ENHANCING BIOAVAILABILITY WHEN

DEVELOPING ORAL SOLID FORMULATIONS

O ral bioavailability is a measure of the amount of an oral administered drug dose that is absorbed in the
bloodstream. Many new chemical entities (NCEs) developed in the pharmaceutical industry have poor
bioavailability because of either lower solubility or extensive first-pass elimination. Because of reduced
bioavailability, these drugs need to be administered in higher doses, which may result in adverse effects for
patients. It also makes dosage form development a challenge. Currently, sophisticated technologies such as
spray drying and hot melt extrusion are acknowledged to improve solubility, and thus bioavailability, of active
pharmaceutical ingredients (APIs). However, these approaches require the use of specialized equipment
and may increase development time and product costs. Drug delivery systems that target the lymphoid
system, such as lipid-based formulations (liposomes and solid lipid nanoparticles) are used to avoid first-pass
metabolism, but these have their own challenges of stability, reproducibility, and scale-up. There are several
more-straightforward formulation aspects to address the bioavailability problem.

Reducing Particle Size

T he particle size of an API plays an important role

in solubilization/dissolution. Solubilization is
directly proportional to the surface area of an API,
which is inversely proportional to its particle size
(see the Noyes-Whitney equation image below).
Therefore, a reduction in the particle size of a poorly
soluble API is the most direct approach to enhance
dissolution during initial phase of formulation
development.

Factors affecting dissolution and solubilty:

Noyes-Whitney equation

C3
dc D.A(C3 - C)
= C
dt h

Diffusion layer
dC/dt: the rate of dissolution of the drug particles
D: the diffusion coefficient of the drug in solution in • Air jet milling
the gastrointestinal fluids
A: the effective surface area of the drug articles in
contact with the gastrointestinal fluids
h: the thickness of the diffusion layer around each
drug particle
Cs: the saturation solubility of the drug in solution in
the diffusion layer
C: the concentration of the drug in the gastrointestinal
fluids
API particle size can be reduced to micron and
sub-micron levels by:
• Bead milling
• Spray drying
Of these, air jet milling is the most widely used,
which uses high-velocity jets of gas to impart
energy to particles for size reduction. Once the
effect of the API particle size on its solubilization is
established, scientists can confirm the improvement
in bioavailability by performing in-vivo studies using
selected dosage forms with a small number of
animals or human subjects.

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Optimizing
Formulation Factors
Surfactants

S urfactants are the agents that lower the interfacial

tension between two liquids, between a gas and
a liquid, and between a solid and a liquid. They can
enhance solubility and thus improve bioavailability
of API. There are three major types of surfactants:
anionic, cationic, and non-ionic. Sodium lauryl
sulphate and sodium stearate are examples of
anionic surfactants. Benzalkonium chloride and
cetylpyridinium chloride are cationic, and Tweens
and Spans are non-ionic surfactants commonly used
in formulations in the pharmaceutical industry. In
addition, there are zwitterionic surfactants, which
have cationic and anionic centers attached to the
same molecule, including lauryldimethylamine
N-oxide and lecithin. It is preferable to dissolve
surfactants in a binder solution, which is then used to
granulate the dry mix to ensure uniform distribution
of surfactants in the formulation.

Microenvironmental pH Complexation

A nother classic and cost-effective approach is to

adjust the microenvironmental pH of the API.
Most APIs are either acidic or basic, with a pH-
dependent solubility. Although the pH profile in the
gastrointestinal (GI) track remains the same, that is,
acidic in the stomach and basic in the small intestine
and colon, the formulation’s microenvironmental pH
can be adjusted to increase drug solubility at the GI
location where it is less soluble. Acidifiers include
citric acid, tartaric acid, maleic acid, malic acid, and
fumaric acid. Alkalizers include sodium carbonate,
sodium bicarbonate, calcium carbonate, magnesium
oxide, meglumine, and sodium hydroxide. For
example, organic acids such as citric acid and tartaric
acid have been used successfully to maintain an
acidic microenvironment in an immediate-release
formulation of Ketokonazole to improve its solubility
and thus bioavailability (Reference –‘’Improved
dissolution and absorption of Ketoconazole in the
presence of organic acids as pH-modifiers’’. Adachi
M, Hinatsu Y, Kusamori K, Katsumi H, et. al. Eur J
Pharm Sci. 2015 Aug 30;76:225-30. doi: 10.1016/j.
ejps.2015.05.015).
C omplexation is the association between two or
more molecules to form a non-bonded entity
with a well-defined stoichiometry. It relies on weak
forces such as London forces, hydrogen bonding,
and hydrophobic interactions. Inclusion complexes
are formed by the insertion of the nonpolar region
of one molecule (known as the guest) into the
cavity of another molecule or group of molecules
(known as the host). The cavity of the host must be
large enough to accommodate the guest and small
enough to eliminate water, so that the total contact
between the water and the nonpolar regions of
the host and the guest is reduced. Cyclodextrins
(CDs) and their derivatives have been widely used
as hosts to increase water solubility, dissolution
rate, and bioavailability of several APIs. There
are three naturally occurring CDs: α-cyclodextrin,
β-cyclodextrin, and γ-cyclodextrin. The CDs that
have improved aqueous solubility are preferred for
pharmaceutical use. Examples of APIs that have had
their solubility and bioavailability enhanced using CD
include rofecoxib, celecoxib, clofibrate, melarsoprol,
taxol, cyclosporin A, and carvedilol.

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Solid Dispersion Gastroretentive Dosage Forms

S olid dispersion (SD) is the scattering of one or

more active ingredients in an inert excipient, a
carrier, or a matrix where the API can exist in a finely
M any drugs have a selective absorption window
in the upper or lower small intestine. If
the residence time at the absorption window
crystalline, solubilized, or amorphous state. These is short, then the absorption of the drug would
can be prepared by spraying (on substrate), melting be incomplete, reducing its bioavailability.
(fusion), or adsorption (on substrate) methods. Once To improve GI residence time for such drugs,
the solid dispersion is exposed to aqueous media and mucoadhesive and floating drug delivery systems
the carrier dissolves, the drug is released as very fine are most commonly used. These are prepared with
colloidal particles with the greatly enhanced surface conventional processes such as direct compression,
area, which is expected to increase dissolution rate dry granulation, wet granulation, and coating.
and bioavailability of poorly water-soluble drugs. Some of the polymeric materials used to prepare
mucoadhesive and floating dosage forms are
Various pharmaceutical approaches for the hydroxypropyl methylcellulose (HPMC), polyethylene
preparation of SDs include fusion and solvent- oxide, polymethacrylates, etc.
deposition; melt agglomeration; solvent evaporation;
crystallization in aqueous solvent; use of adsorbent;
kneading; supercritical fluid; lyophilization; hot
melt extrusion; spray drying; and electrospinning.
Of these, hot melt extrusion and spray drying are
the most widely explored techniques. Alternatively,
spraying, adsorption, and melt granulation are
more executable approaches. With the spraying
method, a mixture of API, carrier, and binder can be
dissolved in solvent and sprayed onto a substrate
such as sugar spheres or celphere beads/pellets.
These can be filled in capsules or compressed with
other excipients to form tablets. In the adsorption
method, the API, carrier, and binder can be dissolved
in solvent and added/poured onto substrate, such
as aluminum magnesium silicate that has high
adsorption potential. The powder/granules can be
filled in capsules or compressed into tablets. With
melt granulation, a jacketed granulator can be used
to produce the granules that can be formulated as
capsules or compressed tablets. Examples of APIs
that have been studied using SD are meloxicam,
naproxen, nimesulide, carbamazepine, celecoxib, and
nevirapine.

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Suspensions and Parenteral Forms

It has been well acknowledged that the

bioavailability of a compound can be improved by
designing liquid dosage forms such as parenteral
preparations, solutions, and suspensions. Parenterals
circumvent the metabolism step and, therefore, offer
high bioavailability. With solutions and suspensions,
the API is either in solubilized form (solutions) or
dispersed as fine particulate matter (suspensions)
and shows superior bioavailability over solid dosage
forms. These formulations broadly use a solvent or
vehicle, preservatives, flavors, and thickening agents.

Liquid-Filled Capsules

D issolving poorly soluble APIs in a non-aqueous

solvent, such as oils, and filling a soft or hard
gelatin capsule with them is a promising approach
to improve bioavailability of compounds. However,
the main drawbacks of liquid-filled capsules are that
specific equipment such as liquid-filling and band-
sealing machines are required and capsules are less
cost-effective than tablet dosage forms.
Lipid-Based Formulations

L ipids have potential to alter biopharmaceutical

properties of a drug, such as improved dissolution
and solubility of APIs in the intestinal fluid through
potentiating bile secretion, protection of the drug
from degradation due to presence of oils, and
formation of lipoproteins to promote lymphatic
transport of highly lipophilic drugs. In the intestinal
region, aggregated lymphoid follicles present
as Peyer’s patches. These patches offer a great
opportunity to deliver the drugs to the lymphatic
system via the oral route. There are a number of
strategies to formulate lipid-based systems, including
self-emulsifying drug delivery, liposomes, solid lipid
nanoparticles, lipid-based liquid adsorption onto
carrier, melt granulation, and the supercritical fluid-
based method. Of these, adsorption onto solid
carrier and melt granulation are the most direct and
cost-effective techniques and present fewer stability,
reproducibility, and scale-up challenges. Mono-, di-
and triglycerides have been widely used to formulate
lipid drug delivery systems to improve bioavailability
of many pharmaceutical APIs.

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More Straightforward Approaches
Yield Faster and Safer Results

M ethods for improving bioavailability are

constantly evolving. Selecting the proper
approach is key to achieving a good formulation
that reduces the frequency of dosing and
improves patient compliance, as well as results
in a low production cost. This depends upon drug
characteristics, e.g., solubility, chemical nature,
melting point, physical nature, absorption site,
pharmacokinetic behavior, dosage form (viz. tablet,
capsule, and liquid), strength, dissolution profile,
regulatory requirements, approved excipients and
analytical accuracy. Harnessing the experience
of working on a variety of formulations, new
formulation technologies, use of readily available
processes in the commercial manufacturing
environment, will yield the most direct approach and
long-term success.

Solubility Enhancement at Piramal

Pharma Solutions

T he team at Piramal Pharmaceutical Development

Services (PPDS) in Ahmedabad, India, has deeply
explored classic as well as specialized techniques for
solubility and bioavailability enhancement of several
drugs with poor solubility. Based on the knowledge
acquired over many years, PPDS has developed
decision trees to derive and assess the best suitable
approach for solubility enhancement of drugs.
PPDS looks closely at API physio-chemistry, dose,
formulation complexities and breadth of applicability
of the solubility enhancement techniques. PPDS
uses a drug micronizer (air jet mill) to facilitate quick
assessment of the impact of reduction in particle size
of API on solubility and bioavailability enhancement.
Moreover, in addition to classic techniques, PPDS
uses a number of precise, specialized technologies
including spray drying to create amorphous powders
in combination with polymers for further processing,
and fluid bed coaters with a range of batch sizes to
coat a drug and polymer mixture onto a carrier as
solid dispersion.

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Piramal Pharma Solutions is a contract development and manufacturing organization (CDMO), where everything we do, we do for
the patient. The company specializes in integrated services and end-to-end development and manufacturing solutions across the
drug life cycle. We serve our clients through a globally integrated network of facilities in North America, Europe, and Asia. This
enables us to offer a comprehensive range of services including drug discovery solutions, process and pharmaceutical development
services, clinical trial supplies, and commercial supply of APIs and finished dosage forms. We also offer specialized services like
the development and manufacture of highly potent APIs, antibody drug conjugations, and manufacturing of hormonal drugs. Our
capability as an integrated service provider and experience with various technologies enables us to serve innovator and generic
companies worldwide. Our development centers and manufacturing sites have accreditations from regulatory bodies in the
U.S., Europe, and Japan. With a pool of 700+ scientists including 150 Ph.D.s across the globe, we are committed to research and
development programs. To know more visit: www.piramalpharmasolutions.com | Social Media: Twitter, LinkedIn

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CORPORATE OFFICE: PIRAMAL PHARMA LIMITED

Gr. Flr., Piramal Ananta, Agastya Corp. Park, Kamani Junction, LBS Marg, Kurla, MUMBAI, Mumbai City, Maharashtra, India, 400070
Email: contact.us@piramal.com | piramalpharmasolutions.com