Piperazine Salt Research Articles

Optimizing Niclosamide for Cancer Therapy: Improving Bioavailability via Structural Modification and Nanotechnology

Inhibition of multiple cancer-related pathways has made niclosamide a promising candidate for the treatment of various cancers. However, its clinical application has been significantly limited by poor bioavailability. This review will discuss current findings on improving niclosamide bioavailability through modification of its chemical structure and utilization of novel nanotechnologies, like electrospraying and supercritical fluids, to improve drug delivery. For example, niclosamide derivatives, such as o-alkylamino-tethered niclosamide derivates, niclosamide ethanolamine salt, and niclosamide piperazine salt, have demonstrated increased water solubility without compromising anticancer activity in vitro. Additionally, this review briefly discusses recent findings on the first pass metabolism of niclosamide in vivo, the role of cytochrome P450-mediated hydroxylation, UDP-glucuronosyltransferase mediated glucuronidation, and how enzymatic inhibition could enhance niclosamide bioavailability. Ultimately, there is a need for researchers to synthesize, evaluate, and improve upon niclosamide derivatives while experimenting with the employment of nanotechnologies, such as targeted delivery and nanoparticle modification, as a way to improve drug administration. Researchers should strive to improve drug-target accuracy, its therapeutic index, and increase the drug’s efficacy as an anti-neoplastic agent.

Study of thermal behavior of 1H,4H-piperazine-N,N′-diium diacetate and its sublimation mechanism: An nonhygroscopic piperazine salt with ionic or cocrystal structure?

Study of thermal behavior of 1H,4H-piperazine-N,N′-diium diacetate and its sublimation mechanism: An nonhygroscopic piperazine salt with ionic or cocrystal structure?

An Evolving Role of Aqueous Piperazine to Improve the Solubility of Non-Steroidal Anti-Inflammatory Drugs

Piperazine (PIP) is a pharmaceutically acceptable molecule and a good co-conformer in crystallographic engineering. Most of the non-steroidal anti-inflammatory drugs (NSAIDs) have poor aqueous solubility, which hinders their clinical application. The reports show that the solubility of many insoluble drugs can be significantly improved through salt formation with the PIP. In this work, we obtained a series of NSAIDs−PIP salts, such as ibuprofen-piperazine (IBU−0.5PIP) salt, indomethacin−piperazine (IND−0.5PIP) salt, sulindac−piperazine (SUL−0.5PIP) salt, phenylbutazone−piperazine (PBZ−0.5PIP) salt, ketoprofen−piperazine (KPF-0.5PIP) salt and flurbiprofen−piperazine (FLB-0.5PIP) salt. The spatial structure, arrangement, interaction and associations were expatiated by single crystal X−ray diffraction. Powder X−ray diffraction, Fourier transform infrared, differential scanning calorimetry, and thermogravimetric analysis were used to characterize the novel salts. The six new salts had more than 10 folds of solubility and a faster dissolution rate improved corresponding to the bulk drugs in pure water, and the significant improvement of solubility is closely related to the structure of salts.

Eco-friendly phosphonic acid piperazine salt toward high-efficiency smoke suppression and flame retardancy for epoxy resins

Eco-friendly phosphonic acid piperazine salt toward high-efficiency smoke suppression and flame retardancy for epoxy resins

Synergistic flame retardant effect of piperazine salt and ammonium polyphosphate as intumescent flame retardant system for polypropylene

AbstractAmino trimethylene phosphonic acid piperazine (ATPIP)salt, as a novel charring agent, is prepared via a simple ionic reaction in distilled water using amino trimethylene phosphate (ATMP) and piperazine as raw materials. The synergistic flame retardant effect of ATPIP and ammonium polyphosphate (APP) as an intumescent flame retardant (IFR) is investigated by various characterization and testing methods. The results show that the polypropylene (PP)/modified APP with piperazine (MAPP)/ATPIP ternary blend passes UL‐94 V‐0 rating and achieve a limiting oxygen index (LOI) of 30% at a loading level of 25 wt% IFR (MAPP:ATPIP = 3:1). Meanwhile, the total smoke production (TSP) value of IFR‐PP samples is 3.3 m2, which decreases by 93.2% compared with that of pure PP, exhibiting excellent smoke suppression performance. Besides, the analysis of gaseous pyrolysis products and char residue indicates that the IFR‐PP samples show a synergistic flame‐retardant mechanism including the gas phase and the condensed phase.

Azilsartan piperazine salt solvate and monohydrate: preparation, crystal structure, enhanced solubility and oral bioavailability

Two azilsartan–piperazine salt solvates and a monohydrate feature crystal structural diversity and improve the azilsartan solubility over that of the free Az form. Az–Pz·EtOH and Az–Pz·H2O improve the plasma azilsartan concentration Cmax and AUC over the free Az form.

Niclosamide piperazine prevents high-fat diet-induced obesity and diabetic symptoms in mice.

Obesity and type 2 diabetes (T2D) have become the major public health challenges globally. Mitochondrial uncoupling, which reduces intracellular lipid loads and corrects the underlying cause of insulin resistance, has emerged as a promising anti-obese and anti-diabetic intervention. Niclosamide is an anthelmintic drug approved by the US FDA with the mechanism of action that uncouples mitochondria of parasitic worms. Recently, niclosamide ethanolamine salt (NEN) was found to be a safe and effective hepatic mitochondrial uncoupler for the prevention and treatment of obesity and T2D in mouse models. The striking features of NEN prompt us to examine the anti-obese and anti-diabetic efficacy of other salt forms of niclosamide, with the ultimate goal to identify a suitable salt formulation for future clinical development. Here, we report the study with niclosamide piperazine salt (NPP), another salt form of niclosamide with documented safety profile. Mitochondrial uncoupling activity of NEN and NPP were determined by oxygen consumption assay with Seahorse XF24e Analyzer, as well as by mitochondrial membrane potential measurement in cultured cells. The in vivo anti-diabetic and anti-obesity activities were determined in C57BL/6J mice fed high-fat diet (HFD) or HFD containing 2000ppm. NPP for 11weeks. Niclosamide piperazine salt showed a comparable mitochondrial uncoupling activity to NEN. Oral administration of NPP significantly reduced HFD-induced obesity, hyperglycemia and hepatic steatosis, and sensitized the insulin responses in mice. Niclosamide piperazine salt may hold the promise to become an alternative to NEN as a drug lead for the treatment of obesity and T2D. No level of evidence Animal study.

Acemetacin cocrystal structures by powder X-ray diffraction.

Cocrystals of acemetacin drug (ACM) with nicotinamide (NAM), p-aminobenzoic acid (PABA), valerolactam (VLM) and 2-pyridone (2HP) were prepared by melt crystallization and their X-ray crystal structures determined by high-resolution powder X-ray diffraction. The powerful technique of structure determination from powder data (SDPD) provided details of molecular packing and hydrogen bonding in pharmaceutical cocrystals of acemetacin. ACM-NAM occurs in anhydrate and hydrate forms, whereas the other structures crystallized in a single crystalline form. The carboxylic acid group of ACM forms theacid-amide dimer three-point synthon R32(9)R22(8)R32(9) with three different syn amides (VLM, 2HP and caprolactam). The conformations of the ACM molecule observed in the crystal structures differ mainly in the mutual orientation of chlorobenzene fragment and the neighboring methyl group, being anti (type I) or syn (type II). ACM hydrate, ACM-NAM, ACM-NAM-hydrate and the piperazine salt of ACM exhibit the type I conformation, whereas ACM polymorphs and other cocrystals adopt the ACM type II conformation. Hydrogen-bond interactions in all the crystal structures were quantified by calculating their molecular electrostatic potential (MEP) surfaces. Hirshfeld surface analysis of the cocrystal surfaces shows that about 50% of the contribution is due to a combination of strong and weak O⋯H, N⋯H, Cl⋯H and C⋯H interactions. The physicochemical properties of these cocrystals are under study.

An efficient mono-component polymeric intumescent flame retardant for polypropylene: preparation and application.

We found in our previous study that ethylenediamine- or ethanolamine-modified ammonium polyphosphates could be used alone as an intumescent flame retardant for polypropylene (PP), but their flame-retardant efficiency was not very high. In this present work, a novel highly-efficient mono-component polymeric intumescent flame retardant, piperazine-modified ammonium polyphosphate (PA-APP) was prepared. The oxygen index value of PP containing 22 wt % of PA-APP reached 31.2%, which increased by 58.4% compared with that of PP with equal amount of APP, and the vertical burning test (UL-94) could pass V-0 rating. Cone calorimeter (CC) results indicated that PP/PA-APP composite exhibited superior performance compared with PP/APP composite. For PP containing 25 wt % of PA-APP, fire growth rate (FGR) and smoke production rate (SPR) peak were reduced by 86.4% and 78.2%, respectively, compared with PP blended with 25 wt % APP. The relevant flame-retardant mechanism of PA-APP was investigated by Fourier transform infrared spectroscopy etc. The P-N-C structure with the alicyclic amine was formed during the thermal decomposition of piperazine salt (-NH2(+)-O-P-), and the rich P-N-C structure facilitated the formation of stable char layer at the later stage, consequently improving the flame-retardant efficiency of APP.

Acemetacin cocrystals and salts: structure solution from powder X-ray data and form selection of the piperazine salt.

Acemetacin (ACM) is a non-steroidal anti-inflammatory drug (NSAID), which causes reduced gastric damage compared with indomethacin. However, acemetacin has a tendency to form a less soluble hydrate in the aqueous medium. We noted difficulties in the preparation of cocrystals and salts of acemetacin by mechanochemical methods, because this drug tends to form a hydrate during any kind of solution-based processing. With the objective to discover a solid form of acemetacin that is stable in the aqueous medium, binary adducts were prepared by the melt method to avoid hydration. The coformers/salt formers reported are pyridine carboxamides [nicotinamide (NAM), isonicotinamide (INA), and picolinamide (PAM)], caprolactam (CPR), p-aminobenzoic acid (PABA), and piperazine (PPZ). The structures of an ACM-INA cocrystal and a binary adduct ACM-PABA were solved using single-crystal X-ray diffraction. Other ACM cocrystals, ACM-PAM and ACM-CPR, and the piperazine salt ACM-PPZ were solved from high-resolution powder X-ray diffraction data. The ACM-INA cocrystal is sustained by the acid⋯pyridine heterosynthon and N-H⋯O catemer hydrogen bonds involving the amide group. The acid⋯amide heterosynthon is present in the ACM-PAM cocrystal, while ACM-CPR contains carboxamide dimers of caprolactam along with acid-carbonyl (ACM) hydrogen bonds. The cocrystals ACM-INA, ACM-PAM and ACM-CPR are three-dimensional isostructural. The carboxyl⋯carboxyl synthon in ACM-PABA posed difficulty in assigning the position of the H atom, which may indicate proton disorder. In terms of stability, the salts were found to be relatively stable in pH 7 buffer medium over 24 h, but the cocrystals dissociated to give ACM hydrate during the same time period. The ACM-PPZ salt and ACM-nicotinamide cocrystal dissolve five times faster than the stable hydrate form, whereas the ACM-PABA adduct has 2.5 times faster dissolution rate. The pharmaceutically acceptable piperazine salt of acemetacin exhibits superior stability, faster dissolution rate and is able to overcome the hydration tendency of the reference drug.

Solubility Advantage of Tenoxicam Phenolic Cocrystals Compared to Salts

Tenoxicam (TNX) belongs to the oxicam family of drugs popularly known as nonsteroidal anti-inflammatory drugs (NSAIDs). Its therapeutic action as a drug is limited by poor aqueous solubility (14 mg/L). Here, we report cocrystals of TNX with benzoic acid, salicylic acid, catechol, resorcinol, pyrogallol, and salts with piperazine, HCl, and methanesulfonic acid and solvates with formic acid, acetic acid, propionic acid, and nitromethane. All the new solid phases (cocrystals and salts) were characterized by infrared spectroscopy, powder X-ray diffraction, differential scanning calorimetry, and confirmed by single crystal X-ray diffraction. Tenoxicam exists in the zwitterionic form in its stable crystalline form, as well as all the novel adducts reported in this study. The crystal structures are assembled via O–H···O– hydrogen bonds further assisted by weaker C–H···O interactions. This is the first report of oxicam cocrystals with phenols to our knowledge. Solubility and intrinsic dissolution rate of TNX cocrystals/salts were carried out to optimize the solid form with the best physicochemical properties. Tenoxicam–resorcinol (1:1) cocrystal exhibited the highest solubility (10-fold compared to the API), and moreover it was stable for up to 24 h in the slurry crystallization conditions of pH 7 phosphate buffer (neutral) and pH 1.2 medium (acidic). Tenoxicam–piperazine (1:0.5) salt is stable for 24 h in the slurry medium of the pH 7 buffer and exhibited 5.5 times higher solubility than tenoxicam. The other cocrystals dissociated slowly while the HCl and mesylate salts dissociated completely to tenoxicam within the same duration. TNX–benzoic acid and TNX–salicylic acid cocrystals were stable for up to 24 h in slurry conditions of pH 1.2 but in pH 7 medium they slowly converted to TNX after 24 h.

Properties of Polyamide 6 Fibres Modified by Silicate Nanoparticles

The first part of contribution is focused to the synthesis of ternary copolyamides containing layered silicate (i.e. Bentonite 11958 or Cloisite 15A). Concentrates were prepared from the basic comonomer, ?-caprolactam and minor polar comonomers, nylon salt AN 2 from adipic acid and 1-(2-aminoethyl)piperazine and nylon salt ADETA from adipic acid and diethylenetriamine in the total amount of 10.7 and 21.4 wt.%. Amount of layered silicates in the concentrates is always the same, 5 wt.%. The second part of contribution deals with the preparation of polyamide 6 (PA 6) fibres non-modified and modified by concentrates and determination of some properties (i.e. mechanical, sorptive, barrier and thermal properties) of modified fibres, too.

Conservative treatment for round worm intestinal obstruction

The ascariasis is one of the most cosmopolitan intestinal parasite infections and it can be in inhospitable regions inhabited by human being, but its biggest prevalence is observed in the tropical and subtropical areas. Intestinal obstruction has been estimated to occur in 2 per 1000 ascaris-infected children per year. We are presenting a study emphasizing the conservative treatment for complete intestinal obstruction due to roundworms without sign and symptom of peritonitis and perforation. A total of 22 patients of roundworm obstruction partial or complete without signs of and symptoms of peritonitis were admitted in the Department of Pediatric Surgery IMS, BHU Varanasi India in the period form 2003-2005. Patients were put nil by mouth, intravenous fluid, antibiotics, piperazine salt through nasogastric tube and glycerine + liquid paraffin emulsion enemas and were evaluated for duration of hospital stay, rate of conversion to surgical treatment and complications. 19 (86%) patients were treated successfully with conservative line of management. Only 3 patients required surgical intervention. No mortality, complication and mean hospital stay was 4.1 days (range 4-5 days). Round worm intestinal obstruction can be effectively treated by conservative line of management.

Round Worm Intestinal Obstruction: A Single Center Study

Introduction: Ascariasis is one of the most cosmopolitan intestinal parasite infections and can be found in inhospitable regions inhabited by human beings, but its highest prevalence is observed in the tropical and subtropical areas. In contrast to silent forms of this illness or chronic symptomatology, massive infestation in children can lead to serious complications requiring urgent surgical attention by experts. Intestinal obstruction has been estimated to occur in 2 per 1000 Ascaris-infected children per year. We are presenting a study emphasizing initial conservative treatment for round worm obstruction, whether partial or complete. Material and Methods: Patients with partial or complete round worm obstruction without signs and symptoms of peritonitis admitted to the Department of Pediatric Surgery IMS, BHU, Varanasi, India, were included in this study. They were given nil by mouth, intravenous fluids, antibiotics, piperazine salt through nasogastric tube and glycerine plus liquid paraffin emulsion enemas and were evaluated for duration of hospital stay, rate of conversion to surgical treatment and complications. Results: One hundred and seventy-five patients (92%) were treated successfully with conservative management. Only 14 patients (8%) required surgical intervention. In one case (0.52%) there was post-operative mortality, in two cases (1.1%) resection and anastomosis was required. Mean hospital stay was 4.3 days for the patients responding to conservative management. Conclusion: Round worm intestinal obstruction can be effectively treated by conservative management.

Modulation of Myocardial Energetics

The traditional paradigm for heart failure management centered on mitigating the hemodynamic changes that occur in response to the failing heart. Subsequently, pharmacological modulation of neurohormonal activation and more recently cardiac resynchronization have been shown to reverse ventricular remodeling and to slow disease progression. Despite these advances in therapy, successful treatment of heart failure remains challenging, with rates of hospitalization in the United States exceeding 1 million per year and the annual number of heart failure–related deaths increasing steadily.1 Unfortunately, the history of drug development for heart failure has been marked by many disappointments, most notably the excess mortality associated with oral positive inotropes that were targeted at improving hemodynamics. In addition, more recent interventions aimed at interrupting endothelin and cytokine signaling or reducing oxidative stress have yet to fulfill hopes for novel biological therapies. Thus, new therapeutic strategies are needed to alter the natural history of the disease and to slow or reverse current epidemiological trends. The report by Lee and colleagues2 in this issue of Circulation points toward the promise of an alternative approach based on favorably influencing the efficiency of myocardial energetics, thereby increasing cardiac performance without depending on changes in oxygen consumption or improvement in hemodynamics. Article p 3280 The study of agents aimed at enhancing myocardial energy efficiency has focused principally on shifting myocardial substrate use toward more oxygen-efficient pathways.3 Although the complete oxidation of fatty acids to CO2 yields more adenosine triphosphate (ATP) per molecule of CO2 produced than does complete oxidation of glucose, a greater amount of oxygen is required to completely oxidize a fatty acid of equivalent carbon-chain length. Therefore, for a given amount of oxygen consumed, metabolism of glucose is more “oxygen efficient,” producing ≈15% more ATP (Figure).3,4 Production of ATP and consumption of …

Phosphonopropionic acid as a building block in supramolecular chemistry: salts with organic diamines.

The structures of seven salts formed by phosphonopropionic acid with organic diamines are reported; in these salts, the hydrogen-bonded substructures formed by the anions can be zero-, one- or two-dimensional, while the overall hydrogen-bonded supramolecular structures are three-dimensional. The 1:1 adduct, compound (1), formed between 1,2-bis(4'-pyridyl)ethene and phosphonopropionic acid is a salt, [[(C(12)H(10)N(2))H(2)](2+)].[(C(12)H(10)N(2))].[(C(3)H(6)O(5)P)(-)](2), in which both diamine components lie across centres of inversion in space group P2(1)/c. The anions form hydrogen-bonded head-to-head dimers, and these are linked by the two diamine units into sheets, which are themselves linked by C-H.O hydrogen bonds. With 2,2'-dipyridylamine the acid forms the hydrated salt [[(C(10)H(9)N(3))H](+)].[(C(3)H(6)O(5)P)(-)].H(2)O (2), in which all components are disordered with occupancy 0.5 in space group Fmm2. The anions form head-to-tail dimers, which are linked into sheets by the cations, and the sheets are linked into a three-dimensional framework by the water molecules. The piperazine salt [[(C(4)H(10)N(2))H(2)](2+)].[(C(3)H(5)O(5)P)(2-)] (3) contains simple anion chains linked into a three-dimensional framework by the two independent cations, both of which are centrosymmetric. In the hydrated salt formed by N,N'-dimethylpiperazine, [[(MeNC(4)H(8)NMe)H(2)](2+)].[(C(3)H(6)O(5)P)(-)](2).(H(2)O)(2) (4), head-to-tail anion chains combine with the water molecules to form a three-dimensional framework, which encloses voids that contain the cations. In the 4,4'-bipyridyl adduct [[(C(10)H(8)N(2))H(0.72)](0.72+)].[[(H(0.5)O)(3)PCH(2)CH(2)COOH(0.78)](0.72-)] (5), there is extensive disorder of the H atoms that are bonded to N and O atoms, and the anion chains are linked by the cations into sheets, which are themselves linked by C-H.O hydrogen bonds. In the 1:2 adduct formed with 1,2-bis(4'-pyridyl)ethane, [[(C(12)H(12)N(2))H(2)](2+)].[(C(3)H(6)O(5)P)(-)](2) (6), where the cation lies across an inversion centre, the anions form molecular ladders. These ladders are linked into sheets by the cations, which are themselves linked by C-H.O hydrogen bonds. In the methanol-solvated salt formed with 2,6-dimethylpiperazine, [[(C(6)H(14)N(2))H(2)](2+)].[(C(3)H(6)O(5)P)(-)](2). (CH(4)O)(0.34) (7), the anions form sheets that are linked into a three-dimensional framework by the cations. The supramolecular structures are compared with those of analogous salts formed by phosphonoacetic acid.

Curing of Epoxy Resins with Citric Acid–Piperazine Salt

Citric acid–piperazine salt was prepared with a molar ratio of acid–piperazine of 2.9. The salt was characterized by thermal calorimetry, 13C NMR and IR spectroscopy. The piperazine content in the salt was 52%. A typical formulation was achieved by mixing the salt with the diglycidyl ether of bisphenol A (DGEBA). The heat of reaction was measured by a calorimeter and the evaluated peak resulted from the simultaneous endothermic salt decomposition and exothermic network formation. The heat of reaction value was −ΔH = 18kJ/eq. for the stoichiometric ratio, and the glass transition temperature, Tg, was 95°C. The heat of reaction evolved and the Tg value of piperazine–epoxy were determined for comparison with the salt–epoxy system.

Double-blind cross-over study of the effect of sultosilic-acid pioerazine salt (A-585) and bezafibrate in primary hyperlipoproteinemia

Sultosilic acid piperazine salt (A-585), a new lipid lowering drug, was compared with the action of bezafibrate. In 20 patients suffering from primary hyperlipoproteinemia a double-blind cross-over study was carried out. A series of parameters of the lipoprotein metabolism, as well as of fibrinolysis and platelet function, was compared before and after administration of the drugs. There was a statistically significant diminution of toral cholesterol, triglycerides, β- and pre-β-cholesterol and an increase of α-cholesterol by both drugs. Furthermore, both drugs caused a significant shortening of the euglobulin lysis time and a significant diminution of platelet adhesiveness. In patients who were under oral anticoagulants the thrombotest levels were not influenced by A-585 but were frequently below the therapeutic range during bezafibrate therapy. The difference in the thrombotest during treatment with the 2 drugs was significant. A slightly elevated γ-GT activity normalized during bezafibrate therapy but was not influenced by A-585. Other parameters did not show significant differences between the 2 drugs.

Norepinephrine metabolism in humans studied by deuterium labelling: turnover of 4-hydroxy-3-methoxyphenylglycol.

D,L(+/-)-4-Hydroxy-3-methoxyphenylglycol (HMPG) labelled with three deuterium atoms was used to study turnover of plasma free HMPG following an intravenous injection. Ten healthy men were given a pulse dose of either 4.3 mumol or 2.2 mumol of labelled HMPG ([2H3]HMPG piperazine salt). Plasma and urine levels of both endogenous and labelled HMPG were subsequently followed by gas chromatography-mass spectrometry with selected ion detection. Kinetic calculations based upon a single-compartment model were consistent with a monoexponential elimination of plasma free HMPG. The half-life of HMPG was 0.46 and 0.78 h (mean values in the two dose groups). The HMPG production rate was 2.01 and 2.35 mumol/hour, and the urinary excretion rate of HMPG (free and conjugated) was 0.48 and 0.47 mumol/h. The endogenous plasma level of free HMPG was 25 and 33 nmol/L. The results show that HMPG turns over rapidly and that HMPG is further metabolized extensively. About one-fourth of the HMPG produced is excreted in urine as free and conjugated HMPG.

A review of some modern equine anthelmintics

Summary Thiabendazole was the first of several benzimidazole anthelmintics and was superior to previously available drugs in both-efficiency and safety. Of the “second generation” of benzimidazoles, mebendazole and cambendazole are widely used inhorses and provide wider efficacy spectra and lowerdose rates compared with thiabendazole. Thiabendazole has proven activity against larval strongyles, but requires high dose rates. Two organophosphates, dichlorvos and haloxon have been formulated as horse anthelmintics. Pyrantel and its analogue morantel, are reported as efficient equine anthelmintics, but only in-feed and pasteformulations are recommended by the manufacturer as suitable for horses. Strains of small strongyles tolerant to benzimidazoles have been reported in U.S.A. and U.K. The addition of a piperazine salt to approximately half recommended dose rate, or the use of pyrantel, removed the tolerant nematodes.