Physicochemical Properties of Drugs Affecting...

BiopharmaceuticsPhysicochemical Properties of Drugs Affecting

Bioavailability

Lec: 4

Assist. Lec. Ali Yaseen Ali BSc Pharmacy, MSc Industrial Pharmaceutical Sciences

Dept. of Pharmaceutics College of Pharmacy

University of Sulaimani

Biopharmaceutics

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Physicochemical properties

Dosage form Route of

Administration

Bioavailability(Rate & Extent)

Overview • Physicochemical Factors• 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

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Dissolution Rate

• The process of dissolving is dissolution

• This process has a certain rate over time called dissolution rate

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Dissolution rate: Noyes-Whitney equation

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dmdt =

D A (Cs − C)ℎ

Noyes-Whitney equation

• 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 • Cs: is the saturation solubility of the drug in solution in the GIT fluids • C: the concentration of the drug in the gastrointestinal fluids.

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dmdt =

D A (Cs − C)ℎ




• Lipid solubility • Molecular size and hydrogen bonding

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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.

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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.

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dmdt

=D A (Cs − C)

ℎ

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.

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dmdt =

D A (Cs − C)ℎ

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 micellization

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dmdt

=D A (Cs − C)

ℎ

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.

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dmdt

=D A (Cs − C)

ℎ

Overview

• Physicochemical Factors• 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

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Drug Factors affecting dissolution rate

1. Particle size & wettability 2. Solubility 3. Form of the drug

a) Salt or free b) Crystalline or amorphous

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1. Particle size and Wettability • Surface area is increased by particle size reduction

(micronisation )

• 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.

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dm/dt= D A (Cs-C)/h

Example • Griseofulvin

• Classic example of which particles size reduction increases its bioavailability.

• Reduction of particle size from about 10 μm to 2.7 μm was shown to produce approximately double the amount of drug absorbed in humans.

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Other Examples

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Does micronisation has problems?

I. Hydrophobic drugs (poorly water soluble)

II. Unstable drugs in the GIT

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I. Hydrophobic drugs:

• Micronisation might result in aggregation of particles to form bigger particles hence reduce surface area.

• E.g. Aspirin, Phenobarbitals

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Solving the problem

• The problem of aggregation can be solved by :A. Micronisation in the presence of wetting agent or hydrophilic

carrier • 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.

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II. Chemical degradation

• Some drugs are unstable in stomach acid

• Erythromycin and Pen G

• Particle size reduction will increase their dissolution rate

• Increases destruction of drugs

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Intrinsic Solubility Cs

• Under sink conditions according to the Noyes-Whitney equation, the dissolution rate of a drug is directly proportional to the solubility Cs.

• Solubility• Molecular interaction between molecules of the solid particle • Intermolecular interaction between the molecules of the solvent and the solid

substance

For drugs (weak electrolytes) pH is also important.

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dmdt =

D A (Cs − C)ℎ


• Dissolution rate depends on• pKa of the drug • Solubility in the diffusion layer

• pH of the diffusion layer depends on • pKa of the drug • Solubility in the GIT

• Difference in the dissolution rate is expected from different GIT regions.

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• 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

• Drug interaction:• Ketoconazole given 2 hours after H2 antagonist cimetidine, results in the

reduction in the rate and extent of absorption

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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.

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Salts

• This increase in the pH is due to neutralising effects of the ions of the salt

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dmdt

=D A (Cs − C)

ℎ

Precipitation

• 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 .

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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

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Acidic Drugs• Strong 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

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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.

• Chlorpromazine Cl dissolves faster in both gastric and intestinal fluids

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Crystal form

• When a drug is found in more than one crystalline form this is called polymorphism• Each one of the crystalline forms are called polymorph.

• TetracyclineChloramphenicol palmitate

• For dissolution limited drugs, this might affect the bioavailability produced by the drug

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Chloramphenicol

• Chloramphenicol palmitate:• A: stable • B: metastable • C : unstable

• C form is too unstable to be used in dosage forms

• B has faster dissolution rate than A, and hence the extent of absorption is higher.

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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.

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Amorphous solids

• Dissolves rapidly

• Difference might occur in bioavailability of a drug that is dissolution rate limited.

• Stability issues

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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.

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Overview

• Physicochemical Factors• 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

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Factors affecting concentration of drug in solution in the GITPhysicochemical propertiesA. Complexation B. Micellar solubilisation C. Adsorption D. Chemical stability

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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 4000

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Beneficial

• Increase drug solubility, poorly water soluble drugs

• Cyclodextrin family: enzymatically modified starch

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b-cyclodextrin: host plus guest

• Seven units• Outer surface – hydrophilic• Inner surface – hydrophobic

• Increase solubility and hence bioavailability

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Examples

• 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

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B. Micellar solubilisation

• It can increase the solubility of drugs

• Bile salts

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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.

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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

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• Talc (excipient)• Which can be included in tablets as a glidant• Might interfere with the absorption of cyanocobalamin by virtue of its ability

to adsorb

D. Chemical stability of the drug in the GIT

• Unstable drugs

• Stability :• Chemical (acidic )• Enzymatic

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Stability issues

• Peptide drugs

To solve the problem:1. Delaying the dissolution of the drug: enteric coating of tablets– Omeprazole, erythromycin

2. Prodrug: erythromycin stearate

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Erythromycin Stearate vs Erythromycin pellets enteric coated

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Poorly soluble drugs (Dissolution Rate Limited)

1. Particle size reduction; Nanosize ion 2. Formulation as solution or, suspension 3. Stabilising drugs in amorphous form 4. Formulation with cyclodextrin

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• Lipid solubility • Chemical stability and complexation potential

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Drug Absorption • Drug in solution is ready for absorption

• Physicochemical properties affecting absorption :1. pKa 2. Lipophilicity 3. Molecular weight

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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.

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pH-partition hypothesis

• 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.

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pH-partition hypothesis

• Absorption can be determined by the extent into which the drug is found in the unionised form.

• This is determined by Handerson-Hasselbalch equation.

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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.

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Ionization

• Acids

• Bases

Example

• Salicylic acid pKa is 3

a. Gastric Juice : pH = 1.2

a. Plasma : pH = 7.4

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

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Limitations of hypothesis

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

• Paracellular pathway• It interacts with endogenous opposite charge ions to form absorbable neutral

species

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• Lipid solubility • Chemical stability and complexation potential

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Lipid solubility

• Two drugs might have similar pKa, according to the pH-partition hypothesis they must be absorbed in similar manner. • Sometimes this does not occur

• Example• Thiopentone (pKa: 7.6)• Barbitone (pKa: 7.8)

• Thiopentone is absorbed better• because thiopentene is more lipophilic

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Measurement

• Calculated by measurement of its partition between lipophilic solvent and water, partition coefficient

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𝑃𝑎𝑟𝑡𝑖𝑟𝑖𝑜𝑛 𝑐𝑜𝑒𝑓𝑓𝑖𝑐𝑖𝑒𝑛𝑡 =𝐶𝑜𝑛𝑐 𝑜𝑓 𝑑𝑟𝑢𝑔 𝑖𝑛 𝑜𝑟𝑔𝑎𝑛𝑖𝑐 𝑝ℎ𝑎𝑠𝑒𝐶𝑜𝑛𝑐 𝑜𝑓 𝑑𝑟𝑢𝑔 𝑖𝑛 𝑎𝑞𝑢𝑒𝑜𝑢𝑠 𝑝ℎ𝑎𝑠𝑒

𝐿𝑜𝑔 𝑃 = 𝐿𝑜𝑔 10 𝑃𝑎𝑟𝑡𝑖𝑡𝑖𝑜𝑛 𝑐𝑜𝑒𝑓𝑓𝑖𝑐𝑖𝑒𝑛𝑡

Polar molecules

• Polar molecules (LogP < 0)

1. Large molecules cannot be absorbed and needs to be taken by other routes.E.g.• Gentamicin (477 Dalton)• Ceftriaxone (554 Dalton) • Heparin (12000 Dalton)

2. Small size can be absorbed via paracellular pathway• E.g. Beta blocker, Atenolol (266 Dalton)

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Non-polar molecules

• 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.

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Poor lipid solubility ?

• Prodrug design

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Cefuroxime Axetil

• Cefuroxime• Log P = - 0.2

• Cefuroxime axetil (prodrug)• Log P = 0.9

Molecular size and hydrogen bonding

• Paracelullar pathway.: • Ideally molecular weight should be < 200 Dalton

• Transcellular ( passive diffusion): • Molecular weight of < 500 is preferable • Bigger than 500 is absorbed less efficiently • Few drugs absorbed > 700

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Molecular size and hydrogen bonding

• Too many hydrogen bonds are detrimental

• Hydrogen bond donors < 5

• Hydrogen bond acceptors < 10 • Sum of nitrogen and oxygen atoms in the molecule is often taken as a rough measure of

hydrogen bond acceptors

• Peptides

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Lipinski Rule of 5

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Conclusion

• Physicochemical 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.

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Further Readings

• Aulton's Pharmaceutics: The Design and Manufacture of Medicines, M.E.Aulton, Churchill Livingstone, 2007.

• Shargel L, Yu AB, (Eds.), Applied Biopharmaceutics and Pharmacokinetics.

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Any Questions ?

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Thank You

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