Compatibility of sildenafil citrate and pharmaceutical excipients by thermal analysis and LC–UV

The evaluation of sildenafil citrate (SC), the best-selling drug for treatment of impotence, for compatibility with various excipients was investigated using thermal and isothermal stress testing. Differential scanning calorimetry (DSC), hot-stage microscopy (HSM) and liquid chromatography (LC) with ultraviolet detection were successfully employed to investigate the compatibility between SC and various excipients commonly used in solid form in the pharmaceutical industry. The studies were performed using 1:1 (m/m) drug/excipient physical mixtures and samples were stored under accelerated stability conditions (40 °C at 75% relative humidity). All excipients tested (such as colloidal silicon dioxide, croscarmellose sodium, lactose, mannitol and sucrose) showed potential incompatibilities by DSC and LC analysis after accelerated stability testing. However, some incompatibilities were not detected by the DSC method and were observed only when LC analysis was performed. HSM was able to differentiate active pharmaceutical ingredient degradation from solubilisation, supporting the interpretation of DSC in excipients where thermal events either overlapped or disappeared. The combination of both the analytical techniques (DSC and LC) and use of a stability chamber is extremely helpful in detecting incompatibilities and providing more robust and accurate approaches for pre-formulation studies.     

Inclusion of α-lipoic acid in β-cyclodextrin. Physical–chemical and structural characterization

The inclusion of α-lipoic acid (LA) in β-cyclodextrin (β-CD) by increasing the aqueous solubility and photostability can enhance its medicinal use in the oral administration. Different preparation methods were employed to obtain an α-lipoic acid-β-cyclodextrin (LA-β-CD) inclusion complex and to determine the physical–chemical characteristics and the interactions present in this compound. The formation of the solid inclusion compound was confirmed by X-ray powder diffraction, differential scanning calorimetry (DSC) and infrared spectroscopy (FTIR). FTIR and DSC data confirm the new obtained compound. The crystalline structure of this compound belongs to the monoclinic system with four molecules in the unit cell. ¹H NMR spectroscopic method was employed to study the inclusion process in aqueous solution. Job plots derived from the ¹H NMR spectral data demonstrated an 1:1 stoichiometry of the inclusion complex in liquid state. 2D NMR data suggest the orientation of LA with the carboxyl group near to narrower rim of the β-CD.     

Labeling of new formulation of tin–sucralfate freeze-dried kit with technetium-99m and its biological evaluation

The present investigation deals with a simple preparation of new formulation of tin?Csucralfate freeze-dried kit (F.D.K.), to be directly labeled with ^99mTc at optimal pH value of 7.0. The lyophilized form containing 100?mg sucralfate and 11.3?mg dihydrated stannous chloride. Other optimal pH values of the preparation were found to be from 4.0 to 11.0. The range of sucralfate amount studied (50?C500?mg) not affected the radiochemical purity of the labeled complex. The radiochemical purity and the stability of the labeled preparation that assessed by filtration were more than 95%. ^99mTc sucralfate was radiochemical stable up to a specific activity of 1,000?mCi per gram which was more stable than earlier published value (700?mCi per gram) without any radiolytic decomposition. The biological behavior of ^99mTc-pertechnetate was evaluated in two groups of animals, the first group (neither fasted nor ulcerated) and the second group (fasted and ulcerated mice). The data of organ distribution of ^99mTc?Csucralfate in ulcerated fasted mice showed that more than 99% of the administered dose was accumulated in the stomach (87.92%) and intestine (11.43%). The radioanalytical results together with the in vivo-biological behavior of the labeled preparation demonstrate it??s stability, efficacy and usefulness in medical applications for the detection of gastrointestinal ulcers.     

Structural and physical–chemical evaluation of Bradykinin Potentiating Peptide and its high soluble supramolecular complex

The supramolecular interactions between a Bradykinin Potentiating Peptide (BPP10c) and β-cyclodextrin (βCD) have been investigated by using several techniques. These new properties acquired by the inclusion phenomena are important in developing a strategy for pharmaceutical formulation. The BPP10c structural elucidation and its inclusion complex formed have been investigated using Nuclear Magnetic Resonance techniques. The peptide secondary structure was investigated using infrared spectroscopy in solution, Circular Dichroism and NMR. In addition, the thermodynamic parameters of the inclusion process were also evaluated using Isothermal Titration Calorimetry. The results obtained by these physical–chemical techniques suggested a 1:1 complex formed by interaction between the Tryptophan amino acid residue and the βCD cavity. The peptide secondary structure was not substantially modified for the inclusion process. In addition, the inclusion process proved to be spontaneous (ΔGº = ?2.53 kcal mol^?1), with an enthalpy reduction (ΔHº = ?3.72 kcal mol^?1) and a favored entropic variation (TΔSº = ?1.19 kcal mol^?1).     

Compatibility studies with pharmaceutical excipients for aripiprazole–heptakis (2,6-di-O-methyl)-β-cyclodextrin supramolecular adduct

Journal of Thermal Analysis and Calorimetry - Aripiprazole (ARP) is one of the newest antipsychotic drugs, exhibiting very low aqueous solubility and high lipophilicity. Considering the necessity...     

Mechanochemical and microwave treatment of precipitated zirconium dioxide and study of its physical–chemical,thermal and photocatalytic properties

Journal of Thermal Analysis and Calorimetry - The effects of the microwave treatment (MWT) and mechanochemical treatment (MChT) on the structure and physicochemical properties of precipitated...     

Amberlyst-15 catalyzed synthesis of novel thiophene–pyrazoline derivatives: spectral and crystallographic characterization and anti-inflammatory and antimicrobial evaluation

Increasing instances of antimicrobial drug resistance and Inflammation-mediated disorders requires the design and synthesis of new small-molecules with higher affinity and specificity for their potential targets to serve as antibiotics or anti-inflammatory drugs, respectively. The current study presents the synthesis of a series of chalcones, 3(a–h) by the reaction of 3-methylthiophene-2-carbaldehyde, 1 and acetophenones, 2(a–h) by Claisen–Schmidt approach. The chalcones were efficiently transformed into thienyl-pyrazolines, 5(a–h) by their reaction with thiosemicarbazide hydrochloride, 4 in the presence of Amberlyst-15 as a catalyst in acetonitrile at room temperature. Alternatively, the compounds 5(a–h) were prepared by conventional method using acetic acid (40%) medium. Structures were characterized by spectral and single crystal X-ray diffraction studies. Preliminary assessment of the anti-inflammatory properties of the compounds showed that, amongst the series, compounds 5b and 5c have excellent anti-inflammatory activities. Further, compound 5c showed excellent activity against Escherichia coli (MIC, 15 µg/mL), Bacillus subtilis (MIC, 20 µg/mL), Aspergillus niger (MIC, 20 µg/mL), and Aspergillus flavus (MIC 15 µg/mL), respectively. Compounds 5a and 5b were also found to be active against the tested microorganisms.     

Inclusion complexes of fluconazole with β-cyclodextrin: physicochemical characterization and in vitro evaluation of its formulation

Fluconazole (FZ) is a triazole antifungal drug administered orally or intravenously. It is employed for the treatment of mycotic infections. However, the efficacy of FZ is limited with its poor aqueous solubility and low dissolution rate. One of the important pharmaceutical advantages of cyclodextrins is to improve pharmacological efficacy of drugs due to increasing their aqueous solubility. The aim of present study was to prepare an inclusion complex of FZ and β-cyclodextrin (β-CD) to improve the physicochemical and biopharmaceutical properties of FZ. The effects of β-CD on the solubility of FZ were investigated according to the phase solubility technique. Complexes were prepared with 1:1 M ratio by different methods namely, freeze-drying, spray-drying, co-evaporation and kneading. For the characterization of FZ/β-CD complex, FZ amount, practical yield %, thermal, aqueous solubility, XRD, FT-IR and NMR (¹H and ¹³C) analysis were performed. In vitro dissolution from hard cellulose capsules containing FZ/β-CD complexes was compared to pure FZ and its commercial capsules and evaluated by f₁ (difference) and f₂ (similarity) factors. Paddle method defined in USP 31 together with high pressure liquid chromatographic method were used in in vitro dissolution experiments. It was found that solubility enhancement by FZ/β-CD complexes depends on the type of the preparation method. High release of active agent from hard cellulose capsules prepared with β-CD complexes compared to commercial capsules was attributed to the interactions between β-CD and active agent, high energetic amorphous state and inclusion complex formation.     

Synthesis,crystal structure and spectroscopic characterization of new neutral and cationic (η-p-cymene)–ruthenium(II) complexes with phosphine–amide ligands

The dimeric starting material [Ru(η⁶-p-cymene)(μ-Cl)Cl]₂ reacts with the phosphino-amides o-Ph₂P–C₆H₄CO–NH–R [R = ⁱPr (a), Ph (b), 4-MeC₆H₄ (c), 4-FC₆H₄ (d)] to give the mononuclear compounds 1a–d [RuCl(η⁶-p-cymene)(o-Ph₂P–C₆H₄–CO–NH–R)]Cl. The subsequent reaction of these complexes with KPF₆ produced the cationic species 2a–d [RuCl(η⁶-p-cymene)(o-Ph₂P–C₆H₄–CO–NH–R)][PF₆] in which phosphino-amides also act as rigid P,O-chelating ligands. The molecular structures of 2b–d were determined crystallographically. Amide deprotonation is achieved when complexes 2a–d were made react with 1 M aqueous solution of KOH, affording the corresponding neutral species 3a–d [RuCl(η⁶-p-cymene)(o-Ph₂P–C₆H₄–CO–N–R)] in which a P,N-coordination mode is suggested.     

Studies of thermal properties of di(methacryloyloxymethyl)naphthalene–divinylbenzene (DMN–DVB) copolymer and its alkyl-bonded derivatives

This paper presents the thermal properties of highly crosslinked di(methacryloyloxymethyl)naphthalene–divinylbenzene (DMN–DVB) copolymeric microspheres containing polar groups in the structure and their alkyl-bonded derivatives. C₈ and C₁₈ alkyl chains were introduced into the aromatic rings of the DMN–DVB porous copolymer by means of the Friedel–Crafts reaction. As a source of C₈ and C₁₈ alkyl chains, octyl and octadecyl chlorides were used. It was necessary to check whether the introduction of alkyl chains into the structure of polymeric packing had an impact on its thermal properties. The studies were carried out by thermogravimetry coupled online with FTIR spectroscopy and differential scanning calorimetry in inert atmosphere (helium). It was stated that the modified materials showed 20 and 50% mass losses at higher temperatures than the non-modified one while 1% mass loss was observed at lower temperatures. Moreover, an analysis of volatile decomposition products was performed.

     

Synthesis and characterization of new D-π-D type Schiff base ligands and its complexes with Cobalt(II), Ruthenium(II)

A Schiff base ligands, N-{(1E,2E)-3-[4-(dimethylamino)phenyl]prop-2-en-1-ylidene}-1,10-phenanthrolin-5-amine(mpa) and (1E,2E)-3-[4-(dimethylamino)phenyl]acrylaldehyde9H-fluoren-9-ylidenehydrazone(mfh), have been synthesized from the reaction of 4,5-diazafluorenone-9-hydrazone and 5-amino-1,10-phenanthroline with 4-(dimethylamino)cinnamaldehyde. The Co(II) and Ru(II) complexes of the ligands were prepared and characterized. The metal-to-ligand ratio of the Co(II) complex was found to be 2: 1 and that of the Ru(II) complex was found to be 1: 1. The ligands and complexes have been characterized by FTIR, UV-visible, ¹H NMR and fluorescence spectra, as well as, elemental analyses, TGA-DSC-DTG and mass spectra.     

Bioactive microparticles (10): thermal and oxidative stability of nicotine and its complex with β-cyclodextrin

The paper presents a comparative thermal and oxidative stability study between nicotine/β-cyclodextrin microparticles and commercial nicotine. It is well known that the nicotine is the bioactive compound in formulations used for smoking cessation and no studies among the stability of nicotine in cyclodextrin-containing formulations were reported. The non-enzymatic and enzymatic oxidation of nicotine can lead to cotinine (an alkaloid/metabolite with a lower toxicity), but another way is the obtaining of the cancerigene N-nitroso-nicotine derivatives by nornicotine derivative intermediates (like nornicotine and myosmine). The present study demonstrates the protecting capacity of β-cyclodextrin for commercial nicotine against thermal and oxidative factors: for the non-complexed nicotine the thermal and oxidative degradation led to a decrease of the relative concentration of nicotine from 96 to 92% for an increasing temperature from 30 to 90 °C (in the presence of air at normal pressure), with an increase of the relative concentration of the corresponding oxidized compounds (like cotinine and furthermore myosmine up to 0.7%, and up to 4.7%, respectively). For the nicotine/β-cyclodextrin complex the interaction selectivity was higher for nicotine and the stability of this bioactive compound against oxidation was also higher in comparison with the non-complexed nicotine (around 98% in all cases).     

Calotropis procera (Aiton) seeds fixed oil: Physicochemical analysis,GC–MS profiling and evaluation of its in-vivo anti-inflammatory and in-vitro antiparasitic activities

Calotropis procera (Aiton) is a wildly grown shrubbery that has been used by traditional healers in various remedies for centuries. Its different organs are reported to possess a variety of biological activities. However, a few reports chemically investigated the seed fixed oil, but they didn’t prospect its bioactivity. Accordingly, this study aimed to investigate the phytochemical composition, physicochemical properties, and biological activity of the seed oil. As well, exploration of the best extraction method that give the highest oil yield with the best composition. Physicochemical properties, total phenolic content and oxidative stability index of the oil were estimated. GC–MS analysis identified the oil content. Anti- inflammatory activity was examined using a carrageenan-induced rat paw edema assay. Immunomodulatory activity was determined by measuring the pro-inflammatory cytokines levels. Moreover, In-vitro anti-parasitic and antioxidant activities were studied. Soxhlet extraction method gives the highest yield of 40.5 ± 0.76% with no time interval. The oil shows a physicochemical property within the AOCS standards and low phenol content. GC-MS analysis reveals unsaturated fatty acids account for 75.25% of the oil, with an abundance of oleic acid (33.64%) and linoleic acid (31.95%). The oil exhibited potent anti-inflammatory and immunomodulatory activity. At various dose levels, paw edoema volume, pro-inflammatory cytokines, tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), and myeloperoxidase (MPO) serum levels were reduced. The seed oil is a promising candidate for the treatment of inflammation and/or inflammatory associated diseases (as parasitic infections) besides its immunomodulatory activity.     

Physical and chemical properties of N ′, N ′-aliphatic acid dioctylhydrazides and their complexing with copper(II) ions

Some physical and chemical properties of aliphatic acid N′N′-dioctylhydrazides[RC(O)NHN(C₈H₁₇)₂] (DOHs) were studied in comparison to 2-ethylhexanoic acid N′N′-dialkylhydrazides, namely, solubility, acid-base properties, entrainment with an aqueous phase, and partition factors depending on the medium and the acyl radical length. The pH ranges of maximal extraction of copper(II) complexes by DOHs to kerosene and the effect of ammonium salts on copper(II) extraction were determined. The compositions of extracted complexes were determined (Cu(II): DOH = 1: 1 and 1: 2); the extraction constant K _extr was calculated for the CuL₂ complex with butyric acid N′N′-dioctylhydrazide. Original Russian Text ? T.D. Batueva, A.V. Radushev, L.G. Chekanova, V.Yu. Gusev, V.I. Karmanov, 2009, published in Zhurnal Neorganicheskoi Khimii, 2009, Vol. 54, No. 1, pp. 146–150.     

An approach to core–shell nanostructured materials with high colloidal and chemical stability: synthesis, characterization and mechanistic evaluation

Silver–polypyrrole (PPy) core–shell nanoparticles have been fabricated by a facile one-step “green” synthesis using silver nitrate as an oxidant and soluble starch as an environmentally benign stabilizer and co-reducing agent. The morphology and optical properties of the particles were significantly affected by the reaction temperature, soluble starch concentration, and ratio of pyrrole monomer to AgNO₃ oxidant. The core–shell nanoparticles exhibited outstanding dispersive properties in deionized water due to residual starch, as compared with PPy nanoparticles in which starch was absent. The mechanism of core–shell nanoparticle formation was elucidated through TEM imaging vs. reaction time. The colloidal and chemical stability of the nanoparticles was demonstrated in a variety of solvents, including acids, bases, and ionic and organic solvents, through monitoring the localized surface plasmon resonance of the nanoparticles. Furthermore, the catalytic properties of these silver–PPy core–shell nanoparticles were also demonstrated.

Synthesis and characterization of two new metal–organic frameworks with interpenetrated structures and luminescent properties

Two new metal–organic compounds, [Ag₂(HADC)₂(bimh)] (1) and [Cd(ADC)(bpp)]_n (2) [H₂ADC = 1,3-adamantanedicarboxylic acid, bimh = 1,6-bis(2-methyl-imidazole-1-yl)hexane, bpp = 1,3-bis(4-pyridyl)propane], have been synthesized and characterized. Compound 1 exhibits a discrete symmetric unit with 0D→2D interpenetrating structure. Compound 2 crystallizes in a chiral space group P212121 and presents a threefold interpenetrated 3D diamondoid network containing three helical chains. Thermal stability, X-ray powder diffraction, and luminescence for 1 and 2 are also measured and discussed.     

Spectroscopic and electroreductive characterization of new μ-oxodiiron(III) compounds with acyclic tetradentate ligands

We report the FT-i.r., FT-Raman, electronic, and Mo¨ssbauer spectra for several new -oxo-monobridge FeIIIOFeIII compounds with acyclic tetradentate ligands. Mo¨ssbauer spectra confirm the oxidation states for these complexes. The symmetric and asymmetric stretching frequencies determined for Fe–O–Fe bonds have allowed changes to be predicted in the M–O–M angle (from 144.6 to 150.7°). The electronic absorption spectra surprisingly resemble features exhibited by the spectrum of hemerythrine.Voltammetric results in DMF with a vitreous carbon electrode reveal three one-electron reduction stages which correspond to the dimeric processes and to the monomeric process.     

Establishment of fingerprint of Gegen Qinlian decoction and its formula compatibility groups using UHPLC–MS/MS and its study to spectrum–effect relationship

Based on the establishment of analytical method of ultra-high performance liquid chromatography-tandem mass spectrometry fingerprint and obtaining pharmacodynamic information of the effects on IL-4, IL-10, TNF-α, and IFN-γ of serum and interstitial fluid of the damp-type ulcerative colitis mice of Gegen Qinlian decoction and its formula compatibility groups, the spectrum–effect relationship study was performed by using the method of principal component analysis. The study built the common pattern of UHPLC–MS/MS fingerprint of Gegen Qinlian decoction and formula compatibility groups and identified eight components which were rooted in monarch and subject drugs and represented the whole pharmacodynamic information of Gegen Qinlian decoction. The research on formula compatibility and spectrum–effect relationship can provide scientific basis for revealing pharmacodynamic material basis and compatibility regularity of Gegen Qinlian decoction.     

Synthesis and characterization of two new inorganic–organic hybrid cobalt molybdenum(V) phosphates

Two new inorganic–organic hybrid cobalt phosphomolybdates (Hdien)₂[Co(dien)]₂[Co(dien)(H₂O)]₂[CoMo₁₂O₂₄(HPO₄)₂(H₂PO₄)₂(PO₄)₄(OH)₆]?···?5H₂O (1) and (H₂dien)₂[Co(dien)]₂[Co(H₂O)₂]₂[CoMo₁₂O₂₄(HPO₄)₄(PO₄)₄(OH)₆]?···?7H₂O (2) (dien?=?diethylenetriamine), involving molybdenum in the V oxidation state and covalently bonded transition metal complexes, have been prepared under mild hydrothermal conditions and structurally characterized by elemental analyses, IR spectra, TG analyses, and single-crystal X-ray diffraction. Compound 1 exhibits a one-dimensional (1D) chain framework, in which dien molecules adopt two kinds of coordination modes. Compound 2 shows a two-dimensional (2D) layer framework with three types of unusual tunnels. To the best of our knowledge, it is the first time [Co(dien)] units are directly incorporated into 1D and 2D skeletons of reduced molybdenum phosphates. The electrochemical properties of the two compounds were studied via the method of bulk-modified carbon paste electrodes. Furthermore, the magnetic properties of compound 2 are reported.