Biological Factors as well as physical-chemical properties of active ingredients and dosage forms design contributing to bioavailability of drugs

1. BIOPHARMACEUTICS (1130-421)
Semester 2 (2017-2018)
Prof. Aly Nada
Chairman
Department of Pharmaceutics

2. DEFINITIONS
Biopharmaceutics:
Study of the impact of the physicochemical
properties of drugs & drug products (DF), and
route of adm. on drug delivery to the body.
The goal of biopharmaceutics is to adjust the
delivery of drugs for optimal therapeutic
activity and safety.
Pharmacokinetics:
Changes of drug conc. in the DF as well as
drug and/or metabolite(s) conc. in the different
body fluids and tissues after administration.

3. LADMER System: changes happen to the
drug after administration of DF ;
liberation, absorption, distribution,
metabolism, elimination, and response
Liberation is the first step after DF
administration by all routes, except IV
and P.O. solutions
Absorption: Uptake of the drug from the
site of administration into the systemic
circulation. The drug must be in the
molecular state, i.e. solution, except in
pinocytosis.

4. Distribution: reversible transfer of drug from one
location to another within the body.
Metabolism (biotransformation) is a way of
deactivating drugs in the body by converting drug
molecules into more polar compounds to decrease
tubular re-absorption in the kidney and thus
increase drug elimination.
Elimination: irreversible removal of drug from the
body by all routes; Excretion (intact) and
biotransformation.
Response: pharmacological effectiveness or toxicity
of the drug after drug-receptor interaction.
Pharmacodynamics: relationship between drug conc.
at the receptor site and the response.

5. Bioavailability: The rate and relative amount of a
drug from administered DF appearing in the blood.
The conc is determined by chemical or
microbiological analysis after taking blood
samples at different time intervals. Blood, plasma,
or serum levels demonstrate the concentration
upon the administration of DFs.
Disposition: loss of drug due to transfer (Distribution)
into other organs/tissues and/or Elimination and
Metabolism.
Excretion: final elimination from the body via kidney,
bile, saliva, intestine, sweat, and milk.
Biophase: actual site of drug action (the surface of a
cell or one of its organelles).

6. Overall scheme of drug absorption, distribution, and elimination
No matter how the drug is given (other
than I.V.) it must pass through a
number of biological membranes before
it reaches the site of action.

7. Physiological Factors Affecting Absorption
1. Membrane physiology
Membranes are boundaries which divide and
connect morphological and functional units.
In pharmacokinetics membrane refers not only to
the structure separating the media outside and
inside cells, but include the entire barrier
separating two functional or anatomic units
(cells comprising the vascular endothelium of
the brain parenchyma represent the blood brain
barrier).

8. Biologic membrane is
mainly lipid in nature
but contains small
aqueous channels or
pores. Surface tension
measurements have
suggested presence of
protein on the
membrane.
Membranes in different parts of the body have
somewhat different characteristics which
influence drug action and distribution.
In particular, pore size and pore distribution.

9. 1. Blood-brain barrier has effectively no pores.
This will prevent many polar materials (often toxic
materials) from entering the brain. Smaller lipid
materials or lipid soluble materials, such as diethyl
ether, halothane, can easily enter the brain.
2. Renal tubules Membranes are relatively non-
porous and drugs may be reabsorbed. Only lipid
soluble compounds or non-ionized species
(dependent of pH and pKa) are reabsorbed.
3. Blood capillaries and renal glomerular membranes
These membranes are quite porous allowing non-
polar and polar molecules (up to a fairly large size,
just below that of albumin, M.W. 69,000) to pass
through. It allows excretion of polar substances
(drugs, metabolites, and waste compounds).

10. 2. Transport across the membranes
A) Carrier mediated absorption
(1) Active (Carrier + Energy)
Glucose and amino acids, 5-fluorouracil.
saturable, against a concentration gradient, competitive inhibition

11. (2) Facilitated transport (carrier only)
A carrier is required but no energy is necessary.
e.g. vitamin B12. Saturable if no enough carrier.
No transport against a concentration gradient.
B) Passive Transport
Most drugs cross biologic membranes by passive
diffusion. Diffusion occurs when the drug
concentration on one side is higher than that on
the other side. Drug diffuses across the
membrane in an attempt to equalize the drug
concentration on both sides of the membrane.
If the drug partitions into the lipid membrane a
concentration gradient can be established.

12. The rate of transport across the membrane is
governed by Fick's first law of diffusion:-
D: diffusion coefficient. This parameter is related
to the size and lipid solubility of the drug and the
viscosity of the diffusion medium (the membrane).
As lipid solubility increases or molecular size
decreases then D increases and thus dM/dt also
increases.
A: surface area. The surface of the intestinal lining
(with villae and microvillae) is much larger than the
stomach. This is why absorption is generally faster
from the intestine than from the stomach.

13. x: Membrane thickness. The membrane in the lung
is quite thin thus inhalation allows rapid absorption.
(Ch -Cl): concentration difference. Since V, the
apparent volume of distribution, is at least four liters
and often much higher, the drug concentration in
blood or plasma will be quite low compared with the
concentration in the GI tract. It is this concentration
gradient which allows the rapid complete absorption
of many drug substances.
Normally Cl << Ch then:-
Absorption of many drugs from G-I tract follows
1st-order kinetics.

15. C) Vesicular transport (Pinocytosis and phagocytosis)
Vesicular transport is the process of engulfing particles
(pahagocyosis) / small solutes or fluid (pinocytosis).
The cell membrane invaginates to surround the material
and then engulfs it and finally incorporating into the cell.
Oleao Vitamins (A, D, E, and K) and polio vaccine.

16. D) Ion-pair transport
Strong electrolyte with extreme pKa values, e.g.
QAC, are ionized at all physiologic pH values and
therefore penetrate poorly.
When these cations are linked with anions, an
ion-pair with an overall zero charge will be
formed. This neutral complex will diffuse more
easily (more lipid soluble).
Propranolol + oleic acid &
quinine + hexylsalicylic acid

17. O N
H
CH3
OH
CH3
N
HO
N
H
H
H2C
H3CO
Propranolol
pKa
= 9.5
Quinine
pKa
= 8.5

18. What happens if:
• Q:A patient taking ampicillin with a lot of orange juice?
• Q: A patient taking propranolol with a lot of orange
juice?
Propranolol
Ampicillin

19. Biopharmaceutic Considerations of DFs
I) Physicochemical Nature of the Drug
pKa and pH: Optimum stability and solubility of
drugs and DFs. Erythromycin is formulated as
enteric coated tablets to avoid decomposition in
acid media. Weak acids precipitate from their
salt solutions in acid media, week bases show
precipitation in alkaline media.
Particle size and distribution: Affects solubility
and dissolution of poorly soluble drugs.
Polymorphism and solvates: Affect the
solubility and dissolution rate. Amorphous
particles generally dissolves more rapidly than
crystals with more rigid structural forms.

20. Salt formation:
May provide slower dissolution, slower bioavailability,
and longer duration.
Na and K salts of week acids are more soluble than
corresponding divalent/trivalent salts.
Some soluble salts are less stable than the non-
ionized form, e.g. Aspirin Na salt.
Chirality:
Optically active stereoisomers may have different
pharmacokinetic and pharmacodynamic activity;
e.g. only S-enantiomer of ibuprofen is active and R-
form undergoes pre-systemic conversion to the
active form. The conversion is site-specific and
formulation dependent; resulting in variable action.

21. Hygroscopicity:
Affect the physical properties, particle size,
polymorphs.., as well as chemical and
microbiological stability.
Partition coefficient:
Reflects the relative affinity of the drug for
particular phase in emulsions. This will affect
release of drugs.
Excipient interactions:
The excipient itself or the impurities may cause
incompatibilities with the active ingredients. The
physical properties of the excipients may also
modify the release characteristic of the drug.

22. II Formulation factors
It is possible to alter drugs’ bioavailability
considerably by formulation changes.
What are the critical criteria in tablets, capsules,
suspensions, suppositories??
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.

23. II Formulation factors
Tablets are carefully formulated, designed, to stay
together in the bottle during transport but break up
quickly once they are in an aqueous environment.

24. Solutions
Drugs are commonly given in 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.
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 absorption
problems.

25. Some drugs which are poorly soluble in water
may be dissolved by co-solvents. This is
particularly useful for compounds with tight crystal
structure, higher melting points that are not ionic.
An oily emulsion or soft gelatin capsules
(SEDDS) have been used for some compounds
to produce improved bioavailability.
Suspensions
A well formulated suspension is second only to a
solution in terms of superior bioavailability.
Absorption may well be dissolution limited,
however a suspension of a finely divided powder
will maximize the potential for rapid dissolution.

26. The addition of a surface active agent will
improve dispersion of a suspension and may
improve the absorption of very fine particle size
suspensions (deflocculated), otherwise caking
may be a problem. How?
The intestinal fluids usually contain some materials (name?)
which can act as wetting agents, however drug dissolution
testing in vitro may neglect this effect.

27. Capsules
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 G-I tract contents.
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.
The rate at which a drug dissolves is dependent
on the solubility of the drug.

28. Tablets
The biggest problem is overcoming the reduction
in effective surface area produced during
compression.
Rapid dissolution and absorption is not always the
objective. Sometimes a slower release is required.
In the case of tolbutamide, used to lower blood
sugar concentrations, a more sustained release is
the target.

29. Modified-Release Drug Products
Modified-release DFs are formulated to deliver
the active ingredient(s) at a controlled
predetermined rate and/or location to accomplish
therapeutic/convenience objectives not offered by
conventional DFs.
1. Extended-Release DFs, reducing the
frequency of dosing (e.g. sustained-R).
2. Delayed-Release DFS, releasing a discrete
part(s) at predetermined time(s) (e.g. enteric
coated products).
3. Targeted-Release DFs which release the drug
at or near the site of action (e.g. colon-targeted
products)

30. Benefits
• Short half-life drugs: less frequent dosing and
thus better compliance.
• Reduce variations in plasma/blood levels.
• Reduce side effects.
Problems
More complicated formulation, may be more
erratic in result. 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 toxic dose.
more expensive technology

31. Techniques/Types of MR products
• Erosion (erodible carriers + AI)
• Reservoir systems (AI inside insoluble coat)
• Osmotic pump (insoluble coat with a small hole)

32. 1. Erodible Systems
Eroding matrix released drug
Time
2. Reservoir system: Drug inside a shell-like system
Time

33. Techniques/Types of MR products (cont.)
• Osmotic pump (insoluble coat with a small hole)

34. In-vitro testing of dosage forms
Disintegration
Disintegration time is the time to pass through a
sieve while agitated in a specified fluid. Indicates
the time to break down into small particles.
Dissolution
The time for the drug to dissolve from the DFs.
Factors affecting dissolution; the dissolution
medium, agitation, temperature are carefully
controlled. The dissolution medium may be water,
simulated gastric juice, buffers or 0.1M HCl.
Surfactants / solvents may be included to
maintain sink conditions.

35. Noyes Whitney Equation

36. Dissolution tests are used as quality control test
to measure variability between batches. Thus the
in vitro test may be a quick method of ensuring in
vivo performance (in-vitro/in-vivo correlation).
The dissolution testing conditions is different with
each formulation (Refer to the given examples).
A reasonable approach involves selecting
dissolution conditions, which can distinguish
between acceptable and unacceptable DFs. This
is usually achieved by maintaining sink conditions
for dissolution (to prevent saturation) by
appropriate choice of dissolution conditions
(volume, type of stirrer, rate of stirring, pH,
solvents, surfactants..).

37. In Vivo-in Vitro Correlation (FDA/CDER)
The issue of in vivo-in vitro correlation (IVIVC) has
been of great importance for pharmaceutical
industry, academics, and regulatory agencies. The
FDA defines the IVIVC as the correlation between an
in vitro property of a dosage form and a relevant in
vivo response, usually the in vitro property is the rate
and extent of drug dissolution and the in vivo
response is the amount of drug absorbed or the
plasma drug concentration-time profile.
Pharmaceutical manufacturers usually attempt to
develop and optimize the conditions of in vitro
dissolution testing procedures for a particular
formulation that can predict the in vivo performance
of that formulation.

38.  The in vivo performance of the formulation is
determined from pharmacokinetic studies
performed in normal volunteers.
 The amount of drug released in vitro from the
formulation at different time points under the
different dissolution conditions is compared with
the rate and extent of drug absorption in vivo.
 When good correlation exists between a certain in
vitro dissolution test performed under specific
conditions and the in vivo rate and extent of drug
absorption, this indicates that good IVIVC is
established between this specific dissolution test
and the in vivo performance of the formulation
under investigation.

39.  When IVIVC is established, the in vitro
dissolution testing data only can be used to
prove that changes in formulation
composition, manufacturing process,
suppliers, equipment, and batch size do not
affect the in vivo drug absorption.
 Without the establishment of the IVIVC, minor
formulation changes will require in vivo
studies in human volunteers to prove that the
modified formulation has the same rate and
extent of drug absorption as the original
formulation, that is, new and old formulations
are bioequivalent.

41. Biopharmaceutics Classification System (BCS)
 The biopharmaceutics classification system
(BCS) classifies drugs according to their
solubility and permeability. This enables
successful prediction of bioavailability from
solid oral dosage forms for drugs.
 This classification system also provides a
guideline for determining the conditions under
which IVIVC is expected [Amidon et al, 1995].
 For BCS class I drugs that have high solubility
and high permeability, the rate determining
step for drug absorption is likely to be drug
dissolution and gastric emptying rate.

42.  The IVIVC for BCS class I drugs is expected if the
dissolution rate of the formulation is slower than
the gastric emptying rate. On the contrary, for
BCS class II drugs that have low solubility and
high permeability, the rate determining step for
drug absorption is the dissolution rate.
 The IVIVC for BCS class II drugs is expected when
the in vitro drug dissolution rate is similar to the
in vivo drug dissolution rate [Dahan et al, 2009].
 Whereas the BCS class III and class IV drugs
have poor permeability and the rate determining
step for drug absorption is most likely to be the
permeability across the GIT membrane. So the
IVIVC is not expected for BCS class III &class IV.