Design, development and evaluation of encapsulated oral controlled release theophylline mini-tablets
- Authors: Munday, Dale Leslie
- Date: 1991
- Subjects: Drugs -- Administration , Drugs -- Bioavailability , Drugs -- Controlled release , Drugs -- Dosage forms , Tablets (Medicine) , Biopharmaceutics , Drugs -- Testing
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:3777 , http://hdl.handle.net/10962/d1003255 , Drugs -- Administration , Drugs -- Bioavailability , Drugs -- Controlled release , Drugs -- Dosage forms , Tablets (Medicine) , Biopharmaceutics , Drugs -- Testing
- Description: Conventional solid dosage forms often lead to fluctuations which exceed the maximum safe therapeutic level and/or decline below the minimum effective level. It is recognised that many drugs for chronic administration should be administered on a schedule that maintains plasma drug concentration within the therapeutic window. Research in controlled release dosage forms aims at designing a system with a zero-order input (eg, ideally to deliver 8.33% of the dose per hour over a 12 hour duration), producing steady state plasma drug levels. Oral dministration of drugs prepared as a controlled release formulation is extremely popular, and has attracted the attention of pharmaceutical scientists during the last decade. This has been due to the simultaneous convergence of various factors (eg, discovery of novel polymers and devices, better understanding of formulation and physiological constraints, expiration of existing patents, prohibitive cost of developing new drug entities), involved in the development of these delivery systems. Controlled release oral products can be formulated as single or multiple unit dosage forms and the relative merits of multiple unit forms with their own rate controlling systems are well established. This work describes the development of a relatively inexpensive multiple-unit capsule dosage form of theophylline containing coated mini-tablets for drug delivery throughout the gastrointestinal tract. Preformulation studies on theophylline anhydrous included solubility and dissolution rate determinations. Techniques including X-ray powder diffraction, differential scanning colorimetry and infrared spectroscopy provided no evidence of true polymorphism after recrystallisation from various solvents. However, scanning electron micrographs showed the effects of solvent polarity and cooling rate on the size and shape of recrystallised particles. Theophylline granules were manufactured by using various binders and were film coated by fluidised bed technology with various proportions of ethylcellulose, containing varying amounts of PEG 1540. In vitro release rates were dependent upon coating thickness and the proportion of PEG, which, being water soluble, created pores in the coating during dissolution studies as observed by a scanning electron microscope. However, substantial proportions of the drug remained unreleased from the granules. In order to overcome the problems of drug retention, plain granules were used and theophylline mini-tablets (3 mm diameter, weighing 15 - 20 mg) were manufactured and film coated with various Eudragits ® and other polymeric mixtures (soluble and insoluble). In vitro dissolution profiles from samples enclosed in hard gelatin capsules were determined using the USPXXI paddle apparatus in test media at pH 1.2 (HCI), pH 5.4 and 7.4 (phosphate buffers) at 37'C. Monitoring of in vitro theophylline release over 12 h, under identical hydrodynamic conditions, showed that the dissolution rate at pH 1.2 is substantially greater (95% of total drug content released in < 10 h) than that in phosphate buffers. The maximum release after 12 h was approximately 20 and 30% of total drug content of the tablet at pH 5.4 and 7.4, respectively. However, in vivo bioavailability after oral administration of tablets to rabbits corresponded to over 95% of total drug, compared with the same dose administered intravenously. The retarded drug release during in vitro dissolution in phosphate buffer was attributed to a possible interaction of phosphate ions with theophylline molecules at the tablet core-coat interface. These findings indicate that both rate and extent of theophylline release from the slow release coated mini-tablets are highly sensitive to phosphate buffers. The data also emphasise the usefulness of an animal model for assessment of in vivo drug release and subsequent absorption during the development of modified release dosage forms. Mini-tablets were subjected to isothermal and cyclic stresses to reach conditions for up to 6 months at different temperatures and relative humidity. The film integrity was maintained but ageing of the coating occurred which impeded dissolution. Reduced drug release was temperature related while the effect of relative humidi% was insignific~t. Encapsulated mini-tablets (uncoated and coated with Eudragit RL and RS 2% w/w) equivalent to a 300 mg dose, were evaluated both in vitro and in vivo using beagle dogs. The pharmacokinetic parameters from single and multiple dose studies showed several advantages over Theo-Dur® 300 mg tablets. Precise dosage titration is possible by careful adjustment of the number of encapsulated mini-tablets. This multiple unit mini-tablet delivery system will allow for greater flexibility in dosage adjustment compared to the currently available preparations, allowing individualised fine dose titration in those patients requiring therapeutic drug monitoring. The developmentof the multiple unit mini-tablet formulation appears to provide an optimal dosage form with maximum flexibility in respect of dose, duration range and ease of production.
- Full Text:
- Date Issued: 1991
Design, development and evaluation of encapsulated oral controlled release theophylline mini-tablets
- Authors: Munday, Dale Leslie
- Date: 1991
- Subjects: Drugs -- Administration , Drugs -- Bioavailability , Drugs -- Controlled release , Drugs -- Dosage forms , Tablets (Medicine) , Biopharmaceutics , Drugs -- Testing
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:3777 , http://hdl.handle.net/10962/d1003255 , Drugs -- Administration , Drugs -- Bioavailability , Drugs -- Controlled release , Drugs -- Dosage forms , Tablets (Medicine) , Biopharmaceutics , Drugs -- Testing
- Description: Conventional solid dosage forms often lead to fluctuations which exceed the maximum safe therapeutic level and/or decline below the minimum effective level. It is recognised that many drugs for chronic administration should be administered on a schedule that maintains plasma drug concentration within the therapeutic window. Research in controlled release dosage forms aims at designing a system with a zero-order input (eg, ideally to deliver 8.33% of the dose per hour over a 12 hour duration), producing steady state plasma drug levels. Oral dministration of drugs prepared as a controlled release formulation is extremely popular, and has attracted the attention of pharmaceutical scientists during the last decade. This has been due to the simultaneous convergence of various factors (eg, discovery of novel polymers and devices, better understanding of formulation and physiological constraints, expiration of existing patents, prohibitive cost of developing new drug entities), involved in the development of these delivery systems. Controlled release oral products can be formulated as single or multiple unit dosage forms and the relative merits of multiple unit forms with their own rate controlling systems are well established. This work describes the development of a relatively inexpensive multiple-unit capsule dosage form of theophylline containing coated mini-tablets for drug delivery throughout the gastrointestinal tract. Preformulation studies on theophylline anhydrous included solubility and dissolution rate determinations. Techniques including X-ray powder diffraction, differential scanning colorimetry and infrared spectroscopy provided no evidence of true polymorphism after recrystallisation from various solvents. However, scanning electron micrographs showed the effects of solvent polarity and cooling rate on the size and shape of recrystallised particles. Theophylline granules were manufactured by using various binders and were film coated by fluidised bed technology with various proportions of ethylcellulose, containing varying amounts of PEG 1540. In vitro release rates were dependent upon coating thickness and the proportion of PEG, which, being water soluble, created pores in the coating during dissolution studies as observed by a scanning electron microscope. However, substantial proportions of the drug remained unreleased from the granules. In order to overcome the problems of drug retention, plain granules were used and theophylline mini-tablets (3 mm diameter, weighing 15 - 20 mg) were manufactured and film coated with various Eudragits ® and other polymeric mixtures (soluble and insoluble). In vitro dissolution profiles from samples enclosed in hard gelatin capsules were determined using the USPXXI paddle apparatus in test media at pH 1.2 (HCI), pH 5.4 and 7.4 (phosphate buffers) at 37'C. Monitoring of in vitro theophylline release over 12 h, under identical hydrodynamic conditions, showed that the dissolution rate at pH 1.2 is substantially greater (95% of total drug content released in < 10 h) than that in phosphate buffers. The maximum release after 12 h was approximately 20 and 30% of total drug content of the tablet at pH 5.4 and 7.4, respectively. However, in vivo bioavailability after oral administration of tablets to rabbits corresponded to over 95% of total drug, compared with the same dose administered intravenously. The retarded drug release during in vitro dissolution in phosphate buffer was attributed to a possible interaction of phosphate ions with theophylline molecules at the tablet core-coat interface. These findings indicate that both rate and extent of theophylline release from the slow release coated mini-tablets are highly sensitive to phosphate buffers. The data also emphasise the usefulness of an animal model for assessment of in vivo drug release and subsequent absorption during the development of modified release dosage forms. Mini-tablets were subjected to isothermal and cyclic stresses to reach conditions for up to 6 months at different temperatures and relative humidity. The film integrity was maintained but ageing of the coating occurred which impeded dissolution. Reduced drug release was temperature related while the effect of relative humidi% was insignific~t. Encapsulated mini-tablets (uncoated and coated with Eudragit RL and RS 2% w/w) equivalent to a 300 mg dose, were evaluated both in vitro and in vivo using beagle dogs. The pharmacokinetic parameters from single and multiple dose studies showed several advantages over Theo-Dur® 300 mg tablets. Precise dosage titration is possible by careful adjustment of the number of encapsulated mini-tablets. This multiple unit mini-tablet delivery system will allow for greater flexibility in dosage adjustment compared to the currently available preparations, allowing individualised fine dose titration in those patients requiring therapeutic drug monitoring. The developmentof the multiple unit mini-tablet formulation appears to provide an optimal dosage form with maximum flexibility in respect of dose, duration range and ease of production.
- Full Text:
- Date Issued: 1991
Formulation and dissolution assessment of a novel repeat action tablet containing a decongestant and an antihistamine
- Authors: Verner, Jennifer Joan
- Date: 2001
- Subjects: Antihistamines , Tablets (Medicine) , Tableting , Ephedrine
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3798 , http://hdl.handle.net/10962/d1003276 , Antihistamines , Tablets (Medicine) , Tableting , Ephedrine
- Description: Controlled and sustained release dosage forms are the focus of worldwide research. These dosage forms facilitate patient compliance by simplifying the dosage regimen, and decrease the risk of adverse effects by reducing large fluctuations in the plasma concentration of the drug. The objective of this study was to formulate a repeat-action tablet to provide a sustained release dose of pseudoephedrine sulfate (PSS), and an immediate release dose of both PSS and loratadine. The release profile was compared to that of a commercially available preparation, Clarityne-D®. This formulation developed presents a novel mechanism of sustaining the release of PSS. The prototype tablet consisted of a sustained release core coated with an ethylcellulose dispersion to introduce a lag phase into the release profile and a second outer film coat incorporating PSS and loratadine. The core comprised an ethylcellulose granulation of PSS compressed into a hydroxypropyl methylcellulose matrix. The release of PSS from prototypes was assessed using USP Apparatus 3, as this apparatus was more representative of in vivo conditions and discriminated more effectively between the different tablet compositions produced during development. All dissolution samples were analysed for PSS and loratadine using validated highperformance liquid chromatographic methods. The prototype sustained release cores were found to be more resistant than the reference product to elevated temperature and humidity (40°C/87% RH) with fewer observed changes to the release profiles following storage for up to six months. This study was a feasibility study to obtain proof of concept. The release profile obtained from the prototype tablets was similar (f₂ = 50.0) to that of the reference product. Further development and optimisation of this dosage form is necessary, including evaluation of the choice of hydrophobic polymer, the effect of compression force and tablet geometry and characterisation of the release mechanism from the coated matrix. Assessment of these factors is necessary in order to optimise the formulation with respect to the desired therapeutic objectives.
- Full Text:
- Date Issued: 2001
- Authors: Verner, Jennifer Joan
- Date: 2001
- Subjects: Antihistamines , Tablets (Medicine) , Tableting , Ephedrine
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3798 , http://hdl.handle.net/10962/d1003276 , Antihistamines , Tablets (Medicine) , Tableting , Ephedrine
- Description: Controlled and sustained release dosage forms are the focus of worldwide research. These dosage forms facilitate patient compliance by simplifying the dosage regimen, and decrease the risk of adverse effects by reducing large fluctuations in the plasma concentration of the drug. The objective of this study was to formulate a repeat-action tablet to provide a sustained release dose of pseudoephedrine sulfate (PSS), and an immediate release dose of both PSS and loratadine. The release profile was compared to that of a commercially available preparation, Clarityne-D®. This formulation developed presents a novel mechanism of sustaining the release of PSS. The prototype tablet consisted of a sustained release core coated with an ethylcellulose dispersion to introduce a lag phase into the release profile and a second outer film coat incorporating PSS and loratadine. The core comprised an ethylcellulose granulation of PSS compressed into a hydroxypropyl methylcellulose matrix. The release of PSS from prototypes was assessed using USP Apparatus 3, as this apparatus was more representative of in vivo conditions and discriminated more effectively between the different tablet compositions produced during development. All dissolution samples were analysed for PSS and loratadine using validated highperformance liquid chromatographic methods. The prototype sustained release cores were found to be more resistant than the reference product to elevated temperature and humidity (40°C/87% RH) with fewer observed changes to the release profiles following storage for up to six months. This study was a feasibility study to obtain proof of concept. The release profile obtained from the prototype tablets was similar (f₂ = 50.0) to that of the reference product. Further development and optimisation of this dosage form is necessary, including evaluation of the choice of hydrophobic polymer, the effect of compression force and tablet geometry and characterisation of the release mechanism from the coated matrix. Assessment of these factors is necessary in order to optimise the formulation with respect to the desired therapeutic objectives.
- Full Text:
- Date Issued: 2001
Formulation and assessment of monolithic beta blocker sustained release tablets prepared by direct compression
- Authors: Kieser, Leith Faye
- Date: 2002
- Subjects: Drugs -- Dosage forms , Drugs -- Administration , Pharmacology, Experimental , Adrenergic beta blockers , Tablets (Medicine) , Tableting , Neuropharmacology
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3764 , http://hdl.handle.net/10962/d1003242 , Drugs -- Dosage forms , Drugs -- Administration , Pharmacology, Experimental , Adrenergic beta blockers , Tablets (Medicine) , Tableting , Neuropharmacology
- Description: Beta blockers are commonly prescribed for the chronic treatment of hypertension, one of the most prolific disease states worldwide. The beta blockers selected for this study include acebutolol hydrochloride, labetalol hydrochloride, metoprolol tartrate oxprenolol hydrochloride and propranolol hydrochloride. All of these compounds have a short elimination half-life, necessitating multiple dose per day regimens and therefore the development of sustained release dosage forms incorporating these agents was considered beneficial in terms of extending the dosing interval, with the aim of improving patient compliance and subsequent therapeutic outcomes. Preformulation studies that were conducted included moisture content analysis by Karl Fischer titration, and DSC, a method used to predict potential interactions between the drugs and tablet excipients. Tablets were manufactured by both wet granulation and direct compression techniques, and the resultant drug release characteristics were evaluated using the USP Apparatus 3(BIO.DIS). A validated isocratic HPLC method, capable of separating the five drug candidates simultaneously, was developed and used for the analysis of drug samples. Tablet quality was assessed using analyses that included the physical assessment of weight, diameter, thickness, hardness and friability, as well as content uniformity of tablets, before and after dissolution testing. Direct compression tablet formulations containing each of the five beta blockers were successfully adapted from a prototype wet granulation matrix tablet containing metoprolol tartrate, and various formulation variables were investigated to establish,their effect on the rate and extent of drug release from these tablets. The grade and quantity of ethylcellulose used in the wet granulation and direct compression formulae influenced the release rate of some drug candidates. In addition, an alternative formulation method, involving freeze-drying of the drug with an ethylcellulose dispersion, was shown to have potential for altering release rates further. Anti-frictional agents, talc and colloidal silicon dioxide, did not affect drug release from these matrices,however, they affected the physical character:istics such as tablet weight and thickness, of the resultant tablets. All of the matrix tablets formulated were shown to release drug according to square root of time kinetics, in a sustained manner over a 22 hour period.
- Full Text:
- Date Issued: 2002
- Authors: Kieser, Leith Faye
- Date: 2002
- Subjects: Drugs -- Dosage forms , Drugs -- Administration , Pharmacology, Experimental , Adrenergic beta blockers , Tablets (Medicine) , Tableting , Neuropharmacology
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3764 , http://hdl.handle.net/10962/d1003242 , Drugs -- Dosage forms , Drugs -- Administration , Pharmacology, Experimental , Adrenergic beta blockers , Tablets (Medicine) , Tableting , Neuropharmacology
- Description: Beta blockers are commonly prescribed for the chronic treatment of hypertension, one of the most prolific disease states worldwide. The beta blockers selected for this study include acebutolol hydrochloride, labetalol hydrochloride, metoprolol tartrate oxprenolol hydrochloride and propranolol hydrochloride. All of these compounds have a short elimination half-life, necessitating multiple dose per day regimens and therefore the development of sustained release dosage forms incorporating these agents was considered beneficial in terms of extending the dosing interval, with the aim of improving patient compliance and subsequent therapeutic outcomes. Preformulation studies that were conducted included moisture content analysis by Karl Fischer titration, and DSC, a method used to predict potential interactions between the drugs and tablet excipients. Tablets were manufactured by both wet granulation and direct compression techniques, and the resultant drug release characteristics were evaluated using the USP Apparatus 3(BIO.DIS). A validated isocratic HPLC method, capable of separating the five drug candidates simultaneously, was developed and used for the analysis of drug samples. Tablet quality was assessed using analyses that included the physical assessment of weight, diameter, thickness, hardness and friability, as well as content uniformity of tablets, before and after dissolution testing. Direct compression tablet formulations containing each of the five beta blockers were successfully adapted from a prototype wet granulation matrix tablet containing metoprolol tartrate, and various formulation variables were investigated to establish,their effect on the rate and extent of drug release from these tablets. The grade and quantity of ethylcellulose used in the wet granulation and direct compression formulae influenced the release rate of some drug candidates. In addition, an alternative formulation method, involving freeze-drying of the drug with an ethylcellulose dispersion, was shown to have potential for altering release rates further. Anti-frictional agents, talc and colloidal silicon dioxide, did not affect drug release from these matrices,however, they affected the physical character:istics such as tablet weight and thickness, of the resultant tablets. All of the matrix tablets formulated were shown to release drug according to square root of time kinetics, in a sustained manner over a 22 hour period.
- Full Text:
- Date Issued: 2002
Comparison of two granulation processes with the view to reduce manufacturing cost
- Authors: Maclean, Aldritt Allister
- Date: 2004
- Subjects: Drugs -- Granulation , Tablets (Medicine) , Pharmaceutical industry
- Language: English
- Type: Thesis , Masters , MTech (Chemistry)
- Identifier: vital:10980 , http://hdl.handle.net/10948/210 , Drugs -- Granulation , Tablets (Medicine) , Pharmaceutical industry
- Description: Aspen Pharmacare, one of the leading pharmaceutical manufacturers in South Africa has embarked on a programme of improving the production processes currently employed at their Port Elizabeth site. With the introduction of new technology at the site and the move towards globalization, it became imperative that Aspen remain competitive in the market. The product of interest in this research, Degoran Plus tablets, is one of the company’s leading brand sellers. Upon investigation, it became apparent that this product created opportunity for process improvement using the new technology. The manufacture of Degoran Plus entails granulation, compression and coating of the product. Most opportunity for improvement was possible in the granulation stage because of the laborious nature of the present process. Degoran Plus tablets had a history of analytical failures, especially with regard to the dissolution rate of the final product, as well as other quality related issues. The product was not considered to be a “through-runner”, which resulted in bad production output, due to continual repeats of not only analysis but also reworks in production. A strategic decision was taken to manufacture Degoran Plus using the Collette Gral granulator as the equipment offered superior mixing capability when compared to the Bear planetary granulator. It was assumed that the granulation process would result in more uniform distribution of the actives. Upon producing a better granule, a final product of superior quality would be attained. The validation protocol stipulates that three samples be taken and tested from the powder mix. Nine samples taken from granulated bulk are treated in the same manner. The validation protocol further stipulates that the first three batches manufactured utilise the new process, and tested according to the protocol. The results obtained from the analysis are evaluated statistically and a conclusion and recommendation were derived based on the evaluation.
- Full Text:
- Date Issued: 2004
- Authors: Maclean, Aldritt Allister
- Date: 2004
- Subjects: Drugs -- Granulation , Tablets (Medicine) , Pharmaceutical industry
- Language: English
- Type: Thesis , Masters , MTech (Chemistry)
- Identifier: vital:10980 , http://hdl.handle.net/10948/210 , Drugs -- Granulation , Tablets (Medicine) , Pharmaceutical industry
- Description: Aspen Pharmacare, one of the leading pharmaceutical manufacturers in South Africa has embarked on a programme of improving the production processes currently employed at their Port Elizabeth site. With the introduction of new technology at the site and the move towards globalization, it became imperative that Aspen remain competitive in the market. The product of interest in this research, Degoran Plus tablets, is one of the company’s leading brand sellers. Upon investigation, it became apparent that this product created opportunity for process improvement using the new technology. The manufacture of Degoran Plus entails granulation, compression and coating of the product. Most opportunity for improvement was possible in the granulation stage because of the laborious nature of the present process. Degoran Plus tablets had a history of analytical failures, especially with regard to the dissolution rate of the final product, as well as other quality related issues. The product was not considered to be a “through-runner”, which resulted in bad production output, due to continual repeats of not only analysis but also reworks in production. A strategic decision was taken to manufacture Degoran Plus using the Collette Gral granulator as the equipment offered superior mixing capability when compared to the Bear planetary granulator. It was assumed that the granulation process would result in more uniform distribution of the actives. Upon producing a better granule, a final product of superior quality would be attained. The validation protocol stipulates that three samples be taken and tested from the powder mix. Nine samples taken from granulated bulk are treated in the same manner. The validation protocol further stipulates that the first three batches manufactured utilise the new process, and tested according to the protocol. The results obtained from the analysis are evaluated statistically and a conclusion and recommendation were derived based on the evaluation.
- Full Text:
- Date Issued: 2004
Formulation and assessment of verapamil sustained release tablets
- Khamanga, Sandile Maswazi Malungelo
- Authors: Khamanga, Sandile Maswazi Malungelo
- Date: 2005
- Subjects: Verapamil , Tablets (Medicine) , Drugs -- Administration , Cardiovascular agents , Calcium -- Antagonists , Drugs -- Controlled release
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3869 , http://hdl.handle.net/10962/d1018236
- Description: The oral route of drug administration is most extensively used due to the obvious ease of administration. Verapamil hydrochloride is a WHO listed phenylalkylarnine, L-type calcium channel antagonist that is mainly indicated for cardiovascular disorders such as angina pectoris, supraventricular tachycardia and hypertension. Due to its relatively short half-life of approximately 4.0 hours, the formulation of a sustained-release dosage form is useful to improve patient compliance and to achieve predictable and optimized therapeutic plasma concentrations. Direct compression and wet granulation were initially used as methods for tablet manufacture. The direct compression method of manufacture produced tablets that exhibited formulation and manufacturing difficulties. Mini-tablets containing veraparnil hydrochloride were then prepared by wet granulation using Surelease® E-7-19010.and Eudragit® NE 30D as the granulating agents after which the granules were incorporated with an hydrophilic matrix material, Carbopol® 974P NF. Granule and powder blends were evaluated using the angle of repose, loose and tapped bulk density, Can's compressibility index, Hausner's ratio and drug content. Granules with good flow properties and satisfactory compressibility were used for further studies. Tablets were subjected to thickness, diameter and weight variation tests, crushing strength, tensile strength, friability and content uniformity studies. Tablets that showed acceptable pharmaco-technical properties were selected for further analysis. Drug content uniformity and dissolution release rates were determined using a validated isocratic HPLC method. Initially, USP apparatus 1 and 3 dissolution apparatus were used to determine in-vitro drug release rates from the formulations over a 22-hour period. USP apparatus 3 was finally selected as it offers the advantages of mimicking, in part, the changes in the physicochemical environment experienced by products in the gastro-intestinal tract. Differences in release rates between the test formulations and a commercially available product, Isoptin® SR were observed at different pH's using USP apparatus 1. The release of veraparnil hydrochloride from matrix tablets was pH dependent and was markedly reduced at higher pH values. This may be due, in part, to the poor solubility of veraparnil hydrochloride at these pH values and also the possible interaction of verapamil hydrochloride with anionic polymers used in these formulations. Swelling and erosion behaviour of the tablets were evaluated and differences in behaviour were observed which may be attributed to the physico-chemical characteristics of the polymers used in this study. In-vitro dissolution profiles were characterized by the difference (j1) and similarity factor (j2) and also by a new similarity factor, Sct. In addition, the mechanism of drug release from these dosage forms was mainly evaluated using the Korsmeyer-Peppas model and the kinetics of drug release assessed using other models, including Zero order, First order, Higuchi, HixsonCrowell, Weibull and the Baker-Lonsdale model. Dissolution kinetics were best described by application of the Weibull model, and the Korsmeyer-Peppas model. The release exponent, n, confirmed that drug release from these dosage forms was due to the mixed effects of diffusion and swelling and therefore, anomalous release kinetics are predominant. In conclusion, two test batches were found to be comparable to the reference product Isoptin® SR with respect to their in-vitro release profiles.
- Full Text:
- Date Issued: 2005
- Authors: Khamanga, Sandile Maswazi Malungelo
- Date: 2005
- Subjects: Verapamil , Tablets (Medicine) , Drugs -- Administration , Cardiovascular agents , Calcium -- Antagonists , Drugs -- Controlled release
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3869 , http://hdl.handle.net/10962/d1018236
- Description: The oral route of drug administration is most extensively used due to the obvious ease of administration. Verapamil hydrochloride is a WHO listed phenylalkylarnine, L-type calcium channel antagonist that is mainly indicated for cardiovascular disorders such as angina pectoris, supraventricular tachycardia and hypertension. Due to its relatively short half-life of approximately 4.0 hours, the formulation of a sustained-release dosage form is useful to improve patient compliance and to achieve predictable and optimized therapeutic plasma concentrations. Direct compression and wet granulation were initially used as methods for tablet manufacture. The direct compression method of manufacture produced tablets that exhibited formulation and manufacturing difficulties. Mini-tablets containing veraparnil hydrochloride were then prepared by wet granulation using Surelease® E-7-19010.and Eudragit® NE 30D as the granulating agents after which the granules were incorporated with an hydrophilic matrix material, Carbopol® 974P NF. Granule and powder blends were evaluated using the angle of repose, loose and tapped bulk density, Can's compressibility index, Hausner's ratio and drug content. Granules with good flow properties and satisfactory compressibility were used for further studies. Tablets were subjected to thickness, diameter and weight variation tests, crushing strength, tensile strength, friability and content uniformity studies. Tablets that showed acceptable pharmaco-technical properties were selected for further analysis. Drug content uniformity and dissolution release rates were determined using a validated isocratic HPLC method. Initially, USP apparatus 1 and 3 dissolution apparatus were used to determine in-vitro drug release rates from the formulations over a 22-hour period. USP apparatus 3 was finally selected as it offers the advantages of mimicking, in part, the changes in the physicochemical environment experienced by products in the gastro-intestinal tract. Differences in release rates between the test formulations and a commercially available product, Isoptin® SR were observed at different pH's using USP apparatus 1. The release of veraparnil hydrochloride from matrix tablets was pH dependent and was markedly reduced at higher pH values. This may be due, in part, to the poor solubility of veraparnil hydrochloride at these pH values and also the possible interaction of verapamil hydrochloride with anionic polymers used in these formulations. Swelling and erosion behaviour of the tablets were evaluated and differences in behaviour were observed which may be attributed to the physico-chemical characteristics of the polymers used in this study. In-vitro dissolution profiles were characterized by the difference (j1) and similarity factor (j2) and also by a new similarity factor, Sct. In addition, the mechanism of drug release from these dosage forms was mainly evaluated using the Korsmeyer-Peppas model and the kinetics of drug release assessed using other models, including Zero order, First order, Higuchi, HixsonCrowell, Weibull and the Baker-Lonsdale model. Dissolution kinetics were best described by application of the Weibull model, and the Korsmeyer-Peppas model. The release exponent, n, confirmed that drug release from these dosage forms was due to the mixed effects of diffusion and swelling and therefore, anomalous release kinetics are predominant. In conclusion, two test batches were found to be comparable to the reference product Isoptin® SR with respect to their in-vitro release profiles.
- Full Text:
- Date Issued: 2005
Preparation, characterization and optimization of carbamazepine based pellets prepared by extrusion-spheronization technique
- Authors: Makoni, Kudzai Gabriella
- Date: 2020-04
- Subjects: Carbamazepine , Pharmacokinetics , Anticonvulsants , Drugs -- Controlled release , Drugs -- Dosage forms , Tablets (Medicine) , Drugs -- Administration , High performance liquid chromatography , International Conference on Harmonisation , Experimental design
- Language: English
- Type: Thesis , Masters , MSc (Pharmacy)
- Identifier: http://hdl.handle.net/10962/140478 , vital:37893
- Description: Carbamazepine (CBZ) is an oral antiepileptic drug (AED) that is prescribed as a first-line treatment for partial seizures. CBZ is a class II compound according to the Biopharmaceutical Classification System (BCS), hence it exhibits low aqueous solubility and high gastrointestinal tract (GIT) permeability...
- Full Text:
- Date Issued: 2020-04
- Authors: Makoni, Kudzai Gabriella
- Date: 2020-04
- Subjects: Carbamazepine , Pharmacokinetics , Anticonvulsants , Drugs -- Controlled release , Drugs -- Dosage forms , Tablets (Medicine) , Drugs -- Administration , High performance liquid chromatography , International Conference on Harmonisation , Experimental design
- Language: English
- Type: Thesis , Masters , MSc (Pharmacy)
- Identifier: http://hdl.handle.net/10962/140478 , vital:37893
- Description: Carbamazepine (CBZ) is an oral antiepileptic drug (AED) that is prescribed as a first-line treatment for partial seizures. CBZ is a class II compound according to the Biopharmaceutical Classification System (BCS), hence it exhibits low aqueous solubility and high gastrointestinal tract (GIT) permeability...
- Full Text:
- Date Issued: 2020-04
Formulation of methyldopa 250 mg tablets by direct compression using a quality by design approach
- Authors: Baguma, Murungi Isaac
- Date: 2022-04
- Subjects: Pharmaceutical chemistry , Tablets (Medicine)
- Language: English
- Type: Master's theses , text
- Identifier: http://hdl.handle.net/10948/58575 , vital:59929
- Description: Various pharmaceutical materials are known to take up moisture during both storage and manufacture. This phenomenon, termed hygroscopy, can result in unacceptable levels of moisture, potentially having deleterious effects on product quality, and consequently product efficacy and safety. Drug inefficacy specifically can result in life-threatening complications for the pregnant mother with uncontrolled blood pressure. Marketed as immediate release tablets, methyldopa is an antihypertensive drug commonly used in South Africa to treat hypertensive disorders of pregnancy. Despite being in use for over 50 years, the physicochemical challenges posed by methyldopa remain ever present. Methyldopa is not only significantly hygroscopic, but also prone to oxidative and hydrolytic degradation that can be accelerated by moisture. Poor compression behaviour, another limitation of methyldopa, leaves the formulation scientist with a constellation of formulation hurdles that must be faced, understood and overcome. This is a task that can be tackled using elements of the Quality by Design (QbD) approach. Using this approach, the impact of these phenomena on tablet quality can be better understood and controlled. This study was aimed at using this approach to develop a formulation of methyldopa 250 mg tablets. Direct compression, a simple and moisture-free process, was selected for the manufacture of methyldopa tablets. After careful review of literature and consultation with experts, excipients were selected for the candidate formulation and preliminary concentrations established for each. Similarly, settings for mixing and compression variables were established. Adopted from the QbD framework, the risk posed to tablet quality by these factors was qualitatively analysed using Preliminary Hazard Analysis (PHA) and quantitatively evaluated using Failure Modes and Effect Analysis (FMEA). Eight (8) factors determined to be high risk were further investigated in a preliminary experiment that followed a 12-batch Plackett Burman design. Data from this experiment was used to draw statistical relationships between the aforementioned factors and tablet quality attributes, thus shedding light on excipients and process parameters with practically significant impact on methyldopa tablet quality. Multivariate Analysis of Variance (MANOVA) of the response data reported SSG concentration, citric acid monohydrate xxvii concentration and mixing speed as key factors (p<0.05), demonstrating the need to control these factors for quality targets to be met. These three factors underpinned the 16-batch definitive experiment that followed, conceived using a Box Behnken design (BBD) including four batches prepared at the centerpoint values in the region of experimentation. The optimal methyldopa tablet formulation was achieved at the following settings: 1.0 % m/m magnesium stearate, 1.0 % m/m colloidal silica, 3.9 % m/m sodium starch glycolate, 1.7 % m/m citric acid monohydrate, mixing speed of 101 rpm, 6 minutes of pre-lubrication mixing, 2 minutes of lubrication and compression speed of 20 rpm. These settings were included in the design space and subsequent control strategy. It was learned that, within the design space, the risk to tablet quality and, by extension, the patient, was insignificant. This demonstrated that, using the QbD approach, challenges to pharmaceutical development can be effectively overcome. , Thesis (MA) -- Faculty of Science, School of Environmental Sciences, 2022
- Full Text:
- Date Issued: 2022-04
- Authors: Baguma, Murungi Isaac
- Date: 2022-04
- Subjects: Pharmaceutical chemistry , Tablets (Medicine)
- Language: English
- Type: Master's theses , text
- Identifier: http://hdl.handle.net/10948/58575 , vital:59929
- Description: Various pharmaceutical materials are known to take up moisture during both storage and manufacture. This phenomenon, termed hygroscopy, can result in unacceptable levels of moisture, potentially having deleterious effects on product quality, and consequently product efficacy and safety. Drug inefficacy specifically can result in life-threatening complications for the pregnant mother with uncontrolled blood pressure. Marketed as immediate release tablets, methyldopa is an antihypertensive drug commonly used in South Africa to treat hypertensive disorders of pregnancy. Despite being in use for over 50 years, the physicochemical challenges posed by methyldopa remain ever present. Methyldopa is not only significantly hygroscopic, but also prone to oxidative and hydrolytic degradation that can be accelerated by moisture. Poor compression behaviour, another limitation of methyldopa, leaves the formulation scientist with a constellation of formulation hurdles that must be faced, understood and overcome. This is a task that can be tackled using elements of the Quality by Design (QbD) approach. Using this approach, the impact of these phenomena on tablet quality can be better understood and controlled. This study was aimed at using this approach to develop a formulation of methyldopa 250 mg tablets. Direct compression, a simple and moisture-free process, was selected for the manufacture of methyldopa tablets. After careful review of literature and consultation with experts, excipients were selected for the candidate formulation and preliminary concentrations established for each. Similarly, settings for mixing and compression variables were established. Adopted from the QbD framework, the risk posed to tablet quality by these factors was qualitatively analysed using Preliminary Hazard Analysis (PHA) and quantitatively evaluated using Failure Modes and Effect Analysis (FMEA). Eight (8) factors determined to be high risk were further investigated in a preliminary experiment that followed a 12-batch Plackett Burman design. Data from this experiment was used to draw statistical relationships between the aforementioned factors and tablet quality attributes, thus shedding light on excipients and process parameters with practically significant impact on methyldopa tablet quality. Multivariate Analysis of Variance (MANOVA) of the response data reported SSG concentration, citric acid monohydrate xxvii concentration and mixing speed as key factors (p<0.05), demonstrating the need to control these factors for quality targets to be met. These three factors underpinned the 16-batch definitive experiment that followed, conceived using a Box Behnken design (BBD) including four batches prepared at the centerpoint values in the region of experimentation. The optimal methyldopa tablet formulation was achieved at the following settings: 1.0 % m/m magnesium stearate, 1.0 % m/m colloidal silica, 3.9 % m/m sodium starch glycolate, 1.7 % m/m citric acid monohydrate, mixing speed of 101 rpm, 6 minutes of pre-lubrication mixing, 2 minutes of lubrication and compression speed of 20 rpm. These settings were included in the design space and subsequent control strategy. It was learned that, within the design space, the risk to tablet quality and, by extension, the patient, was insignificant. This demonstrated that, using the QbD approach, challenges to pharmaceutical development can be effectively overcome. , Thesis (MA) -- Faculty of Science, School of Environmental Sciences, 2022
- Full Text:
- Date Issued: 2022-04
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