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Master Title

ANALYTICAL STUDY OF SOME ESTER AND / OR AMIDE CONTAINING PHARMACEUTICAL PREPARATIONS

Master Abstract

Summary This thesis consists of four parts in addition to the references and a summary in Arabic. Each part includes an introduction, literature review, descriptive experimental work for the studied drugs, results and discussion. Part I: Quantitative Determination of Diacerein in Presence of Its degradate and Impurity in Different Pharmaceutical Formulations This part includes seven sections. Section (A): Introduction and Literature Review This section includes an introduction about the pharmacological action of Diacerein (DIA), its chemical structure, physical properties and summary of the published methods developed for its analysis in binary mixture with its degradation product and active metabolite, Rhein (RH) and in ternary mixtures with RH and its impurity and related substance, Emodin (EMO). Section (B): Determination of Diacerein and its Degradate by Q-Analysis (Graphical Absorbance Ratio) Method In this section, Q-Analysis method was developed for simultaneous determination of Diacerein and Rhein. In this section two wavelengths should be carefully selected, one of the two selected wavelengths is an isoabsorptive point and the other is the wavelength of maximum absorption of one of the two components. Using the absorbance values at 365 nm (? iso) and 257 nm (? max for DIA) gave the best results regarding selectivity. The developed method has been applied for determination of the studied drugs in different laboratory prepared mixtures. The results obtained by applying the investigated method for determination of DIA in Diacerein ® and Osteocerein ® capsules were statistically compared to those obtained by applying a reported HPLC one and no significant difference was found regarding both accuracy and precision. Section (C): Determination of Diacerein and its Degradate by Ratio Subtraction and Extended Ratio Subtraction Spectrophotometric Methods In this section, ratio subtraction (RS) and the recently developed extended ratio subtraction (ERS) methods have been applied for determination of DIA and RH, respectively in their binary mixture using methanol as a solvent. DIA concentrations were determined by measuring the absorbance at its ? max (257 nm) using RS method, while RH concentrations were determined by measuring the absorbance at its ? max (230 nm) using ERS method. The developed methods have been applied for determination of the studied components in different laboratory prepared mixtures and the results obtained by applying the investigated methods for determination of DIA in Diacerein ® and Osteocerein ® capsules were statistically compared to those obtained by applying a reported HPLC one and no significant difference was found regarding both accuracy and precision. Section (D): Determination of Diacerein in presence of its Degradate by Spectrofluorimetric Method. This section deals with the development of simple, sensitive, and specific stability indicating spectrofluorimetric method for the selective determination of DIA in the presence of its degradate, RH, with successive application to spiked human plasma. In this method, the native fluorescence of DIA solutions in the range of 0.04-0.3 µg mL-1 at ? em = 404 nm upon excitation at ? ex = 255 nm was measured and used for calculation of DIA without interference from its degradate. In addition, DIA was determined in spiked human plasma after drug extraction with methanol and good recoveries were obtained. The suggested method was used for determination of DIA in Diacerein ® and Osteocerein ® capsules and the results were statistically compared to those obtained by applying a reported HPLC one and no significant difference was found. Section (E): Determination of Diacerein, its Degradate and its Impurity by Different Spectrophotometric Methods In this section, different spectrophotometric methods have been investigated for determination of DIA, RH, and EMO in their ternary mixture. The developed spectrophotometric methods include first (1DD) and second (2DD) derivative of ratio spectra methods. Diacerein was determined by double divisor method using mixture of 10 µg mL-1 each of RH and EMO as a divisor and measuring the amplitudes at 355 nm. On the other hand, RH and EMO were determined by measuring (2DD) and (1DD) amplitudes, respectively at 229 nm using standard spectrum of 10 µg mL-1 of DIA as a divisor. Specificity of the methods has been assessed by their application to different laboratory prepared mixtures. Also double divisor method has been successfully applied to marketed samples containing DIA. Section (F): Determination of Diacerein, its Degradate, and its Impurity by Chemometric Methods Multivariate calibration models, such as PCR and PLS, have been successfully applied as selective stability indicating methods for determination of the ternary mixture of DIA, RH, and EMO. To validate the predictive ability of the developed models, they were applied to predict the concentrations of DIA, RH, and EMO in an external validation set. Statistical analysis of the results obtained by the developed models was compared with a reported HPLC one and no significant difference was found between them. Section (G): Determination of Diacerein, its Degradate, and its Impurity by TLC-Densitometric Method In this section, a simple and accurate TLC-Densitometric method has been suggested for simultaneous determination of DIA, RH, and EMO in their ternary mixtures. The suitable mobile phase has been selected to achieve the best separation. Quantitative determination of the separated bands was carried out at 230 nm upon using hexane: ethyl acetate: acetic acid (60: 40: 0.8, by volume) as mobile phase in the range of 0.5-10 µg band-1 for DIA and RH and 0.5 - 7 µg band 1 for EMO. The suggested TLC-Densitometric method was successfully applied for analysis of the cited drug in pharmaceutical formulations and the results showed good agreement with the labeled amount. Part II: Quantitative Determination of Metronidazole and Nystatin in Their Binary Mixtures This part consists of five sections. Section (A): Introduction and Literature Review This section includes an introduction about the pharmacological actions of Metronidazole (MET) and Nystatin (NYS), their chemical structures, physical properties and summary of the published methods developed for their analysis in their single form and in their binary mixture. Section (B): Determination of Metronidazole and Nystatin by Dual Wavelength Spectrophotometric Method In this section, dual wavelength method has been developed and optimized for simultaneous analysis of MET and NYS using their zero order spectra. The principle for dual wavelength method is that the absorbance difference at two points on the spectra is directly proportional to the concentration of the component of interest, independent of the interfering component. Absorption values of NYS were the same at 266.5 and 328 nm, so that these wavelengths were selected for the determination of MET. The same as in 291 and 330 nm, the absorbance values of MET were the same and hence those two wavelengths were selected for estimation of NYS The developed method was successfully applied for quantitation of the studied drugs in laboratory prepared mixtures and in pharmaceutical formulations, Amrizole N® vaginal suppositories and Nystazole® vaginal tablets, the standard addition technique has been applied to verify their validity. Section (C): Determination of Metronidazole and Nystatin by Isoabsorptive Point Spectrophotometric Method In this section, the second derivative (2D) amplitudes at 290 nm were used for determination of NYS concentrations, while isosbestic point (ISO) method was applied for determination of the total mixture concentration (MET and NYS) at the isosbestic point (? iso = 322 nm). Since the concentration of NYS in the mixture can be determined by using 2D spectrophotometric method, therefore MET concentration can be obtained by subtraction. The developed methods have been validated according to ICH guidelines and were successfully applied for quantitation of the studied drugs in Amrizole N® vaginal suppositories and Nystazole® vaginal tablets. Section (D): Determination of Metronidazole and Nystatin by TLC-Densitometric Method This section is concerned with the development of sensitive, economic and specific TLC-Densitometric method for determination of MET and NYS in their bulk powder and pharmaceutical formulations. The studied components were well separated using methanol: hexane: triethylamine (80: 20: 2, by volume) as a developing system and the separated bands were scanned at 305nm. Linear relationships were obtained between the mean integrated peak area (× 10-4) and the corresponding concentrations of MET and NYS in the concentration range of 1 - 13 and 0.5 - 10 µg band-1, respectively. The developed TLC-Densitometric method has been applied for determination of the two drugs in their pharmaceutical formulations and the results have been compared with those of the reported chemometric method and no significant difference has been found between them. Section (E): Determination of Metronidazole and Nystatin by RP-HPLC Method A precise, specific, and accurate RP-HPLC method was proposed for the determination of MET and NYS. In this method, an isocratic elution of the two components was performed at ambient temperature on ODS column using acetonitrile: 0.05 M phosphate buffer (30: 70, v/v) pH= 3.5 as a mobile phase with a flow rate of 1 mL min-1 and UV-detection at 305 nm. By applying the suggested RP-HPLC method, MET and NYS could be quantified in the range of 3 - 50 and 15 - 50 µg mL-1, respectively. Statistical comparison of the results obtained by the proposed method and a reported PLS chemometric method was carried out. The values of the calculated t and F are less than the tabulated ones which reveals that there is no significant difference between the two methods with respect to accuracy and precision. Part III: Determination of Aspirin, Caffeine, and Paracetamol in Their Ternary Mixtures This part comprises four sections. Section (A): Introduction and Literature Review This section includes an introduction about the pharmacological actions of Aspirin (ASP), Caffeine (CAF), and Paracetamol (PAR), their chemical structures, physical properties and a summary of the published methods developed for their analysis in their single formulation and in their ternary mixture. Section (B): Determination of Aspirin, Caffeine, and Paracetamol by Different Spectrophotometric Methods The developed spectrophotometric methods are the successive ratio-derivative spectra and indirect spectrophotometric methods. Applying successive ratio-derivative spectra method, ASP and PAR could be selectively determined while, CAF could not be determined by this method, and so, it was determined indirectly using mathematical equation. Aspirin was determined using the amplitudes of the first derivative of the second ratio spectra at 241.2 nm, while PAR was determined using the amplitudes at 228.2 nm. CAF was indirectly determined using mathematical equations computed at 241.2 and 285.6 nm. The proposed methods were used for quantitation of the studied drugs in Aspicure-combi®, Excedrin®, and Markadel® tablets and results of standard addition technique confirmed that tablet additives did not interfere. Section (C): Simultaneous Determination of Aspirin, Caffeine, and Paracetamol by Successive Mean Centering of Ratio Spectra Spectrophotometric Method A recent and simple method was developed for the simultaneous determination of ternary mixture without prior separation steps. In this method, the mean centered second ratio spectra amplitudes peak to peak at 242 to 243, 203 to 204, and 220 to 221 nm were used for quantitation of ASP, CAF and PAR, respectively. Moreover, the suggested method has been applied for determination of the three drugs in their pharmaceutical preparations. Statistical comparison with the reported spectrophotometric method showed no significant difference. Section (D): Simultaneous Determination of Aspirin, Caffeine, and Paracetamol by TLC-Densitometric Method In this section, a simple and accurate TLC-Densitometric method has been suggested for the analysis of the ternary mixtures of ASP, CAF, and PAR in bulk powders and in tablets. The suitable mobile phase has been selected to achieve the best separation. Quantitative determination of the separated bands of ASP, CAF, and PAR was carried out at 230 nm upon using chloroform: methanol: glacial acetic acid: ammonia solution (95: 5: 0.5: 0.2, by volume) as a developing system in the range of 1 – 10 µg band-1 for ASP and PAR and 0.5 - 7 µg band-1 for CAF. The suggested TLC-Densitometric method was successfully applied for analysis of the cited drugs in pharmaceutical formulations. Part IV: Appendix This part includes a brief idea about the instruments, solvents and chemicals used in other parts, in addition to the detailed preparation of the solutions used in each part throughout this work and also method of preparation of DIA degradate, RH.

PHD Title

ANALYTICAL STUDY OF SOME hydroxyl and / or carbonyl groups Containing Drugs

PHD Abstract

Summary This thesis consists of four parts in addition to the references and a summary in Arabic. Part I: Introduction and Literature Review This part includes three sections. Section (A): Introduction and Literature Review of Cetylpyridinium Chloride, Chlorocresol, and Lidocaine Section (B): Introduction and Literature Review of Yohimbine Hydrochloride, Vitamin E Acetate, Vitamin B3, and Caffeine Section (C): Introduction and Literature Review of Sulfacetamide Sodium This part includes an introduction about the pharmacological action of Cetylpyridinium Chloride (CE), Chlorocresol (CH), Lidocaine (LI), Section (A), Yohimbine Hydrochloride (YH), Vitamin E Acetate (VE), Vitamin B3 (VE), Caffeine (CAF), Section (B), and Sulfacetamide Sodium (SCA), section (C), their chemical structures, physical properties and summary of the published methods developed for their analysis alone, with other drugs, or in their ternary mixtures. Part II: Quantitative Determination of Cetylpyridinium Chloride, Chlorocresol, and Lidocaine in Their Ternary Mixtures This part includes two sections. Section (A): Determination of Cetylpyridinium Chloride, Chlorocresol, and Lidocaine by Different Spectrophotometric Methods In this section, mean centering of ratio spectra (MCR) and ratio isoabsorptive point and ratio difference in subtracted spectra (RDSS) spectrophotometric methods were developed for quantitative determination of Cetylpyridinium Chloride (CE), Chlorocresol (CH), and Lidocaine (LI). In MCR method, the second mean centered ratio spectra were obtained where peak amplitudes at maximum or minimum wavelengths were measured so, CE, CH, and LI were determined at peak to peak 231-232, 244-245, and 255-264 nm, respectively while in RDSS method, CH was determined by measuring the absorbance values of the ratio spectra at 290 nm, the plateau region, using 6 µg mL-1 of CH as a divisor then CE and LI absorption spectra were divided by the standard spectrum of 6 µg mL-1 of CH and the differences in absorbance values of the obtained ratio spectra at 242 and 256 nm for CE and 210 and 216 nm for LI were plotted against the corresponding concentrations of CE and LI to construct their respective calibration curves for their determination. The suggested methods were applied for determination of CE, CH, and LI in different laboratory prepared mixtures. The results obtained upon applying the proposed methods on Canyon® oral gel were statistically compared to those obtained by applying the reported HPLC ones and no significant difference was found. Section (B): Determination of Cetylpyridinium Chloride, Chlorocresol, and Lidocaine by Different Chromatographic Methods In this section, simple and accurate TLC-Densitometric and RP-HPLC chromatographic methods have been suggested for simultaneous determination of CE, CH, and LI in their ternary mixtures. The best separation resulted upon using methanol: acetone: acetic acid (7: 3: 0.2, by volume) as a developing system and detecting at 215 nm for TLC-Densitometric method while for RP-HPLC method, a mobile phase of 0.05% phosphoric acid solution: acetonitrile: methanol (15: 24: 61, by volume), pH = 5 with a flow rate of 1 mL min-1 using C18 column and 220 nm as a detection wavelength were the optimum separation conditions. The suggested TLC-Densitometric and RP-HPLC methods were successfully applied for analysis of the cited drugs in Canyon® oral gel and the results showed good agreement with the labeled amount and were compared to the results obtained from the reported methods where no statistical difference was found. Part III: Quantitative Determination of Yohimbine Hydrochloride, Vitamin E Acetate, Vitamin B3, and Caffeine in Their Quaternary Mixtures This part includes two sections. Section (A): Determination of Yohimbine Hydrochloride, Vitamin E Acetate, Vitamin B3, and Caffeine by Different Spectrophotometric Methods In this section, mean centering of ratio spectra (MCR) and triple divisor (TD) spectrophotometric methods were developed for quantitative determination of Yohimbine Hydrochloride (YH), Vitamin E Acetate (VE), Vitamin B3 (VB), and Caffeine (CAF). In MCR method, the amplitudes of the mean entered third ratio spectra at 250 nm and 268 nm for YH and VE, respectively and at peak to peak 272-273 and 262-263 nm for VB and CAF, respectively were used for their respective determination. In TD method, YH was determined by measuring the amplitudes of the first derivative ratio spectra at 222 nm using a spectrum of a mixture containing equal concentrations of VE, VB, and CAF (5 µg mL-1 of each) as a divisor. VE, VB, and CAF were similarly determined measuring the amplitudes of their respective first derivative ratio spectra at 284, 265, and 287 nm, respectively using a spectrum of a mixture containing equal concentrations of the other three drugs (10 µg mL-1 of each) as a divisor. Moreover, the suggested methods have been applied for determination of the four drugs in their pharmaceutical preparation. Statistical comparison with the reported HPLC methods showed no significant difference. Section (B): Determination of Yohimbine Hydrochloride, Vitamin E Acetate, Vitamin B3, and Caffeine by Different Chromatographic Methods In this section, selective and accurate TLC-Densitometric and RP-HPLC chromatographic methods were validated for simultaneous determination of YH, VE, VB, and CAF in their quaternary mixtures. In TLC-Densitometric method, well defined peaks were completely separated on upon using methanol: methylene chloride: ethyl acetate: acetic acid (pH 6.5 ± 0.2) (1: 8: 3: 0.5, by volume) as a developing system and detecting at 220 nm. In RP-HPLC method, a mobile phase of water: acetonitrile: methanol (30: 20: 50, by volume) with a flow rate of 0.8 mL min-1 and the effluent was monitored at 270 nm. The utility of the suggested methods was verified by application to super act® capsules where no interference from additives were found. No significant difference was observed upon comparing the results of the proposed methods and those of the reported HPLC ones. Part IV: Full Stability Study of Sulfacetamide Sodium and Development of Different Stability Indicating Methods of Analysis This part includes two sections. Section (A): Kinetic Study and Characterization of Sulfacetamide Sodium Hydrolytic Degradation Rate In this section, a kinetic study of Sulfacetamide Sodium (SCA) acidic and alkaline degradation as a function of drug concentration, acid and alkaline concentration and temperature has been established utilizing first derivative of ratio spectra spectrophotometric method as a resolving method in analytical chemistry. Measuring the amplitudes at peak maximum ? = 221 nm of the first derivative of ratio spectra of sulfacetamide using 10 µg mL-1 sulfanilamide, SCA degradation product, as a divisor allowed selective determination of SCA in presence of sulfanilamide. The method was applied for determination of SCA in marketed formulation and laboratory prepared mixtures with Sulfanilamide. Moreover it was used for the kinetic study of the hydrolysis of SCA. The kinetic degradation of SCA obeyed Arrhenius equation and was found to follow pseudo-first order kinetics under the established experimental conditions and is pH and temperature dependent. Activation energy at different temperatures, kinetic rate constants, and t1/2 at different pH values were calculated. Section (B): Full Stability Study of Sulfacetamide Sodium and Stability Indicating Chromatographic Methods for Determination of Sulfacetamide Sodium in Presence of its Stress Degradation Products In this section, SCA was subjected to full stability study. The drug was found to be sensitive to most of the studied conditions. Stability indicating TLC-Densitometric and RP-HPLC chromatographic methods have been optimized for determination of (SCA) in presence of its degradation products resulted from different stress conditions. In TLC-densitometric method good separation of (SCA) from its degradation products using ethyl acetate-chloroform-acetic acid (10: 90: 20, by volume) as a developing system with UV detection at 254 nm. While in RP-HPLC method, the drug was completely separated from all degradation products using trifluoroacetic acid solution (0.05%) (TFA)- Methanol (80:20, v/v) as a mobile phase. Quantification was achieved by ultraviolet (UV) detection at 270 nm. The suggested chromatographic methods were successfully applied for analysis of the cited drug in pharmaceutical formulations and the results showed good agreement with the labeled amount and showed no significant difference with those of the reported HPLC one.