A comparative photostability study of four propyl piperzine-substituted phenothiazines
- Authors: Drummond, Patricia Mary
- Date: 1997
- Subjects: Phenothiazine
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3756 , http://hdl.handle.net/10962/d1003234 , Phenothiazine
- Description: Four structurally related phenothiazines available in South Africa in a variety of dosage forms and as fine chemicals were investigated to ascertain whether their structural differences in terms of the 2-chloro-/ trifluoromethyl-substituents on the phenothiazine nucleus and the methyl-/ ß-hydroxethyl groups on the piperazine ring accouning for the differences in pharmacological activity can be correlated with their photostability².The four propyl piperazine-substituted derivatives are ranked in the following decreasing order of neuroleptic activity: fluphenazine> trifluoperazine> perphenazine > rochlorperazine. In order to assess their photostability an HPLC method was developed and validated for linearity, accuracy and precision, selectivity, limit of detection and quantitation and ruggedness. Preliminary solution photostudies under controlled light conditions (UV, sunlight, fluorescent light) indicated that the rate of degradation followed first-order kinetics with perphenazine the most susceptible to.photodegradation under all light conditions studied. In vitro and in vivo metabolism yielding the 5-sulphoxide and its reported presence on decomposition of the phenothiazines25 led to the development of a synthetic procedure suitable for the sutphoxides of all four derivatives based on the method proposed by Owens et al. in order to provide standards for comparison in the photostudies⁷. Since ICH regulations require that impurities> 0.1 % are examined and identified⁷⁴ and semi-preparative isolation of photoproducts proved unsuccessful, LC-MS having been well documented for structural.elucidation⁷⁵ ⁷⁵ ⁷⁶ ⁷⁷ was used to characterize solution (UV, sunlight, fluorescent light) and preliminary solid (UV) photostudies. The chloroderivatives underwent dechlorination and sulphoxidation with subsequent photosubstitution in the case of prochlorperazine to yield the 2-hydroxy derivative and sulphoxidation of the dechloro-derivative of perphenazine. The sulphoxides of both trifluoperazine and fluphenazine were formed with further oxidation to the respective sulphones occurring. Preliminary solid state (UV) photostudies showed fluphenazine to be the least stable with 30.71 % degradation as opposed to 7.57% for prochlorperazine, 4.28% for perphenazine and 7.10% for trifluoperazine witn sulphoxidation observed to be. the major degradation pathway. Since in vitro metabolism of perazine derivatives is reported to occur via N-oxidation, N-demethylation, sulphoxidation and aromatic hydroxylation¹⁸ it does appear that there is some correlation between metabolic and photoproducts. However the fact that solution (UV) photostudies indicates trifluoperazine to be the most and perphenazine the least stable does not concur with the proposed order of pharmacological activity.
- Full Text:
- Date Issued: 1997
- Authors: Drummond, Patricia Mary
- Date: 1997
- Subjects: Phenothiazine
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3756 , http://hdl.handle.net/10962/d1003234 , Phenothiazine
- Description: Four structurally related phenothiazines available in South Africa in a variety of dosage forms and as fine chemicals were investigated to ascertain whether their structural differences in terms of the 2-chloro-/ trifluoromethyl-substituents on the phenothiazine nucleus and the methyl-/ ß-hydroxethyl groups on the piperazine ring accouning for the differences in pharmacological activity can be correlated with their photostability².The four propyl piperazine-substituted derivatives are ranked in the following decreasing order of neuroleptic activity: fluphenazine> trifluoperazine> perphenazine > rochlorperazine. In order to assess their photostability an HPLC method was developed and validated for linearity, accuracy and precision, selectivity, limit of detection and quantitation and ruggedness. Preliminary solution photostudies under controlled light conditions (UV, sunlight, fluorescent light) indicated that the rate of degradation followed first-order kinetics with perphenazine the most susceptible to.photodegradation under all light conditions studied. In vitro and in vivo metabolism yielding the 5-sulphoxide and its reported presence on decomposition of the phenothiazines25 led to the development of a synthetic procedure suitable for the sutphoxides of all four derivatives based on the method proposed by Owens et al. in order to provide standards for comparison in the photostudies⁷. Since ICH regulations require that impurities> 0.1 % are examined and identified⁷⁴ and semi-preparative isolation of photoproducts proved unsuccessful, LC-MS having been well documented for structural.elucidation⁷⁵ ⁷⁵ ⁷⁶ ⁷⁷ was used to characterize solution (UV, sunlight, fluorescent light) and preliminary solid (UV) photostudies. The chloroderivatives underwent dechlorination and sulphoxidation with subsequent photosubstitution in the case of prochlorperazine to yield the 2-hydroxy derivative and sulphoxidation of the dechloro-derivative of perphenazine. The sulphoxides of both trifluoperazine and fluphenazine were formed with further oxidation to the respective sulphones occurring. Preliminary solid state (UV) photostudies showed fluphenazine to be the least stable with 30.71 % degradation as opposed to 7.57% for prochlorperazine, 4.28% for perphenazine and 7.10% for trifluoperazine witn sulphoxidation observed to be. the major degradation pathway. Since in vitro metabolism of perazine derivatives is reported to occur via N-oxidation, N-demethylation, sulphoxidation and aromatic hydroxylation¹⁸ it does appear that there is some correlation between metabolic and photoproducts. However the fact that solution (UV) photostudies indicates trifluoperazine to be the most and perphenazine the least stable does not concur with the proposed order of pharmacological activity.
- Full Text:
- Date Issued: 1997
Application of capillary electrophoresis for the assay of erythromycin and its related substance
- Authors: Lalloo, Anita Kantilal
- Date: 1997
- Subjects: Antibiotics -- Analysis , Capillary electrophoresis , Erythromycin -- Analysis
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3765 , http://hdl.handle.net/10962/d1003243 , Antibiotics -- Analysis , Capillary electrophoresis , Erythromycin -- Analysis
- Description: Capillary Electrophoresis (CE) is a high resolution analytical technique that may be employed in the separation and quantification of a wide range of analytes. The enormous efficiency obtained in CE are well suited for complex mixtures in which resolution of a large number of peaks in a short time is desirable. Therefore, CE has a promising future in pharmaC-eutical analysis. The separation mechanism of CE is based on the differential electrophoretic mobility of the solutes inside a buffer filled capillary upon the application of a voltage. Capillary electrophoresis is especially suitable for ionic species. The full potential of this technique can only be realised through the manipulation of numerous experimental parameters. In the present study, a CE method has been developed for the analysis of the macrolide antibiotics: erythromycin, oleandomycin, troleandomycin and josamycin. The selection of initial analysis conditions and optimisation of selectivity are reviewed. A systematic approach to method development was used to maximise analyte differential electrophoretic mobilities, by adjusting the pH. Thereafter, the influences of electrolyte molarity and electrolyte additives were investigated. In addition, some instrumental parameters, such as capillary length emf diameter, applied voltage and injection conditions were varied. The effect of the sample solvent and oncapillary concentration techniques such as FASI, were investigated. Also, the influence of injecting a water plug on the quantity of sample injected was demonstrated. Full resolution was achieved with the addition of methanol to the electrolyte. The applicability of CE for the assay of erythromycin and its related substances was investigated. Two methods were developed and successfully validated using CE: one for the quantitative determination of erythromycin alone and another for erythromycin related substances in the presence of large quantities of erythromycin A. Several related substances and impurities that result from the fermentation process used to produce erythromycin as well as degradation products are known to be present in commercial sa~ples. These impurities include erythromycin B, C, D, E, F, erythromycin enol ether, anhydroerythromycin and N-demethylerythromycin. Currently both the USP and BP official assays for the analysis of erythromycin involve the use of microbiological assays. These methods are limited as they are unable to differentiate between erythromycin and its related substances and degradation products. Furthermore, the microbiological assays are time-consuming and tedious to perform. 11 The CE methods developed for the analysis of erythromycin and for its related substances were fully validated in terms of precision, linearity, accuracy, sensitivity and stability. In addition, erythromycin was subjected to six stress modes and the stressed samples were analysed. An intemal standard was employed to provide acceptable precision for the migration time « 1.80 % RSD) and peak area « 4.44 % RSD). Optimum sensitivity was obtained using low UV wavelengths, with LOO values of less than 10 % for the related substances. The developed method was accurate for erythromycin C, anhydroerythromycin and N-demethylerythromycin, even in the presence of large concentrations of the parent. The method for~ erythromycin related substances was applied to the determination of impurities in three commercial erythromycin bases. The CE methods developed were rapid, precise, specific and stability-indicating and may be used to provide additional information to augment that attained by HPLC for purity assessment and in stability studies of erythromycin. Capillary electrophoresis is a simple, cost-effective technique that is capable of generating high quality data. This technique will become firmly established within pharmaceutical analysis for main peak and related impurity determination assays as familiarity becomes more widespread across the pharmaceutical industry and improvements in instrumentation are performed.
- Full Text:
- Date Issued: 1997
- Authors: Lalloo, Anita Kantilal
- Date: 1997
- Subjects: Antibiotics -- Analysis , Capillary electrophoresis , Erythromycin -- Analysis
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3765 , http://hdl.handle.net/10962/d1003243 , Antibiotics -- Analysis , Capillary electrophoresis , Erythromycin -- Analysis
- Description: Capillary Electrophoresis (CE) is a high resolution analytical technique that may be employed in the separation and quantification of a wide range of analytes. The enormous efficiency obtained in CE are well suited for complex mixtures in which resolution of a large number of peaks in a short time is desirable. Therefore, CE has a promising future in pharmaC-eutical analysis. The separation mechanism of CE is based on the differential electrophoretic mobility of the solutes inside a buffer filled capillary upon the application of a voltage. Capillary electrophoresis is especially suitable for ionic species. The full potential of this technique can only be realised through the manipulation of numerous experimental parameters. In the present study, a CE method has been developed for the analysis of the macrolide antibiotics: erythromycin, oleandomycin, troleandomycin and josamycin. The selection of initial analysis conditions and optimisation of selectivity are reviewed. A systematic approach to method development was used to maximise analyte differential electrophoretic mobilities, by adjusting the pH. Thereafter, the influences of electrolyte molarity and electrolyte additives were investigated. In addition, some instrumental parameters, such as capillary length emf diameter, applied voltage and injection conditions were varied. The effect of the sample solvent and oncapillary concentration techniques such as FASI, were investigated. Also, the influence of injecting a water plug on the quantity of sample injected was demonstrated. Full resolution was achieved with the addition of methanol to the electrolyte. The applicability of CE for the assay of erythromycin and its related substances was investigated. Two methods were developed and successfully validated using CE: one for the quantitative determination of erythromycin alone and another for erythromycin related substances in the presence of large quantities of erythromycin A. Several related substances and impurities that result from the fermentation process used to produce erythromycin as well as degradation products are known to be present in commercial sa~ples. These impurities include erythromycin B, C, D, E, F, erythromycin enol ether, anhydroerythromycin and N-demethylerythromycin. Currently both the USP and BP official assays for the analysis of erythromycin involve the use of microbiological assays. These methods are limited as they are unable to differentiate between erythromycin and its related substances and degradation products. Furthermore, the microbiological assays are time-consuming and tedious to perform. 11 The CE methods developed for the analysis of erythromycin and for its related substances were fully validated in terms of precision, linearity, accuracy, sensitivity and stability. In addition, erythromycin was subjected to six stress modes and the stressed samples were analysed. An intemal standard was employed to provide acceptable precision for the migration time « 1.80 % RSD) and peak area « 4.44 % RSD). Optimum sensitivity was obtained using low UV wavelengths, with LOO values of less than 10 % for the related substances. The developed method was accurate for erythromycin C, anhydroerythromycin and N-demethylerythromycin, even in the presence of large concentrations of the parent. The method for~ erythromycin related substances was applied to the determination of impurities in three commercial erythromycin bases. The CE methods developed were rapid, precise, specific and stability-indicating and may be used to provide additional information to augment that attained by HPLC for purity assessment and in stability studies of erythromycin. Capillary electrophoresis is a simple, cost-effective technique that is capable of generating high quality data. This technique will become firmly established within pharmaceutical analysis for main peak and related impurity determination assays as familiarity becomes more widespread across the pharmaceutical industry and improvements in instrumentation are performed.
- Full Text:
- Date Issued: 1997
Assessment of amoxycillin suppositories
- Authors: Webster, Jessica Angela
- Date: 1997
- Subjects: Solid dosage forms , Suppositories , Amoxicillin
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3802 , http://hdl.handle.net/10962/d1003280 , Solid dosage forms , Suppositories , Amoxicillin
- Description: The investigations in this dissertation have been 'conducted to investigate the formulation and analysis of a paediatric amoxycillin suppository. The oral administration of antibiotics to young children can at times be roblematic. Compliance is sometimes poor because of a sore throat, nausea, vomiting, a high fever or a dislike for the taste or smell of the medicine:- In-such cases the rectal administration of an antibiotic could provide an alternative route of administration that avoids some of the problems that affect oral administration. Difficulties associated with rectal administration are bioavailability, local irritation, acceptability to patients and rejection of the dosage form. Few data, however, are available on the usefulness in children of suppositories in general, and antibiotic suppositories in particular. The areas of investigation have included the formulation of an amoxycillin suppository in various fatty bases, the quantitation of amoxycillin in both aqueous solution and human serum, assessment of stability of amoxycillin in stored aqueous and biological samples, in vitro drug release testing of suppositories, and bioavailability and pharmacokinetics following administration to human subjects of capsule, suppository, oral suspension and rectal suspension dosage forms. Suppositories containing 250 mg amoxycillin were prepared in theobroma oil and in the semisynthetic bases Witepso[ W35, Suppocire A32, Novata BD and Novata 299. The in vitro release characteristics of amoxycillin from these lipophilic suppository formulations were investigated using the USP rotating basket method. The dissolution of a drug from a solid dosage unit is an important parameter affecting drug bioavialability. High Performance Liquid Chromatography (HPLC) was used as the main analytical technique. An original HPLC method for analysis of amoxycillin in aqueous solution, using ultraviolet detection at 230 nm was develcfped. The validated method was a~plied to the determination of the stability of aqueous amoxycillin solutions, and was utilized to determine the amount of drug released during dissolution testing. Differential scanning calorimetry (DSC) is a technique commonly used in preformulation studies. Dissolution testing was used in conjunction with DSC to select a suppository base suitable for formulation with amoxycillin trihydrate. An HPLC method for analysis of amoxycillin in human serum using UV detection at 230 nm is presented. The method involves a solid phase extraction procedure followed by chromatography on a reversed phase column. The limit of sensitivity of 0.3 ILg/mL in serum is sufficiently sensitive to monitor serum concentrations of amoxycillin in humans after the administration of a single 250 mg oral dose. Pharmacokinetic parameters were calculated from data obtained following the administration of a capsule and oral suspension. These parameters were consistent with previously published results. Following administration of a lipophilic suppository and a rectal suspension, to human volunteers, it was concluded that amoxycillin trihydrate is not readily absorbed from the rectum. Further investigations into the modification of the suppository dosage form with absorption enhancers to improve rectal absorption of amoxycillin, as well as elucidation of the mechanism of absorption of the drug, could assist in improving this formulation so that it is suitable for paediatric use.
- Full Text:
- Date Issued: 1997
- Authors: Webster, Jessica Angela
- Date: 1997
- Subjects: Solid dosage forms , Suppositories , Amoxicillin
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3802 , http://hdl.handle.net/10962/d1003280 , Solid dosage forms , Suppositories , Amoxicillin
- Description: The investigations in this dissertation have been 'conducted to investigate the formulation and analysis of a paediatric amoxycillin suppository. The oral administration of antibiotics to young children can at times be roblematic. Compliance is sometimes poor because of a sore throat, nausea, vomiting, a high fever or a dislike for the taste or smell of the medicine:- In-such cases the rectal administration of an antibiotic could provide an alternative route of administration that avoids some of the problems that affect oral administration. Difficulties associated with rectal administration are bioavailability, local irritation, acceptability to patients and rejection of the dosage form. Few data, however, are available on the usefulness in children of suppositories in general, and antibiotic suppositories in particular. The areas of investigation have included the formulation of an amoxycillin suppository in various fatty bases, the quantitation of amoxycillin in both aqueous solution and human serum, assessment of stability of amoxycillin in stored aqueous and biological samples, in vitro drug release testing of suppositories, and bioavailability and pharmacokinetics following administration to human subjects of capsule, suppository, oral suspension and rectal suspension dosage forms. Suppositories containing 250 mg amoxycillin were prepared in theobroma oil and in the semisynthetic bases Witepso[ W35, Suppocire A32, Novata BD and Novata 299. The in vitro release characteristics of amoxycillin from these lipophilic suppository formulations were investigated using the USP rotating basket method. The dissolution of a drug from a solid dosage unit is an important parameter affecting drug bioavialability. High Performance Liquid Chromatography (HPLC) was used as the main analytical technique. An original HPLC method for analysis of amoxycillin in aqueous solution, using ultraviolet detection at 230 nm was develcfped. The validated method was a~plied to the determination of the stability of aqueous amoxycillin solutions, and was utilized to determine the amount of drug released during dissolution testing. Differential scanning calorimetry (DSC) is a technique commonly used in preformulation studies. Dissolution testing was used in conjunction with DSC to select a suppository base suitable for formulation with amoxycillin trihydrate. An HPLC method for analysis of amoxycillin in human serum using UV detection at 230 nm is presented. The method involves a solid phase extraction procedure followed by chromatography on a reversed phase column. The limit of sensitivity of 0.3 ILg/mL in serum is sufficiently sensitive to monitor serum concentrations of amoxycillin in humans after the administration of a single 250 mg oral dose. Pharmacokinetic parameters were calculated from data obtained following the administration of a capsule and oral suspension. These parameters were consistent with previously published results. Following administration of a lipophilic suppository and a rectal suspension, to human volunteers, it was concluded that amoxycillin trihydrate is not readily absorbed from the rectum. Further investigations into the modification of the suppository dosage form with absorption enhancers to improve rectal absorption of amoxycillin, as well as elucidation of the mechanism of absorption of the drug, could assist in improving this formulation so that it is suitable for paediatric use.
- Full Text:
- Date Issued: 1997
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