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Rate limiting steps in drug absorption

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Rate limiting steps in drug absorption

  1. 1. RATE LIMITING STEPS IN DRUG ABSORPTION Presented By C.Prakash M.Pharm Ceutics
  2. 2. Drug absorption It is defined as the process of movement of unchanged drug from the site of administration to systemic circulation. Absorption can also be 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 rapid absorbed drug attains the therapeutic level easily to elicit pharmacological effect.
  3. 3. Drugs that have to enter the systemic circulation to exert their effect can be administered by 3 major routes:- The Enteral Route The Parenteral Route The Topical Route
  4. 4. Rate Limiting Steps In Drug Absorption In a series of kinetic or rate processes, the rate at which the drug reaches the systemic circulation is determined by the slowest of various steps involved in the sequence. Such a step is called as the rate limiting step. Systemic drug absorption from a drug product consists of a succession of rate processes. For solid oral, immediate-release drug product (tablets, capsules) the rate processes include.  Disintegration of the drug product and subsequent release of the drug,  Dissolution of the drug in an aqueous environment and  Absorption across cell membranes into the systemic circulation.
  5. 5. DISINTEGRATION  For immediate- release, solid oral dosage forms, the drug product must disintegrate into small particles and release the drug.  To monitor uniform tablet disintegration, United States Pharmacopeia (USP) has established an official disintegration test.  Solid drug products exempted from disintegration tests include troches, tablets that are intended to be chewed, and drug products intended for sustained release or prolonged or repeat action.  The process of disintegration does not imply complete dissolution of the tablet and/or the drug.
  6. 6.  Complete disintegration is defined by the USP-NF as ‘’that state in which any residue of the tablet, except fragments of insoluble coating, remaining on the screen of the test apparatus in the soft mass have no palpably firm core’’.  The official apparatus for the disintegration test and procedure is described in the USP-NF.  Separate specifications are given for drug products that are designed not to disintegrate.  These products include troches, chewable tablets, and modified release drug products.  Although disintegration tests allow for measurement of the formation of fragments, granules, or aggregates from solid dosage forms, no information is obtained from these tests on the rate of dissolution of the active drug.
  7. 7.  However, there has been some interest in using only the disintegration test and no dissolution test for drug products that meet the 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 Nifedipine III High Low Variable Permeability Insulin IV Low Low Poorly Absorbed Case By Case Taxol
  8. 8. DISSOLUTION AND SOLUBILITY Dissolution is the process by which a solid drug substance becomes dissolved in a solvent. Solubility is the mass of solute that dissolves in a specific mass or volume of solvent at a given temperature (Eg, 1g of NaCl dissolves in 2.786 mL of water at 25oC )  Solubility is a static property, whereas dissolution is a dynamic property. In biologic systems, drug dissolution in an aqueous medium is an important prior condition for predicting systemic drug absorption.
  9. 9.  The rate at which drugs with poor aqueous solubility dissolve from an intact or disintegration solid dosage form in the gastrointestinal tract often controls the rate of systemic absorption of the drug.  Thus, dissolution tests may be used to predict bioavailability and may be used to discriminate formulation factors that effect drug bioavailability. The dissolution test is required for all US Food and Drug Administration (FDA) approved solid oral drug products.  Noyes and Whitney (1897) and other investigation studied the rate of dissolution of solid drugs.  According to their observations, 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.
  10. 10. The dissolved drug in the saturated solution, known as the stagnant layer, diffuses to the bulk of the solvent from regions of high drug concentration to regions of low drug concentration. The overall rate of drug dissolution may be described by the Noyes-Whitney equation 𝑑𝐶 𝑑𝑡 = 𝐷𝐴 ℎ (𝐶𝑠 − 𝐶) Where , 𝑑𝐶 𝑑𝑡 = rate of drug dissolution at time t, D = diffusion rate constant, A = surface area of the particle, Cs = concentration of drug (equal to solubility of drug) in the stagnant layer, C = concentration of drug in the bulk solvent, and h = thickness of the stagnant layer.
  11. 11.  The rate of dissolution, dC/dt, is the rate of drug dissolved per time expressed as concentration change in the dissolution change in the dissolution fluid.  The Noyes-Whitney equation shows that dissolution in a flask may be influenced by the physicochemical characteristics of the drug, the formulation, and the 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 (D) and to partition between the lipid membranes.  A favourable partition coefficient (Koil/water) will facilitate drug absorption.
  12. 12. Factors that affect drug dissolution of a solid oral dosage form include (1)The physical and chemical nature of the active drug substance (2) The nature of the excipients (3)The method of manufacture (4) The dissolution test conditions. Physical and chemical nature of the active drug substance 1) DRUG SOLUBILITY Solubility of drug plays a prime role in controlling its dissolution from dosage form. Aqueous solubility of drug is a major factor that determines its dissolution rate.
  13. 13. 2 ) SALT FORMATION o It is one of the common approaches used to increase drug solubility and dissolution rate. o It has always been assumed that sodium salts dissolve faster than their corresponding insoluble acids. o E.g. sodium and potassium salts of Penicillin G, phenytoin, barbiturates, tolbutamide etc. o While in case of Phenobarbital dissolution of sodium salt was slower than that of weak acid. Due to decreaseddisintegration of sodium salt. o Hydrochlorides and sulphates of weak bases are commonly used due to high solubility. o E.g. epinephrine, tetracycline. 3) PARTICLE SIZE There is a direct relationship between surface area of drug and its dissolution rate. Since, 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.
  14. 14. Nature of the excipients 1)DILUENTS Studies of starch on dissolution rate of salicylic acid tablet by dry double compression process shows three times increase in dissolution rate when the starch content increase from the 5 – 20 %. Here starch particles form a layer on the outer surface of hydrophobic drug particles resulting in imparting hydrophilic character to granules & thus increase in effective surface area & rate of dissolution. 2)DISINTEGRANTS Disintegrating agent added before & after the granulation affects the dissolution rate. Studies of various disintegrating agents on Phenobarbital tablet showed that when copagel (low viscosity grade of Na CMC) added before granulation decreased dissolution rate but if added after did not had any effect on dissolution rate. Microcrystalline cellulose is a very good disintegrating agent but at high compression force, it may retard drug dissolution.
  15. 15.  Starch is not only an excellent diluent but also superior disintegrant due to its hydrophilicity and swelling property. 3)BINDERS AND GRANULATING AGENTS The hydrophilic binder increase dissolution rate of poorly wettable drug. Large amt. of binder increase hardness & decrease disintegration/dissolution rate of tablet. Non aqueous binders such as ethyl cellulose also retard the drug dissolution. 4)SURFACTANTS They enhance the dissolution rate of poorly soluble drug. This is due to lowering of interfacial tension, increasing effective surface area, which in turn results in faster dissolution rate. E.g. Non-ionic surfactant Polysorbate 80 increase dissolution rate of phenacetin granules.
  16. 16. Method of manufacture 1) METHOD OF GRANULATION Granulation process in general enhances dissolution rate of poorly soluble drug. Wet granulation is traditionally considered superior. 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. 2)DRUG EXCIPIENT INTERACTION These interactions occur during any unit operation such as mixing, milling ,blending, drying, and/or granulating result change in dissolution. The dissolution of prednisolone found to depend on the length of mixing time with Mg-stearate Similar as increase in mixing time of formulation containing 97 to 99% microcrystalline cellulose or another slightly swelling disintegrant result in enhance dissolution rate.
  17. 17. 3)COMPRESSION FORCE The compression process influence density, porosity, hardness, disintegration time & dissolution of tablet. A)Higher compression force increases the density and hardness of tablet, decreases porosity which results in tighter bonding between the particles, which result in the slower dissolution rate of tablet. B) Higher compression forces cause deformation, crushing or fracture of drug particles into smaller one which increase in the surface area thus increase in dissolution rate of tablet. C&D) The influence of compression force on dissolution rate is difficult to predict and a thorough study on formulation should be made to ensure better dissolution and bioavailability
  18. 18. Dissolution test conditions 1) AGITATION Relationship between intensity of agitation and rate of dissolution varies considerably acc. to type of agitation used, the degree of laminar and turbulent flow in system, the shape and design of stirrer and physicochemical properties of solid. Speed of agitation generates a flow that continuously changes the liq/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 low rate. Thus, in general relatively low agitation should be applied. I. BASKET METHOD- 100 rpm II. PADDLE METHOD- 50-75 rpm
  19. 19. 2) TEMPERATURE Drug solubility is temperature dependent, therefore careful temperature control during dissolution process is extremely important. Generally, a temp of 37º ± 0.5 is maintained during dissolution of oral dosage forms and suppositories. However, for topical preparations temp as low as 30º and 25º have been used. 3) DISSOLUTION MEDIUM  Addition of Na – sulfate decrease the dissolution rate.  Addition of urea increase dissolution rate.  Volume generally 500, 900 or 1,000 ml.  Simulated gastric fluid(SGF) - pH 1.2.  Simulated intestinal fluid (SIF)- pH 6.8.  If drug is poorly soluble, a relatively large amount of fluid should be used if complete dissolution is to be expected.
  20. 20. 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 a rate limiting step in drug absorption because the major site of absorption is intestine. Rapid gastric emptying is advisable where:  A rapid onset of action is desired e.g. sedatives  Dissolution of drug occurs in the intestine e.g. enteric coated tablets  The drugs are not stable in gastric fluids e.g. penicillin G and erythromycin For better dissolution and absorption, the gastric emptying can be promoted by taking the drug on empty stomach. Delay in gastric emptying is recommended in particular where: • The food promotes dug dissolution and absorption e.g. griseofulvin • Disintegration and dissolution of dosage form is promoted by gastric fluids • The drugs irritate the gastric mucosa e.g. aspirin, phenylbutazone
  21. 21. A Large number of factors influence gastric emptying as discussed below  Volume of meal  Composition of meal  Physical state and viscosity of meal  Temperature of the meal  Gastrointestinal pH  Body posture  Emotional state  Exercise  Drugs
  22. 22. Refernces Applied Biopharmaceutics and Pharmacokinetics by Shargel. Pg No:363-365 Biopharmaceutics and pharmacokinetics A Treatise, D.M. Brahmankar and Sunil B. Jaiswal., VallabhPrakashan Pg No:27- 29, 35-41, 52-56, 67-69.
  23. 23. THANK YOU

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