absorbtion of drugs biopharmaceutics

1. ABSORPTION OF DRUGS
III
1
2021-11-10

2. PHYSIO-CHEMICAL FACTORS AFFECTING
APSORPTION OF DRUGS
 PHYSICAL FACTORS
 PHYSIO-CHEMICAL FACTORS
2021-11-10 2

3. 1. Particle size
2. Crystal Form
3. Solvates And Hydrates
4. Complexation
5. Adsorption
6. Drug Stability And Hydrolysis In GIT
7. Salts
8. Presence of Surfactant
9. Dissolution
2021-11-10 3
PHYSICAL FACTORS

4. 1. PARTICLE SIZE
Smaller particle size, greater surface area then higher will
be dissolution rate, because dissolution is thought to take place
at the surface area of the solute( Drug).
This study is imp. for drugs that have low aqueous solubility.
Absorption of such drugs can be increased by increasing
particle size by Micronization.
 ex. Griseofulvin, active intravenously but not
effective when given orally.
2021-11-10 4

5. To poorly soluble drugs, disintegration agents and surface
active agents may be added.
 ex. Bioavailability of Phenacetin is increased by tween 80.
 Micronization also reduces the dose of some drugs
• ex. the dose of griseofulvin is reduced to one half while the
dose of spironolactone is reduced to one twentieth.
2021-11-10 5
1. PARTICLE SIZE

6. Lesser particle size is always not helpful
Ex. Micronization of Aspirin, phenobarbital, lesser effective
surface area and hence lesser dissolution rate
Reasons:
On their surface, hydrophobic drugs absorb air and reduce
their wettability
 Particle having size below 0.1 micron re-aggregate to form
large particle
 Particle having certain micro size get electrical charge which
preventing contact with wetting medium
2021-11-10 6
1. PARTICLE SIZE

7. Finally, drug size reduction and subsequent increase in
surface area and dissolution rate is always not useful.
Ex. of such drugs are Penicillin G & Erythromycin
These Drugs are unstable and degrade quickly in solution.
Sometimes, reduction in particle size of nitrofurantoin and
piroxicam increase gastric irritation
These problem can be overcome by Microencapsulation.
2021-11-10 7
1. PARTICLE SIZE

8. 2. CRYSTAL FORM
Substance can exist either in a crystalline or amorphous form.
When substance exist in more than one crystalline form, the
different form are called polymorphs and the phenomena as
polymorphism. Two types of Polymorphism:
1) Enantiotropic polymorph ex. Sulfur
2) Monotropic polymorph ex. Glyceryl Stearates
Polymorphs have the same chemical structure but different
physical properties such as solubility, density, hardness etc.
ex. Chlormphenicol has a several crystal form, and when given
orally as a suspension, the drug concentration in the body was
found to be dependent on the percentage of β - polymorph
in the suspension. The form is more soluble and better
absorbed.
2021-11-10 8

9. 2021-11-10 9
Fig: Comparison of Serum levels obtained with suspensions of
chloramphenicol palmitate after oral adm of a dose equivalent to 1.5g
chloramphenicol
100% Form B
50:50 Form B:A
100% Form A
2. CRYSTAL FORM

10. One of the several form of polymorphic forms is more stable
than other. Such a stable form having low energy state and
high melting point and least aqueous solubility.
The remaining polymorphs are called as metastable forms
which have high energy state, low melting point and high
aqueous solubilities.
About 40% of all organic compounds exhibit polymorphism.
Some drug exists in amorphous form which have no internal
crystal structure. Such drugs have high energy states than
crystal form hence they have greater aqueous solubility than
crystalline form.
Ex. Novobiocin, cortisone acetate.
2021-11-10 10
2. CRYSTAL FORM

11. 3. SOLVATES AND HYDRATES
Many drugs associate with solvent and forms solvates
Solvent is water then it is called as hydrate
eg. Anhydrous form of caffeine and theophylline dissolve more rapidly than
hydrous form of these drugs.
Solvate form of drugs with org. solvent may dissolve fast in water than non
solvated form. eg. Fluorocortisone
4. COMPLEXATION
This property can influence the effective drug concentration in GI fluids.
Complexation of drug and GI fluids may alter the rate and extent of
absorption
eg. Intestinal Mucin form complex with Streptomycin and Dihydro
Streptomycin.
In some cases, Poor water soluble drugs can be administered as water
soluble complexes. eg. Hydroquinone with Digoxin.
2021-11-10 11

12. 5.ADSORPTION
It is a physical and surface phenomena where the drug
molecules are held on the surface of some inert substances by
vanderwall’s forces.
ex. Charcoal used as an antidote; When it is co-administered with
promazine, then it reduces the rate and extent of absorption.
Cholestyramine reduces the absorption of warfarin.
6.Drug Stability And Hydrolysis In GIT
Drugs undergoes various reactions due to wide spectrum of pH
and enzymatic activity of GI fluid namely acid and enzymatic
hydrolysis.
eg. T½ of Penicillin G= 1 min. at pH 1
T½ of Penicillin G= 9 min. at pH2
So it means Penicillin G is stable at less acidic pH
Erythromycin and its esters are unstable at gastric fluid
(T½=Less than 2 min.) 12

13.  Certain salts also may have low solubility and dissolution rate.
7. SALTS
 Na or K salts of weak acid dissolves rapidly than free acid.
ex. Na salts of Novobiocin shows improved bioavailability
ex. Al salts of weak acid and pamoate salt of weak base
8. Presence Of Surfactant
Use of wetting agent and Solubilizing agent improve the Dissolution
rate & absorption of drugs.
Ex. Tween 80 increase the rate & extent of absorption of Phenacetin.
9. DISSOLUTION
Disintegration is the formation of dispersed granules from an
intact solid dosage form whereas the dissolution is the
formation of solvated drug molecules from the drug
2021-11-10 13

14. SOLID DRUG
DRUG AT ABSORPTION
SITE
DRUG IN SYSTEMIC
CIRCULATION
DISSOLUTION
ABSORPTION
2021-11-10 14

15. NOYES AND WHITNEY’S EQUATION
The equation to explain the rate of dissolution when the
process is diffusion controlled and involves no chemical
reaction was given by Noyes & Whitney:
dc/dt = KS(CS-C)
Where,
dc/dt = Rate constant, K = constant, S = surface area
of the dissolving solid, Cs=solubility of the drug in the
solvent, C=concentration of drug in the solvent at time t.
Constant K=D/h
Where, D is the diffusion coefficient of the dissolving
material and h is the thickness of the diffusion layer
Here, C will always negligible compared to Cs
So,
dc/dt = DSCs/h
2021-11-10 15

16. PHYSICOCHEMICAL FACTORS
1) pH PARTITION THEORY:
It explains drug absorption from GIT and its distribution across
biomembranes.
Drug (>100 daltons) transported by passive diffusion depend
upon:
 dissociation constant, pKa of the drug
 lipid solubility, K o/w
 pH at absorption site.
Most drugs are either weak acids or weak bases whose degree
of ionization is depend upon pH of biological fluid.
2021-11-10 16

17. For a drug to be absorbed, it should be unionized and the
unionized portion should be lipid soluble.
The fraction of drug remaining unionized is a function of both
Dissociation constant (pKa) and pH of solution.
The pH partition theory is based on following assumption:
 GIT acts as a lipoidal barrier to the transport of the drug
 The rate of absorption of drug is directly proportional to its
fraction of unionised drug
 Higher the lipophilicity of the unionised degree, better the
absorption.
2021-11-10 17
1) pH PARTITION THEORY:

18. HENDERSON HASSELBATCH EQUATION
For acid,
pKa - pH = log[ Ci/Cu]
For base,
pKa – pH = log[ Cu/Ci ]
Eg. Weak acid aspirin (pKa=3.5) in stomach (pH=1) will have
> 99%of unionized form so gets absorbed in stomach
Weak base quinine (pKa=8.5) will have very negligible
unionization in gastric pH so negligible absorption
Several prodrugs have been developed which are lipid
soluble to overcome poor oral absorption of their parent
compounds.
2021-11-10 18

19. eg. Pivampicilin, the pivaloyloxy-methyl ester of
ampicilin is More lipid soluble than ampicilin.
Lipid solubility is provided to a drug by its partition
coefficient between An organic solvent and water or
an aq. Buffer (same pH of absorption Site)
E.g. Barbital has a p.c. of 0.7 its absorption is 12%
Phenobarbital ( p.c = 4.8 absorption=12%)
Secobarbital (p.c =50.7 absorption=40%)
2021-11-10 19

20. 2) DRUG SOLUBILITY
The absorption of drug requires that molecule be in solution at
absorption site.
Dissolution, an important step, depends upon solubility of drug
substance.
pH solubility profile:
pH environment of GIT varies from Acidic in stomach to slightly
Alkaline in a small intestine.
soluble
1)Basic drug 1) Acidic medium ( stomach)
2)Acidic drug 2) basic medium ( intestine)
2021-11-10 20

21. Improvement of solubility:
Addition of acidic or basic excipient
Ex: Solubility of Aspirin (weak acid) increased by
addition of basic excipient.
For formulation of Controlled Release Drugs ,
buffering agents may be added to slow or modify the
release rate of a fast dissolving drug.
2021-11-10 21

22. PHARMACEUTICAL FACTORS
Here, Absorption rate depends on the dosage
Form which is administred, ingredients used,
procedures used in formulation of dosage forms.
The availability of the drug for absorption from the
dosage forms is in order.
Solutions > Suspensions > capsules > Compressed
Tablets > Coated tablets.
2021-11-10 22

23. SOLUTIONS
Shows maximum bioavailability
2021-11-10 23
Fig: Blood levels of Phenobarbital vs time after IM inj
of three dosage forms
Blood
level
(ugcm
-3
)
Solution
29.96 ug Suspension
6.63 ug Suspension

24. 2021-11-10 24
Factors affecting Absorption from solution are as follows:
1.Chemical stability of drug
2.Complexation: between drug and excipients of
formulation to increase the solubility, stability.
3. Solubilization: incorporation of drug into micelles to
increase the solubility of drugs.
4. Viscosity
5. Type of solution: Whether aqueous or oily solution.
SOLUTIONS

25. SUSPENSIONS:
It comes next after solutions with respect to bioavailability
Factors that affects absorption from suspensions are
1. Particle size and effective surface area of dispersed
phase
2. Crystal form of drug: some drug can change their crystal
structure. Eg. Sulfathiazole can change its polymorphic
form, it can be overcome by addition by adding PVP.
3. Complexation: Formation of non-absorbable complex
between drug and other ingredients.
Eg. Promazine forms a complex with attapulgite.
2021-11-10 25

26. 4. Inclusion of surfactant
Eg. The absorption of phenacitin from suspension is
increased in presence of tween 80.
5. Viscosity of suspension
Eg. Methyl cellulose reduces the rate and absorption of
Nitrofurantoin
6. Inclusion of colorants:
Eg. Brilliant blue in phenobarbitone suspension.
2021-11-10 26
SUSPENSIONS:

27. CAPSULES
Two types of capsule
1.Hard gelatin capsule
2. Soft gelatin capsule
2021-11-10 27

28. HARD GELATIN CAPSULE
The rate of absorption of drugs from capsule is function
Of some factors:
1.Dissolution rate of gelatin shell.
2.The rate of penetration of GI fluids into encapsulated mass
3.The rate at which the mass disaggregates in the GI fluid
4. The rate of dissolution.
5. Effect of excipients;
a).Diluents
b).Lubricants
c). Wetting characteristics of drug
d).Packing density
2021-11-10 28

29. SOFT GELATIN CAPSULE
SGS has a gelatin shell thicker than HGS, but shell is
Plasticized by adding glycerin, sorbitol. SGS may used to contain
non aqueous solution or liquid or semi solid.
SGC have a better bioavailability than powder filled HGC
And are equivalent to emulsions.
Eg. Quinine derivative was better absorbed from SGC
Containing drug base compared with HGC containing
HCl salts.
Grieseoflavin exhibited 88% absorption from soft gelatin
Capsules compared to HGC(30%)
2021-11-10 29

30. TABLETS
1.Compressed tablets
2. Coated tablets
2021-11-10 30

31. Compressed tablets
Bioavailability are more due to large reduction
in surface area.
Intact tablets a granules primary drug particles
A B
Drug in GI fluid
Drug absorbed in body
K1
K2
K3
K4
2021-11-10 31

32. The rate constants decrease in the following order.
K3>>K2>>K1
The overall dissolution rate and bioavailability of a poor
Soluble drugs is influenced by:
1.The physicochemical properties of liberated particles.
2. The nature and quantity of additives.
3. The compaction pressure and speed of compression.
4. The storage and age of tablet
2021-11-10 32

33. 1.Effect of diluents :
Na Salicylates + starch = Faster dissolution
Na salicylates + lactose=Poor dissolution.
2.Effect of Granulating agent:
Phenobarbital + Gelatin solution=Faster dissolution
Phenobarbital+PEG 6000= poor dissolution.
3.Effect of lubricants:
Magnesium stearate will retard the dissolution of
aspirin tablet, Whereas Sodium Lauryl Sulfate
enhance the dissolution.
2021-11-10 33

34. 4.Effect of disintegrants:
Starch tend to swell with wetting and break apart the
dosage form. It is reported that 325mg of salicylic
acid tablet were prepared by using different
concentrations (5%,10%,20%) and
max. dissolution was achieved With 20% starch.
5. Effect of colorants.
6.Effect of Compression force.
2021-11-10 34

35. COATED TABLETS:
There are three types of coating
Sugar coating
Film coating
Enteric coating
SUGAR COATING:
Sugar, Shellac, fatty glycerides, bees wax, silicone resin
Sub coating agent: Talc, acacia, starch.
FILM COATING:
Polymers, dispersible cellulose derivatives like HPMC
CMC.
ENTERIC COATING:
Shellac, cellulose acetate phthalate etc.
2021-11-10 35

36. Factors affecting the drug release are
1.Thickness of coating
e.g.. Quinine shows decrease in rate of absorption
if coated with cellulose acetate phthalate.
2.The amount of dusting powder:
3.Effect of ageing:
e.g. The shellac coated tablets of Para amino salicylic
acid when given after two years plasma concentration
of 6-7mg/100ml. However the tablets stored for 3½
years showed plasma concentration of only 2mg/100ml
which is the sub therapeutic effect.
2021-11-10 36