BIOPHARMACEUTICS studies the in vitro impact of physicochemical properties of drugs and drug products on delivery to body under normal or pathologic conditions.
Biopharmaceutics links the physical and chemical properties of drug and drug product to their performance, in vivo.
The aim of biopharmaceutics is to adjust the delivery of drug from drug products in such a manner as to provide: optimal therapeutic activity and safety for the patient.
2. CONTENTS
Biopharamaceutics definition and aim
Scope of biopharamaceutics
Drug bioavailability
Biopharmaceutics considerations in drug product design
Pharmaceutical development scheme
Biopharmaceutical development scheme
Rate limiting steps in drug absorption
Pharmaceutical factors affecting drug bioavailability
Disintegration
Dissolution and solubility
pH-partition theory
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3. BIOPHARMACEUTICS studies the in vitro impact of
physicochemical properties of drugs and drug products on
delivery to body under normal or pathologic conditions.
Biopharmaceutics links the physical and chemical properties
of drug and drug product to their performance, in vivo.
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4. The aim of biopharmaceutics is to adjust the delivery of drug
from drug products in such a manner as to provide: optimal
therapeutic activity and safety for the patient.
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5. Biopharmaceutic considerations often determine the
ultimate dose and dosage form of a drug product.
For example, the dosage for a drug intended for local
activity, such as a topical dosage form, is often expressed
in concentration or as % of the active drug in the
formulation.
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6. Drug products include the active drug substance combined
with special additional ingredients (excipients) that make up
the dosage form.
Although excipients are considered inert with respect to
pharmacodynamic activity, excipients are important in the
manufacture of the drug product and provide functionality to
the drug product with respect to drug release and dissolution.
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7. • Each route of drug application presents special biopharmaceutic
considerations in drug product design.
• By carefully choosing the route of administration and properly
designing the drug product, the bioavailability of the active drug
can be varied from rapid and complete absorption to a slow,
sustained rate of absorption or even virtually no absorption,
depending on the therapeutic objective.
EXAMPLE
An eye medication may require special biopharmaceutic
considerations including appropriate pH, isotonicity, local irritation
to the cornea, draining by tears, and concern for systemic drug
absorption.
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8. Encompass all the
possible physiological
factors which may effect
the drug in various
dosage forms
Encompass all the
possible effects of
various dosage forms on
biological region
SCOPE OF
BIOPHARMACEUTICS
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9. A primary concern in
biopharmaceutics is the
bioavailability of drugs
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10. BIOPHARMACEUTICS CONSIDERATIONS IN
DRUG PRODUCT DESIGN
• Pharmacodynamic considerations
• Drug considerations
• Drug product considerations
• Patient considerations
• Manufacturing considerations
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12. Drug Product Considerations
• Pharmacokinetics of drug
• BA of drug
• Desired dose of drug
• Dosing frequency
Patient Consideration
• Compliance & acceptability of drug product
• Cost
Manufacturing Considerations
• Cost
• Availability of raw materials
• Stability
• QC
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13. Basic Distinctions: Pharmaceutical vs. Biopharmaceutical
Candidates
Pharmaceutical
• Homogeneous API
Chemical structure defines
product
• Oral Administration
Bioavailability
• Solid dosage form
Powder characteristics
Dissolution rate/solubility
Long-term storage
• Single stability-indicating assay to
define product
• Distinct API and DP development
process
Biopharmaceutical
• Heterogenous BDS
Process defines product
Parenteral Administration
• Liquid/lyophilized dosage
formulation
In-process stability
Aqueous /in-use stability
• Potency assay required
• Multiple assays to define
product
• Integrated BDS and DP
development process
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16. RATE LIMITING STEPS IN DRUG ABSORPTION
For solid oral immediate-release drug products (eg, tablets,
capsules), the rate processes include
1. Disintegration of the drug product and subsequent release of
the drug,
2. Dissolution of the drug in an aqueous environment, and
3. Absorption across cell membranes in to the systemic
circulation.
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17. In the process of drug disintegration, dissolution, and absorption, the rate at
which drug reaches the circulatory system is determined by the slowest step in the
sequence i.e rate limiting step.
Except for controlled-release products, disintegration of solid
oral drug product is usually more rapid than drug dissolution
and absorption.
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18. Drugs that has poor aqueous solubility-rate at which
drug dissolves (dissolution) is often the slowest step and
therefore exerts a rate-limiting effect on drug
bioavailability.
Drugs that has high aqueous solubility-the dissolution
rate is rapid , and the rate at which drug crosses or
permeates cell membranes is slowest or rate limiting step.
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19. PHARMACEUTIC FACTORS EFFECTING DRUG
BIOAVAILABILITY
Considerations in the design of drug product that will deliver
active drug with the desired bioavailability characteristics
include
1. The type of drug product
2. The nature of excipients in the drug product
3. The physicochemical properties of the drug molecule
4. The route of drug administration
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20. DRUG IN
DRUG
PRODUCT
SOLID DRUG
PARTICLES
0 O 0
O O
O 0 O
DRUG IN
SOLUTION
DRUG IN
BODY
Disintegration
release
Dissolution
Absorption
RATE PROCESS OF DRUG BIOAVAILABILITY
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21. DISINTEGRATION
Disintegration is the physical break-up of an intact dosage form to its
component aggregates.
Disintegration depends on the disintegrant used.
• Starch
• Microcrystalline cellulose
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22. It was generally recognized some years ago that a solid
drug product had to disintegrate into small particles and
release the drug before absorption could take place.
For the purpose of monitoring tablet disintegration, USP
established an official disintegration test
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23. USP SPECIFICATIONS
Separate specifications are given for
• uncoated tablets
• plain coated tablets
• enteric coated tablets
• buccal tablets
• sublingual tablets
Solid drug products exempted from disintegration tests
• Troches
• Tablets which are intended to be chewed
• Drug products intended for SR, or prolonged or repeat
action
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24. Complete disintegration is defined by USP as
“that state in which any residue of tablet, except fragments of insoluble
coating, remaining on the screen of the test apparatus in the soft mass
have no palpably firm core”.
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25. DISSOLUTION AND SOLUBILITY
DISSOLUTION
Dissolution is the process in
which solid drug substance
becomes dissolved in a solvent.
Dissolution is a dynamic
property
SOLUBILITY
Solubility is the mass of solute
that dissolves in a specific
mass or volume of solvent at a
given temperature.
(Eg: 1g of NaCL dissolves in
2.786ml of water at 25°C.)
Solubility is static property.
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26. In biologic systems, drug
dissolution in an aqueous
medium is an important prior
condition for systemic
absorption.
The rate at which drugs with
poor aqueous solubility
dissolve from an intact or
disintegrated solid dosage
form in the GIT often
controlles the rate of
systemic absorption of the
drug.
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27. Thus, dissolution tests may be used to predict bioavailability
and may be used to discriminate formulation factors that
effect drug bioavailability.
The dissolution test is required for all USFDA approved solid
oral drug products.
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28. Noyes and Whitney equation
According to Noyes and Whitney observations, the steps in
dissolution include the process of drug dissolution at the
surface of solid particle, thus forming a saturated solution
around the particle i.e. stagnant layer.
Stagnant layer, diffuses to the bulk of solvent from regions of
high drug concentration to regions of low drug concentration.
dC
dt
DA
h
( Cs-C )=
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29. dC/dt = rate of drug dissolution at time t
D = diffusion rate constant
A = Surface area of the particle
Cs = concentration of drug
C = concentration of drug in the bulk solvent
H = thickness of the stagnant layer
The rate of dissolution dC/dt, is the rate of drug
dissolved per time expressed as concentration change in
the dissolution fluid.
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30. There are number of
factors which affect drug
dissolution. One model
that is commonly used is
to consider this process to
be diffusion controlled
through a stagnant layer
surrounding each solid
particle.
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31. • First we need to consider that each particle of drug
formulation is surrounded by a stagnant layer of solution.
• After an initial period we will have a steady state set-up
where drug is steadily dissolved at the solid-liquid interface
and diffuses through the stagnant layer. If diffusion is the rate
determining step we can use Fick's first law of diffusion to
describe the overall process.
• If we could measure drug concentration at various distances
from the surface of the solid we would see that a
concentration gradient is developed.
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33. Dissociation constant (pKa) and lipid solubility of a drug as
well as the pH at absorption site, dictate the absorption
characteristics of drug from solution and interrelationship
among these parameters is known as pH partition theory of
drug absorption.
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34. • Acid and neutral drugs may be absorbed from the stomach
but the basic drugs are not
• The rate of absorption is related to the oilwater partition
coefficient of drug , the more lipophilic the drug, the faster
is absorption.
• The fraction of drug in solution that exists in the
nonionized form is a function of both the pKa and the pH
of the solution
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35. For a drug to cross a membrane barrier it must normally be
soluble in the lipid material of the membrane to get into
membrane, also it has to be soluble in the aqueous phase as
well to get out of the membrane.
Many drugs have polar and non-polar characteristics or are
weak acids or bases. For drugs which are weak acids or bases
the pKa of the drug and the pH of the GI tract fluid and the
pH of the blood stream will control the solubility of the drug
and thereby the rate of absorption through the membranes,
lining the GI tract.
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38. Brodie et al. (in 1957) proposed the pH - partition theory to
explain the influence of GI pH and drug pKa on the extent of
drug transfer or drug absorption.
Brodie reasoned that when a drug is ionized it will not be able to
get through the lipid membrane, but only when it is non ionized
and therefore has a higher lipid solubility.
Brodie tested this theory by perfusing the stomach or intestine of
rats, in situ, and injected the drug intravenously.
He varied the concentration of drug in the GI tract until there
was no net transfer of drug across the lining of the GI tract.
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39. He could then determined the ratio D as:
(BRODIE’S D VALUE)
(BRODIE’S D VALUE IN ANOTHER FORM)
D = TOTAL CONCENTRATION IN BLOOD
TOTAL CONCENTRATION IN GI TRACT
D = [ U ]b + [ I ]b
[ U ]g + [ I ]g
40. pH Partition Theory- D value calculation
• Weakly acidic drug having a single ionizable group (Aspirin, SA etc).
• The H-H equation can be written as:
• [HA] and [A-] are the concentration of unionized and ionized species,
which are in equilibrium in either gastric fluid or blood.
Weakly basic drug having a single ionizable group (chlorpromazine)
the H-H equation can be written as
[B], [BH+] are the concn. of unionized and ionized species, which are
in equilibrium in either gastric fluid or blood
log[HA] / [A- ] K H = pKa - pH
log [B] / [BH+] = pKa - pH
41. • Brodie found an excellent correlation between the calculated D
value and the experimentally determined values.
• Even though the D values refer to an equilibrium state a large D
value will mean that more drug will move from the GI tract to
the blood side of the membrane.
• The larger the D value, the larger the effective concentration
gradient, and thus the faster the expected transfer or absorption
rate.
• Compare D for a weak acid (pKa = 5.4) from the stomach (pH
3.4) or intestine (pH 6.4), with blood pH = 7.4
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42. • By comparison in the intestine, pH = 6.4
• The calculated D value is (100+1)/(10+1) = 9.2
• From this example we could expect significant absorption of
weak acids from the stomach compared with from the intestine.
Remember however that the surface area of the intestine is much
larger than the stomach. This approach can be used to compare a
series of similar compounds with different pKa values.
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43. • Therefore the calculated D value would be
Brodie D Value - Weak Acid (Stomach)
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47. • These values were determined experimentally, but we should be able
to calculate a theoretical value if we assume that only non ionized
drug crosses the membrane and that net transfer stops when [U]b =
[U]g.
• The ratio [U]/[I] is a function of the pH of the solution and the pKa of
the drug; as described by the Henderson - Hasselbach equation
• With this theory it should be possible to predict that by changing the
pH of the G-I tract that we would change the fraction non ionized and
therefore the rate of absorption.This has some application in
understanding drug absorption in overdose situations, but more
readily used in relation to renal excretion.
• Thus kaobserved = ku • fu assuming that the ionized species is not
absorbed. ANUSHA NADIKATLA
49. pH Partition Theory -
Limitations
• Assumption equilibration distribution between stomach
and blood. However, in practice such equilibriation is
rarely achieved because, stomach and blood are not static
and closed compartments
• However, despite of this criticism absorption from
stomach, as determined by direct measurements generally.
Confirms qualitatively to the pH partition hypothesis
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50. • Absorption of drugs from GIT is not depend on the
concentration of unionized species, because some drugs are
poorly absorbed from certain areas of GIT even though there is
high concncentration of unionized species
• For ex, Barbitone (pKa 7.8), which is totally unionized at gastric
pHs and is only poorly absorbed.
• However, Thiopentone with similar pKa value absorbs better
from stomach than Barbitione.The reason for this is because
Thiopentone is more lipid soluble than Barbitone.
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51. • Certain drugs (Tetracyclines and quarternary ammonium
compounds) absorbed readily despite being ionized over the
entire pH range of GIT
• Despite of its limitations the pH –partition theory remains a
useful guide in predicting general trends in drug absorption
as a function of pH and pKa within a specific region of GIT
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52. REFERENCES
1. Shargel, L., Wu-Pong, S., Yu, A.B.C., 2005, Applied
Biopharmaceutics & Pharmacokinetics, 5th Ed., McGraw-
Hill, Boston.
2. Aulton’s Pharmaceutics; The design and manufacture of
medicines.
3. Biopharmaceutics and Pharmacokinetics a Treatise by
D.M.Brahmankar and Sunil B.Jaiswal, Vallabh Prakashan
Publications,[Reprint in 2008] Page no: 32 to 37.
4. Biopharmaceutics and Pharmacokinetics. V.Venkateswarulu,
Pharma Book Syndicate. Reprint 2006 Page no : 28 "This
blog does not contain any plagiarized material"
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