biopharmaceuticalfactorseffectingbioavailability.pptx

biopharmaceutical factors effecting bioavailability-

1. 1 Biopharmaceutical Factors Effecting Bioavailability

2. 2 TABLE OF CONTENTS CONTENTS Introduction Bioavailability Factors I n fluenc i ng A bso r pti o n a) Pharmaceutical Factors. Physicochemical properties of drug molecules Dosage Form Characteristics And Pharmaceutical ingredients b) Patient related factors.

3. Bioavailability can be defined as the fraction of administered drug that reaches the systemic circulation Pharmacokinetics Evaluate the way in which a drug interacts with various barriers within a biological system Pharmacodynamics Study of the relationship between systemic exposure of a drug and it’s biological effects on tissue Absorption can be defined as the movement of active drug (or prodrug) from the site of administration across biologic barriers into a site where it is measured in the blood. This site of measurement is not specified. Note the difference in endpoint measurement sites 3 I n tr o d u ction

4. 4 I n tr o d u ction

5. A. Pharmaceutical Factors 1. Physicochemical properties of drug substances Drug dissolution & solubility rate. Particles size & effective surface area. Polymorphism & amorphism. Solvates & hydrates. 5.salt form of drug. Ionization state. Drug pKa & lipophilicity & GI pH - pH partition hypothesis . Physicochemical properties of drug substances: A detailed study of physicochemical properties of drug molecules may help to enhance the rate as well as the extent of drug absorption. It also serve to formulate the drug in most suitable dosage form. 5 Biopharmaceutical factors effecting drug absorption:

6. A. Pharmaceutical Factors 1. Physicochemical properties of drug substances 1.Drug dissolution & solubility rate : Dissolution is the process of solubilization of a substance in a given solvent. Drug dissolution rate is the amount of drug that goes into solution per unit time under the standard conditions of temperature, pH, solvent composition and constant solid surface area. Dissolution plays a significant role as it is regarded as the rate determining step in the process of absorption. Solutions > Suspensions > Capsules > Tablets > Coated tablets. Drug in particle form 6 Drug in solution form Drug in blood stream Dissolution is rate limiting step for lipophilic drugs e.g. Griseofulvin Permeation is rate limiting step for hydrophilic drugs. e.g., Neomycin

7. A. Pharmaceutical Factors 1. Physicochemical properties of drug substances 1.Drug dissolution & solubility rate : Solubility: The quantity of drug that dissolves in the gastrointestinal fluid is indicative of vivo drug absorption. A drug is said to be undergo appreciable bioabsorption if it exhibits aqueous solubility greater than 10mg/ml at 37 ℃ and pH ranging between 1-7. When the solubility is less than 1mg/ml, it undergoes undesirable GI absorption. Thus with the aid of solubility and dissolution data, potential problems related to bioavailability and therapeutic activity of the drug can be recognized. Both solubilty and absorption can be correlated by the concept of maximum absorbable dose (MAD). 7

8. 8 A. Pharmaceutical Factors 1. Physicochemical properties of drug substances 1.Drug dissolution & solubility rate : maximum absorbable dose (MAD). Biopharmaceutics Classification Systems (BCS).

9. 9 A. Pharmaceutical Factors Physicochemical properties of drug substances Particles size & effective surface area : Smaller the particle size (by micronization i.e reduction in particle size) Greater is the effective surface area More intimate contact b/w solid surface and aqueous solvent Higher is the dissolution Rate increase in absorption efficiency Types of surface area: 1) Absolute surface area: it is the total solid surface area 2) Effective surface area: it is the solid surface area of particle exposed to the dissolution medium. In order to convert the absolute surface area to effective surface area, surfactants like polysorbate 80 or diluents like PEG, dextrose. Griseofulvin, chloramphenicol on micronization show increased absorption and decrease in therapeutic dose.

10. 10 A. Pharmaceutical Factors 1. Physicochemical properties of drug substances 3. Amorphism and Polymorphism : Amorphous forms generally dissolve faster than crystalline forms because no energy is needed to break up the crystal lattice. For this reason, the amorphous form is often preferred over the c r y stalline f orm a n d se v e r al drug s , i n c l udi n g h y d r o c ortis o ne and prednisolone , are marketed in the amorphic form. Amorphous form Crystalline form More soluble R api d l y d i sso l vi n g Readily absorbed Less soluble S l ow er disso l ving Not absorbed to significant extent The crystalline form of drugs may exist as polymorphs or molecular adducts or both.

11. 11 A. Pharmaceutical Factors 1. Physicochemical properties of drug substances 3. Amorphism and Polymorphism : Polymorphism is the ability of compound to exist in more than one crystalline form. These polymorphs may have different physical p r operti e s , su c h as dissolutio n r a t e a n d sol u bilit y . Ex: Chloramphenicol palmitate exists in three crystalline forms, form A, B, C. form B is the most soluble and therefore exhibits more bioavailability than the other forms Stable form L o w e s t e n e r g y s t a t e Highest m.pt. Least aq solubility Dissolution rate limited Metastable form Less stable form H i g h e s t e n e r g y s t a t e Lowest m.pt. H i g h er aq s o l u bi l i t y B e t t er a b s o r p t i o n a n d B i o a v a i l a b i l i t y

12. 12 A. Pharmaceutical Factors 1. Physicochemical properties of drug substances 4. Solvates & hydrates: During their preparation, drug crystals may incorporate one or more solvent molecules to form solvates. The solvent trapped is known as solvent of crystallization. The solvates may exists in varying crystalline forms known as pseudopolymorphs and the phenomenon is known as pseudo polymorphism. The molecular complex is referred as hydrates if water molecules has been reported as solvent. Anhydrous – Drug is not associated with water, monohydrate and Dihydrated – drug is associated with one and more water molecules respectively. The anhydrous form have higher energy states, higher aq solubilities, dissolves at faster rate and hence exhibit higher bioavailability. Ex: anhydrous ampicillin more soluble than their hydrous form

13. A. Pharmaceutical Factors 1. Physicochemical properties of drug substances 5. Salt form of drug: At given pH, the solubility of drug, whether acidic/basic or its salt, is a constant. While considering the salt form of drug, pH of the diffusion layer is important not the pH of the bulk of the solution. E.g. of salt of weak acid. ---Which increases the pH of the diffusion layer, which promotes the solubility and dissolution of a weak acid and absorption is bound to be rapid. 13

14. A. Pharmaceutical Factors 1. Physicochemical properties of drug substances Ionization state: Unionized state is important for passive diffusion through membrane so importan t f or absor p tio n . I on i z ed sta t e i s i m po r t a n t f or sol u bilit y . Drug pKa & lipophilicity & GI pH - pH partition hypothesis. pH – Partition theory states that drug compounds of molecular weight more than 100 daltons , which are primarily transported across the biological membrane by passive diffusion, the process of absorption is governed by - Pka of drug (Dissociation constant) The lipid solubility of unionized drug pH at the absorption site. 14

15. A. Pharmaceutical Factors 1. Physicochemical properties of drug substances 7.Drug pKa & lipophilicity & GI pH - pH partition hypothesis. Pka of drug (Dissociation constant) Amount of drug that exist in unionized form and in ionized form is a function of pKa of drug & pH of the fluid at the absorption site and it can be determined by Henderson- hesselbach equation: - pH = pKa + log [ionized form] [Unionized form] pH = pKa + log [unionized form] F o r , A cidi c dru gs F o r , Basi c dru gs [ionized form] 15

16. A. Pharmaceutical Factors 1. Physicochemical properties of drug substances 7.Drug pKa & lipophilicity & GI pH - pH partition hypothesis. 16 Drugs PKa P H / s i t e o f ab s o r p t i o n V e r y w eak a c i d s e . g . p en t o b a r b i tal Hexobarbital >8 Unionized at all pH va l u e s ; Ab s o r b ed a l o ng t h e en t i r e l en g th o f GI T M o d e r a t e l y w eak a c id s e.g. aspirin Ibuprofen 2.5 – 7.5 U nio n i z ed i n g as t ri c p H& i o n i z ed i n i n t e s t i nal p H ; b e t t er a b s o r p t i o n f r o m stomach S t r o n g er ac i d s E . g . d i s o d i u m c r o m o g y l a t e < 2.0 Ionized at all pH values; P o o r l y a b s o r b ed f r o m GIT V e r y w eak b a s es e.g. theophylline Caffeine < 5.0 Unionized at all pH va l u e s ; Ab s o r b ed a l o ng entire GIT M o d e r a t e l y w eak b a s es e.g. codeine 5 – 11 I o n i z ed at g a st ri c p H , unionized at intestinal pH; be t t er a b s or pt i o n f r o m intestine. St r o n g er b a s es e . g . guanethidine > 11 Ionized at all pH values; P o o r l y a b s o r b ed f r o m GIT

17. A. Pharmaceutical Factors 1. Physicochemical properties of drug substances 7.Drug pKa & lipophilicity & GI pH - pH partition hypothesis. b ) L i p o p hili c ity and d r ug absorption: Ideally for optimum absorption, a drug should have sufficient aq. solubility to dissolve in fluids at absorption site and lipid solubility (Ko/w) high enough to facilitate the partitioning of the drug in the lipoidal membrane i.e. drug should have perfect HLB for optimum Bioavailability. Ko/w = Distribution of drug in organic phase (octanol) Distribution of drug in aq phase As Ko/w or lipid solubility i.e. partition coefficient increases percentage drug absorbed increases. 17

18. A. Pharmaceutical Factors 2. Formulation Factors. 2] Formulation Factors Disin t eg r at io n t i me Manufacturing variables Method of granulation Compression force Nature & type of dosage form Pharmaceutical ingredients P r o d uc t a g e & s t o r a g e c o n d i t io n s 1. Disintegration time (DT): It is defined as the time taken by the solid dosage form to breakdown into smaller particles in the body after their ingestion. O r de r of disi n t eg r ation of th e so l i d dosa g e f orms: Capsules > Tablets > Coated tablets > Enteric coated tablets > sustained release tablets 18

19. A. Pharmaceutical Factors 2. Formulation Factors. Disintegration time (DT): It Harder the tablet, greater is its disintegration time. Disintegration of solid dosage forms can be enhanced by incorporating appropriate amounts of disintegrants in the formulation. 2. Manufacturing variables: Method of granulation: Wet granulation: By selecting a suitable granulating liquid , the dissolution rate of insoluble drugs can be enhanced. Direct compression: dissolution rate of tablets prepared by this method are higher than the wet granulation method. Compression force: Higher compression force yields a tablet with greater hardness and reduced wettability & hence have a long D.T. but on other hand higher compression force cause crushing of drug particles into smaller ones with higher effective surface area which in decrease in D.T. So effect of compression force should be thoroughly studied on each formulation. 19

20. 20 A. Pharmaceutical Factors Formulation Factors. Nature and type of dosage form Depending upon the nature and type of dosage form, the absorption pattern of a drug decreases in the following order So l utio n s > Emulsions > Su s pensio n s > Cap s u l es > T ablets C oa t ed tablets > Enteric coated tablets > Sustained release tablets

21. 21 N o n -A q ueou s w a t er im m iscible E. g .: V e g etable o i l, Sesame oil, P eanut oil. Aqueous E. g .: W a t e r , Syrup Non-Aqueous water miscible E. g .: P r o p y lene gl y c ol, G l y c e r ol, Sorbital. A. Pharmaceutical Factors 2. Formulation Factors. Pharmaceutical ingredients More the no. of excepients in dosage form, more complex it is & greater the potential for absorption and Bioavailability problems. Vehicle: vehicles are used in parenteral and oral liquids preparations. Rate of absorption – depends on its miscibility with biological fluid. Miscible solvents-rapid absorption of drug. Immiscible solvent-slow absorption of drug. Vehicles

22. Inorganic diluents E.g.: Dibasic calcium phosphate, Calcium carbonate. O r ganic diluents E.g.: Dextrose, Sorbitol, M an n i t ol. 22 A. Pharmaceutical Factors 2. Formulation Factors. 4. Pharmaceutical ingredients b) Diluents Diluents are added to increase the bulk of the dosage form, especially in tablets and capsules. Hydrophilic diluents-form the hydrophilic coat around hydrophobic drug particles –thus promotes dissolution and absorption of poorly soluble hydrophobic drug. Diluents

23. A. Pharmaceutical Factors 2. Formulation Factors. Pharmaceutical ingredients Binding Agents Although binders are incorporated to produce cohesive bonding between granules during the process of compaction of tablets. Hydrophilic binders are for enhancing the dissolution rate of poorly soluble drug. e.g. starch, gelatin, PVP. More amount of binder increases hardness of tablet and decrease dissolution & disintegration rate. Disintegrating Agents They are added to the tablet to disrupts the cohesive forces between the granules, thereby causing the breakdown of the tablet to attain faster dissolution. Mostly hydrophilic in nature, increase in disintegration increase the bioavailability. e.g.: Guar gum, Starch, Microcrystalline cellulose 23

24. Insoluble Lubricants E.g.: Mineral oil, Talc Soluble Lubricants E.g.: PEG 4000, PEG 6000. 24 A. Pharmaceutical Factors 2. Formulation Factors. 4. Pharmaceutical ingredients e) Lubricating Agents These agents when added to a tablet formulation decrease the friction between the granules and die wall of the tablet press. Commonly hydrophobic in nature – therefore inhibits penetration of water into tablet and thus dissolution and disintegration. Lubricant

25. A. Pharmaceutical Factors 2. Formulation Factors. Pharmaceutical ingredients Surfactants They are commonly used in the formulations as solubilizers, emulsifiers, w e t ti n g a g en t s e t c. At lower concentrations, they increase the rate of absorption of poorly water soluble drugs. Physiologic surfactants like bile salts they promotes absorption e.g.: Griseofulvin, steroids Complexing Agents T h ey inc r ease th e absor p tio n r a t e of other drug s du e t o Formation of soluble complexes which enhances the dissolution. Increased the lipophilicity which enhances membrane permeability. h) Colorants Water-soluble dyes even inleast concentrations get adsorbed on the crystal faces and delay their dissolution rate. e.g.: Brilliant blue retards dissolution of sulfathiazole. 25

26. A. Pharmaceutical Factors 2. Formulation Factors. P r odu c t a g e and s t o r a g e C ondition s : A l t e r at io n s i n s t o r a g e c on d i t io n s a n d p r olon g ed du r at io n of s t o r a g e of drug products may modify their physicochemical properties resulting in altered drug absorption patterns. B. Patient related factors: Age Gastric Emptying Intestinal Transit Diseases Ef f ect of F ood Blood Flow to GIT First pass metabolism 26

27. 27 B. Patient related factors: Age: Absorption pattern of drugs may vary among different age groups. Infant have less acidic G.I fluids, smaller intestinal surface area and comparatively less blood flow than adults. Intestinal surface area and blood flow, bacterial overgrowth in small intestine, altered gastric emptying, retard the drug absorption Gastric Emptying: Gastric emptying is the entry of gastric content into the small intestine. Gastric emptying rate: It is the rate at which gastric contents empty into the small intestine. Gastric emptying time: It is the time required for gastric content to empty into the small intestine. Rapid Gastric Emptying is required when the consumed drugs Are unstable in gastric pH (Penicillin G) Are better absorbed from the small intestine (Vit B 12 ) Delayed Gastric Emptying is required when The drug (Griseofulvin) dissolves slowly. Food enhances the dissolution and absorption of drugs.

28. B. Patient related factors: 3) Intestinal Transit: The residence time of foodor drug substance in intestine is known as intestinal transit time. As small intestine is major site of absorption longer or delayed transit time is required for the complete absorption of drugs Delayed intestinal transit is recommended for those drugs which Exhibits sustained release action.(Diclofenac sodium) Are enteric coated and hence dissolves only in the intestine. 4) Diseases: GI Diseases and Infections Drug absorption may be influenced by several pathophysiological conditions of GIT. Malabsorption syndrome like celiac disease and Chrons disease. Gastrointestinal Surgery. Gastrointestinal surgery especially gastrectomy may cause drug dumping in the intestine. 28

29. B. Patient related factors: 5) Effect of Food: The presence of food in the GI tract can affect the bioavailability of the drug from an oral drug product. Food contain amino acids, fatty acids, and many nutrients that may affect intestinal pH and solubility of drugs. The effects of food are not always predictable and can have consequences. Some effects are: Delay in gastric emptying Stimulation of bile flow A change in the pH of the GI tract A change luminal metabolism of the drug substance Physical or chemical interaction of the meal with the drug product or drug substance The absorption of some antibiotics, such as penicillin and tetracycline, is decreased with food; whereas other drugs, particularly lipid-soluble drugs such as griseofulvin and metazalone, are better absorbed when given with food containing a high fat content. 29

30. B. Patient related factors: Blood Flow to GIT: Increase in the blood flow to the site of absorption (GIT), increases the drug absorption as rapid removal of drug from its absorption site helps to maintain sink conditions. First pass metabolism: A drug administered orally, passes through the GIT and liver where it undergoes extensive metabolism before reaching the systemic circulation, thereby leading to decreased bioavailability, this phenomenon is called as first pass metabolism. Drug (Administered Orally) Destroyed in the gut Unabsorbed drug Destroyed in the gut wall Destroyed by the liver Reaches the systemic circulation 30

31. 31 R e ferences: 1) Brahmankar D.M., Jaiswal S.B., First edition, “Absorption of Drugs” Biopharmaceutics and Pharmacokinetics – A treatise, Vallabh Prakashan, Delhi 1995, Page No. 5-75.