Bioavailability means the rate and extent to which the active ingredient is absorbed from a drug product and becomes available at the site of action. When the drug is given orally, only part of the administered dose appears in the plasma. By plotting plasma concentrations of the drug versus time, one can measure the area under the curve (AUC). This curve reflects the extent of absorption of the drug.

1. FORMULATION FACTORS
EFFECTING BIOAVAILABILITY
OF DRUGS
BY
NADIKATLAANUSHA
M.Pharm

2. CONTENTS
FORMULATION FACTORS AFFECTING ORALABSORPTION
1. DISINTEGRATION TIME
2. MANUFACTURING VARIABLES
A. METHOD OF GRANULATION
B. COMPRESSION FORCE
3. NATURE & TYPE OF DOSAGE FORM
A. SOLUTIONS
B. SUSPENSIONS
C. CAPSULES
D. TABLETS
E. IN VITRO CORRELATION OF DRUG ABSORPTION
4. PHARMACEUTICAL INGREDIENTS
5. PRODUCT AGE & STORAGE CONDITIONS
ANUSHA NADIKATLA

3. INTRODUCTION
Bioavailability means the rate and extent to which the active
ingredient is absorbed from a drug product and becomes available at
the site of action.
When the drug is given orally, only part of the administered dose
appears in the plasma.
By plotting plasma concentrations of the drug versus time, one can
measure the area under the curve (AUC).
This curve reflects the extent of absorption of the drug.
ANUSHA NADIKATLA

4. Bioavailability of a drug administered orally is the ratio of the area
calculated for oral administration compared with the area calculated
for IV injection.
The bioavailability of a drug can be influenced by factors associated
with the formulation and production of the dosage form.
For a given drug, a 2 to 5 fold difference could be observed in the oral
bioavailability of a drug depending upon the nature and type of the
dosage form.
This difference is due to the relative rate at which a particular dosage
form releases the drug to the biological fluids because a number of
possible intervening steps occur between administration and
appearance of dissolved drug in the systemic circulation.
ANUSHA NADIKATLA

5. COURSE OF EVENTS THAT OCCUR
FOLLOWING ORALADMINISTRATION OF
VARIOUS DOSAGE FORMS
ANUSHA NADIKATLA

6. FORMULATION FACTORS AFFECTING ORAL
ABSORPTION
1. DISINTEGRATION TIME
2. MANUFACTURING VARIABLES
A. Method of granulation
B. Compression force
3. NATURE & TYPE OF DOSAGE FORM
4. PHARMACEUTICAL INGREDIENTS
5. PRODUCT AGE & STORAGE CONDITIONS
ANUSHA NADIKATLA

7. DISINTEGRATION TIME
Rapid disintegration is important to have a rapid absorption, so lower
disintegration time is required.
Now disintegration time of tablet is directly proportional to amount of
binder & Compression force.
And one thing should be remembered that in vitro disintegration test
gives no means of a guarantee of drugs bioavailability because if
disintegrated drug particles do not dissolve then absorption is not
possible.
ANUSHA NADIKATLA

8. MANUFACTURING VARIABLES
a) Method of granulation
Wet granulation yields a tablet that dissolves faster than those made
by other granulating methods.
But wet granulation has several limitations like formation of crystal
bridge or chemical degradation.
Other superior recent method named APOC (agglomerative phase of
communition) that involves grinding of drug till spontaneous
agglomeration and granules are prepared with higher surface area.
So tablet made up of this granules have higher dissolution rate.
ANUSHA NADIKATLA

9. b) Compression force
Higher compression force yields a tablet with greater hardness and
reduced wettability and hence tablet will have long disintegration
time.
But on other hand higher compression force cause crushing of drug
particles into smaller ones with higher effective surface area which
causes decrease in disintegration time.
So effect of compression force should be thoroughly studied on each
formulation.
ANUSHA NADIKATLA

10. NATURE AND TYPE OF DOSAGE FORM
A. SOLUTIONS
B. SUSPENSIONS
C. CAPSULES
D. TABLETS
E. IN VITRO CORRELATION OF DRUG ABSORPTION
I. DISINTEGRATION TESTING
II. DISSOLUTION TESTING
ANUSHA NADIKATLA

11. The role of the drug formulation in the delivery of drug to the site of
action should not be ignored.
With any drug it is possible to alter its bioavailability considerably by
formulation modification.
With some drugs an even larger variation between a good formulation
and a bad formulation has been observed.
Since a drug must be in solution to be absorbed efficiently from the
GIT, 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.
ANUSHA NADIKATLA

12. SOLUTION DOSAGE FORMS
Drugs are commonly given as solution in cough/cold remedies and in
medication for the young and elderly.
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. Since
absorption will generally be more rapid in the intestine.
When an acidic drug is given in the form of a salt, it may precipitate
in the stomach.
However, this precipitate is usually finely divided and is readily
redissolved and thus causes no special absorption problems.
There is the possibility with a poorly water soluble drug such as
phenytoin that a well formulation suspension, of finely divided
powder, may have a better bioavailability.
ANUSHA NADIKATLA

13. 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
and higher melting points that are not ionic.
The crystal structure is broken by solution in the mixed solvent.
An oily emulsion or soft gelatin capsules have been used for some
compounds with lower aqueous solubility to produce improved
bioavailability.
SOLID SOLUTIONS
The solid solution is a formulation in which drug is trapped as a solid
solution or monomolecular dispersion in a water-soluble matrix.
Although the solid solution is an attractive approach to increase drug
absorption, only one drug, griseofulvin, is currently marketed in this
form
ANUSHA NADIKATLA

14. FORMULATION FACTORS AFFECTING
BIOAVAILABILITY OF SOLUTIONS
In most cases absorption of drugs from solution dosage forms is rapid
and complete, where the drug will be available in soluble form ready for
direct absorption.
FACTORS:
The chemical stability exhibited by the drug in aqueous solution and
in the gastro-intestinal fluids.
Chemical nature of the drug.
Effect of viscosity of the solution.
Solubilization.
Complexation.
ANUSHA NADIKATLA

15. SUSPENSION DOSAGE FORMS
A well formulated suspension is second only to a solution in terms of
superior bioavailability.
Absorption may be dissolution limited, however a suspension of a
finely divided powder will maximize the potential for rapid
dissolution. A good correlation can be seen for particle size and
absorption rate.
With very fine particle sizes the dispersibility of the powder becomes
important. The addition of a surface active agent will improve
dispersion of a suspension and may improve the absorption of very
fine particle size suspensions otherwise caking may be a problem.
As a suspension ages there is potential for increased particle size with
an accompanying decrease in dissolution rate. Smaller particles have
higher solubility and will tend to disappear with the drug coming out
of solution on larger particles. ANUSHA NADIKATLA

16. FORMULATION FACTORS AFFECTING
BIOAVAILABILITY OF SUSPENSIONS
This dosage form is useful in administering an insoluble or poorly
water soluble drug.
The absorption of drug from this dosage form is dissolution rate
limited.
Suspensions provide a larger surface area to the drug particles thus
enhancing the dissolution rate and absorption.
FACTORS:
Particle size of suspension
Suspension stability
Viscosity of suspension
Addition of wetting agents
Complexation ANUSHA NADIKATLA

17. FORMULATION FACTORS AFFECTING
BIOAVAILABILITY OF EMULSIONS
These dosage forms are superior to suspensions in administering
poorly aqueous soluble lipophilic drugs.
Eg: Indoxole (NSAID) when it is dissolved in a vegetable oil and
emulsified in water, absorption increases 3-fold over its aqueous
suspension.
FACTORS:
Particle size of the drug.
Addition of emulsifying agents.
Solubility of drug in oily vehicle.
ANUSHA NADIKATLA

18. CAPSULE DOSAGE FORMS
In theory a capsule dosage form should be quite efficient.
The hard gelatin shell should disrupt rapidly and allow the contents to
be mixed with the GIT contents.
The capsule contents should not be subjected to high compression
forces which would tend to reduce the effective surface area, thus a
capsule should perform better than a tablet.
This is not always the case, if a drug is hydrophobic a dispersing agent
should be added to the capsule formulation.
These diluents will work to disperse the powder, minimize
aggregation and maximize the surface area of the powder.
Tightly packed capsules may have reduced dissolution and
bioavailability.
ANUSHA NADIKATLA

19. ANUSHA NADIKATLA

20. FORMULATION FACTORS AFFECTING
BIOAVAILABILITY OF HARD GELATIN CAPSULES
Generally the bioavailability of a drug from a hard gelatin capsules will
be better than or equal to that from the same drug in a compacted tablet
FACTORS:
Dissolution rate of gelatin shell.
The rate of penetration of GI fluids into encapsulated mass.
The rate at which the mass disaggregates in the GI fluid.
The rate of dissolution of dispersed drug particles.
Packing density of the capsule contents.
Inclusion of excipients in the capsule formulation.
Effect of excipients.
ANUSHA NADIKATLA

21. SOFT GELATIN CAPSULE
Soft gelatin capsule has a gelatin shell thicker than hard gelatin
capsules, but shell is plasticized by adding glycerin, sorbitol.
Soft gelatin capsules may be used to contain non aqueous solution or
liquid or semi solid.
Soft gelatin capsules have a better bioavailability than powder filled
hard gelatin capsules and are equivalent to emulsions.
Ex: Quinine derivative was better absorbed from soft gelatin capsules
containing drug base compared with hard gelatin capsules containing
HCl salts.
Grieseoflavin exhibited 88% absorption from soft gelatin capsules
compared to hard gelatin capsules (30%)
ANUSHA NADIKATLA

22. FORMULATION FACTORS AFFECTING
BIOAVAILABILITY OF SOFT GELATIN CAPSULES
Drugs encapsulated in liquid filled capsules are dissolved or dispersed in
non-toxic, non-aqueous vehicles.
Factors:
Solubility of drug in vehicle.
Dissolution and splitting of flexible shell.
Nature of the vehicle.
Inclusion of a surfactant as a wetting or emulsifying agent.
Particle size, density, crystal form of the drug, selection of diluents
etc., influence bioavailability of soft gelatin capsules.
ANUSHA NADIKATLA

23. For hydrophobic drugs with a fine particle size in capsule results in
decrease in porosity of the powdered drug and thus decreased
penetrability by the solvent which results clumping of particle.
Soft elastic capsule dissolve faster than hard gelatin capsule & tablets,
which shows better bioavailability from oily solutions, emulsions, or
suspensions.
The problem with SGC is high water content of shell, moisture
migrate in to the shell causes crystallization of the drug which results
in altered dissolution characteristics
ANUSHA NADIKATLA

24. TABLET DOSAGE FORMS
The tablet is the most commonly used oral dosage form. It is also 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.
INGREDIENTS
Tablet ingredients include materials to break up the tablet formulation.
Drug : may be poorly soluble, hydrophobic.
Lubricant : usually quite hydrophobic.
Granulating agent : tends to stick the ingredients together.
Filler: may interact with the drug, etc., should be water soluble.
Wetting agent : helps the penetration of water into the tablet.
Disintegration agent: helps to break the tablet apart.
ANUSHA NADIKATLA

25. SUSTAINED RELEASE TABLET
BENEFITS
For short half-life drugs, sustained release can mean less frequent
dosing and thus better compliance.
Reduce variations in plasma/blood levels for more consistent result.
PROBLEMS
More complicated formulation, may produce more erratic results.
A sustained release product may contain a larger dose, i.e. the dose for
two or three (or more) 'normal' dosing intervals.
A failure of the controlled release mechanism may result in release of
a large potentially toxic dose.
More expensive technology.
ANUSHA NADIKATLA

26. TYPES OF PRODUCTS
Erosion tablets
Waxy matrix: Matrix erodes or drug leaches from matrix.
Coated pellets: Different pellets (colors) have different release
properties.
Coated ion exchange
Osmotic pump: Insoluble coat with small hole. Osmotic pressure
pushes the drug out at a controlled rate.
ANUSHA NADIKATLA

27. Disintegration time is the time required for the tablet to break down
into particles which can pass through a sieve while agitated in a
specified fluid.
This Indicates the time to break down into small particles not
necessarily solution.
In the process of tablet manufacturing the drug is often formulated
into a granular state (that is small but not fine) particles.
This is done as the granule often has better flow properties than a fine
powder and there is less de-mixing leading to better uniformity. The
granules are then compressed to produce the tablet.
The disintegration test may lead to an end point of tablet to granule
only, although the granules may be larger than the sieve opening.
ANUSHA NADIKATLA

28. FORMULATION FACTORS AFFECTING
BIOAVAILABILITY OF TABLETS
REDUCTION IN EFFECTIVE SURFACE AREA
This is due to granulation and subsequent compression into tablet.
This factor is especially important for tablets containing drugs that
should disintegrate rapidly and completely in the gastro intestinal
fluids if rapid release, dissolution and absorption are required.
PHYSICOCHEMICAL PROPERTIES OF THE DRUG
Nature and quantity of excipient.
Size of the granules and their method of manufacture.
The compaction pressure and speed of compaction used in tableting.
Drug-excipient interactions.
ANUSHA NADIKATLA

29. COATED TABLETS
Coat is generally used to mask unpleasant taste, odor and to protect
the ingredients from decomposition during storage or to improve the
tablets appearance.
This coating acts as barrier between the solid drug and drug in
solution.
This barrier must break down quickly or it may hinder a drug's
bioavailability.
ANUSHA NADIKATLA

30. SUGAR & FILM COATINGS
Presence of water impermeable sealing coat can potentially retard
drug release from sugar coated tablets.
Ex: studies with quinine tablets coated with cellulose acetate pthalate
showed a decrease in both rate and extent of absorption with increase
in thickness of coating.
Sugar coating will take more time than film coating.
Care should be taken while selecting the coating material. Ex: methyl
cellulose which retards the dissolution.
ANUSHA NADIKATLA

31. ENTERIC COATED TABLETS
It is a special film coated design to restrict the gastric fluids & to
dissolve in small intestine.
It protects the drug from the degradation in the stomach. Ex:
erythromycin.
Minimizes the gastric distress caused by some drugs. Ex: aspirin.
These tablets must empty the stomach before the drug absorption can
begin.
The polymers with pKa values ranging from 4-7 have been found to
use.
Thickness of coating will affect the bioavailability in these
formulations.
ANUSHA NADIKATLA

32. IN VITRO CORRELATION OF DRUG ABSORPTION
DISINTEGRATION
It is provided to determine the compliance with the limit on
disintegration stated in the individual monograph.
Formulations tested are un coated, plain coated, enteric coated, buccal,
sublingual tablets and hard gelatin capsules.
For un-coated tablets and capsules the disintegration time is 30 mins,
whereas for coated tablets it is 2 hrs.
Disintegration can be aided by incorporating disintegrants in suitable
amount during formulation. ANUSHA NADIKATLA

33. DISSOLUTION
The time taken for the drug to dissolve from the dosage form is a
measure of drug dissolution. Numerous factors affect dissolution.
Thus the dissolution medium, agitation and temperature are carefully
controlled.
The dissolution mediums might be water, simulated gastric juice, or
0.1M HCl. The temperature is usually 37°C.
The apparatus and specifications may be found in the U.S.P.
ANUSHA NADIKATLA

34. The U.S.P. methods are official however there is a wide variety of
methods based on other apparatus.
These are used because they may be faster, cheaper, easier, sensitive
to a particular problem for a particular drug, or developed by a
particular investigator.
Dissolution tests are used as quality control to measure variability
between batches which maybe reflected by in vivo performance.
Thus the in vitro test may be a quick method of ensuring in vivo
performance.
Thus there has been considerable work aimed at defining the in
vitro/in vivo correlation. ANUSHA NADIKATLA

35. EFFECT OF PHARMACEUTICAL INGREDIENTS OR
EXCIPIENTS ON BIOAVAILABILITY OF DRUGS
More the number of excipients in dosage form, more complex it is &
greater the potential for absorption and bioavailability problems.
Excipients are added to ensure the acceptability, physiochemical
stability, bioavailability and functionability of the drug product.
Excipients are added to a formulation to provide certain functional
properties to the drug and dosage form.
ANUSHA NADIKATLA

36. Excipients are used to improve the compressibility of the active drug,
stabilize the drug against degradation, decrease gastric irritation,
control the rate of drug absorption from the absorption site, increase
drug bioavailability.
Excipients in the drug product may also affect the dissolution kinetics
of the drug, either by altering the medium in which the drug is
dissolving or by reacting with the drug itself.
Excipients may increase the retention time of the drug in the
gastrointestinal tract and therefore increase the total amount of drug
absorbed.
ANUSHA NADIKATLA

37. EXAMPLES
Changing an excipient from calcium sulfate to lactose and increasing
the proportion of magnesium silicate, increases the activity of oral
phenytoin.
Systemic availability of thiamine and riboflavin is reduced by the
presence of Fuller’s earth.
Absorption of tetracycline from capsules is reduced by calcium
phosphate due to complexation.
Tablet lubricants such as magnesium stearate may repel water and
reduce dissolution when used in large quantities.
Coatings particularly shellac, will crosslink upon aging and decrease
the dissolution rate.
ANUSHA NADIKATLA

38. Low concentrations of surfactants decrease the surface tension and
increase the rate of drug dissolution; whereas higher surfactant
concentrations tend to form micelle with the drug and decrease the
dissolution rate.
Some excipients such as sodium bicarbonate may change the pH of
the medium surrounding the active drug substance. Aspirin a weak
acid when formulated with sodium bicarbonate will form water
soluble salt in an alkaline medium, in which the drug rapidly
dissolves.
Most of these types of interactions were reported some time ago and
are unlikely to occur in the current environment of rigorous testing of
new dosage forms and formulations.
ANUSHA NADIKATLA

39. MOST COMMON EXCIPIENTS
Vehicles
Diluents/fillers
Binders
Disintegrants
Lubricants
Suspending agents
Colorants
Surfactants
Complexing agents ANUSHA NADIKATLA

40. VEHICLES
Bioavailability of a drug from vehicles depends on its miscibility with
biological fluid.
Aqueous soluble vehicles are miscible with the body fluids and drugs
from them are rapidly absorbed. Ex: propylene glycol.
In case of water immiscible vehicles the rate of drug absorption
depends upon its partitioning from oil phase to aqueous body fluids.
Viscosity of the vehicles is another factor in the absorption of drugs.
ANUSHA NADIKATLA

41. DILUENTS
Hydrophilic diluents form a coat around hydrophobic drug particles
and thus promotes dissolution and absorption of poorly water soluble
hydrophobic drugs.
Change of diluent from one to another can cause bioavailability
problems.
Ex: In phenytoin formulation calcium phosphate was replaced by
lactose in which dissolution was so fast that phenytoin levels in
plasma rise to toxic levels, due to sudden increase in bioavailability.
ANUSHA NADIKATLA

42. BINDERS AND GRANULATING AGENTS
Hydrophilic binders impart hydrophilic properties to granule surface
and show better dissolution profile with poorly wettable drugs.
Eg: phenacetin, starch, gelatin, PVP.
Large amount of binders increase hardness and decrease disintegration
and dissolution of tablets.
Eg:PEG6000 was found to be a deleterious binder as it forms a poorly
soluble complex with the drug.
ANUSHA NADIKATLA

43. DISINTEGRANTS
Mostly hydrophilic in nature.
These are required to break up capsules, tablets and granules into
primary powder particles in order to increase the surface area of the
drug exposed to the biological fluids.
A decrease in the amount of disintegrant can significantly lower the
bioavailability.
ANUSHA NADIKATLA

44. LUBRICANTS
Both tablets and capsules require lubricants in their formulation to
reduce friction between the powder and metal surfaces during their
manufacture.
The commonly used lubricants are hydrophobic in nature, thus inhibit
penetration of water into tablet and affect their dissolution and
disintegration.
Some lubricants like sodium lauryl sulphate and carbowaxes promote
drug dissolution.
ANUSHA NADIKATLA

45. SUSPENDING AGENTS/VISCOSITYAGENTS
Stabilize the solid drug particles by reducing their rate of settling
through an increase in the viscosity of medium and thus affect drug
absorption.
Viscosity imparters act as a mechanical barrier to diffusion of drug
from its dosage form and retard GI transit of drug.
Macromolecular gum forms unabsorbable complex with drug e.g. Na
CMC.
ANUSHA NADIKATLA

46. COLORANTS
Even a low concentration of water soluble dye can have an inhibitory
effect on dissolution rate of several crystalline drugs.
The dye molecules get absorbed onto the crystal faces and inhibit the
drug dissolution.
For example: Brilliant blue retards dissolution of sulfathiazole.
ANUSHA NADIKATLA

47. SURFACTANTS
These may enhance or retard drug absorption either by interacting
with the drug or the membrane or both.
Surfactants have been considered as absorption enhancers, again
mostly in animals.
Polyoxyethylene ethers have been shown to enhance gastric or rectal
absorption of lincomycin,penicillin, cephalosporins, and fosfomycin
in rats and rabbits.
However, in humans, oral polyoxyethylene-20-oleyl ether resulted in
poor and variable insulin absorption.
ANUSHA NADIKATLA

48. They enhance absorption by promotion of wetting. Eg:polysorbate 80
with phenacetin.
Surfactants also have inhibitory action on drug absorption due to
unabsorbable drug-micelle complex above critical micelle
concentration.
In general, unionic surfactants have little effect on membrane structure
but cationic surfactants have been associated with reversible cell loss
and loss of goblet cells.
Physiologic surfactants – bile salts – promotes absorption – e.g.
Griseofulvin, steroids.
It may decrease absorption when it forms the unabsorbable complex
with drug above CMC.
ANUSHA NADIKATLA

49. BILE SALTS
Bile contains conjugates of cholic acid and chenodeoxycholic acid,
which emulsify dietary fat, facilitate lipolysis, and transport lipid
molecules through the unstirred layer of the intestinal mucosa by
micellar solubilization.
The ability of bile salts to promote lipid absorption has prompted their
investigation as absorption enhancers for drugs, with modest success.
Absorption of insulin can be increased by bile salts, both in
experimental animals and in humans.
ANUSHA NADIKATLA

50. COMPLEXING AGENTS
Complex formation has been used to alter the physicochemical and
biopharmaceutical properties of the drug.
Complexation has been used to enhance drug bioavailability.
Eg: Dissolution of Ergotamine increases through formation of soluble
Ergotamine tartarate-caffeine complex.
Complexation can be deleterious to absorption of some drugs due to
formation of poorly soluble complex.
Eg:Complexation of tetracycline with divalent and trivalent cations
like calcium and iron etc..
ANUSHA NADIKATLA

51. EFFECT OF EXCIPIENTS ON THE PHARMACOKINETIC
PARAMETERS OF ORAL DRUG PRODUCTS

52. PRODUCT AGE AND STORAGE CONDITIONS
A number of changes, especially in the physiochemical properties of a
drug in a dosage from, can result due to aging and alteration in storage
conditions which can adversely affect bioavailability.
Ex: precipitation of drug in solution, particle size of suspension and
hardening of tablet leads to decrease rate of change in drug dissolution
& absorption.
ANUSHA NADIKATLA

53. REFERENCES
1. Brahmankar D.M., Jaiswal S.B., First edition, “Absorption of
Drugs” Biopharmaceutics and Pharmacokinetics – A treatise,
Vallabh Prakashan, Delhi 1995, Page No. 5-75.
2. Shargel L., Andrew B.C., Fourth edition “Physiologic factors
related to drug absorption” Applied Biopharmaceutics and
Pharmacokinetics, Prentice Hall International, INC., Stanford
1999. Page No. 99-128.
3. Pharmaceutics , the Science of Dosage form Design By M.E.
Aulton.
4. Swarbrick J., Boylan J.C., “Absorption” Encyclopedia of
Pharmaceutical Technology, Marcel Dekker, INC., New York
1988:1:1-32.
ANUSHA NADIKATLA