The aim of the present studies was to develop and characterize 2.6 mg sustained release matrix tablets of Nitroglycerin. Tablets were prepared by direct compression method. Methocel K15M CR and Methocel K100LV CR polymers were used as rate retarding agents in nine formulations (F-1 to F-9). The granules were evaluated for angle of repose, loose bulk density, tapped bulk density, Carr’s index, Hausner ratio, moisture content, total porosity and assay. The tablets were subjected to diameter, thickness, assay, uniformity of content, assay after 1Month at 40°C+75%RH, hardness, friability, and in vitro dissolution studies. The granules showed satisfactory flow properties, compressibility, and drug content. All the tablet formulations showed acceptable pharmacotechnical properties and complied with pharmacopoeial specifications for tested parameters. The in vitro dissolution study was carried out for 8 hour using USP-2009 Apparatus-I (Rotating basket method) in distilled water as the dissolution medium. The release mechanisms were explored and explained by Zero order, First order, Higuchi, Korsmeyer-Peppas and Hixson-Crowell equations. Nine formulations were prepared by using three variable ratio of two polymers; Methocel K15M CR (25%, 20% and 15%) and Methocel K100LV CR (15%, 10% and 5%) where all the formulations (F-1 to F-9) contained 0.5% colloidal silicon dioxide and 1% magnesium stearate. Among these nine formulations, six formulations; F-2 (Methocel K15M CR: Methocel K100LV CR = 25% : 10%), F-3 (Methocel K15M CR : Methocel K100LV CR = 25% : 5%), F-4 (Methocel K15M CR : Methocel K100LV CR = 20% : 15%) F-5 (Methocel K15M CR: Methocel K100LV CR = 20% : 10%), F-6 (Methocel K15M CR : Methocel K100LV CR = 20% : 5%) and F-7 (Methocel K15M CR : Methocel K100LV CR = 15% : 15%) met the official specification of release profile. It was also found that the type and the amount of polymers significantly affect the time required for 50% (T50% or MDT) of drug release, release rate constant and diffusion exponent. Higher the MDT value indicates a higher drug retaining capacity of the polymers and vice-versa. Kinetic modeling of in vitro dissolution profiles revealed the drug release mechanism of all proposed formulations followed anomalous type or non-Fickian transport (n>0.43 and n<0.85). These studies explored both of the optimum concentration and effect of polymers on Nitroglycerin release pattern from the tablet matrix for 8 hour period.
Table of Contents
CHAPTER 1: INTRODUCTION
1.1 Introduction
1.2 Historical viewpoints of controlled release drug delivery
1.3 Sustained release drug delivery system
1.3.1 Concept of sustained release drug delivery system
1.3.2 Rationale of sustained release drug delivery system
1.3.3 Oral sustained release drug delivery system
1.3.4 Advantages of sustained release dosage forms
1.3.5 Disadvantages of sustained release dosage forms
1.3.6 Drugs unsuitable for sustained release dosage forms
1.3.7 Factors affecting sustained release dosage forms
1.3.7.1 Physicochemical properties of the drug affecting sustained release dosage forms
1.3.7.2 Biological properties of the drug affecting sustained release dosage forms
1.3.8 Formulation methods used to prepare sustained release dosage forms
1.3.8.1 Particle size modification
1.3.8.2 Matrix system
1.3.8.3 Coating system
1.3.8.4 Beads and sphere
1.3.8.5 Enteric coated beads in capsule
1.3.8.6 Mixed release granules
1.3.8.7 Repeated action tablets
1.3.8.8 Erosion core with initial dose
1.3.8.9 Erosion core only
1.3.8.10 Ion exchange resin
1.3.8.11 Complexation
1.3.8.12 Microencapsulation
1.3.8.13 The osmotic tablet
1.3.8.14 Gel forming hydrocolloids
1.3.8.15 Environmentally responsive system
1.3.9 Methods and mechanisms of sustaining drug action
1.3.9.1 Diffusional systems
1.3.9.2 Dissolution controlled system
1.3.9.3 Water penetration controlled system
1.3.9.4 Chemically controlled systems
1.3.9.5 Hydrogels
1.3.9.6 Ion exchange resins
1.3.10 Technical sophistication based classification of sustained release drug delivery
1.4 Matrix devices
1.4.1 Polymers used in matrix devices
1.4.2 Properties of an ideal polymer
1.4.3 Classification of polymers
1.4.3.1 Matrix devices with insoluble inert polymer
1.4.3.2 Matrix devices with insoluble erodible polymer
1.4.3.3 Matrix devices with hydrophilic polymer
1.4.3.4 Matrix devices with hydrogel polymer
1.4.4 Use of excipients in matrix devices
1.4.5 Release mechanisms from matrices
1.4.6 Mathematical models of release mechanics from matrices
1.4.6.1 Release from soluble retardants
1.4.6.2 Release from insoluble retardants
1.4.6.3 Drug release of low solubility in eluting media
1.4.6.4 Exponential model
1.4.6.5 Geometric dependence of diffusion exponent (n) and variation of n values with mechanism of diffusion
1.5 Thesis topic
1.5.1 Rationale
1.5.2 Active component
1.5.3 Physico-chemical properties of Nitroglycerin
1.5.4 Mechanism of action
1.5.5 Therapeutic use
1.5.6 Therapeutic dose
1.5.7 Contraindications
1.5.8 Pharmacokinetics
1.5.9 Pharmacology and toxicology
1.5.9.1 Mode of action
1.5.9.2 Interactions
1.5.9.3 Nitrate tolerance
1.5.10 Clinical effects
1.5.10.1 Acute poisoning
1.5.10.2 Chronic poisoning
1.5.11 Management of clinical effects
1.5.12 Decontamination
CHAPTER 2 : MATERIALS AND METHODS
2. Materials and methods
2.1 Materials
2.2. Drug profile
2.3. Excipients profile
2.3.1 Methocel
2.3.1.1 Nomenclature
2.3.1.2 Chemistry
2.3.1.3 Degree of substitution
2.3.1.4 Properties of Methocel K15M CR and Methocel K100LV CR
2.3.2 Profile of colloidal Silicon Dioxide (Aerosil 200)
2.3.3 Profile of Magnesium Stearate
2.4 Methods of study
2.4.1 Preparation of matrix tablet
2.4.2 Formulation of Nitroglycerin matrix tablet (F-1 – F-9)
2.5 Characterization of Nitroglycerin matrix tablets
2.5.1 Evaluation of physical properties of formulation granules
2.5.1.1 Bulk density
2.5.1.2 Compressibility index
2.5.1.3 Total porosity
2.5.1.4 Pharmacology and toxicology
2.5.1.5 Moisture content
2.5.1.6 Flow properties
2.5.1.7 Assay
2.5.2 Evaluation of physical properties of matrix tablet
2.5.2.1 Weight variation test
2.5.2.2 Hardness
2.5.2.3 Friability
2.5.2.4 Surface area
2.5.2.5 Moisture content
2.5.3 Chemical assay of Nitroglycerin in matrix tablets
2.5.3.1 Uniformity of content of active Nitroglycerin
2.5.3.2 Assay of Nitroglycerin after preparation of tablets
2.5.3.3 Assay of Nitroglycerin after 1 Month at 40°C + 75%RH
2.5.4 In-vitro release studies of Nitroglycerin matrix tablet
2.5.4.1 In-vitro dissolution medium
2.5.4.2 In-vitro dissolution studies of the tablet matrix
2.5.5 In-vitro release kinetic models
2.5.5.1 Zero order equation
2.5.5.2 First order equation
2.5.5.3 Higuchi square root law
2.5.5.4 Korsmeyer-Peppas model
2.5.5.5 Hixson-Crowell cube root law
2.5.6 Successive fractional dissolution time
CHAPTER 3: RESULTS AND DISCUSSION
3. Results and discussion
3.1 Evaluation of physical properties of Nitroglycerin granules
3.2 Evaluation of physical properties of Nitroglycerin tablets
3.3 Assay of Nitroglycerin matrix tablet
3.3.1 Uniformity of content of active Nitroglycerin
3.3.2 Assay of Nitroglycerin in the matrix tablet
3.3.3 Assay of Nitroglycerin after 1 Month at 40°C+75%RH in the matrix tablet
3.4 In-vitro dissolution and kinetic studies of Nitroglycerin matrix tablet in formulations (F–1 to F–9)
3.4.1 Effect of Methocel K15M CR (25%,20%,15%) and Methocel K100LV CR (15%,10%,5%) on release pattern of Nitroglycerin Matrix tablet
3.4.1.1 Zero order plot
3.4.1.2 First order plot
3.4.1.3 Higuchi plot
3.4.1.4 Korsmeyer-Peppas plot
3.4.1.5 Hixson-Crowell plot
3.4.2 Interpretation of release rate constant and R-square values for different release kinetics of (F–1 to F–9)
3.4.3 The best fitted model and mechanism of drug release from the matrix tablet of Nitroglycerin
3.4.4 Successive fractional dissolution time
3.5 Discussion about formulations (F–1 to F–9)
CHAPTER 4: CONCLUSION
4 Conclusion
CHAPTER 5: BIBLIOGRAPHY
5 Bibliography
Objectives and Topics
This dissertation aims to develop and characterize sustained-release matrix tablets containing 2.6 mg of Nitroglycerin. The research utilizes two distinct viscosity grades of hydroxypropyl methylcellulose (HPMC) polymers—Methocel K15M CR and Methocel K100LV CR—as rate-retarding agents to achieve an 8-hour sustained-release profile. The study evaluates the formulation's physical properties, stability under accelerated stress conditions, and drug release kinetics through various mathematical models to determine the optimal polymer ratios for consistent therapeutic delivery.
- Formulation design of Nitroglycerin matrix tablets using HPMC polymers.
- Evaluation of pre-compression granular properties and post-compression tablet characteristics.
- In vitro dissolution testing to assess release performance over 8 hours.
- Mathematical kinetic modeling (Zero order, First order, Higuchi, Korsmeyer-Peppas, Hixson-Crowell) to identify release mechanisms.
- Stability testing under accelerated conditions (40°C and 75% relative humidity).
Excerpt from the Book
1.3. Sustained release drug delivery system
Sustained release systems include any drug delivery system that achieves slow release of drug over an extended period of time. If the system is successful at maintaining constant drug levels in the blood or target tissue, it is considered as a controlled-release system. If it is unsuccessful at this, but nevertheless the duration of action over that achieved by conventional delivery, it is considered a prolonged-release system.
1.3.1. Concept of sustained release drug delivery system
Most conventional drug products, such as tablets and capsules, are formulated to release the active drug immediately to obtain rapid and complete systematic absorption of the drug. In recent years, various modified drug products have been developed to release drug products are designed for different routes of administration based on the physicochemical, pharmacological, and pharmacokinetic properties of the drug. Sustained release, sustained action, prolonged action, controlled release, extended action, time release, depot, and respiratory dosage forms are terms used to identify drug delivery systems that are designed to achieve a prolonged therapeutic effect by continuously releasing medication over an extended period of time after administration of a single dose. In the case of injectable dosage forms; this period may vary from days to months. In the case of orally administered forms, however, this period is measured in hours and critically depends on the residence time of the dosage form in the GI tract (Ballard, 1978).
A more finite explanation of these types of medication has been provided by Nelson (1961) and Parrot (1963). They indicated that a sustained release or sustained action product provides an initial sufficient amount drug to cause a rapid onset of desired therapeutic response, and an additional amount of drug that maintains the response at the initial level for a desired number of hours beyond the activity resulting from conventional dose; the initial desired therapeutic response is maintained because the rate of release of the desired therapeutic concentration is equal to the rate at which the drug is eliminated or inactivated.
Summary of Chapters
CHAPTER 1: INTRODUCTION: This chapter covers the fundamental concepts of controlled release systems, historical developments, various formulation techniques, factors affecting drug release, and the specific application of matrix devices for sustained action.
CHAPTER 2 : MATERIALS AND METHODS: This chapter details the ingredients, instruments, and methodological procedures used for preparing the matrix tablets and conducting evaluation tests such as granule flow, tablet characterization, and in vitro dissolution studies.
CHAPTER 3: RESULTS AND DISCUSSION: This chapter presents the experimental findings regarding the physical properties of the developed formulations and the analytical results of kinetic studies to evaluate the best-fitted release models.
CHAPTER 4: CONCLUSION: This chapter summarizes the project's achievements, noting that optimized polymer ratios successfully met the desired release criteria for 8-hour sustained-release Nitroglycerin tablets.
CHAPTER 5: BIBLIOGRAPHY: This section lists the scientific literature, pharmacological handbooks, and industrial technical references utilized throughout the research.
Keywords
Nitroglycerin, Sustained Release, Matrix Tablet, HPMC, Methocel, Dissolution, Kinetic Modeling, Higuchi Equation, Korsmeyer-Peppas, Drug Formulation, Controlled Release, Polymer Matrix, Bioavailability, Pharmaceutical Technology, Stability Study
Frequently Asked Questions
What is the core focus of this research?
This work primarily focuses on the design and evaluation of hydrophilic matrix-based sustained-release tablets of Nitroglycerin intended to provide therapeutic effects over an 8-hour duration.
What are the primary themes addressed?
The central themes include the formulation strategies for matrix tablets, the impact of different HPMC polymer ratios, physical characterization of granules and tablets, and detailed kinetic analysis of drug release profiles.
What is the research goal?
The primary goal is to formulate a stable, sustained-release Nitroglycerin tablet that improves patient compliance and reduces side effects compared to conventional dosage forms by maintaining effective drug levels for 8 hours.
Which methodology is employed?
The research uses the direct compression method to manufacture tablets. Evaluation methods include HPLC analysis for assay and content uniformity, as well as USP-2009 Apparatus-I for dissolution studies.
What is covered in the main body?
The main body examines the theoretical foundations of sustained delivery, the specific materials used, the detailed formulation process, the characterization of the physical properties, and a rigorous evaluation of the release kinetics through mathematical models.
Which keywords define this study?
The study is best characterized by terms such as Nitroglycerin, Sustained Release, Matrix Tablet, HPMC, Dissolution, Kinetic Modeling, and Polymer Matrix.
Why are Methocel K15M CR and K100LV CR used?
These HPMC grades are used as rate-retarding agents. Their varied viscosity allows for the fine-tuning of the drug release rate from the hydrophilic matrix, ensuring the release duration is extended effectively.
What do the kinetic models reveal about the release mechanism?
The study found that the release mechanism for all proposed formulations followed an anomalous or non-Fickian transport pattern, suggesting a combination of both diffusion-controlled and erosion-controlled drug release processes.
- Quote paper
- Subrata Bhadra (Author), 2010, Nitroglycerin Sustained Release Tablet. Formulation Design and Evaluation, Munich, GRIN Verlag, https://www.hausarbeiten.de/document/231784
