BIOPHARMACEUTICS

• Biopharmaceutics is the study of how the

physicochemical properties of drugs, dosage forms
and routes of drug administration

rate and extent of absorption

• how much drug and how fast it enters the systemic

circulation
Factors
• physiological factors associated with the structure and
function of GIT

• physicochemical factors and formulation factors

 A) Physicochemical factors

- for a drug to be absorbed it needs to be:

(i) solution (ii) pass across the membrane GI epithelium

• the physicochemical properties of the drug that will influence

its passage into solution and transfer across the membranes
include:

- dissolution rate
- pKa
- lipid solubility
- chemical stability and complexation potential
Dissolution and Solubility

- Solid drugs need to be dissolved before they can be

absorbed

Noyes-Whitney equation

dC/dt = rate of dissolution

dC DA(Cs  C )
 D = diffusion coefficient
dt h A = effective surface area of the drug particles
h = thickness of the diffusion layer
Cs = the saturation solution solubility
C = concentration of the drug in the GIF
 Physicochemical and physiological factors affecting drug dissolution in the git

Factor Physicochemical parameter Physiological parameter

effect of surface area of drug particle size, wettability surfactants in gastric juice & bile
solubility in the diffusion hydrophilicity, crystal structure, pH, buffer capacity, bile, food
layer solubilization components,
amount of drug already permeability, transit
dissolved diffusivity of drug molecular size
viscosity of luminal contents,
boundary layer thickess motility patterns and
volume of solvent available flow rate GI secretions, co-
administered fluids
GI barrier
Diffusional layer

Drug
particle Diffusion of drug molecules Blood
Through GI contents
 Physiological factors affecting the dissolution rate of drugs

The parameters of Noyes-Whitney eqn can be affected by the

environment of GIT:-
i) diffusional coeficient (D) - may be  by substances that  the
viscosity of the fluid, e.g. food
ii) surfactants and bile salts in gastric juice - will affect both the
wettability of the drug, hence affect surface area, A, exposed to GIT
and the solubility of the drug in the git

iii) the thickness of the diffusion layer, h, will be influenced by the

degree of agitation experienced by each drug particle in the
gastrointestinal tract ; hence  gastric/intestinal motility may  the
dissolution of sparingly soluble drugs
iv) the concentration, C, of drug in solution in the bulk of GIF can be
influenced by: rate of removal of dissolved drug by absorption and the
volume of fluid available for dissolution.
 Drug factors affecting the dissolution rate of drugs

Drug factors affecting dissolution rate: particle size, wettability,

solubility and the form of the drug

i) surface area and particle size -  total surface area of drug in contact with the
gastrointestinal fluid will  dissolution rate
Note: Pen G and erythromycin are unstable in gastric fluids, chemical
degradation will be minimized if they remain in the solid state
ii) solubility in the diffusion layer, Cs - dissolution rate is directly proportional
to intrinsic solubility of a drug. As Cs  so does the dissolution rate
- the solubility of weakly acidic drugs  with pH, as the drug moves down the
GIT from the stomach to the intestines, its solubility , while the solubility of
weak bases  with  pH.
E.g. ketoconazole is a weak base - its absorption is sensitive to pH, dosing it 2
hours after the administration of cimetidine results in significantly reduced
rate and and extent of absorption.
Ways of changing the solubility of a drug
 Salt Form
• Salts of weak acids and weak bases generally have much
higher aqueous solubility than the free acid or base,
therefore if the drug can be given as a salt the solubility can
be increased and we should have improved dissolution.
Crystal form
i) Polymorphism
• Many drugs exist in more than than one crystal forms.
• there are potentially large differences in their physical properties so
that they behave as distinct chemical entities.
• solubility, melting point,density, crystal shape, optical and electrical
properties and vapour pressure are different for each polymorph
 different dissolution characteristics.
Chloramphenicol palmitate - exists in at least three polymorphs (A,
B, C). The B form is apparently more bioavailable.
 ii) Amorphous solids

• several delivery technologies for poorly soluble drugs rely on stabilising the drug
in its amorphous form.

• the amorphous form usually dissolves fast than the corresponding crystalline
forms, hence fast dissolution
100
80 Pure drug
2% PM
60
%UC-781dissolved

5% PM
40 2% SD
20 5% SD
0
0 100 200 300
Time (min)

Dissolution profiles of solid dispersions of UC-781 with PVP K30

 iii) Solvates and hydrates

• another variation in the crystalline form of a drug can occur

if the drug is able to be associated with solvent molecules to
produce crystalline forms known as solvate.

• when water is the solvent, the solvate is termed hydrate.

• solvated and no-solvated forms usually exhibit differences in
dissolution rates  they may also exhibit differences in
bioavailability , especially for poorly soluble drugs that exhibit
dissolution-rate limited bioavailability.
 Factors affecting the concentration of the drug in solution
in GI fluids
• rate and extent of absorption of a drug depend on the effective concentration of
that drug

• principal physicochemical properties influencing the effective concentration in the

GIF include:
- complexation
- micellar solubilization
- adsorption and chemical stability

i) Complexation
• complexation of a drug may occur within the dosage form and/or in the GIF
- beneficial or detrimental to absorption

a) Mucin - normal component of GIF, complexes with drugs

e.g. streptomycin - binds to this component thereby  the available conc. for
absorption
b) Tetracyclines - non-absorbable complexes with dietary component: Ca 2+, Fe2+ ,
Al3+
- milk and iron preparations should be avoided
c) the presence of calcium in the excipients (dicalcium phosphate)
in the dosage form of tetracycline can reduce its bioavailability

other examples - amphetamine and carboxymethycellulose; and

between phenorbabitone and PEG 4000.
d) sometimes complexation can be used to increase drug solubility,
poorly soluble drugs e.g. cyclodextrins

• cyclodextrins are enzymatically modified starches. They are composed

of glucopyranose units which form a ring of either six (-cyclodextrin,
seven (- cyclodextrin) or eight (-cyclodextrin).

The outer surface of the ring - hydrophilic; inner cavity - hydrophobic

- lipophilic molecules can fit into the cavity to form soluble inclusion
complexes
Improvement of physical and chemical stability
of
pharmaceutical compounds

The decomposition of vitamin D3 at 80°C

in the free state and in inclusion form
 iii) Micellar solubilization

• micellar solubilisation can also increase the solubility of drugs

in the GIT. The bile salts improve solubility depending on the
lipophilicity of the drug
 iv) Adsorption

• concurrent administration of drugs and medicines containing solid

adsorbents (antidiarrhoea mixtures) may result in the adsorbents
interfering with the absorption of drugs from the GIT

e.g. the adsorption of a drug on to solid adsorbents such as Kaolin or

charcoal may reduce the rate and/or the extent of absorption due to
the decrease of effective conc. in GIF available for absorption

- some examples of adsorbent-drug interaction : promazine

-charcoal, lincomycin-kaopectate; insoluble excipients: talc
(glidant) adsorbs cynocobalamin. Attapulgite an active
component in antidiarrhoeal mixtures is adsorbed by promazine
 iv) Chemical stability of the drug in the GIF

• if the drug is unstable in the GIF, the amount of drug available

for absorption will be reduced; hence bioavailability will be lower
• instability in the GIF is caused by acids or enzymatic hydrolysis
• the concepts of delaying the dissolution of drugs until they reach the
small intestines to improve their biavailability has been employed to
some drugs e.g. Erythromycin : enteric coating of tablets containing
erythromycin free base to protect against the gastric pH
 the enteric coating will resist the gastric fluid but will disrupts or
dissolve at the less acidic environment of the small intestine.
 application of prodrugs

• peptide drugs - poorly absorbed from GIT

 120
%UC-781 remaining 100
80 jejunum+duodenum
60 ileum
40 colon

20
0
0 50 100 150 200
Incubation time (min)

Rabbit
 DRUG ABSORPTION
- for a drug to be absorbed it must be in solution
- absorption of a drug from a solution can be influenced by
many drug
factors:
- pKa
- lipid solubility
- molecular weight and the number of hydrogen bonds
- its chemical stability

Drug dissociation and lipid solubility

- the dissociation constant and lipid solubility of a drug, and the pH at
the absorption site, often influence the absorption characteristics of a
drug throughout the GIT.

- the interrelationship between the degree of ionization of weak

electrolyte drug and the extent of absorption can be explained by
the pH-partition hypothesis
-according to the pH-partition hypothesis, the GI epithelial acts
as a lipid barrier towards drugs which are absorbed by passive
diffusion
 lipid soluble drugs will pass across the membrane.

- as most drugs are weak electrolytes, the unionized form of weakly

acidic or basic drugs will pass across the GI epithelia

- Consequently, according to this theory

the absorption of weak electrolyte will be determined
chiefly by the extent to which the drug exists in its
unionized form at the site of absorption
• The extent to which a weakly acidic or basic drug ionizes in
solution in the GIF may be calculated using the appropriate
form of the Handerson-Hasselbalch equation

- for a weakly acidic drug having a single ionisable group (e.g.

aspirin, phenylbutazone, indocid, salicylic acid) the equation can be
represented as:

pH – pKa = Log[A-]/[HA]

pKa = -log(Ka)
[A-] and [HA], are the respective concentrations of the ionized
and unionized form of the weakly acidic drug, which are in
equilibrium and in solution in the GI fluid
 - for a weakly basic drug possessing a single ionisable group
(e.g. chlorpromazine), the analogous equation will be:

pKa – pH = Log[BH+]/[B]
[BH+] and [B], are the respective concentrations of the ionized and
unionized form of the weakly basic drug, which are in equilibrium
and in solution in the GI fluid
- according to these equations a weakly acidic drug, pKa 3, will be
predominantly unionized in gastric fluid at pH 1.2 (98.4%) and
almost totally ionised in intestinal fluid at pH 6.8 (99.98%),

whereas, a weakly basic drug, pKa 5, will be almost entirely ionized

(99.98%) at gastric pH 1.2 and predominantly unionized at
intestinal pH of 6.8 (98.4%)
-therefore, a weakly acidic drug is likely to be absorbed from
the stomach, and a weakly basic drug from the intestine

Lipid solubility
- a number of drugs are poorly absorbed from the GIT despite the
fact that their unionized form predominates.
Barbiturates: Barbitone and thiopentone have similar dissociation
constants pKa 7.8 and 7.6, respectively, therefore similar degree of
ionization at intestinal pH. However, thiopentone is absorbed much
better than barbitone
why?: absorption of drugs can also be affected by the lipid solubility

• thiopentone is more lipid soluble than barbitone, therefore it will

exhibit a greater affinity for the GI membrane and hence better
absorbed.
An indication of the lipid solubility of a drug, therefore
whether that drug is liable to be transported across the
membrane is given by its ability to partition between a lipid-
like solvent and water or an aqueous buffer.

- this is known as the drug’s partition coefficient (P); it is a

measure of lipophilicity of a drug.

- the value of (P) is determined by measuring the drug partitioning

between water and a suitable organic solvent at constant
temperature.
- octanol is commonly used

P = concentration of drug in organic phase/concentration

of drug aqueous phase
-Lipophilicity of a drug is critical in the discovery process.
Polar molecules, i.e poorly lipid soluble and relatively large,
e.g. gentamicin, heparin and streptokinase, are poorly
absorbed after oral administration and therefore have to
be given by injection

-smaller molecules that are poorly lipid soluble, i.e. hydrophilic

in nature, such as the b-bloker atenolol, can be absorbed via
the paracellular route

- lipid soluble drugs with favourable partition coefficient are

usually absorbed after oral administration
-if the structure of a compound cannot be modified to yield
lipid soluble compound while maintaining the
pharmacological activity  thus possibility of making
prodrug
- a prodrug is a chemical modification (frequently an ester of
existing drug, which converts back to the parent compound as a
result of metabolism.
- a prodrug has no pharmacological activity.

Examples of prodrugs

Parent drug prodrug ester

Ampicillin pivampicillin pivaloyloxymethyl
Ampicillin bacampicillin carbonate
cefuroxime cefuroxime axetil acetylethyl
terbutaline ibuterol dibutyl
- the other drug property that is important in permeability is the
molecular size.

-also too many hydrogen bonds within a molecule are detrimental

to its absorption

-in general no more than five hydrogen bonds donors and no

More than 10 hydrogen bonds acceptors* if a molecule is to be
well absorbed.

*the* sum of nitrogen and oxygen atoms in the molecule

NB: large number of hydrogen bonds within peptides

Formulation Factors
 Influence of the type of dosage form

-the type of dosage form and its method of preparation or

manufacture can influence its bioavailability.
- With any drug it is possible to alter its bioavailability considerably

by formulation modification.

- the type of oral dosage form will influence the number of possible
intervening
. steps between administration and the appearance of
dissolved drug in the GIF
- Since a drug must be in solution to be absorbed
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: aqueous
solution > aqueous suspension = capsule >
tablet of free acid form
 Solutions

formulation of a drug in solution normally eliminates the in

vivo dissolution step and presents the drug in the most readily
available form for absorption

- In most cases 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

- the dilution of aqueous solution of poorly soluble drugs can

result in precipitation of the drug in gastric fluid.
-When an acidic drug is given in the form of a salt, it may
precipitate in the stomach. There is the possibility with a poorly
water soluble drug such as phenytoin that a well formulated
suspension, of finely divided
-powder, may have a better bioavailability.

- Some drugs which are poorly soluble in water may be dissolved

in mixed water/alcohol or glycerol solvents. This is particularly
useful for compounds with tight crystal structure, higher melting
points that are not ionic. The crystal structure is broken by solution
in the mixed solvent.

Factors that can affect the bioavailability from solutions

- chemical stability exhibited by the drug in aqueous solution and GIF
- complexation
- solubilization
- viscosity of the solution
 Aqueous suspensions
- is a useful way for administering insoluble or poorly soluble
drugs. Absorption may well be dissolution limited, however a
suspension of a finely divided powder will maximize the potential
for rapid dissolution.
- the oral administration of aqueous suspensions result in large total
surface area of dispersed drug being immediately presented to the GIF
- this will facilitates dissolution resulting in improved bioavailability, a
drug contained in a tablet or capsule may show similar properties but
only after delay

Factors that can affect the biovailability from aqueous suspensions

- the particle size and effective surface area of the dispersed drug
- the crystal form of the drug
- formation of complex between the drug and an excipient
- the inclusion of a surfactant as a wetting agent
- the viscosity of the suspension
 Liquid-filled capsules
-liquids can be filled into capsules made from soft or hard
gelatin capsules.

- drugs encapsulated in liquid filled capsules for oral

administration are dissolved or dispersed in non-toxic or
non-aqueous vehicles.

Such vehicles may be water immiscible (lipophilic) or water

miscible (hydrophilic).
Vegetable oils  water immiscible vehicles whereas
polyethylene glycols and non-ionic SAA are water miscible

- following release, a water miscible vehicle disperses and/dissolves

readily in the GIF liberating the drug as either a solution or a very
fine suspension which can be absorbed rapidly
- for the case of gelatin capsules containing drugs in
solutions or suspensions in water-immiscible vehicles, the
release of the contents will be followed by dispersion in the
GIF.

Dispersion is facilitated by emusifiers included in the vehicle.

Once dispersed, a drug might end up as an emulsion, a solution, a
fine suspension or a nano or microemulsion

- greater bioavailabilities of poorly soluble drugs from liquid

filled capsule formulations

• digoxin (solution in a mixture of propylene glycol, ethanol,

polyethylene glycol) - absorbed fast from liquid filled capsules
Protease inhibitors - saquinavir reformulated from powder filled
hard gelatin capsules to a complex soft-gelatin formulation
Factors that can affect the biovailability from liquid filled
capsules

- the solubility of the drug in the vehicles

- the particle size of the drug, nature of the vehicle

- inclusion of wetting agents

- suspending agents
- complexation
 Powder-filled capsules
- the bioavailability of a drug from well formulated powder-
filled hard gelatin capsule dosage form will be better than or at
equal to that from the same drug in a compressed tablet.

- provided that the hard gelatin capsule dissolves fast in GIF and the
encapsulated mass disperses rapidly and efficiently, a relatively
large surface area of the drug will be exposed to the GIF, hence
dissolution will be facilitated.

- theinclusion of excipients (diluents, lubricants and SAA) in a

capsule formulation can have a significant effect on the rate of
dissolution of drugs.

- increase in packing density (a decrease in porosity) - of the

encapsulated mass will result in a decrease in liquid
permeability and dissolution
 Factors that can affect the bioavailability from hard
gelatin capsules

- the surface area and particle size of the drug

- the use of salt form of the drug in preference to the parent
weak acid or basic
- the crystal form of the drug
- chemical stability of the drug
- nature and quantity of diluents, lubricants and
wetting agents
- drug-excipient interactions
- the packing density
- interactions between capsule shell and its contents
 Tablets

Uncoated tablets

- most commonly used oral dosage form.

- quite complex in nature. The biggest problem is overcoming
the reduction in effective surface area produced during the
compression process

- One may start with the drug in a very fine powder, but
then proceeds to compress it into a single dosage unit.

• These processes necessitate the addition of excipients, which

serve to the surface area of the drug back to the its original
precompressed state
-
- the overall dissolution rate and bioavailability of a poorly
soluble drug from uncoated conventional tablet is influenced by
the following factors:

the physicochemical properties of the liberated drug

particles in GIF

- the nature and quantity of the binder, diluent,

disintergrants, lubricant and any wetting agent added

- drug-excipient interaction
-compaction pressure and speed of compression
-storage conditions and age of the tablet
-Compaction pressure
Coated tablets: Purpose of coating?

- improve the appearance of tablet or to add up a company logo.

- mask unpleasant taste or odour and -protection

- presence of coat - presents a physical barrier between tablet

and GIF
- coated tablet which is intended to disintegrate and released
rapidly into soln in the GIF, the coating must first be disrupted
before the process

- sugar coated tablets are usually sealed with a thin film of

poorly water soluble polymer eg. Cellulose polyethylene glycol
commonly added to reduce the barrier of release

- hydrophilic polymers will have no significant effect on the rate

of disintegration
 Enteric coated tablets
- enteric coat is designed to resist the low pH of gastric fluid but
to disrupt or dissolve when the tablet enters higher pH

Polymers: -Cellulose acetate phthalate

- copolymers of methacrylic acid
- hydroxypropyl methyl cellulose phthalate

Uses of enteric coating:

- provide means of delaying the release of a drug until
the dosage form reaches the small intestine
- protection of the drug
- gastric irritation and nausea
 Influence of excipients for conventional dosage forms
- drugs are never administered alone, but rather in a form of a
dosage form: drug + other substances

Why excipients?

- to facilitate the preparation,

- patient acceptability
- functioning of the dosage form as a drug delivery system

Common excipients
disintegranting agents, diluents, lubricants, suspending
agents, coloring agents, chemical stabilizers etc
 Diluents
Outbreak of phenytoin intoxication in Australia - changing the
diluent from calcium sulphate dihydrate to lactose

- Lactose resulted into clinical features of phenytoin

overdose, higher bioavailability resulting into Cp which
was above the maximum safe concentration.

Surfactants
SAA used as emulsifying agents, solubilising agents, suspension
stabilizers or wetting agents can disrupt the integrity

and function of biological membrane  drug penetration 

bioavailabilitymay also result in toxic S/E
- inhibition of drug absorption from the micelles
- therefore, solubilization of the drug  absorption

Normal micelles
non-polar compound

- release of poorly soluble drugs from tablets and hard gelatin

capsules may be increased by the inclusion of SAA in their
formulations
 Lubricants
Lubricants are needed to reduce friction between the powder
and metal surfaces during manufacturing

Hydrophobic in nature e.g. mg stearate

Disintegrants

Are required to break up capsules, tablets and granules into

primary in order to increase the surface area of the drug
exposed to GIT.

Failure to disintegrate may result in incomplete

absorption.
 Viscosity enhancing agents

Often employed in the formulation of liquid dosage

form

Purpose: to control palatability, easy of pouring, rate

of sedmentation

- Complex formation between a drug and a hydrophilic

polymer could reduce the concentration of the drug
available for absorption
- can increase the viscosity of GI content