Application of a validated stability-indicating densitometric thin-layer chromatographic method to stress degradation studies on moxifloxacin

A simple, sensitive, selective, precise and stability-indicating high-performance thin-layer chromatographic (HPTLC) method for densitometric determination of moxifloxacin both as a bulk drug and from pharmaceutical formulation was developed and validated as per the International Conference on Harmonization (ICH) guidelines. The method employed TLC aluminium plates pre-coated with silica gel 60F-254 as the stationary phase and the mobile phase consisted of n-propanol-ethanol-6 M ammonia solution (4:1:2, v/v/v). Densitometric analysis of moxifloxacin was carried out in the absorbance mode at 298 nm. Compact spots for moxifloxacin were found at R_f value of 0.58 ± 0.02. The linear regression analysis data for the calibration plots showed good linear relationship with r = 0.9925 in the working concentration range of 100-800 ng spot⁻¹. The method was validated for precision, accuracy, ruggedness, robustness, specificity, recovery, limit of detection (LOD) and limit of quantitation (LOQ). The LOD and LOQ were 3.90 and 11.83 ng spot⁻¹, respectively. Drug was subjected to acid and alkali hydrolysis, oxidation, dry heat, wet heat treatment and photodegradation. All the peaks of degradation products were well resolved from the standard drug with significantly different R_f values. Statistical analysis proves that the developed HPTLC method is reproducible and selective. As the method could effectively separate the drug from its degradation products, it can be employed as stability-indicating one. Moreover, the proposed HPTLC method was utilized to investigate the kinetics of the acidic and alkaline degradation processes at different temperatures. Arrhenius plot was constructed and apparent pseudo-first-order rate constant, half-life and activation energy were calculated. In addition the pH-rate profile for degradation of moxifloxacin in constant ionic strength buffer solutions within the pH range 1.2-10.8 was studied.     

Validated stability-indicating densitometric thin-layer chromatography: application to stress degradation studies of minocycline

A simple, stability-indicating high-performance thin-layer liquid chromatographic (HPTLC) method for analysis of minocycline was developed and validated. The densitometric analysis was carried out at 345 nm using methanol-acetonitrile-isopropyl alcohol-water (5:4:0.5:0.5, v/v/v/v) as mobile phase.The method employed TLC aluminium plates pre-coated with silica gel 60F-254 as the stationary phase. To achieve good result, plates were sprayed with a 10% (w/v) solution of disodium ethylene diaminetetraacetic acid (EDTA), the pH of which was adjusted to 9.0. Compact spots of minocycline were found at R_f = 0.30 ± 0.02. For proposed procedure, linearity (r = 0.9997), limit of detection (3.7 ng spot⁻¹), recovery (99.23-100.16%), and precision (% R.S.D. ≤ 0.364) was found to be satisfactory. The drug undergoes acidic and basic degradation, oxidation and photodegradation. All the peaks of degradation products were well resolved from the pure drug with significantly different R_f values. The acidic and alkaline degradation kinetics of minocycline, evaluated using this method, is found to be of first order.     

Validated high-performance thin-layer chromatography method for determination of trigonelline in herbal extract and pharmaceutical dosage form

A new, simple, sensitive, selective, precise and robust high-performance thin-layer chromatographic (HPTLC) method for analysis of trigonelline was developed and validated for the determination of trigonelline in herbal extracts and in pharmaceutical dosage forms. Analysis of trigonelline was performed on TLC aluminium plates pre-coated with silica gel 60F-254 as the stationary phase. Linear ascending development was carried out in twin trough glass chamber saturated with mobile phase consisting of n-propanol-methanol-water (4:1:4, v/v/v) at room temperature (25 ± 2 °C). Camag TLC scanner III was used for spectrodensitometric scanning and analysis in absorbance mode at 269 nm. The system was found to give compact spots for trigonelline (R_f value of 0.46 ± 0.02). The linear regression analysis data for the calibration plots showed good linear relationship with r² = 0.9991 ± 0.0002 in the concentration range 100-1200 ng spot⁻¹ with respect to peak area. According to the International Conference on Harmonization (ICH) guidelines the method was validated for precision, recovery, robustness and ruggedness. The limits of detection and quantification were determined. The trigonelline content of herbal extracts quantified and estimated from the formulation was found to be well within limits (±5% of the labeled content of the formulations). Statistical analysis of the data showed that the method is reproducible and selective for the estimation of trigonelline.     

Stability indicating high-performance thin-layer chromatographic determination of nelfinavir mesylate as bulk drug and in pharmaceutical dosage form

A sensitive, selective, precise and stability indicating high-performance thin-layer chromatographic method of analysis of nelfinavir mesylate both as a bulk drug and in formulations was developed and validated. The method employed TLC aluminium plates precoated with silica gel 60F-254 as the stationary phase. The solvent system consisted of toluene-methanol-acetone (7:1.5:1.5, v/v/v). This system was found to give compact spots for nelfinavir mesylate (R_f value of 0.45±0.02). Nelfinavir mesylate was subjected to acid and alkali hydrolysis, oxidation, dry heat treatment and photodegradation. Also the peaks of degraded products were well resolved from the pure drug with significantly different R_f values. Densitometric analysis of nelfinavir mesylate was carried out in the absorbance mode at 250 nm. The linear regression analysis data for the calibration plots showed good linear relationship with r²=0.999±0.002 in the concentration range of 1000-6000 ng per spot. The mean value of correlation coefficient, slope and intercept were 0.999±0.002, 0.014±0.001 and 21.73±1.26, respectively. The method was validated for precision, robustness and recovery. The limits of detection and quantitation were 60 and 140 ng per spot, respectively. Statistical analysis proves that the method is repeatable and selective for the estimation of the said drug. As the method could effectively separate the drug from its degradation products, it can be employed as a stability indicating one.     

Stability indicating high-performance thin-layer chromatographic determination of gatifloxacin as bulk drug and from polymeric nanoparticles

A simple, sensitive, selective, precise and stability indicating high-performance thin-layer chromatographic method for determination of gatifloxacin both as a bulk drug and from polymeric nanoparticles was developed and validated as per the International Conference on Harmonization (ICH) guidelines. The method employed thin-layer chromatography (TLC) aluminium plates precoated with silica gel 60F-254 as the stationary phase and the mobile phase consisted of n-propanol-methanol-concentrated ammonia solution (25%) (5:1:0.9, v/v/v). This solvent system was found to give compact spots for gatifloxacin (R_f value of 0.60 ± 0.02). Densitometric analysis of gatifloxacin was carried out in the absorbance mode at 292 nm. The linear regression analysis data for the calibration plots showed good linear relationship with r = 0.9953 with respect to peak area in the concentration range of 400-1200 ng spot⁻¹. The mean value (±S.D.) of slope and intercept were 9.66 ± 0.05 and 956.33 ± 27.67, respectively. The method was validated for precision, accuracy, ruggedness and recovery. The limits of detection and quantitation were 2.73 and 8.27 ng spot⁻¹, respectively. Gatifloxacin was subjected to acid and alkali hydrolysis, oxidation, photodegradation and dry heat treatment. The drug undergoes degradation under acidic and basic conditions and upon wet and dry heat treatment. The degraded products were well separated from the pure drug. The statistical analysis proves that the developed method for quantification of gatifloxacin as bulk drug and from polymeric nanoparticles is reproducible and selective. As the method could effectively separate the drug from its degradation products, it can be employed as stability-indicating one.     

Development and validation of a normal-phase high-performance thin layer chromatographic method for the analysis of sulfamethoxazole and trimethoprim in co-trimoxazole tablets

Pneumocystis carinii pneumonia (PCP) is often the ultimate mortal cause for immunocompromised individuals, such as HIV/AIDS patients. Currently, the most effective medicine for treatment and prophylaxis is co-trimoxazole, a synergistic combination of sulfamethoxazole (SMX) and trimethoprim (TMP). In order to ensure a continued availability of high quality co-trimoxazole tablets within resource-limited countries, Medicines Regulatory Authorities must perform quality control of these products. However, most pharmacopoeial methods are based on high-performance liquid chromatographic (HPLC) methods. Because of the lack of equipment, the Tanzania Food and Drugs Authority (TFDA) laboratory decided to develop and validate an alternative method of analysis based on the TLC technique with densitometric detection, for the routine quality control of co-trimoxazole tablets. SMX and TMP were separated on glass-backed silica gel 60 F₂₅₄ plates in a high-performance thin layer chromatograph (HPTLC). The mobile phase was comprised of toluene, ethylacetate and methanol (50:28.5:21.5, v:v:v). Detection wavelength was 254 nm. The R_f values were 0.30 and 0.61 for TMP and SMX, respectively. This method was validated for linearity, precision, trueness, specificity and robustness. Cochran's criterion test indicated homoscedasticity of variances for the calibration data. The F-tests for lack-of-fit indicated that straight lines were adequate to describe the relationship between spot areas and concentrations for each compound. The percentage relative standard deviations for repeatability and time-different precisions were 0.98 and 1.32, and 0.83 and 1.64 for SMX and TMP, respectively. Percentage recovery values were 99.00% ± 1.83 and 99.66% ± 1.21 for SMX and TMP, respectively. The method was found to be robust and was then successfully applied to analyze co-trimoxazole tablet samples.     

Stability-Indicating Chromatographic Methods for Simultaneous Determination of Mosapride and Pantoprazole in Pharmaceutical Dosage Form and Plasma Samples

Simple, sensitive, selective, precise, and stability-indicating thin-layer chromatography (TLC) and high-performance liquid chromatography (HPLC) methods for the determination of mosapride and pantoprazole in pharmaceutical tablets were developed and validated as per the International Conference on Harmonization guidelines. The TLC method employs aluminum TLC plates precoated with silica gel 60F₂₅₄ as the stationary phase and ethyl acetate/methanol/toluene (4:1:2, v/v/v) as the mobile phase to give compact spots for mosapride (R _f 0.73) and pantoprazole (R _f 0.45) separated from their degradation products; the chromatogram was scanned at 276 nm. The HPLC method utilizes a C18 column and a mobile phase consisting of acetonitrile/methanol/20 mM ammonium acetate (4:2:4, v/v/v) at a flow rate of 1.0 mL min^?1 for the separation of mosapride (t _R 11.4) and pantoprazole (t _R 4.4) from their degradation products. Quantitation was achieved with UV detection at 280 nm. The same HPLC method was successfully used in performing calibrations in lower concentration ranges for both drugs in human plasma using ezetimibe as internal standard. The methods were validated in terms of accuracy, precision, linearity, limits of detection, and limits of quantification. Mosapride and pantoprazole were exposed to acid hydrolysis and then analyzed by the proposed methods. As the methods could effectively separate the drugs from their degradation products, these techniques can be employed as stability-indicating methods that have been successively applied to pharmaceutical formulations without interference from the excipients. Moreover the HPLC method was successfully used in the determination of both drugs in spiked human plasma.     

Stability-indicating high performance thin layer chromatography determination of Paroxetine hydrochloride in bulk drug and pharmaceutical formulations

A simple selective precise and stability-indicating high performance thin layer chromatographic method of analysis of Paroxetine hydrochloride both as a bulk drug and in formulations was developed and validated. The method employed TLC (Thin Layer Chromatography) aluminum precoated with silica gel 60F-254 as the stationary phase. The solvent system consisted of butanol:acetic acid:water (8:2:0.5, v/v/v). This system was found to give compact spots for Paroxetine HCl (Rf, retardation factor, value-0.48 ± 0.02). Paroxteine HCl was subjected to acid and alkali hydrolysis, oxidation and photodegradation, where the degraded product was well separated from the pure drug. Densitometric analysis of Paroxetine hydrochloride was carried out in the absorbance mode at 295 nm. The linear regression analysis data for the calibration spots showed good relationship with (regression) r² = 0.9903 in the amount range of 300-1500 ng (nanogram) per spot. The mean value of co-relation co-efficient, slope and intercept were 0.9903 ± 0.001, 5.38 ± 0.058 and 182.5 ± 2.16 respectively. The method was validated for precision, recovery and robustness. The limits of detection and quantitation were 50 and 150 ng, respectively. The drug doesnot undergo degradation with oxidation, but gets affected in acidic and alkaline conditions. The acid and alkali degradation showed extra peaks at 0.4 and 0.08 Rf, respectively. This indicates that the drug is susceptible to acidic and alkaline medium. As the method could effectively separate the drug from its degradation products, it can be employed as a stability-indicating one.     

Stability-Indicating Chromatographic Methods for Simultaneous Determination of Mosapride and Pantoprazole in Pharmaceutical Dosage Form and Plasma Samples

Simple, sensitive, selective, precise, and stability-indicating thin-layer chromatography (TLC) and high-performance liquid chromatography (HPLC) methods for the determination of mosapride and pantoprazole in pharmaceutical tablets were developed and validated as per the International Conference on Harmonization guidelines. The TLC method employs aluminum TLC plates precoated with silica gel 60F₂₅₄ as the stationary phase and ethyl acetate/methanol/toluene (4:1:2, v/v/v) as the mobile phase to give compact spots for mosapride (R _f 0.73) and pantoprazole (R _f 0.45) separated from their degradation products; the chromatogram was scanned at 276 nm. The HPLC method utilizes a C18 column and a mobile phase consisting of acetonitrile/methanol/20 mM ammonium acetate (4:2:4, v/v/v) at a flow rate of 1.0 mL min⁻¹ for the separation of mosapride (t _R 11.4) and pantoprazole (t _R 4.4) from their degradation products. Quantitation was achieved with UV detection at 280 nm. The same HPLC method was successfully used in performing calibrations in lower concentration ranges for both drugs in human plasma using ezetimibe as internal standard. The methods were validated in terms of accuracy, precision, linearity, limits of detection, and limits of quantification. Mosapride and pantoprazole were exposed to acid hydrolysis and then analyzed by the proposed methods. As the methods could effectively separate the drugs from their degradation products, these techniques can be employed as stability-indicating methods that have been successively applied to pharmaceutical formulations without interference from the excipients. Moreover the HPLC method was successfully used in the determination of both drugs in spiked human plasma.

     

The International Conference on Harmonisation Guidance in Practice: Stress Degradation Studies on Lamivudine and Development of a Validated Specific Stability-Indicating HPTLC Assay Method

A sensitive, selective, precise and stability-indicating high-performance thin-layer chromatographic method of analysis of lamivudine both as a bulk drug and in formulations was developed and validated. The solvent system consisted of carbon tetrachloride – methanol – chloroform - acetonitrile (7.0: 3.0: 2.0: 1.5, v/v/v/v). Densitometric analysis of lamivudine was carried out in the absorbance mode at 275 nm. This system was found to give compact spots for lamivudine (R_F value of 0.36 ± 0.02) following double development of chromatoplates with the same mobile phase. Lamivudine was subjected to acid and alkali hydrolysis, oxidation, dry heat and wet heat treatment and photo degradation. The drug undergoes degradation under acidic, basic conditions, oxidation, wet heat and photo degradation. Also the degraded products were well resolved from the pure drug with significantly different R_F values. Linearity was found to be in the range of 50 – 1000 ng spot^–1 with significantly high value of correlation coefficient. The linear regression analysis data for the calibration plots showed good linear relationship with r² = 0.9994 ± 0.05 in the working concentration range of 300 ng spot^–1 to 1000 ng spot^–1. The mean value of slope and intercept were 0.11 ± 0.08 and 10.47 ± 1.21, respectively. The method was validated for precision, robustness and recovery. The limit of detection and quantitation were 15 ng spot^–1 and 40 ng spot^–1 respectively. As the method could effectively separate the drug from its degradation products, it can be employed as a stability indicating one. Moreover, the proposed HPTLC method was utilized to investigate the kinetics of acid degradation process. Arrhenius plot was constructed and activation energy was calculated.     

Determination of Oxazepam in Pharmaceutical Formulation by HPTLC UV-Densitometric and UV-Derivative Spectrophotometry Methods

Abstract

Methods for determination of oxazepam in pharmaceutical formulation by derivative ultraviolet (UV) spectrophotometry as well as high-performance thin-layer chromatography (HPTLC) UV densitometry were described. For UV-derivative spectrophotometry, some derivatives and wavelengths may be recommended for routine quality control of the drug of interest. On the other hand, HPTLC provided good results, but only when the calibration curve was estimated using nonlinear regression analysis. The HPTLC method was developed with silica F₂₅₄ plates, a mobile phase of benzene/ethanol (5:1, v/v), and densitometric detection at 204 nm receiving R _f  = 0.47. Developed methods were validated and found to be sufficiently precise and reproducible for established conditions.     

Stability indicating HPTLC determination of clopidogrel bisulphate as bulk drug and in pharmaceutical dosage form

A sensitive, selective, precise and stability indicating high-performance thin layer chromatographic method of analysis of clopidogrel bisulphate both as a bulk drug and in formulations was developed and validated in pharmaceutical dosage form. The method employed TLC aluminium plates precoated with silica gel 60F-254 as the stationary phase. The solvent system consisted of carbon tetrachloride-chloroform-acetone (6:4:0.15, v/v/v). This system was found to give compact spots for clopidogrel bisulphate (R_f value of 0.30±0.01). Clopidogrel bisulphate was subjected to acid and alkali hydrolysis, oxidation, photodegradation and dry heat treatment. Also the degraded products were well separated from the pure drug. Densitometric analysis of clopidogrel bisulphate was carried out in the absorbance mode at 230 nm. The linear regression data for the calibration plots showed good linear relationship with r²=0.999±0.001 in the concentration range of 200-1000 ng. The mean value of correlation coefficient, slope and intercept were 0.999±0.001, 0.093±0.011 and 8.83±0.99, respectively. The method was validated for precision, accuracy, ruggedness and recovery. The limits of detection and quantitation were 40 and 120 ng per spot, respectively. The drug undergoes degradation under acidic and basic conditions, oxidation and dry heat treatment. All the peaks of degraded product were resolved from the standard drug with significantly different R_f values. This indicates that the drug is susceptible to acid-base hydrolysis, oxidation and dry heat degradation. Statistical analysis proves that the method is reproducible and selective for the estimation of the said drug. As the method could effectively separate the drug from its degradation products, it can be employed as a stability indicating one.     

Thermochemistry of intercalation of n-alkylmonoamines into lamellar hydrated barium phenylarsonate

Hydrated layered crystalline barium phenylarsonate, Ba(HO₃AsC₆H₅)₂·2H₂O was used as host for intercalation of n-alkylmonoamine molecules CH₃(CH₂)_n-NH₂ (n = 1-4) in aqueous solution. The amount intercalated (n_f) was followed batchwise at 298 ± 1 K and the variation of the original interlayer distance (d) for hydrated barium phenylarsonate (1245 ppm) was followed by X-ray powder diffraction. Linear correlations were obtained for both d and n_f as a function of the number of carbon atoms in the aliphatic chain (n_c): d = (2225 ± 32) + (111 ± 11)n_c and n_f = (2.28 ± 0.15) − (11.50 ± 0.03)n_c. The exothermic enthalpies of intercalation increased with n_c, which was derived from the monomolecular amine layer arrangements with the longitudinal axis inclined by 60° to the inorganic sheets. The intercalation was followed by titration with amine at the solid/liquid interface and gave the enthalpy/number of carbons correlation: ΔH = −(7.25 ± 0.40) − (1.67 ± 0.10)n_c. The negative Gibbs free energies and positive entropic values reflect the favorable host/guest intercalation processes for this system.     

Heat-capacity measurements and thermodynamic functions of crystalline adenine; revised thermodynamic properties of aqueous adenine

The standard molar heat capacity C^°_p,m of adenine(cr) has been measured using adiabatic calorimetry over the range 6<(T/K)<310 and the results used to derive thermodynamic functions for adenine(cr) at smoothed temperatures. At T=298.15 K, C^°_p,m=(142.67±0.29) J · K⁻¹ · mol⁻¹ and the third law entropy S^°_m=(145.62±0.29) J · K⁻¹ · mol⁻¹. The standard molar Gibbs free energy of formation Δ_fG^°_m at T=298.15 K for crystalline adenine was calculated, using the standard molar enthalpy of formation for the compound and entropies of the elements from the literature, and found to be Δ_fG^°_m=(301.4±1.0) kJ · mol⁻¹. The results were combined with solution calorimetry and solubility measurements from the literature to yield revised values for the standard molar thermodynamic properties of aqueous adenine at T=298.15 K: Δ_fG^°_m=(313.4±1.0) kJ · mol⁻¹, Δ_fH^°_m=(129.5±1.4) kJ · mol⁻¹, and S_m^°=(217.68±0.44) J · K⁻¹ · mol⁻¹.     

Spectrophotometric and spectrodensitometric determination of Clopidogrel Bisulfate with kinetic study of its alkaline degradation

Four sensitive, selective and precise stability-indicating methods for the determination of Clopidogrel Bisulfate (CLP) in presence of its alkaline degradate and in pharmaceutical formulations were developed and validated. Method A is a second derivative (D²) spectrophotometric one, which allows the determination of CLP in presence of its alkaline degradate at 219.6, 270.6, 274.2 and 278.4 nm (corresponding to zero-crossing of the degradate) over a concentration range of 4-37 μg mL⁻¹ with mean percentage recoveries 99.81 ± 0.893, 99.72 ± 0.668, 99.88 ± 0.526 and 100.46 ± 0.646, respectively. CLP can be determined in the presence of up to 65% of its degradate. D² method was used to study the kinetic of CLP alkaline degradation that was found to follow a first-order reaction. The t_1/2 was 6.42 h while K (reaction rate constant) was 0.1080 mol/h. Method B is the first derivative of the ratio spectra (DD¹) spectrophotometric method, by measuring the peak amplitude at 217.6 and 229.4 nm using acetonitrile and CLP can be determined in the presence of up to 70% of its degradate. The linearity range was 5-38 μg mL⁻¹ with mean percentage recoveries 99.88 ± 0.909 and 99.70 ± 0.952, respectively. Method C based on the determination of CLP by the bivariate calibration depending on simple mathematic algorithm which provides simplicity and rapidity. The method depends on quantitative evaluation of the absorbance at 210 and 225 nm over a concentration range 5-38 μg mL⁻¹ with mean percentage recovery 99.27 ± 1.115. CLP can be determined in the presence of up to 70% of its degradate. Method D is a TLC-densitometric one, where CLP was separated from its degradate on silica gel plates using hexane:methanol:ethyl acetate (8.7:1:0.3, v/v/v) as a developing system. This method depends on quantitative densitometric evaluation of thin layer chromatogram of CLP at 248 nm over a concentration range of 0.6-3 μg/band with mean percentage recovery 99.97 ± 1.161. CLP can be determined in the presence of up to 90% of its alkaline degradate. The selectivity of the proposed methods was checked using laboratory prepared mixtures. The proposed methods have been successfully applied to the analysis of CLP in pharmaceutical dosage forms without interference from other dosage form additives and the results were statistically compared with the official method.     

High-performance thin layer chromatography method for estimation of andrographolide in herbal extract and polyherbal formulations

A new, simple, sensitive, precise and robust high-performance thin layer chromatographic (HPTLC) method was developed for the estimation of andrographolide in herbal extracts and pharmaceutical dosage forms. Analysis of andrographolide was performed on TLC aluminium plates pre-coated with silica gel 60F-254 as stationary phase. Linear ascending development was carried out in twin trough glass chamber saturated with chloroform:toluene:methanol (66:26:8, v/v/v) at room temperature (25 ± 2 °C). The R_f value of andrographolide was found to be 0.49. Camag TLC scanner III was used for spectrodensitometric scanning and analysis in absorbance mode at 229 nm. The system was found to give compact spots for andrographolide (R_f value of 0.49). The data for calibration plots showed good linear relationship with r² = 0.9986 in the concentration range of 200 ng to 1000 ng with respect to peak area. The present method was validated by precision, recovery, robustness and reproducibility according to ICH guidelines. The limits of detection and quantification were determined and it was found to be 3.5 and 11.7 ng, respectively. Statistical analysis of the data showed that the method is reproducible and selective for estimation of andrographolide.     

Hydridic reactivity of W(CO)(H)(NO)(PMe3)3 - Dihydrogen bonding and H2 formation with protic donors

The hydridic reactivity of the complex W(CO)(H)(NO)(PMe₃)₃ (1) was investigated applying a variety of protic donors. Formation of organyloxide complexes W(CO)(NO)(PMe₃)₃(OR) (R = C₆H₅ (2), 3,4,5-Me₃C₆H₂ (3), CF₃CH₂ (4), C₆H₅CH₂ (5), Me (6) and iPr (7)) and H₂ evolution was observed. The reactions of 1 accelerated with increasing acidity of the protic donor: Me₂CHOH (pK_a = 17) < MeOH (pK_a = 15.5) < C₆H₅CH₂OH (pK_a = 15) < CF₃CH₂OH (pK_a = 12.4) < C₆H₂Me₃OH (pK_a = 10.6) < C₆H₅OH (pK_a = 10).Regioselective hydrogen bonding of 1 was probed with two of the protic donors furnishing equilibrium formation of the dihydrogen bonded complexes ROH···HW(CO)(NO)(PMe₃)₃ (R = 3,4,5-Me₃C₆H_2,3a and iPr, 7a) and the O_NO hydrogen bonded species ROH···ONW(CO)(H)(PMe₃)₃ (R = C₆H₂Me_3,3b and iPr, 7b) which were studied in hexane and d₈-toluene solutions using variable temperature IR and NMR spectroscopy. Quantitative IR experiments at low temperatures using 3,4,5-trimethylphenol (TMP) confirmed the two types of competitive equilibria: dihydrogen bonding to give 3a (ΔH₁ = −5.8 ± 0.4 kcal/mol and ΔS₁ = −15.3 ± 1.4 e.u.) and hydrogen bonding to give 3b (ΔH₂ = −2.8 ± 0.1 kcal/mol and ΔS₂ = −5.8 ± 0.3 e.u.). Additional data for the hydrogen bonded complexes 3a,b and 7a,b were determined via NMR titrations in d₈-toluene from the equilibrium constants K_(Δδ) and K_(ΔR1) measuring either changes in the chemical shifts of H_W(_Δδ) or the excess relaxation rates of H_W (ΔR₁) (3a,b: ΔH_(Δδ) = −0.8 ± 0.1 kcal/mol; ΔS_(Δδ) = −1.4 ± 0.3 e.u. and ΔH_(ΔR1) = −5.8 ± 0.4 kcal/mol; ΔS_(ΔR1) = −22.9 ± 1.9 e.u) (7a,b: ΔH_(Δδ) = −2.3 ± 0.2 kcal/mol; ΔS_(Δδ) = −11.7 ± 0.9 e.u. and ΔH_(ΔR1) = −2.9 ± 0.2 kcal/mol; ΔS_(ΔR1) = −14.6 ± 1.0 e.u). Dihydrogen bonding distances of 1.9 Å and 2.1 Å were derived for 3a and 7a from the NMR excess relaxation rate measurements of H_W in d₈-toluene. An X-ray diffraction study was carried out on compound 2.     

Stability-Indicating TLC Method for the Determination of Dutasteride in Pharmaceutical Dosage Forms

A simple, sensitive, selective, precise and stability-indicating thin-layer chromatographic method for determination of dutasteride both as a bulk drug and as pharmaceutical tablets was developed and validated as per the International Conference on Harmonization guidelines. The method employed thin-layer chromatography aluminium plates precoated with silica gel 60F₂₅₄ as the stationary phase and the mobile phase consisted of acetonitrile:methanol:dichloromethane in the ratio of 2.0:1.0:2.0, v/v/v. This solvent system was found to give compact spots for dutasteride (R _f value of 0.64 ± 0.02). Densitometric analysis of dutasteride was carried out in the absorbance mode at 244 nm. The linear regression analysis data for the calibration plots showed good linear relationship with r = 0.9943 with respect to peak area in the concentration range of 100–600 ng per band. The method was validated for precision, accuracy, ruggedness and recovery. The limits of detection and quantitation were 7.54 and 22.85 ng per band, respectively. Dutasteride was subjected to acid and alkali hydrolysis, oxidation, photo degradation, dry heat and wet heat treatment. The drug undergoes degradation under acidic, basic conditions, photolytic, oxidative and upon wet and dry heat treatment. The degraded products were well separated from the pure drug. The statistical analysis proves that the developed method for quantification of dutasteride as bulk drug and from pharmaceutical tablets is reproducible and selective. As the method could effectively separate the drug from its degradation products, it can be employed as stability-indicating.     

Heat capacity and thermodynamic functions of LuPO4 in the range 0-320 K

The heat capacity of LuPO₄ was measured in the temperature range 6.51-318.03 K. Smoothed experimental values of the heat capacity were used to calculate the entropy, enthalpy and Gibbs free energy from 0 to 320 K. Under standard conditions these thermodynamic values are: (298.15 K) = 100.0 ± 0.1 J K⁻¹ mol⁻¹, S⁰(298.15 K) = 99.74 ± 0.32 J K⁻¹ mol⁻¹, H⁰(298.15 K) − H⁰(0) = 16.43 ± 0.02 kJ mol⁻¹, −[G⁰(298.15 K) − H⁰(0)]/T = 44.62 ± 0.33 J K⁻¹ mol⁻¹. The standard Gibbs free energy of formation of LuPO₄ from elements Δ_fG⁰(298.15 K) = −1835.4 ± 4.2 kJ mol⁻¹ was calculated based on obtained and literature data.     

A series of new zirconium complexes bearing bis(phenoxyketimine) ligands: Synthesis, characterization and ethylene polymerization

A series of new zirconium complexes bearing bis(phenoxyketimine) ligands, bis((3,5-di-tert-butyl-C₆H₂-2-O)R₁CN (2-R₂-C₆H₄))ZrCl₂ {R₁ = Me, R₂ = H (2a); R₁ = Et, R₂ = H (2b); R₁ = Ph, R₂ = H (2c); R₁ = 2-Me-Ph, R₂ = H (2d); R₁ = 2-F-Ph, R₂ = H (2e); R₁ = 2-Cl-Ph, R₂ = H (2f); R₁ = 2-Br-Ph, R₂ = H (2g); R₁ = Ph, R₂ = Me (2h); R₁ = Ph, R₂ = F (2i)}, have been prepared, characterized and tested as catalyst precursors for ethylene polymerization. Crystal structure analysis reveals that complex 2c has a six coordinate center in a distorted octahedral geometry with trans-O, cis-N, cis-Cl arrangement which possesses approximate C₂ symmetry. When activated with methylaluminoxane (MAO), complexes 2a-2i exhibited high ethylene polymerization activities of 10⁶-10⁸ g PE (mol M h)⁻¹. Compared with the bis(phenoxyimine) zirconium analogues bis((3,5-di-tert-butyl-C₆H₂-2-O)CHNC₆H₅)ZrCl₂ (3), the introduction of substituent on the carbon atom of the imine double bond enhanced the catalytic activity and molecular weight of prepared polyethylene. Especially, when the H atom at the carbon atom of the imine double bond was replaced by 2-fluoro-phenyl with strong electronic-withdrawing property, complex 2e displayed the highest catalytic activity, and the polyethylene obtained possessed the highest molecular weight and melt point.