AbstractEpoxidized methyl acetoricinoleate (EMAR) was generated by epoxidation of methyl acetoricinoleate (MAR) in the presence of formic acid and hydrogen peroxide by using ionic liquids as catalysts, and the product was characterized by means of infrared spectroscopy and mass spectrometry. The efficiencies of four different catalysts, 1‐methylimidazole hydrogen sulfate salt ([Hmim]HSO4), 1‐methylpyrrolidone hydrogen sulfate salt ([Hnmp]HSO4), phosphoric acid, and sulfuric acid, were compared. The effects of the formic acid/MAR molar ratio, hydrogen peroxide/MAR molar ratio, reaction temperature, reaction time, and catalyst dosage on the epoxy value of EMAR were investigated by single‐factor experiments.

An Updated Synthesis of the Diazo-Transfer Reagent Imidazole-1-sulfonyl Azide Hydrogen Sulfate.

Imidazole-1-sulfonyl azide and salts thereof are valuable reagents for diazo-transfer reactions, most particularly conversion of primary amines to azides. The parent reagent and its HCl salt present stability and detonation risks, but the hydrogen sulfate salt is significantly more stable. An updated procedure for the large-scale synthesis of this salt avoids isolation or concentration of the parent compound or HCl salt and will facilitate the use of hydrogen sulfate salt as the reagent of choice for diazo transfer.

Backbone Phosphonamide-Functionalized Imidazol-2-ylidene Complexes

The synthesis of M(CO)5 complexes bearing 4-phosphonamide and 4,5-bis(phosphonamide)-imidazol-2-ylidene ligands (NHCP = phosphonamide-based N-heterocyclic carbene) is reported. Deprotonation of respective imidazolium hydrogensulfate salts with potassium tert-butoxide (KOtBu) in the presence of [M(CO)5(CH3CN)] afforded complexes with the formula [M(CO)5(NHCP)]. In a similar fashion, reaction of in situ generated NHCP with [Rh(cod)Cl]2 (cod = 1,5-cyclooctadiene) afforded a complex with the formula [Rh(cod)Cl(NHCP)]. Low-temperature deprotonation of the imidazolium NHCP·H2SO4 with potassium hexamethyldisilazide (KHMDS) in the presence of [AuCl(SMe2)] furnished the corresponding AuI NHC complex. All complexes were characterized by various spectroscopic and spectrometric methods. In addition, further structural confirmation is provided by key single-crystal X-ray structure determinations for three of the new complexes.

Ring-opening polymerization of caprolactone using novel polyaniline salt catalyst

Hybrid composite of polyaniline metal oxide composite, polyaniline-dodecyl hydrogen sulfate salt with ferric oxide, was prepared for the first time via simple one-step process of oxidizing aniline with ferric tris(dodecyl sulfate). Ferric tris(dodecyl sulfate) acts as an oxidant, emulsifier, dopant for polyaniline and also source of ferric oxide. Polyaniline salt composites were prepared via aqueous, emulsion, and interfacial polymerization pathways. Polyaniline salt composite was successfully demonstrated as polymer based solid acid catalysts in the ring-opening polymerization of e-caprolactone for the first time. This methodology gave low molecular weight poly(e-caprolactone) (MW-4035) with highly crystalline polymer of flower petals like morphology in 52 wt% yield (with respect to the amount of e-caprolactone used). Advantages of this methodology are the use of easily synthesizable, easily handlable, recyclable, cheaper, and eco-friendly nature of the catalyst. POLYM. ENG. SCI., 55:2245–2249, 2015. © 2015 Society of Plastics Engineers

Optimization of methyl ricinoleate synthesis with ionic liquids as catalysts using the response surface methodology

Methyl ricinoleate (MR) was synthesized from castor oil and methanol using ionic liquids as catalysts, by a transesterification reaction. The product was characterized using mass spectrometry. The efficiencies of four different catalysts, 1-methyl imidazole hydrogen sulfate salt ([Hmim]HSO4), 1-butyl-3-methylimidazolium hydroxide salt ([Bmim]OH), NaOH, and H2SO4 were compared. The effect of the methanol/castor oil mole ratio, reaction temperature, reaction time, and catalyst dosage on the MR content was investigated by single factor experiments. Based on single factor experiments and the Plackett–Burman design, the transesterification of castor oil and methanol was optimized using the response surface methodology. The results showed that the most effective catalyst was the ionic liquid [Hmim]HSO4. The optimal conditions were as follows: methanol/castor oil mole ratio 6:1, reaction time 4h, reaction temperature 77°C and [Hmim]HSO4 dosage 12%. Under these conditions, the MR content reached 89.82%. The catalytic activity of [Hmim]HSO4 still remained high after 4 cycles.

Alkyl imidazolium ionic liquid based sweeping-micellar electrokinetic chromatography for simultaneous determination of seven tea catechins in human plasma.

Determination of tea catechins in human plasma might provide a means of better evaluation of their benefits. The main difficulty in their analysis is the low catechins concentrations in plasma and their susceptible to oxidation during sample pretreatment. In the current work, a sweeping-micellar electrokinetic chromatography (sweeping-MEKC) by long alkyl chain ionic liquid was investigated for the simultaneous determination of seven principal naturally-occurring tea catechins in human plasma under acidic conditions after the intake of green tea beverage. The effects of type and concentration of three 1-tetradecyl-3-methylimidazolium ionic liquids, namely bromide, acetate and hydrogen sulfate salts were studied. The seven catechins were successfully separated within 5min by micellar running buffer of 5mmolL(-1) 1-tetradecyl-3-methylimidazolium bromide and 15mmolL(-1) phosphate buffer at pH 4.5 under optimal parameters of 50mbar injection for 150s, 10kV, 25°C and 200nm. To prevent the possibility of IL adsorption, an appropriate rinsing protocol was established. The method has analytical ranges from 0.5, 1, 0.5, 1, 2, 1 and 1 to 500ngmL(-1) for GC, C, EC, EGCG, GCG, ECG and EGC, respectively (r ranged from 0.995 to 0.999). The intraday precision and accuracy were 0.1-0.9% RSD (n=10) and 97-106% recovery, respectively. Limits of detections of analytes were ranged from 0.2 to 1.2ngmL(-1). The current sweeping-MEKC achieved sensitivity enhancement factor (SEF) up to 183-fold of analytes concentrations compared to other hitherto published CE reports that is suitable to find out the trace amounts of catechins in plasma.

Mono‐ and Hetero‐Dinuclear Complexes of Janus‐Head NHC Ligands Possessing Backbone Phosphinoyl Groups: the Case of Soft and Hard Metal Centers

AbstractThe synthesis and structures of RhI and IrI complexes bearing 4‐phosphinoyl‐ and 4,5‐bis(phosphinoyl)imidazol‐2‐ylidene ligands (NHCP) is reported. Deprotonation of the corresponding imidazolium hydrogen sulfate salts by KOtBu in the presence of [M(cod)Cl]2 afforded complexes of the formula [M(cod)Cl(NHCP)] [5a/5b: NHCP = 4‐Ph2P(O)‐IiPrMe, 5a: M = Rh, 5b: M = Ir and 7a/7b: NHCP = 4,5‐{Ph2P(O)}2‐InBuMe]. The RhI complexes 5a and 7a were then converted into [Rh(CO)2Cl(NHCP)] 8a and 9a via reaction with carbon monoxide; the average CO stretching frequencies [8a: $\tilde {\nu}$(CO)av = 2036 cm–1 and 9a: $\tilde {\nu}$(CO)av = 2038.4 cm–1] led to the conclusion that mono‐ and bis‐functionalized NHCPs act as relatively weaker donors than backbone unsubstituted NHC. A first examination of Janus‐head ligand properties of complex 7a revealed that reaction with TiCl4 afforded hetero‐dinuclear 10a,a′ as a mixture of isomeric monodentate phosphinoyl titanium(IV) adducts. All products were characterized by elemental analyses, spectroscopic and spectrometric methods and, in addition, complexes 7a and 7b by single‐crystal X‐ray structure analysis.

Study on the Physicochemical Properties of the Mixture of Water and 1-butyl-3-methylimidazolium Hydrogen Sulfate Salt Ionic Liquids

The density, viscosity, conductivity of the mixture of 1-butyl-3-methylimidazolium hydrogen sulfate salt ([Bmim]HSO4) ionic liquids and water have been determined at 25°C and atmospheric pressure. It was found that the density and conductivity of [Bmim]HSO4/water increase with the increase the water concentration at the same temperature, whereas the viscosity of [Bmim]HSO4/water decreases. The relationship between conductivities and temperature are agreed well with the Arrhenius equation.

Analysis of flavonoids by non-aqueous capillary electrophoresis with 1-ethyl-3-methylimidazolium ionic-liquids as background electrolytes

The separation of three flavonoids, kaempferol, quercetin and luteolin, by capillary zone electrophoresis with three 1-ethyl-3-methylimidazolium ionic liquids (ILs), namely chloride, hydrogen sulfate and tetrafluoroborate salts, under non-aqueous conditions using acetonitrile as solvent was investigated. Depending on the IL, the three flavonoids can be separated under positive voltage with a low IL concentration and negative voltage with a high IL concentration. The separations are based on heteroconjungation between the IL anions and the analytes. The heteroconjungation between the anions of the ILs and the analytes is proton sensitive and only a very small amount of protic solvents, such as methanol, added into the electrolyte solution can harm the separation, but higher IL concentrations can overcome this higher amount of protic solvents. Using a high concentration of IL in the sample was used to enhance the flavonoid solubility by as much as 10, overcoming the problem of the low solubility during NACE analysis with ACN as the solvent. Finally, kaempferol, quercetin and luteolin in Semen Plantaginis were analysed by nonaqueous capillary electrophoresis with low concentration of the hydrogen sulfate ionic liquid with excellent results.

Clopidogrel Generic Formulations in the Era of New Antiplatelets: A Systematic Review

Clopidogrel is a thienopyridine that selectively and irreversibly inhibits the ADP purinergic receptor P2Y12 and the subsequent ADP-mediated platelet activation. Clopidogrel has been approved for clinical use as clopidogrel hydrogen sulfate (bisulfate) salt. The clinical usefulness of clopidogrel bisulfate salt has been proved in a wide variety of large scale clinical trials, thus clopidogrel bisulfate has been extensively used in a large spectrum of patients been under thrombotic risk. Recently, several generic clopidogrel formulations have been approved for clinical use. Consequently, clopidogrel is currently a cost-effective antiplatelet agent. Only small studies have compared the pharmacokinetic and pharmacodynamic properties of various clopidogrel generic salt formulations with the innovator bisulfate salt. In addition few data are available concerning the clinical efficacy and safety of these generic clopidogrel formulations in order to guide clinicians in deciding when generic substitution is appropriate. The aim of this review is to summarize the physicochemical properties as well as the pharmacokinetic and pharmacodynamic characteristics of the generic clopidogrel salts. We also critically present existing data on the clinical efficacy and safety of the generic clopidogrel formulations compared with the innovator clopidogrel bisulfate salt in patients with cardiovascular disease.

Bis(4′-(4-pyridyl)-2,2′:6′,2′′-terpyridine)ruthenium(ii) complexes and their N-alkylated derivatives in catalytic light-driven water oxidation

Hydrogen sulfate salts of [Ru(1)2]2+ where 1 = 4′-(4-pyridyl)-2,2′:6′,2′′-terpyridine and four N-alkylated derivatives [Ru(L)2]4+ were used as photosensitizers (λmax ∼510 nm) for water oxidation in light driven reactions with peroxydisulfate as a sacrificial electron acceptor and Na10[Co4(H2O)2(α-PW9O34)2] (Co4POM) as the catalyst in sodium borate buffers at pH 8.0 and 9.0. The N-substituents investigated were benzyl (L+ = 2+), ethyl (L+ = 3+), allyl (L+ = 4+) and 4-cyanobenzyl (L+ = 5+). The O2 yield in the presence of [Ru(L)2]4+ (L+ = 2+–4+) was comparable to that obtained in the presence [Ru(bpy)3]2+ (bpy = 2,2′-bipyridine) using light sources with λmax ≈ 490 nm. The ruthenium(III) complexes [Ru(1)2]3+ and [Ru(L)2]5+ (L+ = 2+–5+) are rather unstable in acidic conditions and could not be isolated. The most efficient photosensitizers [Ru(L)2]5+ (L+ = 2+ and 4+) were the least stable under weakly basic conditions (pH 9.0) with a half-life τ1/2 ∼ 10 ms. The stability of the complexes under photocatalytic turnover conditions is probably controlled by the rate at which ligand L+ is oxidized by Co4POM in its highest oxidation state.

Ultrasound assisted the chemoselective 1,1-diacetate protection and deprotection of aldehydes catalyzed by poly(4-vinylpyridinium)hydrogen sulfate salt as a eco-benign, efficient and reusable solid acid catalyst

Poly(4-vinylpyridinium) hydrogen sulfate solid acid was found to be efficient catalyst for preparation of 1,1-diacetate using ultrasound irradiation at ambient temperature and neat condition. Deprotection of the resulting 1,1-diacetates were achieved using the same catalyst in methanol solvent under ultrasound irradiation at room temperature. This new method consistently has the advantage of excellent yields and short reaction times. Utilization of solvent free, simple reaction conditions, isolation, and purification makes this manipulation very interesting from an economic and environmental perspective. Further, the catalyst can be reused and recovered for several times.

A hydrogen sulfate salt of chlordiazepoxide

Crystals of the hydrogen sulfate salt of chlordiazepoxide (systematic name: 7-chloro-N-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-iminium 4-oxide hydrogen sulfate), C16H15ClN3O+·HSO4 −, were obtained from a solution of chlordiazepoxide and sulfuric acid in methanol. The structure features chlordiazepoxide mol­ecules that are protonated at the imine N atom. The seven-membered ring adopts a boat conformation with the CH2 group as the prow and the two aryl C atoms as the stern. The dihedral angle between the benzene rings is 72.41 (6)°. In the crystal, the HSO4 − anion acts as a bridging group between two chlordiazepoxide cations. The H atom of the protonated imino N forms an N—H⋯O hydrogen bond with a hydrogen sulfate ion. The anion in turn forms two hydrogen bonds, O—H⋯O with the anion as donor and N—H⋯O with the anion as acceptor, to generate an R 2 2(10) loop. Each HSO4 − anion connects two chlordiazepoxide moieties of the same chirality.

Ruthenium cryptates with an unusual selectivity for nitrate

The synthesis of two new tripodal complexes [Ru(L3)](PF(6))(2) and [Ru(L4)](PF(6))(2), encapsulating a ruthenium(II) cation, has been successfully achieved and the products fully characterized, including by X-ray structural determination. The smaller cavity, built around a tris(2-aminoethyl)amido scaffold demonstrated only moderate and predictable interactions with a range of anions and no significant spectroscopic change with nitrate, chloride and bromide, although dihydrogen phosphate did result in an almost stoichiometric precipitation. The expansion of the cavity to include the more rigid 1,3,5-benzenetricarbonylamide group creates a larger cavity, which shows a decrease in the emission on the introduction of chloride, bromide, hydrogen sulfate and nitrate salts, with the (1)H NMR titrations giving a surprisingly high binding affinity for nitrate over the smaller and simpler halides.