An investigation into development of a stable aqeous suspension of Metronidazole Benzoate for oral use
- Authors: Zietsman, Sharon Lynne
- Date: 2005
- Subjects: Metronidazole -- Testing , Excipients -- South Africa -- Testing , Rheology -- South Africa
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:10158 , http://hdl.handle.net/10948/456 , Metronidazole -- Testing , Excipients -- South Africa -- Testing , Rheology -- South Africa
- Description: Metronidazole is a synthetic, nitroimidazole-derivative antibacterial and antiprotozoal agent (ed. McEvoy, 2001). It has been reported that crystallization occurs in aqueous suspensions of metronidazole benzoate, a bland-tasting prodrug of metronidazole, as a result of conversion from the anhydrous to the monohydrate form, thereby compromising the stability and clinical efficacy of the substance due to the particle size growth (Hoelgaard & Moller, 1983). A generic South African based pharmaceutical company commenced formulation of an aqueous metronidazole benzoate suspension and experienced problems with crystallization that occurred in products stored at 2 to 8 °C. This study aimed to continue development of the product in order to identify a formulation that prevents formation of the hydrate form of metronidazole benzoate and the accompanying crystal growth. A variety of metronidazole benzoate suspensions were manufactured on a laboratory scale using a number of natural and synthetic suspending agents, including magnesium aluminium silicate, povidone K90, xanthan gum and Avicel® RC-591 (microcrystalline cellulose and carboxymethylcellulose sodium), over a range of concentrations. Analytical quantification methods were developed and validated, and the physicochemical properties of the raw material and finished products were fully characterized. Rheological tests were performed in order to characterize the suspension flow properties. Real-time and accelerated stability studies and a temperature cycle study were conducted in accordance with the International Conference on Harmonization (ICH) guidelines. Conversion of metronidazole benzoate to the monohydrate form took place in suspensions containing xanthan gum 0.65 percent m/v under real-time and accelerated storage conditions. The suspensions containing Avicel® RC-591 were found to be physically and chemically stable after the temperature cycle and over the 12-week period whilst stored at 25 ºC / 60 percent RH and 5 ºC. The suspensions were chemically stable whilst stored at 40 ºC / 75 percent RH but showed sedimentation at this accelerated condition. The metronidazole benzoate contained in these products remained in the anhydrous state under all storage conditions and were consequently concluded to be the most stable formulations out of all the products analyzed in the current study. The suspending agent system consisting of microcrystalline cellulose and carboxymethylcellulose sodium thus shows promise in preventing the conversion of metronidazole benzoate from the anhydrate to the monohydrate form, thereby inhibited the subsequent increase in particle size due to crystal growth.
- Full Text:
- Date Issued: 2005
- Authors: Zietsman, Sharon Lynne
- Date: 2005
- Subjects: Metronidazole -- Testing , Excipients -- South Africa -- Testing , Rheology -- South Africa
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:10158 , http://hdl.handle.net/10948/456 , Metronidazole -- Testing , Excipients -- South Africa -- Testing , Rheology -- South Africa
- Description: Metronidazole is a synthetic, nitroimidazole-derivative antibacterial and antiprotozoal agent (ed. McEvoy, 2001). It has been reported that crystallization occurs in aqueous suspensions of metronidazole benzoate, a bland-tasting prodrug of metronidazole, as a result of conversion from the anhydrous to the monohydrate form, thereby compromising the stability and clinical efficacy of the substance due to the particle size growth (Hoelgaard & Moller, 1983). A generic South African based pharmaceutical company commenced formulation of an aqueous metronidazole benzoate suspension and experienced problems with crystallization that occurred in products stored at 2 to 8 °C. This study aimed to continue development of the product in order to identify a formulation that prevents formation of the hydrate form of metronidazole benzoate and the accompanying crystal growth. A variety of metronidazole benzoate suspensions were manufactured on a laboratory scale using a number of natural and synthetic suspending agents, including magnesium aluminium silicate, povidone K90, xanthan gum and Avicel® RC-591 (microcrystalline cellulose and carboxymethylcellulose sodium), over a range of concentrations. Analytical quantification methods were developed and validated, and the physicochemical properties of the raw material and finished products were fully characterized. Rheological tests were performed in order to characterize the suspension flow properties. Real-time and accelerated stability studies and a temperature cycle study were conducted in accordance with the International Conference on Harmonization (ICH) guidelines. Conversion of metronidazole benzoate to the monohydrate form took place in suspensions containing xanthan gum 0.65 percent m/v under real-time and accelerated storage conditions. The suspensions containing Avicel® RC-591 were found to be physically and chemically stable after the temperature cycle and over the 12-week period whilst stored at 25 ºC / 60 percent RH and 5 ºC. The suspensions were chemically stable whilst stored at 40 ºC / 75 percent RH but showed sedimentation at this accelerated condition. The metronidazole benzoate contained in these products remained in the anhydrous state under all storage conditions and were consequently concluded to be the most stable formulations out of all the products analyzed in the current study. The suspending agent system consisting of microcrystalline cellulose and carboxymethylcellulose sodium thus shows promise in preventing the conversion of metronidazole benzoate from the anhydrate to the monohydrate form, thereby inhibited the subsequent increase in particle size due to crystal growth.
- Full Text:
- Date Issued: 2005
The application of rheological techniques in the characterization of semisolids in the pharmaceutical industry
- Authors: Jaganath, Nelesh
- Date: 2004
- Subjects: Drugs -- Dosage forms , Rheology
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:10128 , http://hdl.handle.net/10948/380 , Drugs -- Dosage forms , Rheology
- Description: Rheological characterization of pharmaceutical semisolids is of importance as it provides fundamental information required for the assessment of some of the final properties of a product such as viscosity, elasticity, quality and storage stability. The effect of formulation variables on product characteristics such as consistency and correlation of consumer evaluation of consistency can also be attained. (Ramachandran et al., 1999) This study focussed on using rheological techniques to fully characterize the properties of various semisolid formulations being developed or produced at a South African-based generic pharmaceutical company. Various tests were employed to characterize the semisolid dosage forms (creams and ointments), including continuous shear tests such as flow and viscosity curves and yield point measurements, oscillatory tests such as amplitude and frequency sweeps, as well as step and temperature ramp tests. A method to determine justifiable and meaningful viscosity specifications was developed, where excellent reproducibility of results were obtained when compared to the single-point viscosity determinations usually used. An evaluation as to whether rheology can be utilized as an assessment tool for product stability revealed varying results, with the oscillation-frequency sweep test displaying modest predictive capabilities. Observable differences in rheological character were found when evaluating ointment formulations exhibiting deviating quality characteristics. When analysing the effect of varying processing parameters, namely, cooling rate and mixing speed, during the manufacture of a cream, statistically significant rheological differences were obtained, while a thorough characterization of a scale-up procedure was also achieved upon analysis of various rheological properties.
- Full Text:
- Date Issued: 2004
- Authors: Jaganath, Nelesh
- Date: 2004
- Subjects: Drugs -- Dosage forms , Rheology
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:10128 , http://hdl.handle.net/10948/380 , Drugs -- Dosage forms , Rheology
- Description: Rheological characterization of pharmaceutical semisolids is of importance as it provides fundamental information required for the assessment of some of the final properties of a product such as viscosity, elasticity, quality and storage stability. The effect of formulation variables on product characteristics such as consistency and correlation of consumer evaluation of consistency can also be attained. (Ramachandran et al., 1999) This study focussed on using rheological techniques to fully characterize the properties of various semisolid formulations being developed or produced at a South African-based generic pharmaceutical company. Various tests were employed to characterize the semisolid dosage forms (creams and ointments), including continuous shear tests such as flow and viscosity curves and yield point measurements, oscillatory tests such as amplitude and frequency sweeps, as well as step and temperature ramp tests. A method to determine justifiable and meaningful viscosity specifications was developed, where excellent reproducibility of results were obtained when compared to the single-point viscosity determinations usually used. An evaluation as to whether rheology can be utilized as an assessment tool for product stability revealed varying results, with the oscillation-frequency sweep test displaying modest predictive capabilities. Observable differences in rheological character were found when evaluating ointment formulations exhibiting deviating quality characteristics. When analysing the effect of varying processing parameters, namely, cooling rate and mixing speed, during the manufacture of a cream, statistically significant rheological differences were obtained, while a thorough characterization of a scale-up procedure was also achieved upon analysis of various rheological properties.
- Full Text:
- Date Issued: 2004
The evaluation of indomethacin and theophylline oral controlled/modified-release dosage forms in vitro-in vivo correlations
- Tandt, Ludo Alfons Germaan Luc
- Authors: Tandt, Ludo Alfons Germaan Luc
- Date: 1992
- Subjects: Theophylline , Indomethacin , Drugs -- Controlled release , Drugs -- Dosage forms
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3794 , http://hdl.handle.net/10962/d1003272 , Theophylline , Indomethacin , Drugs -- Controlled release , Drugs -- Dosage forms
- Description: Over the past few decades many researchers have investigated the utility of in vitro - in vivo correlations for the assessment of dosage forms. These investigations are, however, dependent on reproducible dissolution data and well conducted biostudies in order to establish meaningful and robust correlations. Despite the fact that the establishment of such correlations is perhaps idealistic, considerable interest has still been shown in this area of research. Various Controlled/Modified Release Dosage Forms (CMRD's) of theophylline, a weakly basic drug, and indomethacin, a weakly acidic drug, were assessed in order to establish in vitro - in vivo correlations. Dissolution rate studies were carried out using either the USP basket or paddle apparatus. The dissolution rate studies were conducted in a range of dissolution media of varying pH. Bioavailability studies were conducted on the dosage forms used by the Biopharmaceutics Research Institute at Rhodes University. The results of these biostudies were kindly made available for use in this research project. Type A correlations were established using a mathematical simulation process whereby expected in vivo responses are simulated and compared to actual profiles obtained for the dosage forms. In order to perform the simulations the dissolution rate profiles were stripped and using linear regression and the methods of residuals the dissolution rate order and the relevant dissolution rates were obtained. The results of the s imulations indicated that the in vivo serum concentration-time curves could be accurately predicted for the theophylline dosage forms but to a lesser extent, for the indomethacin formulations. The dissolution rate studies indicated that the paddle method is a suitable method for dissolution rate studies of theophylline CMRD's, although it appeared that the optimum pH of the dissolution medium was formulation dependent. Dissolution rate studies conducted on indomethacin formulations indicated that the USP specified basket method for extended-release indomethacin formulations was not able to distinguish between two formulations which exhibited different in vivo profiles. The conversion to the paddle method was, however, able to highlight the differences between these formulations. The use of three dimensional topographs to depict dissolution rate profiles was demonstrated for formulations of both theophylline and indomethacin. The topographs enabled the successful differentiation between bioinequivalent formulations. The dissolution rate profiles were also fitted to the Wei bull equation and the parameters obtained from this were compared to the Weibull parameters obtained from the in vivo absorption plots obtained using the Wagner-Nelson method. The results indicated that the Weibull function was suitable to describe both the in vivo and in vitro data. The following recommendations for the preformulation dissolution studies of weakly acidic and weakly basic drugs are proposed. The dissolution rate studies of weakly acid drugs, such as indomethacin, should be carried out over a range of pH utilising the paddle apparatus. Three dimensional topographs based on the dissolution data should be constructed and used as a comparative tool for different formulations. Based on these comparisons the appropriate formulation can then be selected for a pilot scale in vivo bioavailability study. The dissolution rate studies of weakly basic drugs, such as theophylline, should be carried out over a range of pH utilising the paddle apparatus. The dissolution data should then be used to simulate the expected in vivo profile and on this basis the appropriate formulation selected for a pilot scale bioavailability study. The above approach to the preformulation studies of new CMRO's would allow for the more careful selection of new dosage forms and could thus eliminate costly and unnecessary bioavailability studies performed on inferior formulations.
- Full Text:
- Date Issued: 1992
- Authors: Tandt, Ludo Alfons Germaan Luc
- Date: 1992
- Subjects: Theophylline , Indomethacin , Drugs -- Controlled release , Drugs -- Dosage forms
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3794 , http://hdl.handle.net/10962/d1003272 , Theophylline , Indomethacin , Drugs -- Controlled release , Drugs -- Dosage forms
- Description: Over the past few decades many researchers have investigated the utility of in vitro - in vivo correlations for the assessment of dosage forms. These investigations are, however, dependent on reproducible dissolution data and well conducted biostudies in order to establish meaningful and robust correlations. Despite the fact that the establishment of such correlations is perhaps idealistic, considerable interest has still been shown in this area of research. Various Controlled/Modified Release Dosage Forms (CMRD's) of theophylline, a weakly basic drug, and indomethacin, a weakly acidic drug, were assessed in order to establish in vitro - in vivo correlations. Dissolution rate studies were carried out using either the USP basket or paddle apparatus. The dissolution rate studies were conducted in a range of dissolution media of varying pH. Bioavailability studies were conducted on the dosage forms used by the Biopharmaceutics Research Institute at Rhodes University. The results of these biostudies were kindly made available for use in this research project. Type A correlations were established using a mathematical simulation process whereby expected in vivo responses are simulated and compared to actual profiles obtained for the dosage forms. In order to perform the simulations the dissolution rate profiles were stripped and using linear regression and the methods of residuals the dissolution rate order and the relevant dissolution rates were obtained. The results of the s imulations indicated that the in vivo serum concentration-time curves could be accurately predicted for the theophylline dosage forms but to a lesser extent, for the indomethacin formulations. The dissolution rate studies indicated that the paddle method is a suitable method for dissolution rate studies of theophylline CMRD's, although it appeared that the optimum pH of the dissolution medium was formulation dependent. Dissolution rate studies conducted on indomethacin formulations indicated that the USP specified basket method for extended-release indomethacin formulations was not able to distinguish between two formulations which exhibited different in vivo profiles. The conversion to the paddle method was, however, able to highlight the differences between these formulations. The use of three dimensional topographs to depict dissolution rate profiles was demonstrated for formulations of both theophylline and indomethacin. The topographs enabled the successful differentiation between bioinequivalent formulations. The dissolution rate profiles were also fitted to the Wei bull equation and the parameters obtained from this were compared to the Weibull parameters obtained from the in vivo absorption plots obtained using the Wagner-Nelson method. The results indicated that the Weibull function was suitable to describe both the in vivo and in vitro data. The following recommendations for the preformulation dissolution studies of weakly acidic and weakly basic drugs are proposed. The dissolution rate studies of weakly acid drugs, such as indomethacin, should be carried out over a range of pH utilising the paddle apparatus. Three dimensional topographs based on the dissolution data should be constructed and used as a comparative tool for different formulations. Based on these comparisons the appropriate formulation can then be selected for a pilot scale in vivo bioavailability study. The dissolution rate studies of weakly basic drugs, such as theophylline, should be carried out over a range of pH utilising the paddle apparatus. The dissolution data should then be used to simulate the expected in vivo profile and on this basis the appropriate formulation selected for a pilot scale bioavailability study. The above approach to the preformulation studies of new CMRO's would allow for the more careful selection of new dosage forms and could thus eliminate costly and unnecessary bioavailability studies performed on inferior formulations.
- Full Text:
- Date Issued: 1992
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