1. 2 what is biopharmaceutics? biopharmaceutics can be defined as the study of how the...

2

WHAT IS BIOPHARMACEUTICS?

Biopharmaceutics can be defined as the study of

how

• the physicochemical properties of drugs,

• dosage forms and

• routes of administration

affect the rate and extent of drug absorption.

Bioavailability is therefore defined as:

the rate and extent of drug absorption

3

If a drug is given intravenously it is administered

directly into the blood, and therefore we can be

sure that all the drug reaches the systemic

circulation.

The drug is therefore said to be 100% bioavailable

All other routes of administration where a

systemic action is required, involve the

absorption of the drug into the blood.

4

MSC

MEC

Cmax

tmax

AUC

Therapeutic range

(window)

Absorption phase

Eliminationphase

Pla

sm

a

Con

cen

trati

on

Time

A typical blood plasma concentration-time curve obtained

following the peroral administration of a single dose of a

drug in a tablet

5

Cmax: the highest plasma drug concentration observed.

Tmax: the time at which Cmax occurs following administration of an extravascular dose.

AUC: Area under the curve

MSC: Maximum safe concentration

MEC: Minimum effective concentration

Therapeutic range: The range of plasma concentrations between the minimally effective concentration and the maximum safe concentration

Absorption phase: Absorption rate > Elimination rate

Elimination phase: Elimination rate > Absorption rate

6

Routes of drug administration

The route of administration determines

the site of application of the drug product.

Often the goal is to attain a therapeutic drug

concentration in plasma from which drug enters

the tissue (therapeutic window between toxic

concentration and minimal effective

concentration).

7

Routes of administration are classified into:

ENTERAL and PARENTERAL

Enteral means through the GI tract and includes

oral, buccal, and rectal.

Parenteral means not through the alimentary canal

and commonly refers to injections such as IV, IM,

and SC; but could also include topical and

inhalation

8

1. Sublingual (buccal)

Certain drugs are best given beneath

the tongue (sublingual) or retained in

the cheek pouch (buccal) and are

absorbed from these regions into the

local circulation.

A. Enteral RoutesA. Enteral Routes

9

These vascular areas are ideal for lipid-soluble

drugs that would be metabolized in the gut or liver,

since the blood vessels in the mouth bypass the

liver (do not undergo first pass liver metabolism),

and drain directly into the systemic circulation.

This route is usually reserved

for nitrates and certain hormones.

10

Diagram of first pass effectDiagram of first pass effectDiagram of first pass effectDiagram of first pass effect

liver

gut

biliary tract

to circulation

metabolised drug

portal vein

unmetaboliseddrug

11

2. Oral

By far the most common route.

The passage of drug from the gut into the blood is

influenced by biologic and physicochemical

factors and by the dosage form.

For most drugs, 2- to 5-fold differences in the rate

or extent of gastrointestinal absorption can occur,

depending on the dosage form.

Generally, the bioavailability of

oral drugs follows the order:

solution > suspension > capsule >

tablet > coated tablet.

12

3. Rectal

The administration of suppositories is usually

reserved for situations in which oral

administration is difficult.

This route is more frequently used in small

children.

It by-passes the liver

13

1. Intravenous injection

Used when a rapid clinical response is necessary,

e.g., an acute asthmatic episode.

This route allows one to achieve relatively precise

drug concentrations in the plasma, since

bioavailability is 100%.

B. Parenteral Routes

B. Parenteral Routes

14

Most drugs should be injected over 1-2 minutes in

order to prevent the occurrence of very high drug

concentrations in the injected vein, possibly

causing adverse effects.

Some drugs, particularly those with narrow

therapeutic indices or short half-lives, are best

administered as a slow IV infusion or drip.

15

2. Intramuscular injection

Drugs may be injected into the arm (deltoid), thigh

(vastus lateralis) or buttocks (gluteus maximus).

Because of differences in vascularity, the rates of

absorption differ, with arm > thigh > buttocks.

Drug absorption may be slow and erratic.

Lipid solubility and degree of ionization influence

absorption.

It should not be assumed that the IM route is as

reliable as the IV route.

16

3. Subcutaneous injection

Some drugs, notably insulin, are routinely

administered SC.

Drug absorption is generally slower SC than IM, WHY?

due to poorer vascularity.

Absorption can be facilitated by heat, massage or

vasodilators.

It can be slowed by coadministration of

vasoconstrictors, a practice commonly used to

prolong the local action of local anesthetics.

As above, arm > thigh.

18

4. Topical application

a. Eye

For desired local effects.

b. Intravaginal

For infections or contraceptives.

c. Intranasal

For alleviation of local symptoms.

Directly from nasal capillaries into

circulation.

19

d. Skin

Systemic absorption does occur

and varies with the area, site,

drug, and state of the skin.

Dimethyl sulfoxide (DMSO)

enhances the percutaneous

absorption of many drugs.

e. Drug patches

(drug enters systemic circulation

by zero order kinetics – a constant

amount of drug enters the

circulation per unit time).

20

5. Inhalation

Volatile anesthetics, as well as many drugs which

affect pulmonary function, are administered as

aerosols.

The large alveolar area and blood supply lead to

rapid absorption into the blood.

Drugs administered via this route are not subject

to first-pass liver metabolism.

21

6. Other ROA's

Other routes of administration include:

• intra-arterial for cancer chemotherapy to

maximize drug concentrations at the tumor site

• intrathecal directly into the cerebrospinal fluid.

22

Why are there different routes?

1.Solubility or stability of the drug

2.The absorption from the different sites. Many

drugs are absorbed from stomach and small

intestine and not absorbed rectally.

3.Toxic when given by certain routes.

4.Ineffective, destroyed or inactivated in

certain organs e.g. penicillin in stomach.

5.Convenience of the patient

23

Route for Route for

AdministrationAdministrationTime until EffectTime until Effect

IVIV30-60 sec

InhalationInhalation2-3 min

SublingualSublingual3-5 min

IMIM10-20 min

SCSC15-30 min

RectalRectal5-30 min

IngestionIngestion30-90 min

Transdermal (Topical)Transdermal (Topical)Variable (minutes-hours)

24

The concentration of the drug in blood plasma

depends on LADME

L = Liberation

the release of the drug from it's dosage form.

A = Absorption

the movement of drug from the site of administration to

the blood circulation.

D = Distribution

the process by which drug diffuses or is transferred

from intravascular space to extravascular space (body

tissues).

25

The concentration of the drug in blood plasma

depends on LADME

M = Metabolism

the chemical conversion or transformation of drugs into

compounds which are easier to eliminate.

E = Excretion

the elimination of unchanged drug or metabolite from

the body via renal, biliary, or pulmonary processes.

29

Absorption

The absorption of a drug from the GIT is the passage of

the substance from the lumen through several

membranes into the blood stream.

Main factors affecting oral absorption:

• Physiological factors

• Physical-chemical factors

• Formulation factorsGIT BLOOD

30

A- Membrane physiology

B- Passage of drugs across membranes

Active transport

Facilitated diffusion

Passive diffusion

Pinocytosis

Pore transport

Ion pair formation

1. Physiological Factors Affecting Oral Absorption

1. Physiological Factors Affecting Oral Absorption

31

C- Gastrointestinal physiology

GIT physiology and drug absorption

Gastric emptying time and motility

Effect of food on drug absorption

Enterohepatic circulation

First pass effect

32

Membrane structure (Fluid Mosaic Model)

The biologic membrane consists mainly of a lipid

bilayer containing primarily phospholipids and

cholesterol, with imbedded proteins.

The membrane contains also small aqueous

channels or pores.

A. Membrane physiologyA. Membrane physiology

33

Phospholipid Bilayers

Phospholipids are amphiphilic in nature. Polar heads

are oriented toward the water and the fatty acid tails

are oriented toward the inside of the bilayer.

The fatty acid tails are flexible, causing the lipid

bilayer to be flexible. At body temperature, membranes

are a liquid with a consistency that is similar to

cooking oil.

34

Cholesterol

Cholesterol is a major membrane lipid. It may be equal

in amount to phospholipids. It is similar to

phospholipids in that one end is hydrophilic the other

end is hydrophobic.

Cholesterol makes the membrane less permeable to

most biological molecules.

Proteins

Proteins are scattered throughout the membrane.

They may be attached to inner surface,

embedded in the bilayer, or

attached to the outer surface.

36Channel

Functions of Membrane Proteins

37

A. Channel proteins

A protein that allows a particular molecule or

ion to freely cross the membrane as it enters

or leaves the cell.

B. Carrier proteins

A protein that selectively interacts with a

specific molecule or ion so that it can cross

the cell membrane to enter or exit the cell.

38

C. Receptor proteins

A protein that has a specific shape so that

specific molecules can bind to them. The

binding of a molecule, such as a hormone, can

influence the metabolism of the cell.

D. Enzyme proteins

An enzyme that catalyzes a specific reaction.

39

E. Cell-recognition proteins

Glycoproteins that identify the cell. They

make up the cellular fingerprint by which cells

can recognize each other.

F. Cell Adhesion Proteins

Adjacent cells stick together via interlocking

proteins on their membranes

40

The membrane can be viewed as a semipermeable

lipoidal sieve that allows the passage of:

- lipid-soluble molecules across it by passive lipid

diffusion

- water and small hydrophilic molecules through

its numerous aqueous pores.

-other molecules by a number of transporter

proteins or carrier molecules that exist in the

membrane.

B. Passage of Drugs Across MembranesB. Passage of Drugs Across Membranes

41

There are two main mechanisms of drug transport

across the gastrointestinal epithelium:

Paracellular: i.e. between the cells.

Transcellular: i.e. across the cells

The transcellular pathway is further divided into

simple passive diffusion, carrier-mediated

transport (active transport and facilitated

diffusion) and endocytosis.

42

Most (many) drugs cross biological

membranes by passive diffusion.

•Diffusion occurs when the drug

concentration on one side of the

membrane is higher than that on the

other side (according to concentration

gradient).

•Drug diffuses across the membrane in

an attempt to equalize the drug

concentration on both sides of the

membrane.

1. Passive Transport1. Passive Transport

43

• The rate of transport of drug across the membrane

can be described by Fick's first law of diffusion:-

D: diffusion coefficient

This parameter is related to:

• the size of the drug

• lipid solubility of the drug

• viscosity of the diffusion medium, the

membrane.

As lipid solubility increases or molecular size

decreases then D increases and thus diffusion rate

also increases.

44

A: surface area

As the surface area increases the rate of diffusion

also increase. The surface of the intestinal lining

(with villae and microvillae) is much larger than the

stomach. Therefore absorption is generally faster

from intestine compared to stomach.

x: membrane thickness

The smaller the membrane thickness the quicker the

diffusion process.

e.g. the membrane in the lung is quite thin thus

inhalation absorption can be quite rapid.

45

(Ch -Cl): concentration difference. Since V, the apparent volume of distribution, is at

least four liters and often much higher the drug

concentration in blood or plasma will be quite low

compared with the concentration in the GI tract. It is

this concentration gradient which allows the rapid

complete absorption of many drug substances.

Normally Cl << Ch then:-

Thus the absorption of many drugs from the G-I tract

can often appear to be first-order.

46

• Is also the movement of molecules from a high concentration to a low concentration.

• Lipid insoluble substances such as glucose and amino acids are taken across by "carrier proteins".

• No chemical energy is required in this process, WHY?

• eg. amino acids, glucose and other breakdown products of food are absorbed by the small intestine facilitated diffusion

2. Facilitated Transport2. Facilitated Transport

47

Active Transport

It is the movement of molecules across a living membrane

from an area of low concentration to an area of high concentration

with the aid of a carrier protein and

using energy or ATP.

The rate of drug absorption increases with drug concentration until the carrier molecules are completely saturated, the rate then remains constant

3. Active Transport3. Active Transport

49

Mechanism of Drug Transport ?

50

Surrounding a substance with the cell membrane

and the subsequent formation of a vesicle to

bring these substances into the cell.

This process is energy dependent.

4. Endocytosis4. Endocytosis

51

There are two main kinds of Endocytosis:

a. Phagocytosis (cell eating) - involves the

ingestion of particles larger than 500 nm. This

process is important in the absorption of polio

and other vaccines from the GIT.

b. Pinocytosis (cell drinking) - involves the

ingestion of fluids or dissolved particles. Fat

soluble vitamins A, D, E and K are absorbed via

pinocytosis

52

•Very small molecules (hydrophilic, water soluble

such as water, urea and sugar) are able to rapidly

cross cell membrane as if the membrane

contained pores or channels.

•This model of transportation is used to explain

renal excretion of drugs and uptake of drugs into

the liver.

5. Pore Transport5. Pore Transport

•A certain type of protein

may form an open

channel across the lipid

membrane of cell.

53

Strong electrolyte drugs are highly ionized and

maintain their charge at physiological pH.

•These drugs penetrate membranes poorly,

WHY?

•When linked up with an oppositely charged ion,

an ion pair is formed in which the overall

charge of the pair is neutral.

•The neutral complex diffuses more easily

across the membrane, WHY?

•An example of this in case of propranolol, a

basic drugs that forms an ion pair with oleic

acid.

Ion pair formationIon pair formation

54

Two pathways exist for the passage of water

and electrolytes across the intestinal mucosa,

transcellular and paracellular.

The transcellular pathway allows the passage

of hyrophilic molecules of low molecular weight

and with small molecular size through the

water filled pores in the cell membranes.

Paracellular TransportParacellular Transport

55

The paracellular pathway allows access of

larger molecules through the junction between

the cells.

Although the intercellular spaces occupy less

than 1% of the surface area of the epithelium it

is by this way the hydrophilic drug molecules

are absorbed e.g. ranitidine , acyclovir.

56

I- Characteristics of GI physiology and Drug

Absorption

The gastrointestinal tract is a muscular tube

approximately 6 m in length with varying diameters.

It stretches from the mouth to the anus and consists

of four main anatomical areas: - oesophagus

- stomach

- small intestine

- large intestine or colon.

The luminal surface of the tube is not smooth but

very rough, thereby increasing the surface area for

absorption.

C. Gastrointestinal (GI) PhysiologyC. Gastrointestinal (GI) Physiology

58

OrganspHMembrane

Blood Supply

Surface Area

Transit TimeBy-pass liver

Buccalapprox 6

thinGood, fast

absorption with

low dose

smallShort unless controlled

yes

Esophagus

6-7Very thick no

absorption

-smallshort, a few seconds ,

-

Stomach1.7-4.5normalgoodsmall30 min delayed stomach emptying

intestinal absorption

no

Duodenum

5 - 7normalgoodvery large

very short (6" long) ,

no

Small Intestine

6- 7normalgoodvery large

about 3 hoursno

Large Intestine

6.8 - 7-goodnot very large

long, up to 24 hr

lower colon, rectum yes

59

II. Gastric emptying and motility

Generally drugs are better absorbed in the small

intestine, WHY? (because of the larger surface

area) than in the stomach, therefore quicker

stomach emptying will increase drug absorption.

e.g. a good correlation has been found between

stomach emptying time and peak plasma

concentration for acetaminophen. The quicker

the stomach emptying the higher the plasma

concentration.

60

Also slower stomach emptying can cause

increased degradation of drugs in the stomach's

lower pH; e.g. L-dopa.

61

Volume of Ingested Material

Bulky material tends to empty more slowly than liquids

Type of MealFatty foodDecrease

CarbohydrateDecrease

Temperature of Food

Increase in temperature, increase in emptying rate

Body Position

Lying on the left side decreases emptying rate. Standing versus lying (delayed)

DrugsAnticholinergics (e.g. atropine) ,

Narcotic (e.g. morphine, alfentanil), Analgesic (e.g. aspirin)

Decrease

Metoclopramide, Domperidone, Erythromycin, Bethanchol

Increase

Factors Affecting Gastric Emptying

62

III. Effect of Food

The presence of food in the gastrointestinal

tract can influence the rate and extent of

absorption

Complexation of drugs with components in the

diet

e.g. Tetracycline forms non-absorbable

complexes with calcium and iron (don’t take milk

or iron preparations at the same time of day as

the tetracycline WHY?).

63

Alteration of pH

In general, food tends to increase stomach pH by

acting as a buffer. This is liable to decrease the

rate of dissolution and subsequent absorption of

a weakly basic drug and increase that of a weakly

acidic one.

Alteration of gastric emptying

Particularly fatty foods, and some drugs, tend to

reduce gastric emptying and thus delay the onset

of action of certain drugs.

64

Stimulation of gastrointestinal secretions

e.g. pepsin produced in response to food may

result in the degradation of drugs that are

susceptible to enzymatic metabolism, and hence

in a reduction in their bioavailability.

Food, particularly fats, stimulates the secretion

of bile. Bile salts are surface active agents and

can increase the dissolution of poorly soluble

drugs, thereby enhancing their absorption.

e.g. Griseofulvin (antifungal)

65

Competition between food components and

drugs for specialized absorption mechanisms

In the case of those drugs that have a chemical

structure similar to nutrients required by the

body for which specialized absorption

mechanisms exist, there is a possibility of

competitive inhibition of drug absorption.

66

Increased viscosity of gastrointestinal contents

The presence of food in the gastrointestinal

tract provides a viscous environment which may

result in a reduction in the rate of drug

dissolution and the rate of diffusion of a drug in

solution from the lumen to the absorbing

membrane.

67

Food-induced changes in presystemic

metabolism

Certain foods may increase the bioavailability of

drugs that are susceptible to presystemic

intestinal metabolism by interacting with the

metabolic process.

e.g. Grapefruit juice is capable of inhibiting the

intestinal cytochrome P450 and thus, taken with

drugs that are susceptible to cytochrome P450

metabolism, is likely to result in their increased

bioavailability.

68

IV. Enterohepatic circulation (Biliary recycling)

•Some drugs when absorbed from intestine they

are carried via the portal vein into the liver.

•In the liver they are metabolized and secreted

into the bile

69

•As a conjugated drug they are transported again

via bile duct into intestine (In the conjugated

form they are not absorbed again from

intestine).

•After meals the secretion of bile is stimulated.

The bile release the drug from its conjugate, thus

it will be reabsorbed again as if a new dose was

given.

•Biliary recycling of a drug results in prolonging

drug action.

70

liver

gutunconjugateddrug

biliary tract

to circulation

conjugated drug

portal vein

Diagram of biliary recyclingDiagram of biliary recyclingDiagram of biliary recyclingDiagram of biliary recycling

71

IV. First pass effect

Is a phenomenon of drug metabolism whereby

the concentration of a drug is greatly reduced

before it reaches the systemic circulation.

After a drug is swallowed, it is absorbed by the

digestive system and enters the hepatic portal

system. It is carried through the portal vein into

the liver before it reaches the rest of the body.

72

The liver metabolizes many drugs, sometimes to

such an extent that only a small amount of active

drug emerges from the liver to the rest of the

circulatory system.

This first pass through the liver thus greatly

reduces the bioavailability of the drug.

73

Diagram of first pass effectDiagram of first pass effectDiagram of first pass effectDiagram of first pass effect

74

• pH-partition theory

• Lipid solubility of drugs

• Dissolution and pH

• Salts

• Crystal form

• Drug stability and hydrolysis in GIT

• Complexation

• Adsorption

2. Physicochemical Factors Affecting Oral

Absorption

2. Physicochemical Factors Affecting Oral

Absorption

75

The pH - partition theory explains the influence

of GI pH and drug pKa on the extent of drug

absorption.

A. pH - Partition TheoryA. pH - Partition Theory

As most drugs are weak electrolytes, the

unionized form of weakly acidic or basic drugs

(i.e. the lipid-soluble form) will pass across the

gastrointestinal epithelia, whereas the

gastrointestinal epithelia is impermeable to the

ionized (i.e. poorly lipid-soluble) form of such

drugs.

76

According to the pH-partition hypothesis, the

absorption of a weak electrolyte will be

determined chiefly by the extent to which the

drug exists in its unionized form at the site of

absorption.

77

The extent to which a weakly acidic or basic drug

ionizes in solution in the gastrointestinal fluid is

determined by:

its pKa & the pH at the absorption site and may

be calculated using the appropriate form of the

Henderson-Hasselbach equation

78

What is acid?acid is a substance that liberates hydrogen ions [H+] in solution.

What is a base?A base is a substance that can bind H+ and remove them from solution.

pH = - log [H+]

Strong acids, strong bases, as well as strong electrolytes are essentially completely ionized in aqueous solution.

Weak acids and weak bases are only partially ionized in aqueous solution and yield a mixture of the undissociated compound and ions.

79

HA H+ + A-

Ka = [H+] [A-]

[HA]

In solutions of weak acids

equilibria exist between

undissociated molecules and

their ions.

The ionization constant Ka of

a weak acid can be obtained

by applying the Law of Mass

Action:

80

pKa = pH - log [A-]

[HA]

log [A-]

[HA] = pH - pKa

Henderson - Hasselbalch

Equation

pKa = the negative

logarithm of Ka

From the pKa, one can

calculate the proportions

of drug in the charged

and uncharged forms at

any pH:

For acidic drugs, the lower

the pKa the stronger the

acid

81

Some Typical pKa Values for Weak Acids at 25 °C

Weak AcidpKa

Acetic4.76

Acetylsalicyclic3.49

Boric9.24

Penicillin V2.73

Phenytoin8.1

Salicyclic2.97

Sulfathiazole7.12

82

In solutions of weak bases equilibria

exist between undissociated

molecules and their ions.

The ionization constant Ka of a

protonated weak base can be

obtained by applying the Law of

Mass Action:

B + H+ BH+

Ka = [H+] [B]

[BH+]

83

pKa = the negative logarithm of Ka

From the pKa, one can

calculate the proportions

of drug in the charged

and uncharged forms at

any pH:

pKa = pH - log [B]

[BH+]

Henderson - Hasselbalch

Equation

log [B]

[BH+] = pH - pKa

For basic drugs, the higher the

pKa the stronger the base

84

Therefore, according to these equations:

a weakly acidic drug, pKa 3.0, will be:

predominantly unionized in gastric fluid at pH 1.2

(98.4%) and almost totally ionized in intestinal

fluid at pH 6.8 (99.98%),

a weakly basic drug, pKa 5, will be:

almost entirely ionized (99.98%) at gastric pH of

1.2 and predominantly unionized at intestinal pH

of 6.8 (98.4%).

85

This means that, according to the pH-partition

hypothesis, a weakly acidic drug is more likely to

be absorbed from the stomach where it is

unionized,

and a weakly basic drug from the intestine where

it is predominantly unionized.

However, in practice, other factors need to be

taken into consideration.

86

Lipid solubility :weak acids and weak Lipid solubility :weak acids and weak basesbases

HA <==> H+ + A- B + HCl <==> BH+ + Cl-

[ UI ] [ I ] [ UI ] [ I ]

pKa=pH + log (HA/A-) pKa= pH + log(BH+/B)

ASPIRIN pKa = 4.5 (weak acid)100mg orally

99.9 = [ UI ] [ UI ]

Stomach pH = 2

BloodpH = 7.4

0.1 = [ I ]

Aspirin is reasonably absorbed Strychnine not absorbed until from stomach (fast action) enters duodenum

0.1 = [ UI ] [ UI ]

BloodpH = 7.4

99.9 = [ I ]

STRYCHNINE pKa = 9.5 (weak base)100mg orally

Stomach pH = 2

87

Limitations of the pH-partition hypothesis

Weak acids are also absorbed from the small

intestine due to:

The significantly larger surface area that is

available for absorption in the small

intestine in contrast to stomach

The longer small intestinal residence time

The microclimate pH, that exists at the

surface of the intestinal mucosa and is

lower than that of the luminal pH of the

small intestine

88

The pH -partition hypothesis cannot explain the

fact that certain drugs (e.g. tetracyclines) are

readily absorbed despite being ionized over the

entire pH range of the gastro intestinal tract.

One suggestion for this is that such drugs

interact with endogenous organic ions of

opposite charge to form an absorbable neutral

species - an ion pair - which is capable of

partitioning into the lipoidal GIT barrier and be

absorbed via passive diffusion.

89

Barbitone and thiopentone, have similar

dissociation constants - pKa 7.8 and 7.6,

respectively - and therefore similar degrees of

ionization at intestinal pH.

However, thiopentone is absorbed much better

than barbitone. WHY? the absorption of drugs is

also affected by the lipid solubility of the drug.

Thiopentone, being more lipid soluble than

barbitone, exhibits a greater affinity for the

gastrointestinal membrane and is thus far better

absorbed.

B. Lipid Solubility of Drugs

B. Lipid Solubility of Drugs

90

An indication of the lipid solubility of a drug, and

(its absorption) is given by its ability to partition

between a lipid-like solvent (usually octanol) and

water.

This is known as the drug's partition coefficient,

and is a measure of its lipophilicity.

How can we measure lipid

solubility??

91

The partition coefficient P is the ratio of the drug concentration in the organic phase to its concentration in the aqueous phase

Partition coefficient (p) = [ L] conc / [W] conc

[ L] conc is the concentration of the drug in lipid phase, [W] conc is the concentration of the drug in aqueous phase.

The higher p value, the more absorption is observed.

Polar molecules, i.e. those that are poorly lipid soluble and relatively large, such as heparin are poorly absorbed after oral administration and therefore have to be given by injection.

92

A prodrug is a chemical modification, frequently an ester of an existing drug.

The ester linkage increases the lipophilicity of the compound thus enhances the absorption.

A prodrug has no pharmocological activity itself but it converts back to the parent compound as a result of metabolism by the body. (e.g. Rivampicillin a prodrug for ampicillin)

The drug is too hydrophilic, what can be done??

Prodrug is one of the options that can be used

to enhance p value and absorption as sequence.

93

So far we have looked at the transfer of drugs in

solution in the G-I tract, through a membrane,

into solution in the blood.

However, many drugs are given in solid dosage

forms and therefore must dissolve before

absorption can take place.

C. Drug

Dissolution

C. Drug

Dissolution

94

The rate of solution may be explained using

Fick’s First Low of Diffusion: It is the rate at which

a dissolved solute particle diffuses through the

stagnant layer to the bulk solution

If absorption is slow relative to dissolution then

all we are concerned with is absorption. However,

if dissolution is the slow, rate determining step

(the step controlling the overall rate) then factors

affecting dissolution will control the overall

process.

95

Fick's first law

By Fick's first law of diffusion:

D diffusion coefficient, A surface area,

Cs solubility of the drug,

Cb concentration of drug in the bulk solution,

h thickness of the stagnant layer.

As Cb is much smaller than Cs

the equation reduces to :

Solid

Stagnant Layer

Cs Cbh

Bulk Solution

96

There are a number of factors which affect drug

dissolution:

Surface area, A

The surface area per gram (or per dose) of a solid

drug can be changed by altering the particle size.

e.g. a cube 3 cm on each side has a surface area of

54 cm2. If this cube is broken into cubes with sides

of 1 cm, the total surface area is 162 cm2.

97

Generally as A increases the dissolution rate will

also increase. Improved bioavailability has been

observed with griseofulvin, digoxin, etc.

Methods of particle size reduction include mortar

and pestle, mechanical grinders, fluid energy

mills, solid dispersions in readily soluble

materials (PEG's).

98

Diffusion layer thickness, h

This thickness is affected by the agitation in the

bulk solution.

In vivo we usually have very little control over

this parameter.

It is important though when we perform in vitro

dissolution studies because we have to control

the agitation rate so that we get similar results in

vitro as we would in vivo.

99

Diffusion coefficient, D

The value of D depends on the size of the

molecule and the viscosity of the dissolution

medium.

Increasing the viscosity will decrease the

diffusion coefficient and thus the dissolution

rate.

This could be used to produce a sustained

release effect by including a larger proportion of

something like sucrose or acacia in a tablet

formulation.

100

Drug solubility, CsSolubility is another determinant of dissolution

rate.

As Cs increases so does the dissolution rate.

We can look at ways of changing the solubility of

a drug:

101

base, therefore if the

drug can be given as a

salt the solubility can be

increased and we should

have improved

dissolution. One example

is Penicillin V.

D. (1) Salt FormD. (1) Salt Form

If we look at the dissolution profile of various

salts.

Salts of weak acids and weak bases generally

have much higher aqueous solubility than the

free acid or

102

Some drugs exist in a number of crystal forms or

polymorphs.

These different forms may well have different

solubility properties and thus different

dissolution characteristics.

Chloramphenicol palmitate is one example which

exists in at least two polymorphs.

E. (2) Crystal FormE. (2) Crystal Form

103

Plot of Cp versus Time

for Three Formulations

of Chloramphenicol

Palmitate

The B form is apparently more bioavailable. This

is attributed to the more rapid in vivo rate of

dissolution. The recommendation

might be that

manufacturers should

use polymorph B for

maximum solubility

and absorption.

104

In addition to different polymorphic crystalline

forms, a drug may exist in an amorphous form.

Because the amorphous form usually dissolves

more rapidly than the corresponding crystalline

forms there will be significant differences in the

bioavailabilities.

e.g. antibiotic novobiocin. The more soluble and

rapidly dissolving amorphous form of novobiocin

was readily absorbed.

However, the less soluble and slower-dissolving

crystalline form of novobiocin was not absorbed

to any significant extent thus therapeutically

ineffective.

105

Acid and enzymatic hydrolysis of drugs in GIT is

one of the reasons for poor bioavailability.

Penicillin G (half life of degradation = 1 min at

pH= 1)

Rapid dissolution leads to poor bioavailability

WHY? (due to release large portion of the drug in

the stomach, pH = 1.2)

How to protect the drug from the gastric juice?

1. Enteric coating the tablet containing the drug.

2. Prodrug that exhibits limited solubility in

gastric fluid but liberates the parent drug in

intestine to be absorbed.

F. Drug Stability and Hydrolysis in GIT

F. Drug Stability and Hydrolysis in GIT

106

G. Adsorption

G. Adsorption

Certain insoluble substances may

adsorb co-administrated drugs

leading to poor absorption.

Charcoal (antidote in drug

intoxication).

107

Complexation of a drug in the GIT fluids may alter

rate and extent of drug absorption.

1. GIT component- drug interaction:

Intestinal mucosa + Streptomycin = poorly

absorbed complex

2. Food-drug interaction:

Calcium + Tetracycline = poorly absorbed

complex

3. Tablet additive – drug interaction:

Carboxyl methylcellulose (CMC) +

Amphetamine = poorly absorbed complex

H. ComplexationH. Complexation

108

4. Complexing agent + polar drugs:

Dialkylamides + prednisone = well-absorbed

lipid soluble complex

5. Lipid soluble drug + water soluble complexing

agent

Miconazole + cyclodextrine = water soluble

complex

109

Role of dosage forms

Solutions

Suspensions

Capsules

Tablets

- uncoated

- coated

3. Formulation Factors Affecting Oral

Absorption

3. Formulation Factors Affecting Oral

Absorption

110

With any drug it is possible to alter its

bioavailability considerably by formulation

modification.

Since a drug must be in solution to be absorbed

efficiently from the G-I tract, you may expect the

bioavailability of a drug to decrease in the order:

solution > suspension > capsule > tablet > coated

tablet.

This order may not always be followed but it is a

useful guide.

One example is the results for pentobarbital.

Here the order was found to be:

aq solution > aq suspension = capsule > tablet of

free acid form.

111

Drugs are commonly given in solution in

cough/cold remedies and in medication for the

young and elderly.

In general, drugs must be in solution in

gastrointestinal fluids before absorption can

occur.

For drugs that are water soluble and chemically

stable in aqueous solution, formulation as a

solution normally eliminates the in vivo

dissolution step and presents the drug in the

most readily available form for absorption

I. Solution dosage form

I. Solution dosage form

112

therefore absorption from an oral solution is

rapid and complete, compared with

administration in any other oral dosage form.

The rate limiting step is often the rate of gastric

emptying since absorption will generally be more

rapid in the intestine.

•However, dilution of an aqueous solution of a

poorly water-soluble drug whose aqueous

solubility had been increased by:

formulation techniques such as 1cosolvency, 2complex formation or 3solubilization can result

in precipitation of the drug in the gastric fluids.

113

•Similarly, exposure of an aqueous solution of a

4salt of a weak acidic compound to gastric pH

can also result in precipitation of the free acid

form of the drug.

In most cases the extremely fine nature of the

resulting precipitate permits a more rapid rate of

dissolution than if the drug had been

administered in other types of oral dosage

forms, such as aqueous suspension, hard gelatin

capsule or tablet.

114

A well formulated suspension is second to a

solution (nonprecipitating) in terms of

superior bioavailability.

Absorption may well be dissolution limited,

however a suspension of a finely divided

powder and hence large surface area will

maximize the potential for rapid dissolution.

With very fine particle sizes the dispersibility

of the powder becomes important.

II. Suspension dosage formII. Suspension dosage form

115

The addition of a surface active agent will

improve dispersion of a suspension.

As a suspension ages there is potential for

increased particle size with an accompanying

decrease in dissolution rate.

116

Provided: the hard gelatin shell

dissolves rapidly in the GI

fluids

encapsulated mass

disperses rapidly and

efficiently,

a relatively large effective

surface area of drug will be

exposed to the

gastrointestinal fluids,

thereby facilitating

dissolution.

The capsule contents should

not be subjected to high

compression forces which

would tend to reduce the

effective surface area, thus

tightly packed capsules may

have reduced dissolution

and bioavailability.

The inclusion of excipients

(e.g. diluents, lubricants and

surfactants) in a capsule

formulation can have a

significant effect on the rate

of dissolution of drugs,

particularly those that are

poorly soluble and

hydrophobic.

III. Capsule dosage form

III. Capsule dosage form

117

The capsule contents should not be subjected to

high compression forces which would tend to

reduce the effective surface area, thus tightly

packed capsules may have reduced dissolution

and bioavailability.

The inclusion of excipients (e.g. diluents,

lubricants and surfactants) in a capsule

formulation can have a significant effect on the

rate of dissolution of drugs, particularly those

that are poorly soluble and hydrophobic.

118

However, the diluent should

exhibit no tendency to adsorb or

complex with the drug, as either

can impair absorption from the

gastrointestinal tract.

If a drug is hydrophobic a dispersing agent should

be added to the capsule formulation.

A hydrophilic diluent (e.g. sorbitol, lactose) often

serves to increase the rate of penetration of the

aqueous gastrointestinal fluids into the contents

of the capsule, and to aid the dispersion and

subsequent dissolution of the drug in these fluids.

120

Uncoated tablets

Tablets are the most widely used dosage form.

When a drug is formulated as a compressed tablet

there is an enormous reduction in the effective

surface area of the drug, owing to the granulation

and compression processes involved in tablet

making.

The tablets should disintegrate rapidly and

completely in the GIT fluids so that a fine, well

dispersed suspension of drug particles in the GIT

fluids is generated following the administration of

a tablet.

IV. Tablet dosage form

IV. Tablet dosage form

121

The overall rate of tablet disintegration

influenced by several interdependent factors: the

concentration and type of drug, diluent, binder,

disintegrant, lubricant and wetting agent as well

as the compaction pressure.

122

Film Coated Tablet

Tablet coatings may be employed

to:

- mask an unpleasant taste or odour

or

- to protect an ingredient from

decomposition during storage.

123

Enteric coating protects drugs

which would otherwise be

destroyed if released into

gastric fluid and also protects

the stomach against drugs

which can produce nausea or

mucosal irritation (e.g.

aspirin, ibuprofen) if released

at this site.

Enteric Coated Tablet

An enteric coat is designed to:

resist the low pH of gastric fluids but to disrupt or

dissolve when the tablet enters the higher pH of

the duodenum.

124

The presence of a coating presents a physical

barrier between the tablet core and the

gastrointestinal fluids.

Coated tablets therefore not only possess all the

potential bioavailability problems associated

with uncoated conventional tablets, but are

subject to the additional potential problem of

being surrounded by a physical barrier.