Rate limiting steps in drug absorption [autosaved]
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The document discusses rate limiting steps in drug absorption, focusing on the movement of unchanged drugs from administration sites to plasma and the factors influencing this process, including disintegration, dissolution, and absorption rates. Key factors affecting drug absorption include drug solubility, properties of excipients, and manufacturing methods. The conclusion emphasizes the importance of understanding these processes to determine the rate and extent of drug absorption.
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Rate limiting steps in drug absorption [autosaved]
- 1. RATE LIMITING STEPS IN DRUG ABSORPTION Presented to Submitted by Prof R. Nagaraju Ch. Neeharika M.pharm,1st year 2018MPH40AO14
- 2. CONTENTS Introduction Rate limiting factors Conclusion References
- 3. INTRODUCTION DRUG ABSORPTION It is defined as the process of movement of unchanged drug from the site of administration to the site of measurement i.e., plasma. A drug that is completely but slowly absorbed may fail to show therapeutic response as the plasma concentration for desired effect is never achieved. On the contrary, a rapidly absorbed drug attains the therapeutic level easily to elicit pharmacological effect.
- 4. In a series of kinetic or rate processes, the rate at which the drug reaches the systemic circulation is determined by the slowest of the various steps involved in the sequence. Such a step is called as the rate-determining or rate-limiting step. Systemic drug absorption from a drug product consists of a succession of rate processes. For solid oral, immediate release drug products (eg: tablets, capsules) the rate processes include Disintegration of drug product and its release Dissolution of drug in aqueous environment Absorption across cell membranes into systemic circulation
- 5. The rate and extent of drug absorption from its dosage form can be influenced by a number of factors 1.Disintegration time 2.Dissolution and solubility 3.Physical and chemical nature of active drug substance 4.Nature of excipients 5.Method of granulation 6.Dissolution test conditions 7.Gastric emptying
- 6. DISINTEGRATION TIME In vitro disintegration test is by no means a guarantee of drugs bioavailability because if the disintegrated drug particles do not dissolve, absorption is not possible. The process of disintegration does not imply complete dissolution of the tablet or the drug. The official apparatus used for disintegration test and procedure is described in the USP Separate specifications are given for drug products that are designed not to disintegrate such as troches, chewable tablets etc.
- 7. Biopharmaceutical Classification System(BCS) for highly soluble and highly permeable drugs. In general, the disintegration test serves as a component in the overall quality control of tablet manufacture. Class Solubility Permeability Absorption pattern Rate limiting step in absorption Examples I High High Well absorbed Gastric emptying Diltiazem II Low High Variable Dissolution Nifidipine III High Low Variable Permeability Insulin IV Low Low Poorly absorbed Case by case Taxol
- 8. DISSOLUTION Dissolution is the process by which a solid drug substance becomes dissolved in a solvent. The steps in dissolution include the process of drug dissolution at the surface of the solid particle, thus forming a saturated solution around the particle. The dissolved drug in the saturated solution, known as the stagnant layer, diffuses to the bulk of the solvent from regions of higher drug concentration to regions of low drug concentration.
- 9. The overall rate of drug dissolution may be described by the Noyes-Whitney equation Where, dc/dt = rate of drug dissolution at time t D = diffusion rate constant A = surface area of the particle Cs = concentration of drug in the stagnant layer C = concentration of drug in the bulk solvent h = thickness of the stagnant layer
- 10. This equation shows that dissolution in a flask may be influenced by the physicochemical characteristics of the drug, formulation and solvent. The dissolution of drug in the body, particularly in the gastrointestinal tract, is considered to be dissolving in an aqueous environment. Permeation of drug across the gut wall is affected by the ability of the drug to diffuse and to partition between the lipid membranes. A favourable partition coefficient (K oil/water) will facilitate drug absorption.
- 11. PHYSICAL AND CHEMICAL NATURE OF ACTIVE DRUG SUBSTANCE DRUG SOLUBILITY SALT FORMATION • It is one of the common approaches used to increase drug solubility and dissolution rate. • It has always been assumed that sodium salts dissolve faster than their corresponding insoluble acids.
- 12. E.G :- sodium and potassium salts of Pencillin G, phenytoin, barbiturates, tolbutamide etc. • Hydrochlorides and sulphates of weak bases are commonly used due to high solubility. E.G :- epinephrine, tetracycline PARTICLE SIZE • Surface area increases with decrease in particle size, higher dissolution rates may be achieved through reduction of particle size. • Micronization of sparingly soluble drug to reduce particle size, there is no guarantee of better dissolution and bioavailability.
- 13. NATURE OF EXCIPIENTS DILUENTS studies of starch on dissolution rate of salicylic acid tablet by dry double compression process. DISINTEGRANTS Studies of various disintegrating agents on Phenobarbital tablet showed that when Copagel(low viscosity grade of sodium CMC) added before granulation decreased dissolution rate but added after did not had any effect on dissolution rate • Eg :- Microcrystalline cellulose Starch
- 14. BINDERS AND GRANULATING AGENTS Hydrophilic binder increase dissolution rate of poorly wettable drug. Large amount of binder increase hardness and decrease disintegration/dissolution rate of tablet. SURFACTANTS They enhance the dissolution rate of poorly soluble drugs. Eg :- Non-ionic surfactant polysorbate 80 increase dissolution rate of phenacetin granules.
- 15. METHOD OF MANUFACTURE METHOD OF GRANUALATION A newer technology called as APOC “Agglomerative Phase of Comminution” was found to produce mechanically stronger tablets with higher dissolution rates than those made by wet granulation. A possible mechanism is increased internal surface area of granules produced by APOC method. DRUG EXCIPIENT INTERACTION These interactions occur during any unit operation such as mixing, milling, blending, drying or granulating results in change in dissolution. Eg :- Prednisolone
- 16. COMPRESSION FORCE The compression force influence density, porosity, hardness, disintegration time and dissolution of tablet.
- 17. DISSOLUTION TEST CONDITIONS AGITATION • Speed of agitation generates a flow that continuously change the liquid/solid interface between solvent and drug. • In order to prevent turbulence and sustain a reproducible laminar flow which is essential for obtaining reliable results, agitation should be maintained at a relatively flow rate. In general relatively low agitation should be applied 1. Basket method- 100rpm 2. Paddle method- 50-75rpm
- 18. TEMPERATURE Drug solubility is temperature dependent. A temperature of 37º ± 0.5 is maintained during dissolution of oral dosage forms and suppositories. Topical preparations - 25° and 30° are used. DISSOLUTION MEDIUM Addition of sodium sulphate decrease the dissolution rate. Addition urea increases dissolution rate. If drug is poorly soluble, a relatively large amount of fluid should be used if complete dissolution is to be expected.
- 19. GASTRIC EMPTYING Apart from dissolution of a drug and its permeation through the bio membrane, the passage from stomach to the small intestine, called as gastric emptying, can also be aa rate limiting step in drug absorption in intestine. Rapid gastric emptying is advisable where: A rapid onset of action is desired Dissolution of drug occurs in the intestine The drugs are not stable in gastric fluids Delay in gastric emptying is recommended in particular where: The food promotes drug dissolution and absorption Dis integration and dissolution of dosage form is promoted by gastric fluids The drugs irritate the gastric mucosa
- 20. Factors influence gastric emptying are • Volume of meal • Composition of meal • Physical state and viscosity of meal • Temperature of the meal • Gastrointestinal pH • Body posture • Emotional state • Exercise • Drugs
- 21. CONCLUSION In this process the drug disintegration and rate of drug reaches the circulatory system can be determined. The rate and extent of the drug absorption is determined.
- 22. REFERENCES Applied Biopharmaceutics and pharmacokinetics by Shargel Biopharmaceutics and Pharmacokinetics A Treatise by D.M. Brahmankar www.google.com