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Bio – life
Pharmaceutics
– general area of study concerned with the
formulation, manufacture, stability and effectiveness of
pharmaceutical dosage forms.
Biopharmaceutics
• Scope of Biopharmaceutics
1. Encompasses all possible effects observed following the administration of
the drug in the various dosage forms.
2. Encompasses all possible effects of various dosage forms on biological
response
3. Encompasses all possible physiological factors which may affect the drug
in various dosage forms.
Pharmacokinetics
Definition
-Pharmacokinetics (in Greek:〝pharmacon〞meaning drug and
〝kinetikos〞meaning putting in motion , the study of time
dependency) is a branch of pharmacology dedicated to the
determination of the fate of substances administered externally
to a living organism.
Routes Of Drug
Administration
Parenteral Enteral
MTC
Therapeutic range
Intensity
MEC
Duration
Onset time
100
90
80
concentration
70
60 IV
50 Oral
40 Rectal
30
20
10
0
0 5 10 20 30 60 120 180
minutes
Pharmacokinetic models
★Drugs are in a dynamic state with the body.
★Physicochemical considerations
1.pKa and degree of ionization
2.lipid solubility
3.dissolution of rate
PHYSICOCHEMICAL FACTORS
1) Drug solubility & dissolution rate :
The rate determining steps in absorption of orally administered
drugs are:
1. Rate of dissolution
2. Rate of drug permeation through the biomembrane.
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Solid
dosage
form
Solid
drug
particles
Drug in
solution at
absorption
site
Drug in the
body
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Prerequisite for the absorption of a drug is that it must be present
in aqueous solution & this is depends on drug’s aqueous solubility
& its dissolution rate.
a) HYDROPHILIC DRUGS:
In hydrophilic drugs the small particles have higher energy than
the bulk of the solid resulting in an increased interaction with the
solvent.
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Examples,
1.Griesiofulvin – Dose reduced to half due to micronisation.
2.Spironolactone – the dose was decreased to 20 times.
3.Digoxin – the bioavailability was found to be 100% in
micronized tablets.
b) HYDROPHOBIC DRUGS:
In this micronisation techniquies results in decreased effective
surface area & thus fall in dissolution rate.
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2) The particles reaggregates to form large particles due to
their high surface free energy, which either float on the
surface or settle on the bottomof the dissolution medium.
3) Electrically induced agglomeration owing to surface
charges prevents intimate contact of the drug with the
dissolution medium.
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3) Polymorphism & Amorphism:
Depending upon the internal structure, a solid can exist either in a
crystalline or amorphous form. When a substance exists in more
than one crystalline form, the different forms are designated as
polymorphs, and the phenomenon as polymorphism.
Polymorps are of two types:
1) Enantiotropic polymorph is the one which can be reversibly
changed into anthor form by altering the temperature or
pressure.E.g. Sulfur.
2) Monotropic polymorph is the one which is unstable at all the
temperature or pressures. E.g. glyceryl strarates.
But sometimes more soluble salt form of drug may result in poor
absorption. e.g. sodium salt of phenobarbitone viz., its tablet swells
and did not get disintegrate, thus dissolved slowly and results in
poor absorption.
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GI Barrier
diffusion layer
higher pH(5- Bulk of Blood
6) solution GI Lumen
relatively
lower pH(1-3)
Soluble
Salt form of
of Diffusion
of the drug
wea Drug
k soluble in
drug rapid drug in blood
acid
particles dissolutio solution
n
fine precipitate
of weak acid
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A) DRUG pKa AND GI pH:
Amount of drug that exists in un-ionized form and in ionized
form is a function of pKa of drug and pH of the fluid at the
absorption site, and it can be determined by Handerson-Hasselbach
equation:
•For weak acids,
pH = pKa + log [ionized]
[un-ionized] ..(1.1)
Ra = CGIT = 1+10pHGIT-pKa
Cplasma 1+10pHplasma-pKa …. (1.5)
Rb = CGIT = 1+10pKa-pHGIT
Cplasma 1+10pKa-pHplasma .... (1.6)
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B) LIPOPHILICITY AND DRUG ABSORPTION:
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8) Drug stability:
A drug for oral use may destabilize either during its shelf life or in
the GIT.
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Physiological factors
1.Age
2.Gastric Empting
3.Intestinal Transit
4.GI pH
5.Blood Flow to
GIT
6.Diseased State
7.GI Content
8.First pass effect
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1. Age
• In infants GI pH is high and intestinal surface
and blood flow to GIT is low as compared to
adults results in poor drug absorption.
• In elderly people, alteration in drug
absorption becuase of alteration in gastric
emptying, and incidents of achlorhydria and
bacterial over growth in small intestine.
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2. Gastric emptying
Defined, as passage of contents of stomach
into the intestine.
Rapid gastric emptying is advisable where:
• Rapid onset action is required, eg; sedatives.
• Dissolution of drug occurs in intestine.
eg; Enteric coated tablets.
• Drug is unstable in gastric fluids.
• Drug is best absorbed from distal part of small
intestine, eg vitamin B 12 .
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Kinetics of GI emptying
GI emptying is first-order kinetics many parameters
are used to quantify a gastric emptying;
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1.Volume of meal: Larger the bulk of the meal, longer the gastric
time and however an initial rapid rate of emptying is observed with
large meal volume and initial lag phase in emptying of small volume
meals.
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5.Exercise: Vigorous physical training retards
gastric empting.
2.Dissolution: A large no. of drugs either weak acids or weak bases, their
3.Absorption: Depending upon drug pKa whether its an acidic or basic drug
Eg; erythromicin
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5. Blood flow to git
GIT is extensively supplied by blood capillary,
about 28% of cardiac output is supplied to
GIT portion, most drug reach the systemic
circulation via blood only.
Any factor which affects blood flow to GIT may
also affect absorption.
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6. Disease state
Several disease state may influence the rate and
extent of drug absorption.
Three major classes of disease may influence
bioavailability of drug.
• GI diseases
• CVS disease
• HEPATIC disease
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GI diseases
A. GI infections :
1.Celiac disease: (characterized by destruction of
villi and microvilli) abnormalities associated with
this disease are increase GI emptying rate and GI
permeability, alter intestinal drug metabolism.
2.Crohn’s disease: alter gut transit time and
decreased gut surface area.
B. GI surgery:
Gastrectomy may cause drug dumping in intestine,
osmotic diarrhoea and reduce intestinal transit
time.
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7. Gastro intestinal contents
1.Food- drug interaction: In general presence of
food either delay, reduce, increase or may not affect
absorption.
• Aspirin Delayed
• Penicillin's Decreased
• Griseofulvin Increased
• Methyldopa Unaffected
2.Interaction of drug with normal GI contents: GIT
contains no. of normal constituents such as mucin,
bile salts and enzymes, which influence the drug
absorption. Eg; Inhibitory action of bile on GI motility.
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3.Drug-Drug interaction in the GIT:
Physico chemical drug- drug interaction:
Adsorption: Eg; anti diarrhial preparations
contains adsorbents like kaolin, prevents a
absorption of many drugs co-administered
with them.
Complexation: Eg; penicillin derivative with
ca-gluconate.
pH changes: Basic drugs changes gastric pH
Eg; tetracycline with antacids
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8. First pass metabolism
Four primary systems which affect pre
systemic metabolism of a drugs.
1. Luminal enzymes.
2.Gut wall enzymes or mucosal
enzymes. 3. Bacterial
enzymes.
4. Hepatic enzymes.
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• Lumenal enzymes: These are enzymes present in gut fluids and include
enzymes from intestinal and pancreatic secretions.
• Gut wall enzymes: Also called mucosal enzymes they are present in gut
and intestine, colon.
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Pharmaceutical Factors
Different dosage forms:-
Solutions Suspensions
Tablets Capsules
Coated tab Enteric coated tab
Disintegration test
Dissolution test
Excipients and adjuvant
Product age and storage conditions.
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Dosage forms
• Order of bioavailability of drugs.
• Solutions>suspensions>capsules>tablets>coated
tablets
SOLUTIONS
• Drugs absorbed more rapidly in this form.
• When this formulation is taken after meal gastric
emptying is the rate limiting step.
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Tablets
• This is the most widely used dosage form.
• Problem with this arises from reduction in the
effective surface area due to granulation &
subsequent compression in to dosage form.
• Tab disintegration and granule deaggreation
are the imp steps in absorption process.
• Compression force also may be an important
factor.
• Disintegration is the rate limiting step for this.
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Enteric coated tablets
• It is a special film coated design to restricts the gastric
fluids & to dissolve in small intestine.
• Protect the drug from the degradation in the stomach Ex:
erythromycin.
• Minimize 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 effects the bioavailability in
these formulations.
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Pharmaceutical Excipients
Excipients are add to ensure the acceptability,
physiochemical stability, bioavailability and
functionability of the drug product.
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Commonly used excipients:
Diluents
Binders
Disintegrants
Lubricants
Coatings
Suspending agents
Surfactants
Buffers
Complexing agents
Colorants
Sweeteners.
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Product Age and Storage Condition
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.
• Solution dosage form.
• Solid dosage form.
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PHARMACEUTICAL FACTORS
1) Disintegration time (tablets/capsules):
Rapid disintegration is important to have a rapid absorption so
lower disintegration time is required.
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2) Dissolution time:
Dissolution is a process in which a solid substance solubilises in a
given solvent i. e… mass transfer from the solid surface to the
liquid phase.
3) Manufacturing variables:
Several manufacturing processes influence drug dissolution from
solid dosage forms.
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Method of granulation:
The wet granulation process is the most conventional technique
The tablets that dissolve faster than those made by other
granulation methods.
But wet granulation has several limitations like formation of
crystal bridge or chemical degradation.
The method of direct compression force has been utilized to yield
the tablets that dissolve at a faster rate.
Compression force:
The compression force employed in tableting process influence
density, porosity, hardness, disintegration time and dissolution rate
of tablets.
Higher compression force increases the density and hardness of
the tablet, decreases porosity and hence penetrability of the solvent
into the tablet and thus in slowing of dissolution and absorption
(Fig .A)
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On the other hand, higher compression force causes deformation,
crushing or fracture of drug particles into smaller ones and causes a large
increase in effective surface area. This results in an increase in
dissolution rate of tablets (Fig B)
a) Vehicle:
Rate of absorption – depends on its miscibility with
biological fluid
Miscible vehicles causes rapid absorption e.g.
propylene glycol.
Immiscible vehicles – Absorption depends on its
partitioning from oil phase to aqueous body fluid.
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b) Diluents:
Hydrophilic diluents – Imparts Absorption
Hydrophobic diluents – Retards Absorption
Also, there is a drug-diluent interaction, forming insoluble
complex and retards the absorption. E.g. Tetracycline-DCP
d) Disintegrants:
Mostly hydrophilic in nature.
Decrease in amount of disintegrants – significantly lowers
bioavailability.
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e) Lubricants:
Commonly hydrophobic in nature – therefore inhibits penetration
of water into tablet and thus dissolution and disintegration.
g) Surfactants:
May enhance or retards drug absorption by interacting with drug
or membrane or both.
e.g. Griseofulvin, steroids
It may decrease absorption when it forms the un-absorbable
complex with drug above CMC.
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h) Coating:
In general, deleterious effects of various coatings on the drug
dissolution from a tablet dosage form are in the following order.
Enteric coat > sugar coat > non-enteric coat.
The dissolution profile of certain coating materials change on
aging; e.g. shellac coated tablets, on prolonged storage, dissolve
more slowly in the intestine. This can be however, be prevented by
incorporating little PVP in the coating formulation.
i) Buffers:
Buffers are sometimes useful in creating the right atmosphere for
drug dissolution as was observed for buffered aspirin tablets.
However, certain buffer systems containing potassium cations
inhibit the drug absorption as seen with Vitamin B2 and
sulfanilamide.
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j) Colorants:
Even a low concentration of water soluble dye can have an
inhibitory effect on dissolution rate.
The dye molecules get absorbed onto the crystal faces and inhibit
the drug dissolution.
For example: Brilliant blue retards dissolution of sulfathiazole.
k) Complexing agents:
Complex formation has been used to alter the physicochemical &
biopharmaceutical properties of a drug.
Example
1)Enhanced dissolution through formation of a soluble complex.
E.g. ergotamine tartarate-caffeine complex & hydroquinone-
digoxin complex.
2)Enhanced lipophilicity for better membrane permeability.
E.g. caffeine-PABA complex.
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5) Nature & type of dosage form:
Apart from the proper selection of the drug, clinical success often
depends to a great extent on the proper selection of the dosage form
of that drug.
As a general rule, the bio-availability of a drug form various
dosage forms decrease in the following order:
Solutions > Emulsions > Suspensions > Capsules > Tablets >
Coated Tablets > Enteric Coated Tablets > Sustained Release
Products.
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6) Product age & storage condition:
Product aging and storage conditions can adversely affect the
bio-availability by change in especially the physico-chemical
properties of the dosage forms.
For example:
1.Precipitation of the drug in solution
2.Hardening of tablet
3.Change in particle size of suspension.
Mechanism of drug absorption
The principal mechanisms for transport of drug molecules
across the cell membrane are:
1. Membrane Transport
- Passive diffusion
- Active diffusion
2. Pore transport
3. Facilitated diffusion
4. Active transport
5. Ionic or electrochemical diffusion
6. Ion pair transport
7. Endocytosis
Physiological considerations on drug absorption
〝 Cell membrance 〞
★Passive diffusion : most drugs
--The movement of drug from a region of high to one low concentration
and no work required.
★Pinocytosis :
--The absorption of small fat, oil droplets, solid particle, starch,
vitamin A, D, E, K.
★Pore transport :
--Very small molecules (urea, water, sugar) are able to rapidly cross
cell membranes as the membrane contained pores.
Passive diffusion
It is also called non-ionic diffusion. The driving force for this process is
the electrochemical gradient.
Passive diffusion is best expressed by Fick’s first law of diffusion, which states that
the drug molecules diffuse from a region of higher concentration to one of lower
concentration until equilibrium is attained and that the rate of diffusions directly
proportional to the concentration gradient across the membrane.
Mathematically,
[da/dt =DcPcS dc/dx]
Where,
Dc is the diffusion coefficient of the drug through the membrane
Pc if the partition coefficient between membrane and the donor medium containing
drug
S is the membrane surface area
And dc & dx are concentration differential across the membrane & membrane
thickness
Active Diffusion:
Endocytosis
It involves engulfing extra cellular materials with in a segment of the cell
membrane to form a saccule or a vesicle, which is then pinched off
intracellularly.
dissolution absorption
Tablet, Capsule Drug in solution
disintegration dissolution
Granules, Aggregates
Factors affecting the dissolution rate
★The effective surface area of the drug:
--Particle size: the smaller the drug particles, the greater of surface
area for a given amount of drug, especially for a
hydrophobic drug. (ex: aspirin, digoxin, phenobarbital)
-- Manufacturing process: such as lubricant, disintegrating agent and
compression force.