Ajay D.

Kshirsagar et al: Bioavailability and bioequivalence study

Journal of Pharmaceutical and Scientific Innovation

www.jpsionline.com
Review Article

BIOAVAILABILITY AND BIOEQUIVALENCE STUDY IN CORRELATION OF BIOPHARMACEUTICS

CLASSIFICATION SYSTEM (BCS) AND POSSIBLE MODIFICATION
Ajay D. Kshirsagar1*, Omkar N. Shikare2, Haidarali M. Shaikh2
1
Department of Pharmacology, Faculty of School of Pharmacy, SRTM Nanded, India
2
Padmashree Dr. D. Y. Patil Institute of Pharmaceutical Sciences and Research, Pimpri, Pune, India
*Corresponding Author Email: ksagar.ajay@gmail.com
DOI: 10.7897/2277-4572.02681
Published by Moksha Publishing House. Website www.mokshaph.com
All rights reserved.

Received on: 07/10/13 Revised on: 24/11/13 Accepted on: 28/11/13

ABSTRACT
In the last decade, the regulatory bioequivalence (BE) requirements of drug products have undergone major changes. Now a day the bioavailability and
bioequivalence study is emerging area in the generic world. Today, the discovery of drug substances with increasing lipophilicity and resultant poor aqueous
solubility is a more and more common problem in the development of orally administered new formulations. The Biopharmaceutics Classification System
(BCS) is the technique used to differentiate the drugs on the basis of their solubility and permeability is a guide for predicting the intestinal drug absorption.
The knowledge of the BCS characteristics of a drug in a formulation can also be utilized by the formulation scientist to develop a more optimized dosage form
based on fundamental mechanistic, rather than empirical, information. The possible changes in the class three and four drugs we increase the solubility and
permeability and achieve great success in the field of generic market. Here in this review we compile the information on all four class drugs of BCS and their
possible modification.
Keywords: Bioequivalence, Bioavailability, Biopharmaceutics Classification System (BCS)

INTRODUCTION Price Competition and Patent Term Restoration Act of 1984

The growth of the generic pharmaceutical industry has
increased enormously during the last 10-25 years. This
growth has been driven by a number of factors, in particular
the need to contain public spending on health care, including
drug products. The demand of generic drug product is
intended as a substitute for innovator pharmaceutical
company product must be 'equivalent'. When a generic drug
product for an innovator drug product requires that the
products must not only be pharmaceutically equivalent, but
also bioequivalent. In general, for a generic product to be
concerned as bioequivalent with the pioneer product, any
difference in the rate and extent of absorption of the active
moiety to the site of drug action must be judged to be
clinically insignificant. The fundamental reason for
performing bioequivalence testing is to ensure, as far as
possible, the quality of generic drug products. In particular,
such testing is intended to prove that there are not likely to be
any differences in safety and efficacy between a generic and
an innovator drug product; that is, that the products are
therapeutically equivalent. Thus, in essence, bioequivalence
is considered as alternate of therapeutic equivalence. Many
countries have established the law that allows for the
approval of generic products on the basis of the evidence of
bioequivalence with an innovator product. The process
usually involves the submission of an 'abbreviated new drug
application' to the applicable drug regulatory agency. Such a
submission must contain demonstration establishing
bioequivalence, as well as pharmaceutical and other relevant
information, but it need not contain preclinical (e.g. Toxicity)
data or the full range of demonstration of clinical safety and
efficacy, which is required within a full 'new drug
application' for a pioneer product. In many countries, law
controlling the approval of generic drug products has been
happening by legal mechanisms to provide an motivator for
pioneer pharmaceutical companies to undertake research and
development of new drugs. A notable example is the Drug
(the so-called Waxman-Hatch Amendment of 1984) that
amended the United States Federal Food, Drug and Cosmetic
Act1.
Bioavailability
The rate and extent to which active ingredient is absorbed
from a drug product and becomes available at the site of
action. The drug product that is not intended to be absorbed
into the bloodstream, bioavailability may be evaluated by
measurements resulted to reflect the rate and extent to which
the active ingredient becomes available at the site of action.
One regulatory objective is to evaluate, through appropriately
designed BA studies, the performance of the formulations
used in the clinical trials that provide a demonstration of
safety and efficacy (21 CFR 320.25 (d)1. Before marketing a
drug product, the performance of the clinical trial dosage
form can be possible, in the circumstances of evidencing
safety and efficacy. The general exposure profiles of clinical
trial material can be used as a benchmark for consequent
formulation changes and can be useful as a reference for
future BE studies. Although BA studies have many
pharmacokinetics objectives beyond formulation
performance as described above. We note that subsequent
sections of this guidance focus on using relative BA (referred
to as product quality BA) and in particular, BE studies as a
means to document product quality. In vivo performance, in
terms of BA/BE, can be conceived to be one aspect of
product quality that provides a link to the performance of the
drug product used in clinical trials and to the database
containing a demonstration of safety and efficacy.
Bioequivalence
The term ‘Bioequivalence’ is defined as differently in each of
the studied guidelines, although both guidelines refer to the
same methods of PK analysis. It should also be observed that
although numerous fragments of the AB Guideline are true

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 Ajay D. Kshirsagar et al: Bioavailability and bioequivalence study
copies of the HB guidelines, this does not apply to the
definition. Other agencies and institutions that produce
documents related to BE studies does not accept from this
pattern. An example is the definition of BE presented by the
World Health Organization (WHO)2. Moreover, the AB
definition introduces information on finding of the active
drug in the blood plasma. That is not an appropriate place for
this type of elucidation especially considering BE studies
conducted on the basis of not only the determination of drug
concentration in blood plasma, but also in serum, whole
blood, urine and tissues. CVMP advocates that pilot data
would be yielded before to starting the pivotal study but AB
guidelines does not provide details on how to plan pilot
studies before the pivotal pharmacokinetic studies are
conducted. Other agencies (e.g. Food and Drug
Administration – FDA, and Health Canada – HC) have long
treated this form of analysis as a preliminary to the proper
optimization of BE study design3-5. Pilot studies are often
utilized as a means for designing optimized BE studies. Pilot
studies assist to identify inter- and/or intra-subject variability,
and to verify the scope and the distribution of sampling
points, as well as critical assigns of the Bioanalytical method
such as the lowest limit of quantitation (LLOQ) and the
highest limit of quantitation (HLOQ). Documents of some
agencies (e.g. FDA) also reference pilot studies as an
important element in identifying the flip-flop
pharmacokinetics. An example is the FDA document that
stresses the role of pilot studies in the analysis of this effect
(FDA, 2006). This document gives great attention to the role
of pilot studies in designing the appropriate BE studies of
veterinary drugs2-6. Bioequivalence of two drug formulations
is currently defined by drug regulatory authorities in terms of
the mean responses (average bioequivalence) following
administration of the test and reference formulations. The
discovering that the average bioavailability of the test and
reference formulation is similar does not mean that the
bioavailability metrics of the test and reference product are
similar in all or even most individuals. It has been discovered
that the safety for the substitution of a reference drug product
with a test drug product in patients, whose concentrations
might have been titrated to a steady efficacious and safe
level, could be a concern. Therefore, it is proposed that
individual bioequivalence within each subject should be
assessed to assure the safety of the drug switchability.
Switchability actually demands that, within the same patient,
the drug concentrations of the test formulation remain within
the same therapeutic window achieved by the reference
formulation. The statistical evaluation of the individual
bioequivalence examines that the pharmacokinetics windows
for the test and reference formulations are similar. The
various potential shortcomings of average bioequivalence are
now understood, and switchability, and thus individual
bioequivalence, has become a reasonable expectation when
changing from one pharmaceutically equivalent drug product
to another. The advance has been made in developing criteria
for individual bioequivalence, and a classification of most of
the different approaches to the assessment of individual
bioequivalence has been achieved. We review and discuss
some technical statistical issues and practical execution issues
associated with the use of individuals as opposed to
population average bioequivalence to express the relative
bioavailability of alternative formulations of a drug. During
the last two to three decades, biopharmaceutics has been
undergoing a revolution from drug discovery to drug
regulatory standards and harmonization. Biopharmaceutics is
based on the chemical and physical properties of drug
content, and the formulation, physiology of the route of
administration. Nowadays, many particles are classified
through screening processes, and promising candidates enter
into drug pipelines for further in vitro and in vivo tests. At the
end of the development process stands the approval by the
regulatory agencies. From a strict economic point of view,
this is the important step for moving from a drug candidate to
a product which improves health and to cover the discovery
costs. Some national and international societies and agencies
are doing workshops and conferences to harmonize the
standards and documentation needed for drug safety and
quality1, but there is still work in front.
Class I
BCS class I drugs are defined as being highly soluble and
highly permeable. For illustrate, metoprolol, propranolol, and
theophylline are categorized into this class7. For BCS class I
drugs, there should be no rate-limiting step for absorption of
oral route. IR solid oral dosage forms, for example, capsule
formulations or conventional tablet, are usually planned to
ensure quick dissolution in the gastrointestinal tract. This
class which helps the tablet easily pass first pass metabolism
and there is less problem with the patient, related to adverse
event and side effect compare to the other BCS class.
Class II
Nowadays, the discovery of drug substances with
intensifying lipophilicity and outcome poor aqueous
solubility is a more and more common problem in the
development of orally administered Modern formulations.
The majority of registered drugs falls into Biopharmaceutics
Classification System (BCS) class II (high permeability, low
solubility) or IV (low permeability, low solubility)8,9. For the
BCS class II drugs, the oral absorption is mostly limited by
the solubility and/or dissolution in the gastrointestinal (GI)
tract. In such case, it should be of value to have an in vitro
dissolution test that could be used to omen the in vivo
behaviour during the various steps in formulation
development. Biorelevant media simulating the fasted and
fed states in the small intestine have been developed and
utilized to increase the in vivo predictability10-12. These
simplified media, called as fasted state simulated intestinal
fluid (FaSSIF) and fed state simulated intestinal fluid
(FeSSIF), contain the most important physiological
amphiphiles, bile salts (BS) and lecithin (LC) and consider
the pH, buffer capacity and osmolality of the gut lumen. To
improve image the solubilization capacity in the fed state,
digestion products, such as fatty acids and monoglycerides,
have additionally been included in the media13–16.
Class III
Class 3 contains high solubility/low permeability drug
substances. Hence, it is safe to consider that the intestinal
permeability is considered to be the rate-controlling step in
oral drug absorption. This shows that the absorption kinetics
of BCS Class 3 drugs from the gastrointestinal (GI) tract
could be controlled by the biopharmaceutical and
physiological properties of the drug substance, rather than
preparation factors, provided excipients do not affect drug
permeability or drug intestinal large time. The assumptions
that excipients do not affect drug permeability and intestinal
transit time are significant assumptions that merit further
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 Ajay D. Kshirsagar et al: Bioavailability and bioequivalence study

investigation. Human studies to determine excipient effects in Class IV

a dose-response fashion could be considered unethical, not
practical, and cost prohibitory. In vitro culture studies using
Caco-2 cells have been conducted to determine the effect of
some common excipients. Cell culture methods are easily
impacted by solvents used to make easier the solubility of
drugs and or excipients due to volume limitations. In
addition, studies clearly show that the behaviour of the
gastrointestinal tract is controlled by immunological,
neuronal and hormonal controlling mechanisms13. The failure
of in vitro dissolution to predict bioavailability might be
related to the principle of solute-solvent interactions and its
influence on solubility and solubilization, which has been
studying in large amount16–23. The Hildebrand–Scatchard
model16,17 has been distanced to handle the solubility
production of drugs in polar solvents.
The very great pharmaceutical research in understanding the
causes of low oral bioavailability has led to the development
of new technologies to address these challenges. One of the
technologies is to design a prodrug with the required
physical-chemical properties to improve the oral
bioavailability15. The main technologies to achieve the
increased oral bioavailability of drugs with poor aqueous
solubility include the use of micronization, nanosizing,
crystal engineering, solid dispersions, cyclodextrins, solid
lipid nanoparticles and other colloidal drug delivery systems
such as microemulsions, self-emulsifying drug delivery
systems, self microemulsifying drug delivery systems and
liposomes16,17. Currently, approximately 42 % of the
marketed immediate release (IR) oral drugs are categorized
as practically insoluble (<100 g/ml)18. Combinatorial
chemistry and high-throughput screening used in drug
discovery have resulted in an increase of poorly water soluble
drug prospects22,23.

Table 1: BE Dissolution Proposal

BCS Drug Solubility Drug Solubility Drug Preferred Procedure

Class pH 1.2 pH 6.8 Permeability
I High High High >85 % Dissolution in 15 min; 30 min, f2., pH = 6. 8.

II Low High High 15 minutes at pH=1.2, then 85 % Dissolution in 30 minutes,

pH = 6.8; F2 > 50; 5 points minimum; not more than one point > 85 %.
III High High Low >85% Dissolution in 15 minutes, pH = 1.2, 4.5, 6.8.
IV Low High Low 15 minutes at pH = 1.2; then 85 % Dissolution in 30
min., pH = 6.8,; F2 > 50; 5 points minimum.; not
more than one point > 85 %.

Table 2: BCS Class Inferences

Solubility Permeability Absorption Rate

High High Well absorbed drugs. Controlled by
Gastric Emptying for rapidly dissolving drug products. Cmax is the critical in vivo parameter*.
Low High The drug may be well absorbed. Controlled by Dissolution. Cmax is the critical in vivo parameter*.
High Low Limited oral absorption. Controlled by High Low Permeability. Cmax and AUC critical in vivo parameters.
Low Low Poorly absorbed. Cmax and AUC critical in vivo parameters.

Since high permeability drugs are rapidly absorbed, solubilized drug24. These formulations can quickly form oil in
maximum plasma concentrations (Cmax), are indicative of water (w/o) fine emulsions when dispersed in an aqueous
overall AUC and long-duration in vivo studies is not required. phase under mild agitation. SEDDS are additionally
In class four drugs have the low permeability and solubility classified into self-microemulsification drug delivery systems
drug. And some modification is necessary to improve these (SMEDDS) and self-nanoemulsification drug delivery
qualities such as. systems (SNEDDS) according to the size range of their oil
droplets25. SMEDDS form microemulsions ranging in droplet
· Self-emulsification size from 100 to 250 nm. Finer microemulsions of less than
· Amorphization 100 nm can be obtained using SNEDDS. The rapid
· Cyclodextrin complexation emulsification of these formulations in the gastrointestinal
· pH modification tract can provide both improved oral bioavailability and a
· Particle size reduction reproducible plasma concentration profile. The droplet size of
Micronization the emulsion would influence the extent of absorption of the
Nanocrystals orally administered drugs. Neoral®, a cyclosporin SNEDDS
· Crystal modifications formulation, is a good example of the effectiveness of the
Metastable polymorphs utilization of droplets of a smaller size. Neoral® showed
Salt formation increased Cmax and AUC compared with Sandimmune®, a
Cocrystal formation coarse SMEDDS formulation, in human26. SEDDS would
require a relatively high intrinsic lipophilicity of the drug
Self-emulsification substance since the active ingredient should be dissolved in a
In recent years, self-emulsification drug delivery systems limited amount of oil. High chemical stability of the
(SEDDS) have been utilized to enhance the oral dissolved drug in oil phase would also be required for the
bioavailability of poorly water-soluble drugs, especially for lipid formulations.
highly lipophilic drugs. Self-emulsification formulations are
isotropic mixtures of oil, surfactant, cosolvent, and

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 Ajay D. Kshirsagar et al: Bioavailability and bioequivalence study
Amorphization
Amorphous solids have higher energy than crystalline solids.
Typically, the solubility of an amorphous drug is higher than
that of the corresponding crystalline drug. The differences of
the solubility between amorphous form and crystalline form
have been reported to be between 1.1 and 1000-fold. The
marked enhancement in the saturated solubility of amorphous
drug may lead to a significant improvement of oral
bioavailability. Stable amorphous formulations can be
obtained by solid dispersion techniques. Amorphous solid
dispersion (ASD) is defined as a distribution of active
ingredients in molecular and amorphous forms formed by
inert carriers27. The ASD formulations can be prepared by
spray drying, melt extrusion, lyophilisation, and use of
supercritical fluids with polymeric carriers and/or
surfactant28. Numerous studies have demonstrated the marked
enhancement of oral absorption by ASD approaches29-32. The
ASD approaches were found to show 1.5–82-fold and 1.6–
113.5-fold enhancements in Cmax and AUC compared with
crystalline formulation containing bulk API or a physical
mixture of API and carriers. The AUC enhancement ratio of
the majority of the listed drugs was found to be less than 20-
fold. However, a more than 20-fold improvement in the
pharmacokinetic parameters was noticed in a few cases. ER-
34122 (Eisai) is a 5-lipoxygenase/cyclooxygenase inhibitor
with low aqueous solubility (<10 ng/ml)33. Surprisingly, the
amorphous formulation of ER-34122 showed ca. 200-fold
enhancement in the solubility in JP 2 medium compared with
ER- 34122 alone, and both Cmax and AUC after oral
administration of the amorphous formulation were ca. 100
times higher than those of pure drugs in dog. Generally, ASD
formulations tend to be chemically and physically less stable
than the corresponding crystalline solid. The change from
amorphous form in crystalline form in ASD formulation
would lead to a reduction of oral bioavailability of the
incorporated drugs. In contrast to the CSD formulations, the
ASD approaches may be unsuitable for amorphous drugs
with low stability.
Cyclodextrin complexation
Cyclodextrins are oligosaccharides containing a relatively
hydrophobic central cavity and hydrophilic outer surface34.
Cyclodextrins have been widely used in pharmaceutical
product development, and there are currently more than 10
marketed cyclodextrin-containing solid dosage forms.
Cyclodextrins and their derivatives enhance the apparent
solubility of poorly water-soluble drugs by forming inclusion
complexes. Numerous studies have shown the enhancement
of the oral bioavailability of poorly water-soluble drug, goes
by the cyclodextrin inclusion complex35. The physical
mixture of drug and Cyclodextrins has been reported to show
no or limited bioavailability enhancement after oral
administration. However, enhanced bioavailability was
noticed by forming a complex of drug and Cyclodextrins, and
the AUC enhancement ratio by complication has been
reported to be 1.1–46-fold matched with that of control
formulations such as crystalline drugs and lyophilised
drugs36.
pH modification
pH modification in solid dosage forms is assumed to be an
alternative option for an ionizable drug to improve the
solubility and dissolution rate. The pH change significantly
influences the saturation solubility of an ionizable drug by
dissociation. The incorporation of pH modifiers in the dosage
form can alter the microenvironmental pH.
Microenvironment is a term used to represent a microscopic
layer surrounding a solid particle in which the solid forms a
saturated solution of adsorbed water37. The
microenvironmental pH would affect the performance of the
solid dosage form, such as the chemical stability of the drug
substance and the dissolution profile38. There have been
several studies evidencing the pH-independent release of
basic drugs form controlled release dosage forms by using pH
modification technologies39. However, the examples of
application of pH modification system to IR formulation are
few40. BMS- 561389 (razaxaban, Bristol-Myers Squibb) is a
weak basic drug with a poor intrinsic solubility (˜0. 2 µg/ml).
BMS-561389 showedan enhanced dissolution rate from IR
tablet by incorporating tartaric acid in the tablet compared
with that of the tablet without tartaric acid under non-sink
condition (pH 5.5). Furthermore, the tartaric acid-containing
tablets showed significant improvements in AUC and Cmax
compared with the control tablets in famotidine pretreated
dogs. These results suggested that pH modification in dosage
form could reduce the variability in the absorption of
administered drugs. The solubility, dissolution rate, and pKa
of pH modifier would change the dissolution rate of the drug.
To obtain the complete dissolution of the drug from dosage
form, the pH modifier may need to coexist with the drug
particles in tablet or granule until the containing drug is
completely dissolved. Accordingly, the excipients and
manufacturing methods would affect the dissolution
performance of the drug from the pH-modified solid dosage
forms. The estimation of the microenvironmental pH in the
dosage form is thought to be helpful in designing pH-
modified dosage forms.
Particle size reduction
Micronization
Particle size reduction approach is broadly used to increase
the dissolution rate as well as salt formation. The dissolution
rate of a drug proportionally enhances with an enhancing
surface area of drug particles41. According to the Prandtl
boundary layer equation, the decrease of diffusion layer
thickness by reducing particle size, particularly down to <5
µm, would result in accelerated dissolution42. Thus, the
increased surface area and the decreased diffusion layer
thickness would lead to an enhanced dissolution rate of the
drug. Micronization approach successfully enhanced the
bioavailability of poorly water-soluble drugs such as
griseofulvin, digoxin, and felodipine43. The common method
to obtain micronized drug particles is the mechanical crush of
larger drug particles. Jet milling, ball milling, and pin milling
are commonly used for dry milling. For solid powders, the
lowest particle size that can be achieved by conventional
milling is about 2–3 µm. The milling does not always result
in significantly enhancing the dissolution rate of the drug.
Micronization sometimes increases agglomeration of the drug
particles, which may decrease the surface area available for
the dissolution. In such case, wetting agents, such as a
surfactant, would play a major role in increasing the effective
surface area.
Nanocrystals
Particle size reduction to nano-meter range (<1 µm) is an
attractive\ approach for poorly water-soluble drugs. Particle
size reduction could lead to an increase of the surface area
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 Ajay D. Kshirsagar et al: Bioavailability and bioequivalence study
and a decrease of the diffusion layer thickness, which could
provide an enhanced dissolution rate for drugs. In addition to
these factors, an increase in the saturation solubility is also
liked by reducing the particle size to less than 1 µm, as
described by Ostwald–Freundlich’s equation44. The
nanocrystal formulations are commonly produced by wet-
milling with beads, high-pressure homogenization, or
controlled precipitation45. Hydrophilic polymer and/or
surfactant are typically used to stabilize nanocrystal
suspension. The nanocrystalline drug particles are dispersed
into inert carriers after a drying process, such as spray drying
or lyophilization. Herein, the solidified nanocrystal
formulations can be defined as crystalline solid dispersion
(CSD). There have been numerous studies demonstrating the
enhanced oral bioavailability of pharmaceuticals and
neutraceuticals by nanocrystal technologies46. Nanocrystal
formulations have been found to show 1.7–60-fold and 2–30-
fold enhancement in Cmax and AUC compared with
crystalline formulations with micrometer particle size.
Crystal modifications
Different physiological and formulation factors are
responsible for the bioavailability of drugs from the dosage
form. One of the most important physical factors, which
affect the bioavailability and therapeutic efficacy of drug, is
the existence of active ingredients in various crystal forms
having different internal structure and physical properties47.
The different crystal form of a drug has different
physicochemical characteristics, namely crystal shape, crystal
size, melting point, density, flow properties solubility pattern,
dissolution characteristics and XRD pattern, though they are
chemically identical. A physical form having an improved
dissolution rate and solubility is useful for improving the
bioavailability of a drug48,49. The crystal habit is an important
variable in pharmaceutical manufacturing, where some
factors, such as the polarity of crystallization solvent and the
presence of impurities in the solvent, affect crystallization50-
52
. Among them, solvent strongly affects the habit of
crystalline materials; however, the roleplayed by solvent
interactions in enhancing or inhibiting crystal growth is still
not completely understood53.
Metastable polymorphs
Polymorphism in crystalline solids is defined as materials
with the same chemical composition, but different molecular
conformations54. The huge majority of drugs can be
crystallized into several polymorphs. Each polymorph has a
different energy, showing different physicochemical
properties, such as melting point, density, solubility, and
stability. Generally, the solubility of metastable polymorphs
is kinetically higher than that of a thermodynamically more
stable polymorph55. The differences of the solubility among
polymorphs were reported to be typically less than 2.0-fold56.
Although the practical purpose of metastable polymorphs is
one of the effective approaches to enhance the dissolution
rate of a drug, the metastable forms eventually convert to the
thermodynamically stable form. It is necessary to monitor the
polymorphic transformation during both manufacturing and
storage of dosage forms to make certain of reproducible
bioavailability after oral administration57.
Salt formation
In the pharmaceutical industry, the salt formation approach is
commonly used for an ionizable drug to increase solubility
and dissolution rate. Salts are formed via proton transfer from
an acid to a base. A stable ionic bond can be formed when the
co-relate to peak between an acid and a base (peak) is greater
than 358. The counter ion containing salt changes the pH in -
the dissolving surface of a salt particle in the diffusion layer,
resulting in a higher dissolution rate of the salts compared
with that of the matching free forms59. According to the
Henderson-Hasselbalch equations, the change of pH highly
affects the aqueous solubility of an ionizable drug60. In
theory, the solubility of a weak basic drug increases
exponentially with decreasing pH in the pH range between its
pKa and pHmax (pH of maximum solubility in the pH-
solubility profile). The increased saturation solubility on the
dissolving surface contributes to the higher the dissolution
rate by salt formation. Celecoxib, a poorly water soluble
weak acidic drug, showed an enhanced dissolution rate and
oral bioavailability with a combination of Na salt formation
and the use of a precipitation inhibitor compared with the
corresponding free acid form61. The solubility and dissolution
rate of salt are influenced by the counter ion containing the
salt. The solubility of haloperidol mesylate was significantly
higher than that of its hydrochloride salt at a lower pH
range62. The aqueous solubility of a moderately soluble
hydrochloride salt for a basic drug is sometimes reduced in a
solution containing chloride ion, such as gastric fluids
(common-ion effects). An appropriate salt form should be
developed from the viewpoints of both physicochemical and
biopharmaceutical properties, especially for poorly water-
soluble drugs.
Cocrystal formation
In recent years, much attention has been drawn to cocrystal
for changing the dissolution rate of poorly water-soluble
drugs. Cocrystal is widely defined as crystalline materials
exchanged of at least two different components63.
Pharmaceutical cocrystal is typically composed of an API
and a nontoxic guest molecule (cocrystal former) in a
stoichiometric ratio. Unlike salt formation, proton transfer
between the API and cocrystal former does not take place in
cocrystal formation. In many cases, the API and cocrystal
former require hydrogen bonding to form a stable crystal.
Generally, pKa is one of the good indicators for
distinguishing between salts and cocrystals, and the
molecular complexes can be defined as a cocrystal when the
pKa is less than zero58. When the pKa is between 0 and 3,
they can be salts or cocrystals or can contain sheared protons
or mixed ionization states that cannot be assigned to either
category. There have been several studies demonstrating the
increased dissolution rate and oral bioavailability by crystal
formation64. AMG-517 (Amgen) is a potent and selective
VR1 antagonist65. AMG-517 is a free base, but insoluble at
physiological pH because there is no pKa value in the
physiological range. The cocrystal of AMG 517 and sorbic
acid proved a higher dissolution rate in the fasted state
simulated intestinal fluid, and 9.4-fold enhancement in
AUC0–Inf was observed compared with that of its free base
form after oral administration to dog (500 mg/kg). In addition
to other crystal engineering approaches, such as metastable
polymorphs and salt formation, cocrystal approach could be
an alternative option for improving the dissolution rate of
poorly water-soluble drugs, especially for the drug candidates
that are not ionized at physiological pH.
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 Ajay D. Kshirsagar et al: Bioavailability and bioequivalence study
CONCLUSION
In the bioavailability and bioequivalence study the
permeability and solubility parameter pay a great attention
because any pharmaceutical company wants to achieve great
position in the generic market. In this review add some
modification technique such as complex formation, clathrets,
and the addition of cyclodextrin addition we increase the BA
and BE parameter. Researchers now focus on the
modification of class for drug by introducing newer
technique.
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