Characterization and evaluation of multi-component crystals of hydrochlorothiazide.

PURPOSE: The present work aims at improving the physicochemical properties of hydrochlorothiazide, a poorly water soluble antihypertensive drug by preparing its multi-component crystals with nicotinic acid (HCT-NA) and 2-picolinic acid (HCT-PIC). METHODS: The crystals prepared by solution crystallization were investigated by thermoanalytical techniques. The crystal structures of HCT-NA (1) and HCT-PIC (2) were determined by the single crystal X-ray diffraction and were assessed for their aqueous solubility, antihypertensive activity and acute toxicity in rats. RESULTS: Both 1 and 2 crystallized in the orthorhombic space group P212121 and formation of salts were confirmed. The solubility profiles of 1 and 2 in basic media showed a maximum release of 2.5 mg/ml and 1.9 mg/ml, respectively, in comparison to the drug (0.82 mg/ml). The in-vivo antihypertensive activity of 1 in deoxycorticosterone acetate salt induced hypertensive rats showed 1.5 fold improvement. No increase in the signs of toxicity were revealed in rats during the acute toxicity studies even at doses of 2,000 mg/kg by body weight in comparison to the free drug. Histopathological findings supported the safety of these multi-component crystals. CONCLUSIONS: The new solid phases exhibit potential to be explored for the oral drug delivery of HCT with improved solubility and therapeutic outcome.

One pot, rapid and efficient synthesis of water dispersible gold nanoparticles using alpha-amino acids.

A detailed study on the synthesis of spherical and monodispersed gold nanoparticles (AuNPs) using all of the 20 naturally occurring α-amino acids has been reported. The synthesized nanoparticles have been further characterized using various techniques such as absorbance spectroscopy, transmission electron microscopy, dynamic light scattering and nuclear magnetic resonance. Size control of the nanoparticles has been achieved by varying the ratio of the gold ion to the amino acid. These monodispersed water soluble AuNPs synthesized using non-toxic, naturally occurring α-amino acids as reducing and capping/stabilizing agents serve as a remarkable example of green chemistry.

Quantification of adsorbed and dangling citrate ions on gold nanoparticle surface using thermogravimetric analysis.

A novel approach involving thermo-gravimetricanalysis (TGA) for the quantification of citrate ions present on the surface of gold nanoparticles has been reported. TGA study was carried out on AuNPs in response to parameters such as concentration of tri-sodium citrate and pH of gold nanoparticles depicting that the number of citrate ion present on gold nanoparticles is highly pH dependent. In general, the citrate ions were observed to be higher in alkaline conditions contradicting earlier beliefs. These results also underline the significance of TGA as a novel tool for quantification of citrate molecules present on gold nanoparticle surface. Thus, the present approach not only provides with an insight into mechanistic details of gold nanoparticle synthesis but also opens the usage of TGA for understanding the nano range association of molecules.

Quantitative analysis of in vitro compatibility of binary and ternary mixtures of nitroimidazole and macrolides in combination with omeprazole using a calorimetric technique.

In the present study, in vitro interactions between nitroimidazoles, macrolides and omeprazole in binary and ternary mixtures were examined by measuring their enthalpy of solution (delta(sol)H) using a calorimetric technique. A comparison of the enthalpy of solution of the pure drugs with those of binary and ternary mixtures at pH 2 and 6 was made to indicate the magnitude of interaction between them. The delta(sol)H for all the nitroimidazoles is endothermic at pH 2 and 6 but both the macrolides show exothermic behavior, whereas the enthalpy of solution of omeprazole changes from -40.52 to 4.35 kJmol(-1) as the pH changes from 2 to 6. The results have been quantified by determining the excess enthalpy of solution for both binary and ternary systems. The small deviations from ideality for all the binary systems are attributed to various non-bonding interactions between different functional groups on both the drug molecules. The results suggest compatibility of drug pairs in their binary mixtures. However, ternary mixtures show somewhat larger interactions. The magnitude of interaction enthalpy of a ternary mixture comprising tinidazole, clarithromycin and omeprazoles which are available as a marketed kitshas been calculated to be significant, suggesting that the three drugs cannot be co-formulated.

Microcalorimetric evaluation of the in vitro compatibility of amoxicillin/clavulanic acid and ampicillin/sulbactam with ciprofloxacin.

Solution calorimetric technique has been used to determine the compatibility of binary and ternary systems of ampicillin trihydrate (AMP), sulbactam sodium (SS), amoxicillin trihydrate (AM), potassium clavulanate (PC) and ciprofloxacin hydrochloride (CP). The enthalpy of solution (DeltasolH) were obtained over a wide range of composition in the pH range 2-9. For all the pure drugs the DeltasolH is endothermic in nature. The molar enthalpies of interaction of binary (DeltaHbi.E) and ternary (DeltaHter.E) mixtures of the drugs in aqueous buffers have been determined. The DeltaHbi.E for all binary systems is negative and pH dependent (maximum pH 6-8) indicating the interaction among charged species of the drugs. In case of binary systems with CP the magnitude of DeltaHbi.E indicate strong interactions. The variation and magnitude of DeltaHbi.E for the systems is discussed in terms of hydrogen bonding and van der Waal's interaction in the solution. The interaction parameter for ternary systems (A) is positive indicating repulsive interaction among the drugs. The coefficients hi's calculated from Redlich-Kister equation for binary systems (DeltaHbi.E) and ternary interaction parameter (A) were used to predict the compatibility of the marketed formulations in pH range studied.

Microcalorimetric studies to determine the enthalpy of solution of diclofenac sodium, paracetamol and their binary mixtures at 310.15 K.

A sensitive and selective microcalorimetric technique has been used to determine the enthalpy of solution of diclofenac sodium (DS), paracetamol (PC) and their binary mixtures over a wide range of composition in the pH range 4-12. The systems showed endothermic behavior. The molar enthalpies of solutions of DS vary between 42.26+/-0.16 and 50.48+/-0.03 kJ mol(-1) at pH 4-9 and for PC from 24.28+/-0.05 to 36.03+/-0.01 kJ mol(-1) at pH 5-12. The excess molar enthalpy of their mixtures has also been determined. The values of excess molar enthalpy of solutions are negative and very low in magnitude indicating no specific interaction between DS and PC in solution.

Kinetic studies of the degradation of an aminopenicillin antibiotic (amoxicillin trihydrate) in aqueous solution using heat conduction microcalorimetry.

Recent developments in isothermal microcalorimetry allow the direct determination of kinetic and thermodynamic parameters for slow reactions from studies conducted at appropriate temperatures and under designated environmental control. The degradation kinetics of amoxicillin trihydrate has been investigated as a function of pH (1-10) and temperature (303.15-318.15 K) at 0.5 M ionic strength using heat conduction microcalorimetry. Equations were developed incorporating calorimetric accessible data, rate constants and change in enthalpy, which showed that the degradation of amoxicillin trihydrate in aqueous solution followed pseudo-first-order kinetics under our experimental conditions. The enthalpy of degradation reaction was found to be exothermic in nature. The values of the rate constant k for individual steps were determined from the values of the overall rate constants at different pH. Energy of activation of overall reaction as a function of pH and for individual rate constants was determined. The log k-pH profiles indicated specific-acid and specific-base catalysis and there were inflection points near pH 3 and pH 7 corresponding to the pKa1 and pKa2 values. Quantitatively, there was good correlation between calorimetric determined half-life (t1/2) and the literature value in the acidic region determined by other methods at 310.15 K. The presence of a beta-lactam ring and of an alpha-amino group in the C-6 side chain played a critical role in the degradation of amoxicillin trihydrate and the zwitterionic form of the drug was found to be more stable.

Calorimetric studies of diclofenac sodium in aqueous solution of cyclodextrin and water-ethanol mixtures.

The technique of solution calorimetry has been employed to study the interaction between diclofenac sodium and beta-cyclodextrin by determining the enthalpies of solution of the drug in water and in aqueous beta-cyclodextrin solution. Thermodynamic parameters characterizing the binding process such as enthalpy deltaH0, equilibrium constant K, free energy deltaG0 and entropy deltaS0 have been calculated to be 12.00 kJ mol(-1), 1670 dm3 mol(-1), -19.03kJ mol(-1) and 22.98 J K(-1) mol(-1), respectively. Enthalpies of solution of diclofenac sodium have also been determined in water-ethanol mixtures.

Kinetics of degradation of diclofenac sodium in aqueous solution determined by a calorimetric method.

An isothermal heat conduction microcalorimeter has been used to study the stability of diclofenac sodium both alone and its inclusion complex with beta-cyclodextrin in aqueous solution. The rates of heat evolved during degradation of diclofenac sodium have been measured by a highly sensitive microcalorimetric technique as function of concentration, pH and temperature. The calorimetric accessible data have been incorporated in the equations for determination of rate constants, change in enthalpy and order of reaction. The decomposition of diclofenac sodium both alone and its inclusion complex with beta-cyclodextrin in solution corresponds to a pseudo-first order reaction. The values of rate constants, k's at 338.15 K, (calculated from the variation of heat evolution with the time) for the degradation of diclofenac sodium at pH 5, 6, 7, 8 and its inclusion complex with beta-cyclodextrin at pH 7 are found to be 4.71 x 10(-4), 5.69 x 10(-4), 6.12 x 10(-)4, 6.57 x 10(-4) and 4.26 x 10(-4) h(-1) respectively. There is good agreement between calorimetric determined t(0.5) and literature values. It has been found that beta-cyclodextrin retards the degradation of diclofenac sodium. The kinetic parameters have been calculated for the reaction. The negative entropy of activation suggests the formation of an ordered transition state.

Valsartan inclusion by methyl-ß-cyclodextrin: thermodynamics, molecular modelling, Tween 80 effect and evaluation.

The rationale of present study is to investigate the effect of Tween 80 on encapsulation ability of valsartan (VAL) by methyl-ß-cyclodextrin (M-ß-CD) and to determine the exact mode of binding. Phase solubility studies indicated 1:1 stoichiometry between VAL and M-ß-CD both in the presence and absence of Tween 80. The NMR and molecular modelling studies indicated the insertion of both aromatic and aliphatic regions of VAL into the M-ß-CD cavity suggesting the coexistence of two 1:1 complexes in equilibrium with each other. The stability constants, K1 (aromatic) and K2 (aliphatic), were enhanced in the presence of Tween 80 as evident by higher value of stability constants (K1 1992.0M(-1), K2 1864.0M(-1)) for ternary system in comparison to binary system (K1 1741.6M(-1), K2 1499.2M(-1)). Efficacy of ternary complex was established by significant decrease in the systolic blood pressure of deoxycorticosterone acetate (DOCA) induced hypertensive rats.

Interaction of artesunate with ß-cyclodextrin: Characterization, thermodynamic parameters, molecular modeling, effect of PEG on complexation and antimalarial activity.

Inclusion of artesunate in the cavity of ß-cyclodextrin (ß-CD) as well as its methyl and hydroxypropyl derivatives was investigated experimentally and by molecular modeling studies. The effect of PEG on the inclusion was also studied. A 1:1 stoichiometry was indicated by phase-solubility studies both in the presence and absence of PEG and suggested by the mass spectrometry. The mode of inclusion was supported by 2D NMR and results were further verified by docking studies utilizing Fast Rigid Exhaustive Docking acronym. The thermodynamic parameters were determined for both binary and ternary systems using solution calorimetry and were found to be best for the methyl-ß-cyclodextrin (Me-ß-CD) system. However, the presence of PEG improves the complexation ability as evident from elevation in the numerical value of the stability constant (K). Solubility and dissolution profile of binary complex is enhanced in the presence of PEG, which is approximately at par with drug Me-ß-CD complexes. In vivo studies showed 100% survivability in artesunate-Me-ß-CD complexes.