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Application of quality by design to the manufacture of a multiparticulate prednisone dosage form

  • Authors: Manda, Arthur
  • Date: 2020-04
  • Subjects: Drugs -- Quality control , Drugs -- Design -- Quality control , Drugs -- Dosage forms , Drug development -- Quality control , Pharmaceutical industry -- Quality control , Prednisone , High throughput screening (Drug development)
  • Language: English
  • Type: text , Thesis , Masters , MSc (Pharmacy)
  • Identifier: http://hdl.handle.net/10962/117986 , vital:34583
  • Description: For many years, quality by testing was the only approach to guarantee quality of drug products before the Food and Drug Administration launched the concept of current Good Manufacturing Practice. In order to gain more knowledge of the manufacturing process, a new system known as Quality by Design was introduced into the pharmaceutical industry. Quality by Design is based on thorough understanding of how materials, process parameters and interaction thereof impact final product quality. Quality by Design is a systematic approach to product development which ensures that quality is built into a product during product development and not just tested into it. The aim of Quality by Design is to achieve optimum product quality with consistent dosage form performance and minimal risk of failure in patients. The objective of these studies was to implement a Quality by Design approach to establish a design space for the development and manufacture of a safe, effective and stable multi-partite solid oral dosage form for prednisone as an alternative to currently marketed prednisone formulations. Multi-particulate dosage forms offer significant advantages over conventional technologies. In addition to lowering the incidence of gastrointestinal irritation they exhibit a reduced risk of dose dumping and a large surface area which favours dissolution. Furthermore, their free flowing nature facilitates reproducible capsule filling and consequently uniformity of dosing. Different multi-particulate dosage forms exist however a multiple-unit pellet system was investigated during these studies. Quality by Design principles were used to develop and establish a reversed-phase high performance liquid chromatographic method for quantifying prednisone from solid oral dosage forms. A Central Composite Design was used to generate multivariate experiments and to investigate the impact of input variables on the quality and performance of the analytical method. The optimized method was validated according to International Council for Harmonization guidelines and was found to be linear, precise, accurate and specific for the quantitation of prednisone. Pre-formulation studies were conducted and included the assessment of particle size, particle shape, powder flow properties and compatibility studies. Carr’s index, Hausner ratio and the Angle of Repose were used to evaluate powder flow properties and results generated from all studies suggest the need for adding a glidant and lubricant to improve pellet flow. The images generated from Scanning Electron Microscopy were used to analyze particle shape and size. Differential Scanning Calorimetry and Fourier Transform Infrared Spectroscopy were used to evaluate API-excipient compatibility. All excipients investigated were found to be compatible with prednisone and suitable for formulation development studies. Extrusion-spheronization was used to manufacture prednisone pellets. Extrusion-spheronization is a multi-step process involving many factors. Quality risk management tools particularly an Ishikawa Fishbone (cause and effect) diagram and failure mode and effects analysis were used to narrow down potentially significant factors to a reasonable number that could be investigated experimentally. Risk priority numbers were used to quantify risk and factors above a set threshold value were considered to be of high risk. A total of eleven risk factors were identified as high. A Plackett-Burman study was conducted to narrow down the eleven high risk factors to identify the most impactful factors viz., microcrystalline cellulose content, sodium starch glycolate content, extrusion speed and spheronization time. Evaluation of four factors was carried over to optimization studies using a Box-Behnken Design and following identifaction of the optimum process settings and excipient content a design space for the manufacture of a multi-partite dosage form containing prednisone was established.
  • Full Text:
  • Date Issued: 2020-04

Preparation, characterization and optimization of carbamazepine based pellets prepared by extrusion-spheronization technique

Development, assessment and optimisation of oral famciclovir formulations for paediatric use

  • Authors: Magnus, Laura
  • Date: 2012
  • Subjects: Drugs -- Dosage forms , Drugs -- Analysis , Capsules (Pharmacy) , Antiviral agents , Pediatrics
  • Language: English
  • Type: Thesis , Masters , MSc
  • Identifier: vital:3870 , http://hdl.handle.net/10962/d1018244
  • Description: Many Active Pharmaceutical Ingredients (API) such as the antiviral agent famciclovir (FCV) are required for paediatric treatment but are not commercially available in age-appropriate dosage forms. It is common practice to prepare oral liquid dosage forms using commercially available tablets, capsules or powdered API and then dispersing or dissolving the crushed and/or powdered materials in a vehicle that the patient can swallow. Vehicles that are commonly used for this purpose include methylcellulose, syrup or combinations of these carriers where possible or commercially available suspending agents such as Ora-Sweet®, if available, can be used. However, several critical factors are overlooked when manufacturing extemporaneous formulations including, but not limited to, physical and chemical properties of the API, excipients, compatibility, stability and bioavailability issues. A stability-indicating High Performance Liquid Chromatography (HPLC) method for the analysis of FCV was developed and validated according to the International Conference on Harmonization (ICH) guidelines. The method is sensitive, selective, precise, accurate and linear over the concentration range 2-120 μg/ml. The stability of 25 mg/ml FCV formulations was assessed in vehicles manufactured from syrup simplex, hydroxypropyl methylcellulose (HPMC), Ora-Sweet® and an aqueous buffer (pH 6) following storage at 25 °C/60% RH and 40 °C/75% RH over six (6) to eight (8) weeks. The shelf life of the products was calculated as the longest period of storage for approximately 90% of the added FCV to be recovered. Formulations were manufactured using syrup simplex or HPMC with methylparaben and propylparaben individually or in combination and with sodium metabisulphite, ascorbic acid or citric acid as antioxidants. The resultant products were subject to quality control analysis for API content, viscosity, pH and appearance and the resultant data were subject to statistical analysis. The degradation rates were calculated for each product and a degradation profile plotted. The degradation rates of FCV in extemporaneous formulations were compared to those of FCV manufactured using a commercially available suspending agent and a buffered vehicle. FCV undergoes major degradation in the presence of sucrose, as observed for formulations in which the vehicle was syrup and Ora-Sweet®. FCV was found to be most stable when dissolved/dispersed in an HPMC vehicle incorporating sodium metabisulphite and a combination of parabens. The formulation that exhibited the maximum stability was manufactured using an aqueous solution buffered to pH 6. Due to the enhanced stability of FCV when added to a buffered vehicle a formulation in which an HPMC vehicle buffered to pH 6 with sodium metabisulphite, methylparaben and propylparaben was selected for optimisation using a Central Composite Design approach (CCD). In this way it was possible to establish a relationship between input variables such as pH, % w/v HPMC, % w/v antioxidant and % w/v preservative and the responses selected for monitoring by means of response surface modelling. A quadratic model was found to be the most appropriate to describe the relationship between input and output variables. Thirty batches of product were randomly manufactured according to the CCD and analysed to establish the stability in respect of viscosity, pH and the amount of FCV remaining following storage and the data were fitted to models using Design-Expert® software. A correlation between input variables and the responses was best described by a quadratic polynomial model. Analysis of Variance indicated that the response surface models were significant (P-value < 0.0001). The pH to which a FCV formulation was buffered was the most significant factor to effect the % drug content and the ultimate pH of the formulation, while the % w/v HPMC had the most significant effect on the viscosity of the product. The optimum composition for the manufacture of an oral liquid FCV formulation was predicted using the optimisation function of the Design-Expert® software. A low % error of prediction was established, indicating that the model is robust and that RSM is an appropriate formulation optimisation tool as it has a high prognostic ability. A liquid FCV formulation was developed, optimised and found to be suitable for its intended purpose. However further optimisation is required in respect of colourants, sweeteners and/or flavourants. The approach followed is useful in ensuring the development of quality products and can be applied in future.
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  • Date Issued: 2012

Development and assessment of minocycline sustained release capsule formulations

  • Authors: Sachikonye, Tinotenda Chipo Victoria
  • Date: 2010
  • Subjects: Drugs -- Controlled release , Drugs -- Dosage forms , Capsules (Pharmacy) , Drugs -- Administration , Acne -- Treatment , Tetracyclines , Antibiotics -- Side effects
  • Language: English
  • Type: Thesis , Masters , MSc
  • Identifier: vital:3854 , http://hdl.handle.net/10962/d1013127
  • Description: The use of minocycline for the treatment of a broad range of systemic infections and for severe acne has been associated with vestibular side effects. The severity of side effects may lead to poor adherence to therapy by patients. The use of sustained release formulations of minocycline that display slow dissolution of minocycline following administration may be beneficial in reducing the incidence and severity of side effects. Therefore, sustained release capsule dosage forms containing 100 mg minocycline (base) were manufactured and assessed for use as sustained release oral dosage forms of minocycline. Minocycline sustained release capsules were manufactured based on matrix technologies using hydroxypropylmethyl cellulose (HPMC) and Compritol® as release retarding polymers. The rate and extent of minocycline release from the capsules was evaluated using USP Apparatus 1 and samples were analysed using a validated High Performance Liquid Chromatographic (HPLC) method with ultraviolet (UV) detection. Differences in the rate and extent of minocycline release from formulations manufactured using HPMC or Compritol® were influenced by the concentration of polymer used in the formulations. The rate and extent of minocycline release was faster and greater when low concentrations of polymer were used in formulations. The effect of different excipients on the release pattern(s) of minocycline and particularly their potential to optimise minocycline release from experimental formulations was investigated. The use of diluents such as lactose and microcrystalline cellulose (MCC) revealed that lactose facilitated minocycline release when HPMC was used as the polymer matrix. In contrast, the use of lactose as diluent resulted in slower release of minocycline from Compritol® based formulations. The addition of sodium starch glycolate to HPMC based formulations resulted in slower release of minocycline than when no sodium starch glycolate was used. Compritol® based formulations were observed to release minocycline faster following addition of sodium starch glycolate and Poloxamer 188 to experimental formulations. In vitro dissolution profiles were compared to a target or reference profile using the difference and similarity factors, ƒ1 and ƒ2 , and a one way analysis of variance (ANOVA). In addition, the mechanism of minocycline release was elucidated following fitting of dissolution data to the Korsmeyer-Peppas, Higuchi and Zero order models. Minocycline release kinetics were best described by the Korsmeyer-Peppas model and the values of the release exponent, n (italics), revealed that drug release was a result of the combined effects of minocycline diffusion through matrices and erosion of the matrices. These in vitro dissolution profiles were better fit to the Higuchi model than to the Zero order model. Two formulations that displayed a fit to the Zero order model were identified for further studies as potential dosage forms for sustained release minocycline.
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  • Date Issued: 2010

Development and assessment of an oxytocin parenteral dosage form prepared using pluronic ® F127

Development and assessment of azithromycin paediatric suppository formulations

  • Authors: Mollel, Happiness
  • Date: 2006
  • Subjects: Azithromycin , Pediatrics , Clinical pharmacology , Pharmacokinetics , Suppositories , Drugs -- Dosage forms
  • Language: English
  • Type: Thesis , Masters , MSc
  • Identifier: vital:3774 , http://hdl.handle.net/10962/d1003252 , Azithromycin , Pediatrics , Clinical pharmacology , Pharmacokinetics , Suppositories , Drugs -- Dosage forms
  • Description: The use of the oral route of administration for the treatment of young children with antibiotics can at times be problematic since, factors such as nausea, vomiting, taste and/or smell, in addition to the challenges associated with the administration of suspensions, may contribute to poor patient compliance. In such cases, the use of the rectal route of administration may be appropriate. Therefore, suppositories containing 250 mg azithromycin (AZI) were manufactured and assessed for potential as an antibiotic suppository dosage form. Suppositories, containing AZI dihydrate were manufactured by the fusion method, using different grades of PEG, Witepsol® and Suppocire® bases. The rate and extent of AZI release was evaluated using USP apparatus I, and samples were analyzed using a validated HPLC method. Differences in the rate and extent of AZI release were observed with the greatest amount of AZI being released from PEG formulations. The rate and extent of AZI release from formulations manufactured using fatty bases were influenced by physicochemical properties, such as melting rate and hydroxyl value, of the bases. In addition drug partitioning appeared to favor the lipid phase and had a negative impact on AZI release characteristics. Two different formulation approaches were used in an attempt to increase the rate and extent of AZI release from fatty base formulations. The use of surfactants significantly increased AZI release from formulations manufactured with fatty bases with high hydroxyl values. The use of urea or Povidone K25 in combination with AZI as a physical mixture or solid dispersion did not increase the rate and extent of AZI release from the fatty suppositories, to any significant extent. The mechanism of drug release was evaluated using several mathematical models, including the Higuchi, Korsmeyer- eppas, Zero and, First order models. In addition, in vitro dissolution profiles were characterized by the difference and similarity factors, f1 and f2 and by use of the Gohel similarity factor, Sd. AZI release kinetics were best described by the Higuchi and Korsmeyer-Peppas models and the values of the release exponent, n, revealed that drug release was a consequence of the combined effects of AZI diffusion, rate of melting of the base and partitioning of the drug which can be considered to be anomalous release.
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  • Date Issued: 2006

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.
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  • Date Issued: 2004

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

The evaluation of indomethacin and theophylline oral controlled/modified-release dosage forms in vitro-in vivo correlations

  • 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.
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  • Date Issued: 1992

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

The comparative bioavailability and in vitro assessment of solid oral dosage forms of paracetamol

  • Authors: Braae, Karen
  • Date: 1981 , 2013-04-02
  • Subjects: Acetaminophen , Bioavailability , Drugs -- Bioavailability , Drugs -- Dosage forms , Analysis of variance
  • Language: English
  • Type: Thesis , Masters , MSc
  • Identifier: vital:3827 , http://hdl.handle.net/10962/d1006288 , Acetaminophen , Bioavailability , Drugs -- Bioavailability , Drugs -- Dosage forms , Analysis of variance
  • Description: The dissolution profiles of eight lots of paracetamol tablets representing seven different tablet brands are determined in a USP rotating basket assembly and a stationary basket-rotating paddle apparatus. The in vitro data are expressed in terms of dissolution parameters and inter-tablet differences are assessed statistically using analysis of variance (ANOVA) and the Scheffe test. Highly significant differences are observed between a number of the tablets at the 95% confidence level. Representative tablets from the dissolution rate study and a control dose of paracetamol dissolved in water are subsequently investigated in a 4 x 4 latin square design bioavailability trial. Serum and urine samples are collected and assayed for paracetamol alone (serum) and together with its metabolites (urine) by means of high pressure liquid chromatography. The in vivo data are expressed in terms of bioavailability parameters and differences between the test doses are assessed by means of ANOVA. No significant differences are observed between the dosage forms at the 95% confidence level.
  • Full Text:
  • Date Issued: 1981

Development of a high pressure liquid chromatographic method for the simultaneous analysis of sulphamethoxazole and trimethoprim and its application to biological fluids and dissolution rate studies on solid oral dosage forms

  • Authors: Gochin, Rosa
  • Date: 1980
  • Subjects: High performance liquid chromatography , Body fluids -- Analysis , Drugs -- Dosage forms
  • Language: English
  • Type: Thesis , Masters , MSc
  • Identifier: vital:3735 , http://hdl.handle.net/10962/d1001524
  • Description: Co-trimoxazole, a combination of a 5-to-l ratio of Sulphamethoxazole (SMZ) and Trimethoprim (TMP) , is a highly effective, broad-spectrum antibacterial agent. Since its introduction in 1968, it has been extensively used in infections of the respiratory and urinary tracts. Co-trimoxazole was developed by the systematic investigation of a series of compounds whose mechanism of action was already known. As early as 1950 synergy between sulphonamides and 2,4-diaminopyrimidines was reported. This was to be expected as both groups of drugs exert their antibacterial activity by interfering with the same biochemical pathway in bacteria. TMP was chosen from among many 2,4-diaminopyrimidines tested because of its good antibacterial activity and low toxicity. SMZ was chosen from the sulphonamides available for combination with TMP because of similarity of their biological half-lives. The widespread use of the combination coupled with the fact that monitoring of the levels of all drugs in the body is becoming increasingly important has stimulated research into rapid and efficient methods for the analysis of TMP and SMZ in biological fluids. Another consequence of the immense popularity of the combination is the appearance on the market of several generic preparations of Co-trimoxazole. It is now generally recognized that drug products from different manufacturers which are chemically equivalent may not be therapeutically equivalent. This is due to the fact that the absorption rate and/or bioavailability (extent of absorption) of a poorly soluble drug may be markedly affected by its release rate from the product and by its subsequent dissolution rate in gastrointestinal fluids. Hence bioequivalence of these various products should be established
  • Full Text:
  • Date Issued: 1980
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