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Biopharmaceutics
29
∑ adequate protection and suffi cient stability of the active drug present duly within the dosage form
(or drug product),
∑ rate of drug release profi le emanated from the drug product,
∑ rate of dissolution of the drug substance at the specifi c, absorption site and
∑ critical and precise availability of the drug at the very site of action.
2. Biopharmaceutics Classification System (BCS)
Amidon et al. (1995)
5
made an excellent breakthrough by establishing the remarkable correlation between
∑ in vitro drug dissolution studies and
∑ in vivo bioavailability studies
that are designed solely upon the theoretical basis. The broader perspective and systematic approach is
relied exclusively on following two important aspects:
∑ aqueous solubility profi le of the ‘active drug’ and
∑ critical permeation of the ‘active drug’ via GIT.
The biopharmaceutics classifi cation system (BCS) is particularly based upon the Fick’s fi rst law as appli-
cable to a biological membrane by the following expression:
J
w
= P
w
C
w
where
J
w
is the drug fl ux (mass/area/time) via the intestinal lumen (inner wall) at any position and material time,
P
w
is the permeability of the membrane and
C
w
is the drug concentration at the surface of the intestinal membrane.
Assumptions: It is necessary to state here that the aforesaid logical suggestion assumes that no other
components in the formulation do affect the following two aspects, namely:
∑ membrane permeability and/or
∑ intestinal transport.
Amidon et al. (1995)
6
carried out an extensive investigative study regarding the solubility and permeabil-
ity characteristic features of a host of representative drug substances (belonging to different categories).
Thus, they successfully established a biopharmaceutics-drug-classifi cation system, as given in Table 2.2,
that in the precise prediction of the in vitro drug dissolution pertaining to the immediate-release profi le
of solid-oral drug products having a specifi c in vivo absorption.
In short, it may be added that US-FDA may help in the waiver towards the requirement for carrying
out the following two specifi c aspects:
7
∑ in vivo bioavailability studies and
∑ bioequivalence studies pertaining to certain immediate release solid oral dosage forms,
5
Amidon et al.: Pharm. Res, 12: 413–420, 1995.
6
Ibid.
7
US FDA: Guidelines for Industry–Bioanalytical Method Validation, 1997.
Essentials of Biopharmaceutics and Pharmacokinetics
30
which may fulfi ll some highly critical and specifi c criteria, such as:
∑ solubility,
∑ permeability and
∑ dissolution of drug substance.
Besides, these properties essentially comprise the in vitro dissolution of the respective dosage form in dif-
ferent media, information(s) regarding drug permeability and above all the anticipated ideal behaviour
of dosage form—dissolution profi le absorption in GIT.
3. In Vitro–In Vivo Correlation (IVIVC): An Introspection
Jorgensen and Bhagwat (1998)
8
evaluated the urgency and priority for the much needed requirement
of a pharmaceutical industry towards a rapid-drug development and its due approval from a competent
authority (viz. respective Government Agency); whereas, the drug-regulatory agencies (viz. US-FDA)
essentially and primarily ask for the following two cardinal pre-requisites:
∑ assurance of ‘product quality’ and
∑ optimized performance of ‘drug product’ (or dosage form).
This has led the researchers across the globe to establish a fool-proof, feasible and achievable ‘link’
between the so-called ‘dissolution testing’ and ‘bioavailability’. Nevertheless, the aforesaid concept and
ideology have remarkably paved the way for the much talked about in vitro–in vivo correlation (IVIVC)
Table 2.2 Biopharmaceutics drug classifi cation system*
Biopharmaceutics
drug class
Solubility profi le
Permeability
pattern
Special remarks
Class 1 High High Drug gets dissolved quickly and is well absorbed;
remote chances of any probable bioavailability
problems for immediate release drug products.
Class 2 Low High Drug offers restricted dissolution profi le and is well
absorbed systemically; drug product (dosage form)
controls both bioavailability and rate of release of
drug.
Class 3 High Low Drug exhibits limited permeability; bioavailability may
be rendered incomplete provided drug never gets
duly released and dissolved very much within the
absorption phase (window).
Class 4 Low Low Drug product formulation encounters serious
problem(s) which may deliver consistent drug bio-
availability; may indirectly suggest an alternative
route of administration, e.g., SC, IM, IV.
* US-FDA Guidance for Industry: Waiver of in vivo bioavailability and bioequivalence studies for Immediate Release
Solid Oral Dosage Forms containing Certain Active Moieties/Active Ingredients: Based on a Biopharmaceutics
Classifi cation System (2000).
8
Jorgensen ED and Bhagwat D: Development of Dissolution Tests for Oral Extended Release Product, PSST, 1(3):
128–135, 1998.
Biopharmaceutics
31
in our day-to-day drug development activities in the Research and Development (R&D) wing of a
pharmaceutical industry, e.g., Dr. Reddy’s Laboratory, Hyderabad; Ranbaxy Laboratories, New Delhi;
Glaxo Smith Kline, London (UK); Pfi zer Laboratories, New York.
3.1. Genesis of IVIVC
Early 1980s witnessed vigorous initiative and well-organized collaborative research focused on IVIVC
(duly sponsored by US-FDA/American Drug Industries) putting forward useful fi ndings, such as:
∑ extended release (ER) product and
∑ encouraged more meaningful intensive research in this direction (Skelley et al. 1987).
9
Skelley et al. (1993)
10
reported an unusual unique trend depicting enhanced level of confi dence in IVIVC
for ER-Oral Drug Products [USP XXIII (1995)] which specifi cally included this aspect as a USP chapter
(1088). Soon after, US-FDA (1997) established elaborated guidelines for industry under the head:
ER-Oral Dosage Forms: Development–Evaluation–Application of IVIVC.
In short, it may be appropriate to have comprehensive details with respect to IVIVC vs. dissolution
factors in
∑ development of IVIVC and
∑ critical progress in IVIVC.
3.2. FDA Definition for IVIVC
US-FDA defi nes IVIVC as “a predictive mathematical model describing relationship between in vitro
properties of a drug product and its relevant response in vivo.”
Obviously, an in vitro property reveals explicitly the rate-degree of drug dissolution—drug release
profi le; whereas, the in vivo response represents adequately the plasma-drug concentration or exact quan-
tum of drug absorbed systemically.
3.3. Important Factors for Development of IVIVC
It has been duly established that there exist two important factors for the development of IVIVC, namely:
∑ stereochemistry and
∑ fi rst-pass effect.
(a) Stereochemistry: It refers to that branch of chemistry which deals with the atoms in their spatial
relationship, and the effect of such a relationship on the action and effects of the molecule.
In other words, the observed difference is caused duly in the ‘pharmacokinetics’ or ‘pharmacodynamics’
behaviour profi le of two enantiomers (i.e., stereoisomers). Evidently, the overall applicability of in vitro dis-
solution retrieved data of a racemic mixture (or dl-mixture) alone may not perhaps be quite useful for the
development of IVIVC; and, therefore, the correct prediction of in vivo availability of the active enantiomer.
(b) First-Pass Effect: It refers to the dosage form having an exceptionally high hepatic-extraction
ratio. This dosage form undergoes critical biotransformation before entering the ensuing systemic circu-
lation thereby lowering the usual availability of the ‘parent drug’.
9
Skelley JP et al.: Pharm. Res., 4(1): 75–77, 1987.
10
Skelley et al.: Dosage Forms, 10(12): 1800–1805, 1993.
Essentials of Biopharmaceutics and Pharmacokinetics
32
In this manner, the precise quantum of drug actually available in the systematic circulation may not
match up to the amount of drug-released in GIT.
Sirisuth and Eddington (2002)
11
showed that the observed infl uence of the fi rst-pass effect upon the
development and validation of IVIVC was established justifi ably between the
∑ fraction of ‘metaprolol’ dissolved and
∑ fraction of ‘total drug absorbed’ due to altogether differed drug release-rate formulations.
3.4. IVIVC Utilization in Novel Dosage Forms
The excellent usage of IVIVC has been largely exploited in the following six novel dosage forms, namely:
1. Controlled Release (CR) or Sustained Release (SR) drug delivery system,
2. Transmitted Drug Delivery System (TDDS),
3. Nasal Drug Delivery System (NDDS),
4. Enteric Coated Multiple Unit Dosage Form,
5. Buccal Tablets and
6. Suppositories.
3.5. Applications of IVIVC
These essentially comprise the following:
1. Recommended and suggested to use in vitro dissolution studies as surrogate for the human
bioequivalence (BE) studies in order to accomplish specifi cally the following two aspects, namely:
∑ reduction in the number of human bioequivalence (BE) studies and
∑ minimize the cumbersome task of initial approval process, and certain ‘scale up post approval
changes (SUPAC)’.
2. Spectacular success in the early development of ‘drug product’ (or dosage form) together with its
critical optimization criteria.
Venkatesh and Lipper (2000)
12
studied thoroughly the development of drug products which are
solely characterized by certain in vitro systems. Besides, some in vivo studies in animal models to
address the following two aspects critically:
∑ toxicity features and
∑ effi cacy studies.
These researchers also emphasized that if the preliminary relationship existing between in vitro and
in vivo characteristic features may be established appropriately, it might substantially provide the
following two aspects:
∑ better visionary in drug design and
∑ crucial development of drug product.
Consequently, the valid IVIVC developed formulation may be optimized based upon the in vitro
dissolution studies.
3. Biowaiver for Minor Formulation and Process Changes: The relationship established between the
critical manufacturing variants and in vitro dissolution rate has been spelled out explicitly for both
controlled-release (CR) Formulation and IVIVC, which ultimately enables the usage of in vitro
11
Sirisuth N and Eddington ND: Eur. J. Pharm. Biopharm., 53: 301–309, 2002.
12
Venkatesh S and Lipper RA: J. Pharm. Sci., 89(2):145–154, 2000.
Biopharmaceutics
33
dissolution data extended suitably to ‘minor formulations’ and appreciable ‘process changes’
consisting of:
∑ colour,
∑ size,
∑ shape,
∑ fl avour,
∑ preservative,
∑ coating procedure,
∑ composition of materials,
∑ ingredients (both active and inactive),
∑ equipment(s) and
∑ manufacturing site.
4. Passage of Drugs across Biological Barrier
A biological barrier refers to a selective boundary, or separation pertaining biology.
It has been duly observed that a membrane (or a barrier) having highly specialized structural features
may cause undesirable permeability restriction with respect to the distribution of drugs to certain tissues
in a human body. Following are some typical examples of simple and specialized physiologic or biologic
barriers, namely:
∑ Capillary endothelial barrier (CEB),
∑ Cell membrane barrier (CMB),
∑ Blood–brain barrier (BBB),
∑ Blood–cerebrospinal fl uid barrier (BCSFB),
∑ Placental barrier (PB) and
∑ Blood–testis barrier (BTB)
These physiological/biologic barriers solely responsible for the passage of drugs across certain tissues
shall now be treated individually in the following sections.
4.1. Simple Capillary Endothelial Barrier (CEB)
The ability of drug substances to get diffused via capillary walls into tissue spaces is usually termed as
capillary permeability. It is infl uenced by hypoxia
13
, adrenocortical hormone
14
and the concentration of
Ca
2+
ions present in the blood. However, it is pertinent to state here that the membrane of capillaries,
which supply blood to most tissues, does not serve as a barrier to drug molecules. Therefore, most drug
substances, unionized form or ionized form, having a molecular size lower than 600 Da get eventually
diffused via the capillary endothelium right inside the intestinal fl uid.
Note
Interestingly, only such drug molecules that get critically bound to the respective blood components
(viz. blood proteins) are usually restricted by the capillary endothelial barrier due to its distinct ‘larger
molecular size’ of the resulting drug–protein complex so formed by the interaction of drug and protein.
13
Hypoxia: A decreased concentration of oxygen in the inspired air.
14
Adrenocortical Hormone: A group of hormones secreted by the adrenal cortex that are duly classifi ed by
biological activity into glucocorticoids, mineralocorticoids, adrenogens, estrogens and progestine.
Essentials of Biopharmaceutics and Pharmacokinetics
34
4.2. Cell Membrane Barrier (CMB)
The ‘cell membrane’ (or plasma membrane) refers to the membrane that forms the outer boundary
of a cell and is made up of protein, carbohydrates and phospholipids on its outer surface, as shown in
Figure 2.2.
The cell membrane may be described as a dynamic bimolecular layer of phospolipids with scattered
protein molecules fl oating in them as icebergs in sea.
In Figure 2.2 one may observe the following characteristic features, namely:
∑ lipid layers are represented as more or less arranged in a orderly fashion, packed compactly, lamellar
array of phospholipid entities located strategically tail-to-tail,
∑ each tail being an alkyl-chain or a steroidal moiety and
∑ each head is designated as a polar moiety, viz. glycerate groups—having their polar functional seg-
ments as ether, carbonyl-oxygens and phosphates with intimately attached polar moieties.
Salient Features: These predominantly comprise (see Figure 2.2) the following:
1. The lamellar
15
segment is not arranged in an orderly manner because its inherent composition
seems to be quite complex.
2. The ‘chains of fatty acids’ of different degrees of saturation and ‘cholesterol’ do not usually array
themselves in rather simple parallel arrangements.
3. Interestingly, the aforesaid lamellar segment is duly penetrated by means of large globular proteins,
the inner portion of which essentially processes a high hydrophobicity (very much akin to lipid
layers), and certain typical fi brous proteins.
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Figure 2.2 Diagrammatic illustration of a cell membrane.
15
Lamellar: That is, arranged in this plates or scales.
Note
Differences have been observed between the membrane of the endoplasmic reticulum and the
cell membrane (or plasma membrane), even though they are co-extensive.
Biopharmaceutics
35
4. The cell membrane usually could be seen as perforated duly by water-fi lled pores of various sizes,
ranging between 4 and 10 Å, but mostly they are ~7 Å.
5. Importantly, all major ion-channels do exist via the large globular proteins which eventually
traverse the cell membrane, and through these pores, several inorganic ions together with small
organic molecules pass.
Na
+
ions are relatively bigger than the corresponding K
+
ions and Cl
−
ions, since the former gets more
hydrated than the latter and, therefore, cannot pass across the pores as freely as the K
+
and Cl
−
ions.
Examples
6. Vascular endothelium have pores ~40 Å; however, these invariably do serve as interstitial passages
16
rather than transmembrane pores.
The physicochemical characteristic features which normally exert their direct infl uence upon the
permeation of drug substances very much across the simple cell membrane barrier (CMB) may be
illustrated explicitly in Figure 2.3.
Passive Diffusion: It may be defi ned as ‘movement of drug molecules from a region of higher con-
centration to a region of lower concentration via a membrane that does not participate in the process’.
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Figure 2.3 Cell membrane barrier and diffusion of drug molecule across.
16
Interstitial Passages: Refer to passages pertaining to spaces within an organ or tissue.
Essentials of Biopharmaceutics and Pharmacokinetics
36
In this particular instance, the membrane is referred to as the cell membrane (or plasma membrane).
Importantly, one may express explicitly the passive diffusion quantitatively by Fick’s fi rst law of diffusion.
Active Transport: It refers to the specifi c biological process by which drugs and other substances are
critically transported across body membranes, e.g., intestines, skin, cells.
The various interesting aspects of Figure 2.3 may be explained easily as given below:
1. Drug molecules having particle size less than 50 Da can pass through blood into the extracel-
lular fl uid (ECF), which may sail across the intracellular fl uid (ICF) as the major bulk fl ow.
2. Most lipophilic drugs (viz. steroids) having a particle size ranging between 50 and 500 Da
easily pass through the blood right into ECF and subsequently, via passive diffusion into ICF
through the cell membrane.
3. The ionized (or polar) drugs having a particle size either equal or more than 50 Da to exhibit
a tendency to sail across to ICF via cell membrane due to the active transport phenomenon.
4. Interestingly, the protein-drug complexes formed duly, being bulkier in size vis-à-vis normal
drug molecules, lipophilic drugs and ionized drugs, distinctly remain fl oating in the circulat-
ing blood only.
Explanations
4.3. Blood–Brain Barrier (BBB)
Blood–brain barrier (BBB) may be defi ned as ‘the specialized capillary membrane existing between cir-
culating blood and the brain so as to prevent harmful substances from entering the brain’.
BBB invariably allows fat-soluble, but not water-soluble drug substances to pass across the brain.
4.3.1. Permeability of Cell and Capillary Membranes
It has been amply proven and demonstrated that cell membranes do vary in their permeability character-
istic features depending on the tissue exclusively. However, it may be further substantiated and exemplifi ed
by the fact that the capillary membranes specifi cally confi ned to the kidneys and liver are observed to be
rather, more permeable to the ‘transmembrane-drug movement’ vis-à-vis the ensuing capillaries located
strategically in the brain.
1. Role of Sinusoidal Capillaries: The sinusoidal capillaries refer to a large, permeable capillary,
often lined with microphages, usually found in organs, e.g., liver, spleen, bone marrow, adrenal
glands. Nevertheless, their permeability explicitly allows either large proteins or cells to gain an
easy access or prompt departure from the blood.
2. Capillary Endothelial Cells: The capillary endothelial cells are critically surrounded by a thin-
layer of glial cells (i.e., concerning the non-nervous or supporting tissue of the brain and spinal
cord), that predominantly comprise enough tight intercellular functions.
Obviously, the aforesaid additional layer of cells intimately present around the so-called capillary
membranes does exert its effective activity profi le by slowing down the rate of drug diffusion right
inside the brain by acting as a distinct thicker lipid barrier. Eventually, the resulting ‘lipid barrier’
that largely retards the penetration as well as diffusion of
∑ water-soluble drug substances and
∑ polar (or ionized) drug
right inside the brain and spinal cord is invariably termed as the blood–brain barrier (BBB).
Biopharmaceutics
37
3. Typical Pathophysiological Parameter: The specifi c and crucial permeability of cell membranes
(including the capillary cell membranes) usually get changed under the infl uence of certain typical
pathophysiological parameters.
There are two marked and pronounced specifi c examples as given below:
1. Meningitis: It essentially involves the infl ammation of the membranes located in the brain
or spinal cord, thereby enhancing the ensuing drug-uptake right into the brain.
2. Severe Burns: In the particular instance of severe burns, one may evidently notice an
apparent change with respect to
∑ permeability profi le of skin layer and
∑ passage of drug substances plus relatively larger molecules to permeate either inward or
outward.
Examples
Figure 2.4 depicts the diagrammatic representation of BBB.
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Figure 2.4 Diagrammatic representation of blood–brain barrier (BBB).
The various aspects of BBB essentially include the following:
1. Blood–brain barrier (BBB) designates a vital and important line-of-control (LOC) between
the peripheral and CNS invariably by means of a critical permeability barrier to the ensu-
ing ‘passive diffusion’ of various drug substances right from the blood stream into different
segments of the CNS.
2. Nevertheless, the crucial existence of the aforesaid permeability barrier may be observed
explicitly due to the appearance of relatively large reduced rate of access of chemical entities
from the plasma to the brain.
Explanations
Essentials of Biopharmaceutics and Pharmacokinetics
38
3. Generally, the lipid-soluble drugs may obviously get specifi cally diffused very much inside
the ‘interstitial fl uid’ of the brain and spinal cord exclusively.
4. The critical presence of highly specialized cells usually termed as astrocytes,
17
do form a
sort of solid-envelope around the brain-capillaries. This consequently causes blockade of the
intracellular passage (see the lower part of Figure 2.4). Therefore, for enabling a ‘drug’ to have
a proper access from the ensuing capillary circulation in the brain, it may have to get across
through the cell instead of between them.
4.3.2. Highlights of BBB as a Lipoidal Barrier
Following are some of the highlights of BBB as a lipoidal barrier:
1. BBB permits solely the passage of such drug substances with a distinctly high o/w partition coeffi -
cient in order to cause an effective passive diffusion, whereas, both partially ionized drug molecules
and moderately ionized drug molecules (see Figure 2.4) do penetrate at a slow rate.
Note
There exist certain specifi c sites strategically located in the brain, wherein BBB has virtually no
role to play, such as:
1. trigger area and
2. median hypothalamic zone.
17
Astrocytes: It refers to the elements of the supporting issue located strategically at the base of the endothelial
membrane.
Thiopental, a hypnotic drug, which being an extremely lipid-soluble drug, shows an effective par-
tition coeffi cient that is almost 50 folds in comparison to pentobarbital and, therefore, gets across
the BBB much more readily and effi caciously.
Example
Note
It has been observed duly that a host of other structurally similar foreign molecules may also get
across the BBB almost via the identical mechanism, e.g., carbohydrates, amino acids (derived from
in vivo protein hydrolysates).
2. Importantly, the highly ‘selective permeability’ of specifi c lipid-soluble functional moieties do
exhibit an appreciable tendency to sail through the BBB; and thus defi nitely ascertains the most
credible and appropriate choice towards the ‘selection of a drug’ so as to treat the disorders of CNS
effi caciously as an essential component of the therapeutic armamentarium.