Biopharmaceutics. Lec: 4

Transcription

1 64 Biopharmaceutics Physicochemical Properties of Drugs Affecting Bioavailability Lec: 4 1 Assist. Lecturer Ali Yaseen Ali BSc Pharmacy MSc Industrial Pharmaceutical Sciences Dept. of Pharmaceutics School of Pharmacy University of Sulaimani

2 Biopharmaceutics Physicochemical properties Bioavailability (Rate & Extent) Dosage form Route of Administration 2

3 Overview Physicochemical Factors 3 Dissolution rate Dissolution rate and Noyes-Whitney equation Physiological Factors affecting Dissolution Rate Drug Factors affecting dissolution rate Factors affecting Concentration in the GIT after dissolving Poorly soluble drugs Dissociation of the drug molecules (pka) ph-partition hypothesis Lipid solubility Molecular size and hydrogen bonding

4 Dissolution Rate The process of dissolving is dissolution This process has a certain rate over time called dissolution rate 4

5 Dissolution rate: Noyes-Whitney equation dm/dt= D A (C s -C)/h 5

6 dm/dt = D A (Cs-C) /h dm/dt: rate of dissolution of drug particles D: diffusion coefficient of drug in solution in GIT fluids A : effective surface area of the drug particles in contact with GIT fluids h: thickness of the diffusion layer around each drug particle C s : is the saturation solubility of the drug in solution in the GIT fluids C: the concentration of the drug in the gastrointestinal fluids. 6

7 Overview Physicochemical Factors 7 Dissolution rate Dissolution rate and Noyes-Whitney equation Physiological Factors affecting Dissolution Rate Drug Factors affecting dissolution rate Factors affecting Concentration in the GIT after dissolving Poorly soluble drugs Dissociation of the drug molecules (pka) ph-partition hypothesis Lipid solubility Molecular size and hydrogen bonding

8 Physiological Factors affecting Dissolution Rate The environment of the gastrointestinal tract can affect the parameters of the Noyes- Whitney equation and hence the dissolution rate of a drug. 8

9 Physiological Factors affecting Dissolution Rate The diffusion coefficient, D, of the drug in the gastrointestinal fluids may be decreased by the presence of substances that increase the viscosity of the fluids. dm/dt= D A (C s -C)/h 9

10 Food in the GIT Food may cause a decrease in dissolution rate of a drug by reducing the rate of diffusion of the drug molecules away from the diffusion layer surrounding each undissolved drug particle. dm/dt= D A (C s -C)/h 10

11 Surfactants Surfactants in gastric juice and bile salts Wettability of the drug, and hence the effective surface area, A, exposed to gastrointestinal fluids solubility of the drug in the gastrointestinal fluids via micellisation. dm/dt= D A (C s -C)/h 11

12 Motility The thickness of the diffusion layer, h, will be influenced by the degree of agitation experienced by each drug particle in the GIT. This is can be seen by the GI motility both gastric and intestine. dm/dt= D A (C s -C)/h 12

13 Overview Physicochemical Factors 13 Dissolution rate Dissolution rate and Noyes-Whitney equation Physiological Factors affecting Dissolution Rate Drug Factors affecting dissolution rate Factors affecting Concentration in the GIT after dissolving Dissociation of the drug molecules (pka) Lipid solubility Chemical stability and complexation potential

14 Drug Factors affecting dissolution rate 1. Particle size & wettability 2. Solubility 3. Form of the drug a) Salt or free b) Crystalline or amorphous 14

15 1. Particle size and Wetability Surface area is increased by particle size reduction (micronisation ) dm/dt= D A (C s -C)/h Increase in the surface area will increase the rate of dissolution Provided that all the particles are intimately wetted by GIT fluids Dissolution rate limited drugs, particle size reduction ( increase A) is likely to increase bioavailability of the drug. 15

16 Example Griseofulvin: classic example of which particles size reduction increases its bioavailability. Many poorly soluble drugs or slowly dissolving drugs are presented in micronised form to improve their dissolution profile. 16

17 Other Examples 17

18 Does micronisation has problems? I. Hydrophobic drugs (poorly water soluble) II. Unstable drugs in the GIT 18

19 I. Hydrophobic drugs: Micronisation might result in aggregation of particles to form bigger particles hence reduce surface area. E.g. Aspirin, Phenobarbitals 19

20 Solving the problem The problem of aggregation can be solved by : A. Micronisation in the presence of wetting agent or hydrophilic carrier A. E.g. danazol, bioavailability increased by 400% B. Addition of wetting agent to the formulation E.g. Polysorbate 80 added to aqueous suspension of phenacetin, improved rate and extent of absorption. 20

21 II. Chemical degradation Some drugs are unstable in stomach acid. Erythromycin and Pen G Particle size reduction will increase their dissolution rate Also increases destruction of drugs 21

22 Drug Factors affecting dissolution rate 1. Particle size & wettability 2. Solubility 3. Form of the drug a) Salt or free b) Crystalline or amorphous 22

23 Intrinsic Solubility C s Under sink conditions according to the Noyes-Whitney equation, the dissolution rate of a drug is directly proportional to the solubility Cs. dm/dt= D A (C s -C)/h Solubility Molecular interaction between molecules of the solid particle Intermolecular interaction between the molecules of the solvent and the solid substance Entropy changes For drugs (weak elecrtolytes) ph is also important. 23

24 Intrinsic Solubility C s Dissolution rate depends on the pka of the drug and the solubility in the diffusion layer. ph of the diffusion layer depends on the pka of the drug and solubility, pka and solubility of buffers in the GIT Difference in the dissolution rate is expected from different GIT regions. 24

25 Intrinsic Solubility C s Weak acids: solubility increases with increasing ph down the GIT Weak bases: solubility decreases with increasing ph Theses drugs needs to be dissolved in the stomach prior to the transit to the intestine Ketoconazole given 2 hours after H 2 antagonist cimetidine, results in the reduction in the rate and extent of absorption 25

26 Drug Factors affecting dissolution rate 1. Particle size & wettability 2. Solubility 3. Form of the drug a) Salt or free b) Crystalline or amorphous 26

27 Salts The dissolution of weak acid drugs in the stomach is relatively low? Dissolution of these drugs can be increased by changing chemical nature of the drug and make them in the salt form, sodium Na + or potassium K + salts. 27

28 28 Salts

29 This increase in the ph is due to neutralising effects of the ions of the salt dm/dt= D A (C s -C)/h 29

30 Precipitation However when the drug diffuses to the bulk ph precipitation might occur when the concentration of the drug is higher than the saturation concentration of the solvent to dissolve it. 30

31 Does the precipitation matter? The precipitates redisslove easily Very fine particles and highly wetted The concentration of the drug in the lumen reduces Absorption into the circulation Secretion and availability of other fluids Emptying into the intestine 31

32 Acidic Drugs Strong basic salts of weak acids drugs Tolbutamide sodium: has dissolution rate 500 times faster than of free form, the absorption is faster Naproxen Na Barbiturates are designed in the form of Na salt to produce faster onset of action 32

33 Basic drugs Drugs to be delivered to the absorption site in solution In order to ensure that complete and fast dissolution occurs in the stomach, drug is made in the salt form. Chorpromazine Cl dissolves faster in both gastric and intestinal fluids 33

34 Crystal form When a drug is found in more than one crystalline form this is called polymorphism and each of the crystalline forms are called polymorph. Tetracycline, chloramphencol palmitate Metastable form has faster dissolution rate than more stable forms. For dissolution limited drugs, this might affect the bioavailability produced by the drug 34

35 Chloramphenicol Chloramphenicol palmitate: A: stable B: metastable C : unstable C is too unstable to be used in dosage forms B has faster dissolution rate than A, and hence the extent of absorption is higher. 35

36 Solvates It is the ability to associate with solvent molecules to make crystals. Solvent is water it is called hydrate. The greater the solvation of the crystal the lower the solubility and dissolution rate in the solvent identical to the solvation molecules. This difference in dissolution might reflect differences in bioavailability of dissolution limited drugs. 36

37 Amorphous solids Dissolves rapidly Difference might occur in bioavailability of a drug that is dissolution rate limited. Stability issues Oral suspension of Novobiocin: amorphous form is effective while the crystalline form is ineffective. This is because of he dissolution profile between the 2 forms The amorphous is changing to the crystalline?? 37

38 Amorphous solids The amorphous form of ampicillin is faster dissolving and has greater extent of absorption than ampicillin trihydrate, in both hard gelatine capsules and suspensions. 38

39 Overview Physicochemical Factors 39 Dissolution rate Dissolution rate and Noyes-Whitney equation Physiological Factors affecting Dissolution Rate Drug Factors affecting dissolution rate Factors affecting Concentration in the GIT after dissolving Dissociation of the drug molecules (pka) Lipid solubility Chemical stability and complexation potential

40 Factors affecting concentration of drug in solution in the GIT Physicochemical properties A. Complexation B. Micellar solubilisation C. Adsorption D. Chemical stability 40

41 A. Complexation Beneficial or detrimental Dosage form or GIT GIT complexation : Tetracycline with food components Dosage forms: common in liquid dosage forms Presence of calcium as diluent ( dicalcium phosphate) in the dosage forms of tetracyclines reduces its bioavailability Phenobarbital and PEG

42 Beneficial Increase drug solubility, poorly water soluble drugs Cyclodextrin family: enzymatically modified starch 42

43 b-cyclodextrin: host plus guest Seven units Outer surface hydrophilic Inner surface hydrophobic Increase solubility and hence bioavailability 43

44 Miconazole : poor bioavailability because of poor water solubility Complexation enhances its solubility and dissolution rate Doubling in its bioavailability Itraconazole (Sporanox) the first drug in the UK, piroxicam and indomethacin 44

45 B. Micellar solubilisation It can increase the solubility of drugs Bile salts 45

46 C. Adsorption Adsorbents can interfere with absorption of drugs from GIT. Found as drugs or in the formulation of drugs and medicines Kaolin, charcoal Reduce the rate and extent of absorption through reducing the effective concentration of the drug available for absorption. 46

47 Reduction in the rate or extent Depends on the nature of interaction between the drug and adsorbent Reversible Irreversible e.g. lincomycin-kaopectate, promazine-charcoal 47

48 D. Chemical stability of the drug in the Unstable drugs GIT Stability : Chemical (acidic ) Enzymatic 48

49 Stability issues Peptide drugs Solution 1. Delaying the dissolution of the drug: enteric coating of tablets Omeprazole, erythromycin 2. Prodrug: erythromycin stearate 49

50 Erythromycin Stearate vs Erythromycin pellets entereic coated 50

51 Poorly soluble drugs (Dissolution Rate Limited) 1. Nanosize ion 2. Formulation as solution or, suspension 3. Stabilising drugs in amorphous form 4. Formulation with cyclodextrin 51

52 Overview Physicochemical Factors 52 Dissolution rate Dissolution rate and Noyes-Whitney equation Physiological Factors affecting Dissolution Rate Drug Factors affecting dissolution rate Factors affecting Concentration in the GIT after dissolving Poorly soluble drugs Dissociation of the drug molecules (pka) ph-partition hypothesis Lipid solubility Chemical stability and complexation potential

53 Drug Absorption Drug in solution is ready for absorption Physicochemical properties affecting absorption : 1. pka 2. Lipophilicity 3. Molecular weight 53

54 Drug dissociation and lipid solubility 1. Dissociation constant 2. Lipid solubility 3. ph of the environment in the GIT always affects absorption The interrelationship between degree of ionisation of weak electrolyte drugs in the GIT and the extent of absorption is explained by ph-partition hypothesis. 54

55 ph-partition hypotheis GIT epithelium acts as a lipid barrier to drugs which are absorbed by passive diffusion. Lipid soluble drugs can pass the membrane. Most drugs are weak acids and bases, the unionised of form of the drug will pass across the membrane. However, the membrane is impermeable to the ionised form of the drugs. 55

56 Absorption can be determined by the extent into which the drug is found in the unionised form. This is determined by Handerson-Hasselbalch equation. 56

57 Handerson-Hasselbalch Weak acids : ph = pka + log [ionised] / [unionised] Weakly acidic drugs (pka=3) will be predominantly unionised at the stomach ph, and almost totally ionised at intestinal ph. Weak bases ph = pka + log [unionised] / [ionised] o Weakly basic, pka 5, almost entirely ionised at gastric ph, and predominantly unionised at intestinal ph. 57

58 Limitations of hypothesis 1. Degree of ionisation is not the only factor in determining absorption. weak acids although are ionised in the intestine, they are well absorbed. The rate of absorption in the intestine is higher than in the stomach. Large surface area Long residence time Microclimate ph on the epithelium which is lower than the lumen 58

59 2.Unstirred water layer is not accounted for 3. It cannot explain the absorption of some drugs that are ionised across the GIT. e.g. Quaternary ammonium compounds The membrane is not completely impermeable to ionised drugs It interacts with endogenous opposite charge ions to form absorbable neutral species 59

60 Overview Physicochemical Factors 60 Dissolution rate Dissolution rate and Noyes-Whitney equation Physiological Factors affecting Dissolution Rate Drug Factors affecting dissolution rate Factors affecting Concentration in the GIT after dissolving Poorly soluble drugs Dissociation of the drug molecules (pka) ph-partition hypothesis Lipid solubility Chemical stability and complexation potential

61 Lipid solubility Two drugs might have similar pka, according to the ph-partition hypothesis they must be absorbed in similar manner. However, sometimes this does not occur Thiopentene (pka: 7.6)and barbitone(pka: 7.8), thiopentene is absorbed better. because thiopentene is more lipophilic 61

62 Measurement It is calculate by measurement of its partition between lipophilic solvent and water, partition coefficient 62

63 Polar molecules Polar molecules (LogP < 0) and large molecules cannot be absorbed and needs to be taken by other routes. E.g gentamicin, ceftriaxone and heparin Polar molecules with smaller size can be absorbed via paracellular pathway. E.g. Beta blocker, Atenolol 63

64 Lipid-soluble drugs ( Log P > 0) are well absorbed after oral administration. Very Lipid-soluble drugs ( Log P > 3) are well absorbed, but they are more likely to be metabolised and excreted by biliary clearance. Although it is not applied to all drugs, but increase in lipophilicity with in homologous group improves absorption Beta-blockers 64

65 Poor lipid solubility? Prodrug design 65

66 Molecular size and hydrogen bonding Paracelullar pathway.: ideally molecular weight should be < 200 Dalton ( there are also examples of larger molecules ) Transcellular ( passive diffusion): Molecular weight of < 500 is preferable Bigger than 500 is absorbed less efficiently Few drugs absorbed >

67 Too many hydrogen bonds are detrimental Hydrogen bond donors <5 Hydrogen bond acceptors <10 Peptides the sum of nitrogen and oxygen atoms in the molecule is often taken as a rough measure of hydrogen bond acceptors 67

68 Home work What is Lipiniski Rule of 5? Give an example of poorly water soluble drug (dissolution rate limited)? Hand in in person and ping an to 68

69 Conclusion Physicohcemical properties of the drug are major determinant of the dissolution and absorption of drugs. Therefore, rate and extent of absorption is influenced to large extent. 69

70 Further Readings Aulton's Pharmaceutics: The Design andmanufacture of Medicines, M.E.Aulton, Churchill Livingstone, Shargel L, Yu AB, (Eds.), Applied Biopharmaceutics and Pharmacokinetics. 70

71 71 Any Questions?

72 72 Thank You