Drug Absorption Mechanism and Factors.pptx

Mechanisms of drug absorption as Transport models, Biopharmaceutical processes curves, PHYSICO-CHEMICAL FACTORS, and factors affecting the absorption

1. Mechanisms of Drugs Absorption By: Dr . Rameshwar Dass Guru Gobind Singh College of Pharmacy, Yamuna Nagar

2. Drug Absorption from GI Tract Gastrointestinal tract, Mechanism of drug absorption, Factors affecting drug absorption, pH–partition theory of drug absorption. Formuulation and physicochemical factors: Dissolution rate, Dissolution process, Noyes–Whitney equation and drug dissolution Factors affecting the dissolution rate 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

3. Drug Absorption from GI Tract Transport model : Permeability-Solubility-Charge State The pH Partition Hypothesis, Properties of the Gastrointestinal Tract (GIT), pH Microclimate Intracellular pH Environment Tight-Junction Complex

4. Transport model It show the relationship between ionization constants, solubility, and permeability as a function of pH, using the Fick ’ s laws of diffusion. a vessel divided into two chambers, separated by a homogeneous lipid membrane DONOR CELL RECEPTOR CELL D D D D D D D D D D D D D D D D dC m/dx = (Cmo – C mh) /h Cmo Cmh D MEM/W = C mh / C R D MEM/W = CmO / CD CD C R

5. Transport model DONOR CELL RECEPTOR CELL D D D D D D D D D D D D D D D D dC m/dx = (Cmo – C mh) /h Cmo Cmh J = Dm dCm/dx = D m (Cmo – Cmh)/h = Dm D MEM/W (C D – C R ) / h = Pe (C D – C R ) D MEM/W = C mh / C R D MEM/W = CmO / C D C D C R J = the flux Dm = membrane diffusivity Cmo and Cmh = conc , of the uncharged solute within the membrane at the two water - membrane boundaries At positions x = 0 and x = h in Figure, where h is the thickness of the membrane dCm / dx , within the homogeneous membrane is linear, replaced by Dm (Cmo – Cmh)/h

6. Transport model The distribution coefficients between bulk water and the membrane, log D MEM/W The pH - dependent apparent partition coefficient, J = Dm. D MEM/W (C D -C R )/h ---- (2.2) where the substitution of D MEM/W , Dm, and h, by ( Pm= Dm D mem /w /h) At sink ” conditions, where C R = 0, J =Pm.C D Flux (J) depends on the product of membrane permeability of the solute times the concentration of the solute The intrinsic permeability does not depend on pH, but its cofactor in the flux equation, C = the concentration of the uncharged species is always equal to or less than the intrinsic solubility ( S ) J =P C ≤ P S --- 2.5

7. Transport model Example: Log flux – pH profiles at dosing concentrations: Ketoprofen (acid, p Ka 3.99), verapamil (base, p Ka 9.06), piroxicam (ampholyte, p Ka 5.17). The permeability and the concentration of the uncharged species are denoted P0 and C0 J = Dm dCm/dx = D m (Cmo – Cmh)/h ------------ 2.1 = Dm D MEM/W (C D – C R ) / h = Pe (C D – C R )

8. Drug Absorption The process of movement of unchanged drug from the site of administration to the systemic circulation Or The process of movement of unchanged drug from the site of administration to the site of measurement. i.e., plasma.

9. Plasma Drug Concentration versus Time Curve Time ( Hrs ) Plasma Concentration Elimination Phase Duration of Action Area Under Curve Onset of action T max C max Absorption rate = Elimination rate MSC (Max. Safe Conc.) MEC (Min. Effective Conc. ) Therapeutic Range Absorption phase Post Absorption phase X- axis Y- axis termination of action Plasma drug concentration versus Time curve

10. Plasma Membrane Channels proteins

11. Biopharmaceutical Process of Drug Absorption Drug in Dosage form Drug particles in GIT fluid Drug in soluble form Absorption of Drug Dissolution Disintegration Drug Excretion Drug in central compartment GIT Drug in bound & free form Distribution Drug in peripheral tissues Drug Response

12. Flow Diagram of Biopharmaceutical Process of Drug Absorption Tablet Distribution Excretion of drug Metabolism Response Drug in Circulation

13. Mechanisms of Drug Absorption Passive diffusion Pore Transport Ionic or Electrochemical diffusion Ion-pair transport Endocytosis Carrier- mediated transport: Active diffusion Facilitated diffusion

14. Passive Diffusion The spontaneously process of drug diffusion according to concentration gradients. Characteristics: Drug moves from higher to lower conc. Transfer rate α to concentration gradient Equilibrium is achieved when conc. equal on both side of membrane. If drug ionizable then only unionizable drug moves. Greater the partition coefficient higher the absorption of drugs.

15. Passive Diffusion Mathematical expression : Fick’s first law of diffusion Where, dQ/dt = rate of drug diffusion (mass/time), D = diffusion coefficient of the drug through the membrane (area/time) A = surface area of the membrane through which drug diffusion is taking place (area), Km/w = Partition coefficient of the drug between the lipoid membrane and the GI-fluids (no units). Several factors influence the passive diffusion of the drug: The degree of lipid solubility of the drug (Km/w ) i.e. large value of Km/w, highly lipid soluble drug and hence has higher rate of transport. Surface area of the membrane ( A )

16. Carrier Mediated Transport The passage of polar molecules like glucose, amino acids, through the cell membrane is carry out by carrier proteins in the membrane. Characteristics: Structure specific : bind drug reversibly. Competition: no. of carriers are limited and show competition between same chemical structure drug. Saturation : due to limited no. of carriers are show capacity limited. Concentration gradient Absorption: Drug move from the side of higher to the side of lower concentration by means of membrane carriers. Energy requirement : Cellular energy is not required. Example vitamins like B 1 , B 2 and B 12

17. Active Transport Relatively unusual. Absorption occurs against concentration gradients Requires specific carrier Structure Specific Saturable/ capacity limited Expenditure of energy Inhibited by metabolic poisons : like F, cyanide and dinitrophenol and lack of oxygen Example : Iron ,K , Na , Ca, uptake of levodopa by brain, Certain amino acids and Vitamins like niacin, pyridoxine and ascorbic acid.

18. Facilitated Diffusion It is also a carrier mediated transport system but it moves along a concentration gradient (i.e. from higher to lower concentration) and hence it does not require any energy . A carrier mediated transport system Saturable and structurally selective for a drug and shows competition kinetics for drugs having similar structures Does not require any energy expenditure Diffusion of ions takes place through proteins embedded in the plasma membrane, Some types of gated ion channels: ligand-gated mechanically-gated voltage-gated light-gated Example : Acetylcholine (ligand) binds to certain synaptic membrane and opens Na + channels and initiate a nerve impulse.

19. Vesicular Transport Vesicular transport is the process of engulfing particles or dissolved materials by the cell. two types of vesicular transport : Pinocytosis refers to the engulfment of small solutes or fluid. Phagocytosis refers to the engulfment of larger particles or macromolecules, generally by macrophages. Endocytosis and exocytosis are the processes of moving macromolecules into and out of a cell, respectively. e.g. Vesicular transport is the proposed process for the absorption of orally administered Sabin polio vaccine and large proteins. Transport of proteins, polypeptides like insulin from insulin producing cells of the pancreas into the extracellular space.

20. Assignment Flow diagram of absorption process. Table for Mechanism of drug absorption with their characteristics and examples.

21. Thank You

22. FACTORS INFLUENCING ABSORPTION Mr. Rameshwar Dass Guru Gobind Singh College of Pharmacy, Yamuna Nagar

23. Drug Absorption from GI Tract Gastrointestinal tract, Mechanism of drug absorption Factors affecting drug absorption, pH–partition theory of drug absorption. Formuulation and physicochemical factors: Dissolution rate, Dissolution process, Noyes–Whitney equation and drug dissolution Factors affecting the dissolution rate 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

24. FACTORS INFLUENCING ABSORPTION

25. PHYSICO-CHEMICAL FACTORS Drug solubility and dissolution rate and process Particle size and effective surface area Polymorphism and amorphism Pseudopolymorphism (hydrates / solvates) Salt form of the drug Lipophilicity of the drug – (pH partition hypothesis) pKa of the drug and pH – (pH partition hypothesis) Drug stability

26. PHYSIOLOGICAL FACTORS relating to the anatomic, physiologic and pathologic characteristics of the patient. Age Gastric emptying time Intestinal transit time Gastrointestinal pH Disease states Blood flow through the GIT Gastrointestinal contents: a) Other drugs b) Food c) Fluids d) Other normal GI contents Pre-systemic metabolism by a) Luminal enzymes b) Gut wall enzymes c) Bacterial enzymes d) Hepatic enzymes

27. PHARMACEUTICAL FACTORS Disintegration time (tablets / capsules) Dissolution time Manufacturing variables Pharmaceutical ingredients ( excipients / adjutants) Nature and type of dosage form Product age and storage conditions

28. PHYSICOCHEMICAL FACTORS Drug solubility and dissolution rate Dissolution : the process of solute molecules mixing with solvent molecules and can be studied mathematically as a rate process. Solubility is the extent to which a drug dissolves in a given solvent at a given temperature Poorly water- soluble : dissolution is the rate controlling step for the absorption ( dissolution rate limited) e.g. griseofulvin , spironolactone . Highly water-soluble: drugs dissolution is rapid, rate determining step is permeation for the absorption ( permeation rate limited) e.g., cromlyn sodium, neomycin sulfate etc.  

29. Dissolution Rate and Process Tablet Capsule Or Disintegration Disaggregation Granules Very fine particles Permeation rate limiting Drug in Solution form Drug absorption ------------ Dissolution In-vitro Or In-vivo ------------ Plasma membrane Rate limiting step Hydrophobic drug Hydrophilic drug

30. Factors affecting Dissolution Rate and Process Physicochemical Properties of Drug Drug Product Formulation Processing Factor Dissolution Apparatus Dissolution Test Parameters

31. Particle size and effective surface area of the drug particles From Noyes-Whitney’s equation of dissolution: where, D= diffusion coefficient or diffusivity of the drug molecule A= surface area of the dissolving solid exposed to the dissolution medium K O/W = water/oil partition coefficient of the drug V= volume of dissolution medium h= thickness of the stagnant layer Cs – C B = concentration gradient of the diffusing drug molecule . Two types of surface area: Absolute surface area : the total area of solid surface of any particle. Effective surface area: surface area exposed to the dissolution medium. e.g. Micronization of poorly water soluble drugs like griseofulvin , chloramphenicol and several salts of tetracycline results in superior dissolution rates.

32. Limitation of Particle size In case of hydrophobic drugs results in a decrease in effective surface area due to the following reasons. Absorb air onto their surface –inhibit their wet-ability, (powders float on the dissolution medium) Re-aggregate to form larger particles –high surface free energy. Impart surface charges (extreme particle size reduction) –prevent wetting; due to reduce contact of the drug with the dissolution medium. Example: aspirin, phenacetin and phenobarbital micronization

33. Polymorphism and Amorphism Based on the internal structure, a solid can exist either in Crystalline Amorphous When, a substance exists in more than one crystalline form, ( polymorphs ) and the phenomenon as polymorphism . Polymorphs can be prepared by crystallizing the drug from different solvents under diverse conditions. Stable polymorph Lowest energy state, has Highest melting point and Least aqueous solubility.

34. Meta-stable Forms Higher energy state Unstable form Higher aqueous solubility Higher bioavailability Metastable forms of the drug convert into less soluble, stable polymorph Chloramphenicol palmitate has three polymorphs A, B and C. The B -form shows best bioavailability and A form is virtually inactive biologically. Polymorphic form-III of riboflavin is 20 times more water soluble than the form-I. More soluble crystalline form-III of cortisone acetate converts to less soluble form-V in an aqueous suspension resulting in caking of solid.

35. Amorphous form (super-cooled liquids) Having no internal structure Drugs represents the highest energy state and They have greater aqueous solubility than their crystalline form. Example : The amorphous form of the Novobiocin is 10 times more soluble than the crystalline form. The order for dissolution of different solid forms of drug is Amorphous > Metastable > Stable .

36. Pseudopolymorphism Hydrates Solvates Solvent molecules into the crystal lattice of the solid in stoichiometric proportion –(solvates) and the solvent molecules is known as solvent of crystallization. The solvates again may be in different polymorphic states, called as pseudopolymorphs & phenomenon is called as pesudopolymorphism . When the solvent is water, known as hydrate . During crystallization solvent Hydrates/ Solvates

37. Pseudopolymorphism Effect of absorption of solvent in crystal : Anhydrous has greater solubility than the hydrates the hydrates are already in equilibrium with water and have less demand for water. Example : anhydrous form of theophyline and ampicillin have higher aqueous solubilities , dissolve at faster rate and show better bioavailability in comparison to their monohydrates and trihydrate forms respectively. Nonaqueous solvates have greater aqueous solubility than the nonsolvates . Example : n- pentanol solvate of fludricortisone and succinyl sulfathiazole and the chloroform solvates of griseofulvin are more water soluble than their non-solvate forms.

38. Salt form of the drug Most drugs are either weak acids or weak bases. The solubility and dissolution rate of drugs increases with their salt forms. Weak acid is more soluble in basic pH and Weak base is more soluble in acidic pH by the formation of salt. Example : in-situ salt formation in drugs like aspirin and penicillin are prepared as buffered alkaline tablets (buffered aspirin tablets). Reduce the gastric irritation and ulcerogenic tendency of the drug Drug in dry form have better stability (less hydrolytic) Increased bioavailability by escalating the dissolution. Smaller the size of the counter ion (of the salt form of a drug) greater the solubility of the salt. e.g. bioavailability of novobiocin from its Na, Ca, free acid

39. pKa of the drug and pH Drug pKa and lipophilicity (pH partition theory by Brodie et.al.) It states that drug compounds of molecular weight >100, which are primarily absorbed by passive diffusion. The process is governed by Dissociation constant (Ka) Lipid solubility of the unionized drug ( K o /w ) The pH at the absorption site  The above statement of the hypothesis was based on the assumptions that: The GIT is simple lipoidal barrier to the transport of drug. Larger the fraction of unionized drug, faster the absorption. Greater the lipophilicity (K o/w ) of the unionized drug, better the absorption.

40. pKa of the drug and pH Henderson-Hasselbalch equation For weak acid For weak base

41. pKa of the drug and pH Drugs pKa pH at the site of absorption Very weak bases Theophyline Caffeine Oxazepam Diazepam (pKa < 5.0) 0.7 0.8 1.7 3.7 Unionized at all pH values: absorbed along the entire length of GIT. Moderately weak bases Reserpine Heroin Codeine Amitriptyline (5 < pKa < 11) 6.6 7.8 8.2 9.4 Ionized at gastric pH, relatively unionized at intestinal pH better absorbed from intestine. Stronger base Mecamylamine Guanethidine (pKa > 11.0) 11.2 11.7 Ionized at all pH values: poorly absorbed form GIT.

42. PHYSIOLOGICAL FACTORS Physiology of GIT Stomach It is a bag like structure having a smooth mucosa and thus small surface area. Its acidic pH, due to its secretion of HCl , It favors absorption of weakly acidic drugs like aspirin. pH=1-3 HCl weakly acidic drugs smooth mucosa Small SA bag like structure

43. PHYSIOLOGICAL FACTORS Small intestine It have fold of Kerckring that increase in SA, 3 fold . It possess finger like projections as villi , increases the SA 30 times. The villi protrude several microvilli resulting in 600 times increase in S.A. All these combined to impart a large surface area of more than 200 sq.m . The blood flow is 6 – 10 times more than stomach. pH range is 5 to 7.5 The peristaltic movement of intestine is slow, transit time is long, and penetrability is high. Note: All this factors make intestine the best site for absorption of most drugs. SA 3 SA 30 SA 200 sq.m . pH = 5 to 7.5

44. PHYSIOLOGICAL FACTORS Large intestine Its length and mucosal surface area is very small ( villi and microvilli are absent) compared to small intestine The absorption of drug from this region is very small. It have the long residence time (6 to 12 hrs), It helps in the absorption of some poorly soluble drugs and sustained release dosage forms.

45. GIT parts pH Membrane Blood Supply Surface Area Transit Time By-pass liver Buccal approx 6 thin Good, fast absorption with low dose small Short unless controlled yes Esophagus 6 Very thick, no absorption - small short - Stomach 1 – 3 Normal Lipophilic , acidic and neutral drugs good small 30 - 40 minutes, reduced absorption no Duodenum 5 – 7 Normal Mainly lipohilic and neutral drugs good large very short (6" long) no Small Intestine 6 -7 Normal All types of drugs good very large 10 - 14 ft, 80 cm 2 /cm about 3 hours no Large Intestine 6.8 - 7 - good not very large 4 - 5 ft long, up to 24 hr lower colon, rectum yes

46. Patient related factors Age In infants gastric : pH is high intestinal surface is small blood flow is less. In elderly persons : Altered gastric emptying Decreased intestinal surface area Decreased GI blood flow Achlorhydria Bacterial overgrowth in small intestine. Note: In both of these age drug absorption is impaired.

47. Gastric Emptying Rapid gastric emptying: Rapid onset of action is required e.g. sedatives. Drug dissolved in the intestine e.g. enteric coated tablets Drugs are unstable in gastric fluid e.g. penicillin-G and erythromycin. Drug is best absorbed from small intestine e.g. vitamin B 12 Delay in gastric emptying : Food promotes drug dissolution and absorption e.g. griseofulvin Disintegration and dissolution of dosage form is promoted by gastric fluid Drugs are absorbed from the proximal part of the small intestine e.g. vitamin B 2 and vitamin C Passage of content from stomach to small intestine Note: vivo gastric emptying can be studied by using radio-opaque materials (e.g. BaSO 4 )

48. Effect of Meal 1. Volume of meal : Larger the volume of meal longer the gastric emptying time. 2. Composition of meal : The rate of gastric emptying for various food materials is in the following order: carbohydrates > protein > fats 3. Physical state and viscosity of meal : Liquid meals take less than an hour to empty solid meals take as long as 6 – 7 hours to empty. Viscous material empty at a slow rate in comparison to less viscous materials. 4. Temperature of the meal : High or low temperature of the ingested fluid (compared to body temperature) reduce gastric emptying rate. 5. Gastrointestinal pH : Gastric emptying is retarded at low stomach pH and is promoted at higher or alkaline pH.

49. Effect of Meal 6. Electrolyte and osmotic pressure : Water, isotonic, and solutions of low salt concentration empty the stomach rapidly whereas higher electrolyte concentration decreases gastric emptying rate. 7. Body posture : Gastric emptying is favoured while standing and while lying on the right side; while lying on the left side or in supine position retards it. 8. Emotional state : Stress and anxiety promote gastric motility whereas depression retards it. 9. Exercise : Vigorous physical exercise retards gastric emptying. 10 Disease states : Diseases like gastroenteritis, gastric ulcer, pyloric stenosis , diabetes and hypothyroidism retard gastric emptying. 11. Drugs : Drugs that retard gastric emptying includes ( i ) poorly soluble antacids e.g. aluminium hydroxide

50. Effect of GI pH on drug absorption Disintegration: The dosage forms have pH sensitive. With enteric coated formulations, the coat dissolves only in the intestinal pH Dissolution : the drugs are either weakly acidic or weakly basic whose solubility is greatly affected by pH. A pH that favours the formation of salt of the drug enhances the dissolution rate. e.g. Weakly acidic drugs dissolve rapidly in the alkaline pH Absorption : Depending upon the pKa of the drug and the pH of the GI fluid some drug remain in ionized state and some in unionized state, absorbed quickly than the ionized form. Stability : GI pH influences stability of drugs. e.g. The acidic stomach pH is known to affect degradation of Penicillin-G and erythromycin.

51. Effect of GI content A number of GI contents can influence drug absorption. Food-drug interaction: Presence of food may either The drugs are better absorbed under fasting conditions and presence of food retards or prevents it. Food does not significantly influence absorption of a drug taken before half an hour/two hrs after meals Delayed or decrease drug absorption by food can be due to: Delayed gastric emptying, drugs unstable in the stomach e.g. penicillin, erythromycin. Preventing the transit of enteric tablets into the intestine Formation of poorly soluble complex e.g. tetracycline-calcium complex. Increased viscosity due to food thereby preventing drug dissolution. Delayed Decreased Increased Unaffected Aspirin Penicillins Griseofulvin Methyldopa Paracetamol Erythromycin Diazepam Sulfasomidine Diclofenac Tetracyclines Levodopa , Iron

52. Drug-drug interaction Drug-drug interactions can be either physicochemical or physiological. (a) Physicochemical drug-drug interactions can be due to –   Adsorption : Antidiarrheal preparations containing adsorbents like k aolin-pectin retard / inhibit absorption of promazine and lincomycin . Complexation : Antacids containing heavy metals such as aluminium , calcium, iron, retard absorption of tetracyclines due to the formation of complexes. pH change : Basic drugs dissolve in gastric pH. Co-administration of sodium bicarbonate with tetracycline increase stomach pH and hence decreases dissolution rate

53. Drug-drug interaction (b) Physiologic interaction can be due to following reasons: Decreased GI transit : Anticholinergic drugs such as propantheline retard GI motility and promote absorption of drugs like ranitidine and digoxin . Increased gastric emptying : Metoclopramide promotes GI motility and enhances absorption of tetracycline, pivampicillin , levodopa etc. Altered GI metabolism : Antibiotics inhibit bacterial metabolism of drugs e.g. erythromycin enhances efficacy of digoxin by this mechanism.

54. Presystemic metabolism / First pass effects The loss of drug through biotransformation by GIT and liver before enter into systemic circulation in called First pass or presystemic metabolism . The 4 primary systems which affect presystemic metabolism of drugs are: Lumenal enzymes Gut wall enzymes /mucosal enzymes Bacterial enzymes, and Hepatic enzymes

55. Presystemic metabolism / First pass effects Lumenal enzymes The enzymes from intestinal and pancreatic secretions. Pancreatic enzymes contains hydrolases , ester drugs like chloramphenicol palmitate . Peptidases split amide ( –CONH) linkages break protein /polypeptide drugs.   Gut-wall enzymes (also called mucosal enzymes) They are present in stomach, intestine and colon. Alcohol dehydrogenase (ADH) inactivates ethanol.   Bacterial enzymes The colonic microbes generally render a drug more active or toxic on biotransformation:e.g . sulfasalazine (used in ulcerative colitis) is hydrolyzed to sulfapyridine and 5-amino salicylic acid. Hepatic enzymes : example: isoprenaline , propranolol , alprenolol , pentoxyfylline , nitroglycerin, diltiazem , nifedipine , lidocaine , morphine etc

56. PHARMACEUTICAL FACTORS Disintegration time It is importance in case of solid dosage forms like tablets and capsules. Rapid disintegration is thus important in the therapeutic success of a solid dosage form. It increases with increasing the amount of binder in tablet. Disintegration improved by using disintegrants in suitable amounts in formulation

57. Manufacturing / process variables Dissolution from a solid dosage form depends on: Excipients Manufacturing process

58. Excipients A drug is rarely administered in its original form. All dosage forms contains a number of suitable excipients (non-drug components of a formulation). (a) Vehicle Vehicle or solvent system that carries a drug is the major component of liquid orals and parenterals . The three categories of vehicles generally used are: ( i ) aqueous vehicles e.g. water, syrup etc. (ii) nonaqueous but water miscible e.g. propylene glycol, glycerol, sorbitol . (iii) nonaqueous and water immiscible vehicle e.g. vegetable oils. Bioavailability of a drug from vehicle depends, to a large extent, on its miscibility with biological fluids. Aqueous and water miscible vehicles are rapidly miscible with body fluids and drugs are rapidly absorbed from them. Propylene glycol, glycerol etc. are used as co-solvent to increase the solubility of a drug in water. such as Tween 80 are used to promote solubility

59. Excipients b) Binders and granulating agents Are used to hold powders together to form granules or promote cohesive compacts for directly compressible materials and ensure that the tablet remains intact after compression. Large amount of binders increase hardness and thus decrease disintegration / dissolution rates of tablets. Non-aqueous binders like ethyl cellulose also retard dissolution. c) Diluents (Fillers): Diluents are commonly added to tablet (and capsules) Hydrophilic diluents are starch, lactose, microcrystalline cellulose etc. These hydrophilic powders forms a coating over the hydrophobic drugs particles (e.g. spironolactone and triamterene ) and rendering them hydrophilic. Inorganic diluents like dicalcium phosphate (DCP) forms divalent calcium-tetracycline complex which is poorly soluble in water and thus unabsorbable .

60. Excipients d) Disintegrants Overcome the cohesive strength of tablet and break them up on contact with water. The disintegrants are hydrophilic in nature. A decrease in the amount of disintegrant can significantly lower the bioavailability.   e) Lubricants In tablet formulations to aid flow granules, to reduce interparticular friction and to reduce sticking or adhesion of particles to dies and punches. The commonly used lubricants are hydrophobic in nature ( stearates and waxes). They reduce the wettability of particle surface, penetration of water into tablet. Soluble lubricants like sodium lauryl sulphate and carbowax which promotes drug dissolution.

61. Excipients f) Suspending agents /Viscosity building agents Agents like vegetable gums (acacia, tragacanth etc.), semisynthyetic gums ( carboxy methyl cellulose, methyl cellulose) and Synthetic gums which reduces the sedimentation rate of a suspension The macromolecular gums often form unabsorbable complex with amphetamine. An increase in viscosity by these agents acts as a mechanical barrier to the diffusion of drug from the dosage form into the bulk of GI fluids.  

62. Excipients G) Surfactants Widely used in formulations as wetting agents, solubilizers , emulsifiers, etc. Surfactants increase the absorption of a drug by the following ways: Promotion of wetting (through increase in effective surface area) and dissolution of drugs e.g. Tween80 with phenacetin . Better membrane contact of the drug for absorption Enhanced membrane permeability of the drug . Decreased absorption of drug in the presence of surfactants has been suggested to be due to : Formation of unabsorbable drug-micelle complex at surfactant concentrations above critical micelle concentration. Laxative action induced by a large surfactant concentration.

63. Excipients i ) Complexing agents : to enhance drug bioavailability are: Enhanced dissolution through formation of a soluble complex e.g. ergotamine-caffeine complex, hydroquinone- digoxin complex. Enhanced lipophilicity for better membrane permeability e.g. caffeine-PABA complex (PABA = para amino benzoic acid) and Enhanced membrane permeability e.g. enhanced GI absorption (normally not absorbed from the GIT) in presence of EDTA (ethylene diamine tetraacetic acid) which chelates Ca ++ and Mg ++ ions of the membrane.  Disadvantages of complexation :- Complexation may produce poorly absorbable drugs complexes e.g. tetracycline with calcium (milk, antacids), iron ( hematinics ), magnesium (antacids) and aluminium (antacids). Large molecular size of drug-protein cannot diffuse through the cell membrane.

64. Excipients j) Colorants Even a very low concentration of water-soluble dye can have an inhibitory effect on dissolution rate of several crystalline drugs. The dye molecules get adsorbed onto the crystal faces and inhibit drug dissolution – e.g. brilliant blue retards dissolution of sulphathiazole . Dyes have also been found to inhibit micellar solubilizaion effect of bile acids which may impair the absorption of hydrophobic drugs like steroids.

65. Manufacturing Processes Method of granulation and Compression force Intensity of packing of capsules Method of granulation The wet granulation process is the most conventional technique of manufacturing tablet granules. The limitation of this method include – Formation of crystal bridge due to the presence of solvent, The liquid may act as medium for chemical reactions such as hydrolysis , and the drying may harm the thermolabile drugs. It includes greater number of steps than dry granulation or direct compression which can adversely affect the dissolution.

66. Manufacturing Processes b) Compression force The force applied in tableting process influence density, porosity, hardness, disintegration time and dissolution. The curve obtained by plotting compression force versus rate of dissolution can take one of the 4 possible shapes shown in the figures:

67. Manufacturing Processes b) Compression force A. Higher compression force   density and hardness of tablet  porosity, hence penetrability of the solvent into the tablet  wettability by forming a firmer and more effective sealing layer by the lubricant B. Higher compression force  causes deformation, or fracture of drug particles into smaller ones or convert a granules into a disc shaped particle with large increase in effective surface area   in dissolution rate C and D are combination of both the causes of A and B. In short, the influence of compression force on the dissolution is difficult to predict

68. Density packing in capsule Packing density in case of capsule can either inhibit or promote dissolution. Diffusion of GI fluids into the tightly filled capsules creates a high pressure within the capsule results in rapid bursting and dissolution of contents. In some cases capsules with tight packing Pore size of the compact mass is decreased Poor penetrability of GI – fluid Poor rate of drug release

69. NATURE AND TYPES OF DOSAGE FORM The order of bioavailability of a drug from various dosage forms: Solution > Emulsions > Suspensions > Capsules > Tablets > Coated tablets > Enteric coated tablets > Sustained release tablets . Thus, absorption of a drug from solution is fastest whereas absorption from sustained release product is lowest with greatest bioavailability.

70. Tissue Permeability of Drugs Two major rate-determining steps in the distribution are: Rate of blood perfusion Rate of tissue permeability If the blood perfusion is high then permeability will be the rate limiting step in the process of distribution. The tissue permeability of a drug depends upon the Physicochemical properties Physiological barriers.

71. Tissue Permeability of Drugs Physicochemical properties : Mol. Wt.: less than 500 to 600 Daltons easily cross the capillary membrane to diffuse into the extracellular fluid (ECF). Ionization : cannot penetrate the lipoidal cell membrane and tissue permeability is the rate determining step. e.g. penicillins are polar, and ionized at plasma pH, hence does not cross the blood-brain-barrier. Physiological barriers : Simple capillary endothelial barrier Simple cell membrane barrier Blood-Brain-Barrier (BBB) Cerebro Spinal Fluid Barrier (CSF Barrier) Placental Barrier Blood-Testis Barrier