physicochemical properties of drugs affecting...
TRANSCRIPT
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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
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Biopharmaceutics
2
Physicochemical properties
Dosage form Route of
Administration
Bioavailability(Rate & Extent)
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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 • 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
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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
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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 • Poorly soluble drugs
• Dissociation of the drug molecules (pKa) • pH-partition hypothesis
• 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
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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
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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
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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
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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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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
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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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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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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
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Intrinsic Solubility Cs
• 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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Intrinsic Solubility Cs
• 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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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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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
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• 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
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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
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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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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 • 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
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Example
• Salicylic acid pKa is 3
a. Gastric Juice : pH = 1.2
a. Plasma : pH = 7.4
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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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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 • 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
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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
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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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