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
Rainfall variability in Southern Africa, its influences on streamflow variations and its relationships with climatic variations
- Authors: Valimba, Patrick
- Date: 2005
- Subjects: Rain and rainfall -- Africa, Southern Climatic changes -- Africa, Southern Streamflow -- Africa, Southern
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:6030 , http://hdl.handle.net/10962/d1006159
- Description: Hydrological variability involving rainfall and streamflows in southern Africa have been often studied separately or have used cumulative rainfall and streamflow indices. The main objective of this study was to investigate spatio-temporal variations of rainfall, their influences on streamflows and their relationships with climatic variations with emphasis on indices that characterise the hydrological extremes, floods and droughts. It was found that 60-70% of the time when it rains, daily rainfalls are below their long-term averages and daily amounts below 10 mm are the most frequent in southern Africa. Spatially, climatologies of rainfall sub-divided the southern African subcontinent into the dry western/southwestern part and the “humid” eastern and northern part. The daily amounts below 20 mm contribute significantly to annual rainfall amounts in the dry part while all types of daily rainfall exceeding 1 mm have comparable contributions in the humid part. The climatologies indicated the highest likelihood of experiencing intense daily events during the core of the wet seasons with the highest frequencies in central Mozambique and the southern highlands of Tanzania. Interannual variations of rainfall indicated that significant changes had occurred between the late-1940s and early-1980s, particularly in the 1970s. The changes in rainfall were more evident in the number of daily rainfall events than in rainfall amounts, led generally to increasing early summer and decreased late summer rainfall. It was also found that intra-seasonal dry day sequences were an important parameter in the definition of a rainy season’s onset and end in southern Africa apart from rainfall amounts. Interannual variations of the rainy season characteristics (onset, end, duration) followed the variations of rainfall amounts and number of events. The duration of the rainy season was affected by the onset (Tanzania), onset or end (tropical southern Africa - southwestern highlands of Tanzania, Zambia, northern Zimbabwe and central Mozambique) and end (the remaing part of southern Africa). Flow duration curves (FDCs) identified three types of rivers (ephemeral, seasonal and perennial) in southern Africa with ephemeral rivers found mainly in the dry western part of the region. Seasonal streamflow patterns followed those of rainfall while interannual streamflow variations indicated significant changes of mean flows with little evidences of high and low flow regime changes except in Namibia and some parts of northern Zimbabwe. It was, however, not possible to provide strong links between the identified changes in streamflows and those in rainfall. Regarding the influences of climate variability on hydrological variability in southern Africa, rainfall variations in southern Africa were found to be influenced strongly by ENSO and SST in the tropical Indian ocean and moderately by SST in the south Madagascar basin. The influence of ENSO was consistent for all types of daily rainfall and peaks for the light and moderate (< 20 mm) events in the southern part and for the intense events in the northern part. SST in the tropical Indian ocean influence the light and moderate events while SST close to the region influence the heavy events. However, the relationships experienced significant changes in the mid-1950s and in the 1970s. The former changes led to improved associations while the latter deteriorated or reversed the relationships. The influences of climatic variables on streamflows and rainy season characteristics were inferred from the rainfall-streamflow and rainfall-climatic variables relationships.
- Full Text:
- Date Issued: 2005
- Authors: Valimba, Patrick
- Date: 2005
- Subjects: Rain and rainfall -- Africa, Southern Climatic changes -- Africa, Southern Streamflow -- Africa, Southern
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:6030 , http://hdl.handle.net/10962/d1006159
- Description: Hydrological variability involving rainfall and streamflows in southern Africa have been often studied separately or have used cumulative rainfall and streamflow indices. The main objective of this study was to investigate spatio-temporal variations of rainfall, their influences on streamflows and their relationships with climatic variations with emphasis on indices that characterise the hydrological extremes, floods and droughts. It was found that 60-70% of the time when it rains, daily rainfalls are below their long-term averages and daily amounts below 10 mm are the most frequent in southern Africa. Spatially, climatologies of rainfall sub-divided the southern African subcontinent into the dry western/southwestern part and the “humid” eastern and northern part. The daily amounts below 20 mm contribute significantly to annual rainfall amounts in the dry part while all types of daily rainfall exceeding 1 mm have comparable contributions in the humid part. The climatologies indicated the highest likelihood of experiencing intense daily events during the core of the wet seasons with the highest frequencies in central Mozambique and the southern highlands of Tanzania. Interannual variations of rainfall indicated that significant changes had occurred between the late-1940s and early-1980s, particularly in the 1970s. The changes in rainfall were more evident in the number of daily rainfall events than in rainfall amounts, led generally to increasing early summer and decreased late summer rainfall. It was also found that intra-seasonal dry day sequences were an important parameter in the definition of a rainy season’s onset and end in southern Africa apart from rainfall amounts. Interannual variations of the rainy season characteristics (onset, end, duration) followed the variations of rainfall amounts and number of events. The duration of the rainy season was affected by the onset (Tanzania), onset or end (tropical southern Africa - southwestern highlands of Tanzania, Zambia, northern Zimbabwe and central Mozambique) and end (the remaing part of southern Africa). Flow duration curves (FDCs) identified three types of rivers (ephemeral, seasonal and perennial) in southern Africa with ephemeral rivers found mainly in the dry western part of the region. Seasonal streamflow patterns followed those of rainfall while interannual streamflow variations indicated significant changes of mean flows with little evidences of high and low flow regime changes except in Namibia and some parts of northern Zimbabwe. It was, however, not possible to provide strong links between the identified changes in streamflows and those in rainfall. Regarding the influences of climate variability on hydrological variability in southern Africa, rainfall variations in southern Africa were found to be influenced strongly by ENSO and SST in the tropical Indian ocean and moderately by SST in the south Madagascar basin. The influence of ENSO was consistent for all types of daily rainfall and peaks for the light and moderate (< 20 mm) events in the southern part and for the intense events in the northern part. SST in the tropical Indian ocean influence the light and moderate events while SST close to the region influence the heavy events. However, the relationships experienced significant changes in the mid-1950s and in the 1970s. The former changes led to improved associations while the latter deteriorated or reversed the relationships. The influences of climatic variables on streamflows and rainy season characteristics were inferred from the rainfall-streamflow and rainfall-climatic variables relationships.
- Full Text:
- Date Issued: 2005
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