Drug Absorption from GI Tract

Gastrointestinal tract, Mechanism of drug absorption, Factors
affecting drug absorption, pH–partition theory of drug absorption. Formulation and physicochemical factors: Dissolution rate, Dissolution process, Noyes–Whitney equation and drug dissolution, Factors affecting the dissolution rate. Gastrointestinal absorption: Role of the dosage form: Solution (elixir, syrup and solution) as a dosage form ,Suspension as a dosage form, Capsule as a dosage form, Tablet as a dosage form ,Dissolution methods ,Formulation and processing factors, Correlation of in vivo data with in vitro dissolution data. Transport model: Permeability-Solubility-Charge State and the pH Partition Hypothesis, Properties of the Gastrointestinal Tract (GIT), pH Microclimate Intracellular pH Environment, Tight Junction Complex.

1. DRUG ABSORPTION FROM GI TRACT SILAMBARASAN I M PHARM(PHARMACEUTICS) MTPG & RIHS

2. DEFINITION Drug absorption is defined as process of movement of unchanged drug from the site of administration to systemic circulation. Effectiveness depends on rate and extent of absorption at particular site.

3. GI TRACT The primary function is secretion, digestion ,and absorption. The mean length of entire GIT is 450 cm. It is lined by a thin layer of mucopolysaccharides which act as an impermeable barrier to particulates such as bacteria, cells or food particles .

4. STOMACH Bag like structure having small surface area due to absence of microvilli . Drugs which are acid sensitive must not be in contact with acidic environment of the stomach. Gastric residence time is limited due to which there is limited opportunity for gastric uptake of drug.

5. SMALL INTESTINE It is the major site for absorption of most drugs due to its special characteristics: Large surface area Great length of small intestine : results in more than 200sq meters of which is several times that of stomach. Greater blood flow : 6 to 10 times more than stomach Favorable pH range : 5-7.5 Slow peristaltic movement : Prolongs residence time of drugs High permeability

6. LARGE INTESTINE Length and mucosal surface area is very small (Villi & Microvilli is absent) in comparison to small intestine. Its contents are neutral or alkaline . The main role of large intestine is absorption of water and electrolytes . Surface area : 4-5 ft

7. CELL MEMBRANE STRUCTURE & PHYSIOLOGY Movement of drug across the membrane is called as drug transport . Consists of a double layer of amphiphilic phospholipid molecules . Bimolecular layer of lipids is contained between two parallel monomolecular layers of proteins( Mayonnaise sandwich ). Aqueous filled pores or perforations of 4 to 10 Å in diameter through which small inorganic ions like Urea can pass.

8. MECHANISM OF DRUG ABSORPTION Three broad Categories 1)Transcellular /Intracellular transport A)Passive transport process -Passive diffusion -Pore transport -Ion pair transport -Facilitated or mediated diffusion B)Active transport process -Primary active transport -Secondary active transport 2) Paracellular / Intercellular transport 3) Vesicular transport

9. 1)TRANSCELLULAR/INTRACELLULAR TRANSPORT PROCESS It is defined as the passage of drugs across the GI epithelium . 3 steps involved : Permeation of GI epithelial cell membrane Movement across the intracellular space (cytosol). Permeation of the lateral or basolateral membrane .

10. A. Passive Transport Processes These transport processes do not require energy other than that of molecular motion (Brownian motion) to pass through the lipid bilayer . Passive transport processes can be further classified into following types Passive diffusion. Pore transport. Ion-pair transport. Facilitated- or mediated-diffusion.

11. PASSIVE DIFFUSION Also called non-ionic diffusion. A bsorption of more than 90% of the drugs. The driving force is concentration or electrochemical gradient. Passive diffusion is best expressed by Fick’s first law of diffusion. dQ / dt = rate of drug diffusion D = diffusion coefficient of the drug A = surface area of the absorbing membrane Km/w = partition coefficient of the drug between membrane and the aqueous phase ( C GIT – C ) = difference in the concentration of drug in GI fluid & the plasma h = thickness of the membrane (length)

12. PORE TRANSPORT It is also called as convective transport , bulk flow or filtration . The driving force is hydrostatic pressure or the osmotic pressure differences across the membrane. The process is important in the absorption of low molecular weight (less than 100), generally water-soluble drugs through narrow, aqueous-filled channels ex: urea, water and sugars. Chain-like or linear compounds of molecular weight up to 400 Daltons can be absorbed by filtration. Drug permeation through water-filled channels is importance in renal excretion, removal of drug from the cerebrospinal fluid and entry of drugs into the liver.

13. ION-PAIR TRANSPORT Absorption of drugs like quaternary ammonium compounds and sulphonic acids , which ionise under all pH conditions, is ion-pair transport. Despite their low o/w partition coefficient values, such agents penetrate the membrane by forming reversible neutral complexes with endogenous ions of the GIT like mucin. Such neutral complexes have both the required lipophilicity as well as aqueous solubility for passive diffusion. Such a phenomenon is called as ion-pair transport . Propranolol, a basic drug that forms an ion pair with oleic acid, is absorbed by this mechanism.

14. Ion-pair transport of a cationic drug

15. CARRIER MEDIATED TRANSPORT The mechanism is involved is carrier that binds reversibly or non-covalently with the solute molecules to be transported. This carrier-solute complex traverses across the membrane to the other side where it dissociates and discharges the solute molecule . The carrier then returns to its original site to complete the cycle by accepting a fresh molecule of solute. Carriers in membranes are proteins (transport proteins) and may be an enzyme or some other component of the membrane.

16. FACILITATED DIFFUSION It is a carrier-mediated transport system that operates down the concentration gradient ( downhill transport ) but at a much a faster rate than can be accounted by simple passive diffusion. The driving force is concentration gradient (hence a passive process). Since no energy expenditure is involved. Facilitated diffusion of vitamin B12

17. B)ACTIVE TRANSPORT PROCESS This transport process requires energy from ATP to move drug molecules from extracellular to intracellular milieu. These are of two types Primary active transport Secondary active transport Symport (co-transport ) Antiport (counter-transport )

18. Primary active transport In this process, there is direct ATP requirement . The process transfers only one ion or molecule and in only one direction , and hence called as uniporter . e.g . absorption of glucose. Secondary active transport In these processes, there is no direct requirement of ATP i.e . it takes advantage of previously existing concentration gradient. The energy required in transporting an ion aids transport of another ion or molecule ( co-transport or coupled transport ) either in the same direction or in the opposite direction . Accordingly this process is further subdivided into Symport (co-transport) – involves movement of both molecules in the same direction. e.g. Na + -glucose symporter Antiport (counter-transport) –involves movement of molecules in the opposite direction. e.g. H + ions using the Na + gradient in the kidneys.

19. 20

20. 2)PARACELLULAR/INTERCELLULAR TRANSPORT It is defined as the transport of drugs through the junctions between the GI epithelial cells . This pathway is of minor importance in drug absorption . The two paracellular transport mechanisms involved in drug absorption are Permeation through tight junctions of epithelial cells – this process basically occurs through openings which are little bigger than the aqueous pores . Eg: Compounds such as insulin and cardiac glycosides Persorption – is permeation of drug through temporary openings formed by shedding of two neighbouring epithelial cells into the lumen.

21. 3)VESICULAR OR CORPUSCULAR TRANSPORT(ENDOCYTOSIS) It is energy dependent processes but involve transport of substances within vesicles into a cell . It involves engulfing extracellular materials within a segment of the cell membrane to form a saccule or a vesicle (hence also called as corpuscular or vesicular transport) which is then pinched off intracellularly . Eg: cellular uptake of macromolecular nutrients like fats and starch, oil soluble vitamins like A, D, E and K, water soluble vitamin like B 12 and drugs such as insulin. Vesicular transport of drugs can be classed into two categories – 1)Phagocytosis 2)Pinocytosis

22. PHAGOCYTOSIS (CELL EATING) Adsorptive uptake of solid particulates

23. PINOCYTOSIS (CELL DRINKING) Uptake of fluid solute . E.g . Sabine polio vaccine (orally administered)

24. FACTORS AFFECTING DRUG ABSORPTION AND BIOAVAILABILTY Physicochemical factors: 1 ) Drug solubility & dissolution rate 2 ) Particle size & effective surface area 3 ) Polymorphism & amorphism 4 ) Pseudoploymorphism (hydrates/solvates) 5 ) Salt form of the drug 6 ) Lipophilicity of the drug 7) pKa of drug & gastrointestinal pH 8 ) Drug stability

25. B. Pharmaceutical factors : 1 ) Disintegration time (tablets/capsules) 2 ) Dissolution time 3 ) Manufacturing variables 4 ) Pharmaceutical ingredients (excipients/adjuvants) 5 ) Nature & type of dosage form 6 ) Product age & storage condition

26. A ge G astric emptying time I ntestinal transit time G astrointestinal pH D iseased states B lood flow through the GIT G astrointestinal contents - O ther drugs - Food - F luids -Other normal G.I contents P resystemic metabolism by -Luminal enzymes -Gut wall enzymes - B acterial enzymes -Hepatic enzymes C.PATIENT RELATED FACTOR

27. 1) DRUG SOLUBILITY AND DISSOLUTION RATE Rate determining process in the absorption of orally administered drugs are :- 1.Rate of dissolution 2.Rate of drug permeation through the bio membrane Hydrophobic-RDS- Dissolution Eg :- griseofulvin , spironolactone Hydrophilic-RDS-permeation rate limited Eg : - cromolyn sodium or neomycin

28. The concept of maximum absorbable dose (MAD) is used to correlate drug absorption with its solubility. MAD = K a S GI V GI t r K a = Intrinsic absorption rate constant S GI = Solubility of drug in GI fluid V GI = volume of GI fluid t r = residence time of drug in GI From these equation we can find the, - Solubility od drug in GI tract -Intrinsic absorption rate constant specific to drug in solution

29. Important prerequisite for absorption of drug are, 1)Absolute or intrinsic solubility -Maximum of solute dissolved in given solvent under standard condition of temperature ,pressure ,pH. -It is Static property. 2)Dissolution rate -Amount of solid substance that goes into solution per unit time under standard condition of temperature ,pH,solvent composition and constant solid surface area. -It is dynamic property.

30. THEORIES OF DISSOLUTION Three Theories: 1 . Diffusion layer model / Film theory 2 . Danckwert’s model / Penetration or Surface renewal theory 3 . Interfacial barrier model / Double barrier or Limited solvation theory

31. 1) DIFFUSION LAYER MODEL It involves two steps : 1. Solution of the solid to form stagnant film or diffusive layer which is saturated with the drug. 2. Diffusion of the soluble solute from the stagnant layer to the bulk of the solution; this is rate determining step in drug dissolution .

32. The rate of dissolution is given by Noyes and Whitney: dC/ dt = k (C s - C b ) where , dC/ dt = dissolution rate of the drug k = dissolution rate constant C s = concentration of drug in stagnant layer C b = concentration of drug in the bulk of the solution at time t

33. . Nernst and Brunner incorporated Fick’s first law of diffusion and modified the Noyes-Whitney’s equation to : dC/ dt = DAK w /o (Cs-Cb ) Vh where, D = diffusion coefficient of drug A = surface area of dissolving solid K w/o = water/oil partition coefficient of drug V = volume of dissolution medium h = thickness of stagnant layer ( C s – C b ) = conc. gradient for diffusion of drug

34. Limitation : The Noyes-Whitney’s equation assumes that the surface area of the dissolving solid remains constant during dissolution , which is practically not possible for dissolving particles. Hence, dissolution methods that involves use of constant surface area discs are employed to determine the rate of dissolution. To account for the particle size decreases and change in the surface area accompanying dissolution, Hixson and Crowell’s cubic root law of dissolution is used: Wo 1/3 –W 1/3 = K.t where, W = mass of drug remaining to be dissolved at time t K = dissolution rate constant Wo = original mass of the drug

35. 2) DANCKWERT’S MODEL Danckwert takes into account the eddies or packets that are present in the agitated fluid which reach the solid-liquid interface, absorb the solute by diffusion and carry it into the bulk of solution. These packets get continuously replaced by new ones and expose to new solid surface each time, thus the theory is called as surface renewal theory . The Danckwert’s model is expressed by equation: V . dC/ dt = dm / dt = A ( C s -C b ). √( γ. D) where , m = mass of solid dissolved γ = rate of surface renewal

36. 3) INTERFACIAL BARRIER MODEL The diffusion layer model and Danckwert’s model were based on two assumptions: 1 . The rate determining step that controls dissolution is the mass transport. 2 . Solid-solution equilibrium is achieved at the solid/liquid interface . According to the interfacial barrier model, an intermediate concentration can exist at the interface as a result of solvation mechanism and is a function of solubility rather than diffusion . Such a concept is given by the following equation : G = K i (C s -C b ) where , G = dissolution rate per unit area K i = effective interfacial transport constant

37. DISSOLUTION PROCESS

38. FACTORS AFFECTING DISSOLUTION RATE 1) PHYSICOCHEMICAL PROPERTIES OF DRUG -Solubility of drug -Salt formation -Particle size -Polymorphism 2) DRUG PRODUCT FORMULATION FACTORS -Diluents -Disintegrants -Binders and Granulating agent -Lubricants 3) PROCESSING FACTORS -Method of Granulation -Compression force -Storage condition 4)FACTORS RELATING DISSOLUTION APPARTUS & TEST PARAMETERS -Agitation -Sampling probe position -Temperature -Dissolution medium

39. DISSOLUTION METHODS Apparatus are used according to standards specified. The USP includes seven apparatus design for drug release and dissolution testing of immediate release and for oral dosage form, for extended release, enteric coated, transdermal drug delivery system . Rotating basket method Paddle method Flow-through method Reciprocating cylinder method Paddle over disk method Rotating cylinder method Reciprocating disk method

40. 2)PARTICLE SIZE & EFFECTIVE SURFACE AREA Particle size may play a major role in drug absorption. Smaller the particle size, greater the surface area . Particle size reduction has been used to increase the absorption of a large number of poorly soluble drugs. E.g . Bishydroxycoumarin, digoxin, griseofulvin Two types of surface area 1 ) Absolute surface area 2 ) Effective surface area

41. In absorption studies, the effective surface area is of much important than absolute . To increase the effective surface area, we have to reduce the size of particles up to 0.1 micron. So these can be achieved by “ micronisation process ’’. K eep in mind that which type of drug is micronized if it is : a ) HYDROPHILIC DRUGS: In hydrophilic drugs the small particles have higher energy than the bulk of the solid resulting in an increased interaction with the solvent b ) HYDROPHOBIC DRUGS: In this micronisation techniques results in decreased effective surface area & thus fall in dissolution rate.

42. 3) POLYMORPHISM & AMORPHISM Depending upon the internal structure, a solid can exist either in a crystalline or amorphous form. When a substance exists in more than one crystalline form , the different forms are designated as polymorphs, and the phenomenon as polymorphism . Polymorphs are of two types: Enantiotropic polymorph is the one which can be reversibly changed into another form by altering the temperature or pressure.E.g. Sulphur . 2) Monotropic polymorph is the one which is unstable at all the temperature or pressures. E.g. glyceryl stearates.

43. AMORPHISM: Some drugs can exist in amorphous form (i.e. having no internal crystal structure ). Such drug represents the highest energy state . They have greater aqueous solubility than the crystalline forms because a energy required to transfer a molecule from the crystal lattice is greater than that required for non-crystalline (amorphous form). For example: the amorphous form of Novobiocin is 10 times more soluble than the crystalline form . Thus, the order of different solid dosage forms of the drugs is Amorphous > Meta-stable > stable

44. 4) PSEUDOPLOYMORPHISM When the solvent molecules are entrapped in the crystalline structure of the polymorph, it is known as pseudo-polymorphism . Solvates: The stoichiometric type of adducts where the solvent molecules are incorporated in the crystal lattice of the solid are called as the solvates , and the trapped solvent as solvent of crystallization . Hydrates: when the solvent in association with the drug is water , the solvate is known as a hydrate . Hydrates/Solvates are pseudo-polymorphs where hydrates are less soluble and solvates are more soluble and thus affect the absorption accordingly. For example: n- pentanol solvates of fludrocortisone and succinyl -sulfathiazole have greater aqueous solubility than the non-solvates.

45. 5)SALT FORM OF THE DRUG While considering the salt form of drug, pH of the diffusion layer is important not the pH of the bulk of the solution. Example of salt of weak acid- It increases the pH of the diffusion layer, which promotes the solubility and dissolution of a weak acid and absorption is bound to be rapid. Other approach to enhance the dissolution and absorption rate of certain drugs is the formation of in – situ salt formation i.e. increasing in pH of microenvironment of drug by incorporation of a buffering agent. E.g. aspirin, penicillin But sometimes more soluble salt form of drug may result in poor absorption. e.g. sodium salt of phenobarbitone viz., its tablet swells and did not get disintegrate, thus dissolved slowly and results in poor absorption.

46. 6 & 7) DRUG pKa AND LIPOPHILICITY AND GI PH-PARTION HYPOTHESIS The theory states that for drug compounds of molecular weight more than 100, which are primarily transported across the bio-membrane by passive diffusion, the process of absorption is governed by: 1. The dissociation constant pKa of the drug 2. The lipid solubility of the un-ionized drug 3. The pH at the absorption site

47. Drug pKa and GI pH : Amount of drug that exists in un-ionized form is a function of pKa of drug and pH of the fluid at the absorption site. The relative amount of ionized and unionized drug in solution at particular pH and the percent of drug ionized at this p H can be determined by Henderson Hasselbach equation. For weak acids, pH = pKa + log [ionized] [un-ionized]   % Drug ionized = 10 pH-pKa x 100 1+10 pH-pKa For weak bases, pH = pKa + log [un-ionized] [ionized] % Drug ionized = 10 pKa-pH x 100 1+10 pKa-pH

48. If there is a membrane barrier that separates the aqueous solutions of different pH such as the GIT and the plasma, then the theoretical ratio R of drug concentration on either side of the membrane can be given by the following equations :   For weak acids ,   R a = C GIT = 1+10 pHGIT-pKa C plasma 1+10 pHplasma-pKa For weak bases, R b = C GIT = 1+10 pKa-pHGIT C plasma 1+10 pKa-pHplasma

49. B) Lipophilicity and Drug absorption :   The lipid solubility of the drug is measured by parameter called as log p ,where p is oil/water partition co-efficient ( Ko /w) value, whereby the increase in this value indicates the increase in percentage drug absorbed.   Ko /w = Distribution of the drug in the organic phase ( octanol ) Distribution of the drug in the aqueous phase LIMITATION OF pH PARTITION HYPOTHESIES: Presence of virtual membrane pH Absorption of ionized drug Influence of GI surface area and residence time of drug Presence of aqueous unstirred diffusion layer

50. 8)DRUG STABILITY A drug for oral use may destabilize either during its shelf life or in the GIT . Two major stability problems resulting in poor bioavailability of an orally administered drug are - D egradation of the drug into inactive form - interaction with one or more different component either of the dosage form or those present in the GIT to form a complex that is poorly soluble or is absorbable.

51. B)PHARMCEUTICAL FACTORS DISINTEGRATION TIME (TABLETS/CAPSULES): Rapid disintegration is important to have a rapid absorption . D isintegration time of tablet is directly proportional to amount of binder & Compression force . In vitro disintegration test gives no means of a guarantee of drugs bioavailability because if the disintegrated drug particles do not dissolve then absorption is not possible. E.g. Coated tablet have long disintegration time. Fast dispersible tablets have short disintegration time

52. 2) DISSOLUTION TIME: Dissolution is a process in which a solid substance solubilizes in a given solvent i . e mass transfer from the solid surface to the liquid phase. Dissolution time is also an important factor which affect the drug absorption. 3) MANUFACTURING VARIABLES : Several manufacturing processes influence drug dissolution from solid dosage forms . For example: For tablet it is Method of granulation Compression force

53. Method of granulation: The wet granulation process is the most conventional technique . The tablets that dissolve faster than those made by other granulation methods. But wet granulation has several limitations like formation of crystal bridge or chemical degradation while drying . The method of direct compression force has been utilized to yield the tablets that dissolve at a faster rate . Compression force : The compression force employed in tableting process influence density, porosity, hardness, disintegration time and dissolution rate of tablets . Higher compression force increases the density and hardness of the tablet, decreases porosity and hence penetrability of the solvent into the tablet and thus in slowing of dissolution and absorption (Fig .A)

54. On the other hand, higher compression force causes deformation, crushing or fracture of drug particles into smaller ones and causes a large increase in effective surface area. This results in an increase in dissolution rate of tablets (Fig B) A combination of both the curves A and B is also possible as shown in curves C & D. Fig.Influence of compression force on the dissolution rate of tablets

55. 4) PHARMACEUTICAL INGREDIENTS (EXCIPIENTS/ADJUVANTS): More the number of Excipients in the dosage form, more complex it is & greater the potential for absorption and Bioavailability problems . Commonly used excipients in various dosage forms are, VEHICLE: Major component of liquid oral and parenteral . Rate of absorption – depends on its miscibility with biological fluid. Miscible vehicles causes rapid absorption e.g. propylene glycol. Immiscible vehicles – Absorption depends on its partitioning from oil phase to aqueous body fluid.

56. B) DILUENTS: Used to produce the necessary bulk . Hydrophilic diluents – Imparts Absorption Hydrophobic diluents – Retards Absorption Also , there is a drug-diluent interaction, forming insoluble complex and retards the absorption . E.g. Tetracycline-DCP C) BINDERS & GRANULATING AGENT: Used to hold the particles together to form granules . Hydrophilic binders – Imparts hydrophilic properties to the granule surface – gives better dissolution properties. E.g. Starch, Gelatin. PVP. More amount of binder increases the hardness of the tablet and retards the absorption rate .

57. D) DISINTEGRANTS: Mostly hydrophilic in nature. Decrease in amount of disintegrants – significantly lowers bioavailability . Eg: Microcrystalline cellulose E) LUBRICANTS: These agent added to tablets formulation to aid flow of granules ,to reduce interparticle friction and adhesion of particles to dies and punches. Commonly hydrophobic in nature – therefore inhibits penetration of water into tablet and thus dissolution and disintegration.

58. F ) SUSPENDING AGENTS/VISCOSITY AGENT Stabilized the solid drug particles by reducing the rate of settling through an increase in the viscosity of medium . Macromolecular gum forms un-absorbable complex with drug e.g . Na CMC form poor soluble complex with amphetamine. Viscosity imparters – act as a mechanical barrier to diffusion of drug from its dosage form and retard GI transit of drug. G) SURFACTANTS May enhance or retards drug absorption by interacting with drug or membrane or both. e.g. Griseofulvin, steroids It may decrease absorption when it forms the un-absorbable complex with drug above CMC.

59. H ) BUFFERS: Buffers are sometimes useful in creating the right atmosphere for drug dissolution as was observed for buffered aspirin tablets . However, certain buffer systems containing potassium cations inhibit the drug absorption as seen with Vitamin B 2 and sulfanilamide . I) Colorants: Even a low concentration of water soluble dye can have an inhibitory effect on dissolution rate. The dye molecules get absorbed onto the crystal faces and inhibit the drug dissolution. For example: Brilliant blue retards dissolution of sulfathiazole.

60. J ) COMPLEXING AGENTS: Complex formation has been used to alter the physicochemical & biopharmaceutical properties of a drug. Example 1)Enhanced dissolution through formation of a soluble complex. E.g . ergotamine tartarate -caffeine complex & hydroquinone-digoxin complex . 2)Enhanced lipophilicity for better membrane permeability. E.g . caffeine-PABA complex.

61. 5) NATURE & TYPE OF DOSAGE FORM: Apart from the proper selection of the drug, clinical success often depends to a great extent on the proper selection of the dosage form of that drug . As a general rule, the bio-availability of a drug form various dosage forms decrease in the following order: Solutions > Emulsions > Suspensions > Capsules > Tablets > Coated Tablets > Enteric Coated Tablets > Sustained Release Products.

62. 6) PRODUCT AGE & STORAGE CONDITION Product aging and storage conditions can adversely affect the bio-availability by change in especially the physico-chemical properties of the dosage forms . For example : Precipitation of the drug in solution Hardening of tablet Change in particle size of suspension.

63. C)PATIENT RELATED FACTOR 1) AGE In infants, the gastric pH is high and intestinal surface and blood flow to the GIT is low,resulting in altered absorption pattern in comparison to adults. In elderly persons, causes of impaired drug absorption include altered gastric emptying, decreased intestinal surface area and GI blood flow , higher incidents of achlorhydria and bacterial over growth in small intestine.

64. 2) GASTRIC EMPTYING AND MOTILITY The passage from stomach to small intestine called as gastric emptying . Several parameters are used to quantify gastric emptying such as: Gastric emptying rate: which is the speed at which the stomach contents empty into the intestine. Gastric emptying time: which is the time required for the gastric contents to the SMALL INTESTINE. Gastric emptying half-life: which is the time taken for half the stomach contents to empty.

65. 3) INTESTINAL TRANSIT Small intestinal is the major site of absorption of most of drugs, long intestinal transit time is desirable for complete absorption of drugs . It is influenced by various factors such as food, diseases and drugs. Transit time for contents from different regions of intestine Intestinal region Transit time Duodenum 5 minutes Jejunum 2 hours Ileum 3 to 6 hours Caecum 0.5 to 1 hour Colon 6 to 12 hours

66. 4) GASTROINTESTINAL PH GI fluid pH affect in several ways : Disintegration : The Disintegration of some drugs is pH sensitive with enteric coating the coat dissolves in only the intestine at specific PH. Dissolution : A large no of drugs whose solubility is greatly affected by pH are either weak acids or weak bases. Stability : GI pH also affect the chemical stability of drugs . Eg: the acidic stomach pH gives a degradation of penicillin G and erythromycin. So such drugs to be formulated by preparing prodrugs.

67. 5) DISEASES A ) Gastric diseases: The influence of achlorhydria (decreased gastric acid secretion and increases stomach pH) on gastric emptying and drug absorption, especially that of acidic drugs (decreased absorption e.g. aspirin) has been studied. B) Intestinal diseases: Two of the intestinal disorders related with malabsorption syndrome that influence drug availability are Celiac disease and Chron’s disease .   C) Cardio-vascular diseases: Several changes associated with congestive cardiac failure influence bio-availability of a drug viz., oedema of the intestine, decreased blood flow to the GIT and gastric emptying rate and altered GI pH, secretions and microbial flora. D) Hepatic diseases: Disorders such as hepatic cirrhosis influence bio-availability mainly of drugs that undergo considerable first-pass hepatic metabolism e.g. propranolol

68. 6) BLOOD FLOW THROUGH GIT: The GIT is extensively supplied by blood capillary network and blood flow rate to GIT (splanchnic circulation) is 28% of the cardiac output . Therefore, it helps in maintaining sink conditions and concentration gradient for drug absorption by rapidly removing drug from the site of action. Table : Influence of blood flow effect on various types of drugs   DRUGS BLOOD FLOW EFFECT A) For highly lipid soluble drugs More B) For many lipophilic drugs such as ethanol, glycerol, etc. Intermediate C) Polar compounds such as ribitol Less

69. 7) GASTRO INTESTINAL CONTENTS: Food - drug interactions : presence of food will affect absorption in following way a) D elay absorption : ex . Aspirin , paracetamol , diclofenac , nitrofurantoin ,digoxin etc . b) D ecreased absorption : ex. Penicillin, erythromycin, ethanol, tetracycline, levodopa etc. c) Increased absorption : griseofulvin, diazepam, vitamins etc. d) In some cases it do not affect : methyldopa, propylthiouracil etc. F luid volume : administration of a drug with large fluid volume results in better dissolution , rapid gastric emptying and enhanced absorption- Eg . erythromycin is better absorbed when taken with a glass of water under fasting condition than when taken with meals.

70. Interaction of drug with normal GI constituents : The GIT contains a number of normal constituents such as mucin –which is a protective mucopolysaccharides that lines the GI mucosa , interact with streptomycin. Bile salts- which affect the absorption of lipid soluble drugs like grieseofulvin and vitamins . D rug-drug interactions : They can either be physiological or physiochemical.

71. 8) Pre-systemic metabolism For a drug administered orally, the 2 main reasons for its decreased bio-availability are: 1 . Decreased absorption 2 . First-pass/pre-systemic metabolism The four primary systems which affect the pre-systemic metabolism of a drug Lumenal Enzymes Gut wall enzymes/mucosal enzymes Bacterial enzymes Hepatic enzymes.

72. ROLE OF DOSAGE FORM SOLUTIONS: Solutions is most rapidly absorbed Drug dissolution is absent Factors influencing absorption of solution are : - Viscosity -Surfactants -Solubilizes -Stabilizers -Stability

73. SUSPENSION Drug dissolution which is generally rapid due to the large surface area of the particles Factors affecting absorption -Particle size -Polymorphism -Wetting agents -Viscosity of the medium -Suspending agents

74. CAPSULES Powders & granules are administered in hard gelatin capsules whereas viscous fluids & oils in soft elastic shells Factors of importance in case of hard gel- Drug particle size Density Polymorphism Intensity of packing Influence of diluents & excipients

75. TABLETS Compressed Tablets > Film Coated Tablets > Sugar Coated Tablets > Enteric Coated Tablets > Sustained Release Products Factors: -Effective surface area -Dissolution -Deaggregation -Permeabilty -Excipients\API

76. IVIVC-DEFINITION FDA : A predictive mathematical model describing the relationship between an in vitro property of dosage form (usually the rate or extent of drug dissolution or release) and a relevant in vivo response , e.g., plasma drug concentration or amount of drug . USP : The establishment of a relationship between a biological property or a parameter derived from a biological property ( Cmax , AUC) produced by a dosage form, and a physicochemical characteristic (in vitro release) of the same dosage form.

77. LEVELS OF CORRELATION Based on the ability of the correlation to reflect the complete plasma level profile, which will result from administration of the given dosage form . 1 . Level A 2 . Level B 3 . Level C

78. Level A : Highest category of correlation . Linear correlation. Represents point to point correlation between in vitro dissolution time course and in vivo response time course . The major advantage of a Level A correlation is that a point to- point correlation is developed. All in vitro dissolution data and all in vivo plasma drug concentration–time profile data are used . Once a Level A correlation is established, an in vitro dissolution profile can serve as a surrogate for in vivo performance . A change in manufacturing site, method of manufacture, raw material supplies, minor formulation modification, and even product strength using the same formulation can be justified without the need for additional human studies.

79. Level B : The mean in vitro dissolution time is compared either to the mean residence time (MRT) or to the mean in vivo dissolution time . Uses the principles of statistical moment analysis . Is not a point-to-point correlation. Reason - because a number of different in vivo curves will produce similar mean residence time values. Level B correlations are rarely seen in NDAs.

80. Level C : A Level C correlation is not a point-to-point correlation . A Level C correlation establishes a single-point relationship between a dissolution parameter such as percent dissolved at a given time and a pharmacokinetic parameter of interest such as AUC and Cmax . Level C correlation is useful for formulation selection and development but has limited application . Several examples of Level C correlation are given below. 1 . Dissolution rate versus absorption rate. 2 . Percent of drug dissolved versus percent of drug absorbed. 3 . Maximum plasma concentrations versus percent of drug dissolved in vitro . 4. Serum drug concentration versus percent of drug dissolved.

81. COMPARISON OF PROFILES In vivo Data Plasma concentration time profile. Pharmacokinetic parameters. Percent drug absorbed time profile. Statistical movement analysis. In vitro Data Percent drug dissolution profile. Kinetic parameters. Percent drug dissolved time profile. Statistical movement analysis.

82. Tight junction complex Tight junction also known as occluding junction . Tight junction are composed of branching network of sealing strands , each strand acting independently from the other . The function of tight junction is to hold the cell together & also the tight junction are help to maintain the polarity of cell by preventing the lateral diffusion of integral membrane protein between apical and lateral/basal surface.

83. REFERENCES Biopharmaceutics and pharmacokinetics by D M BRAHMANKAR

84. THANK YOU