This document discusses various solubilization techniques for improving the solubility of poorly soluble drugs, including physical and chemical modifications. Under physical modifications, it covers crystal modification techniques like polymorphism and salt formation. It also discusses particle size reduction methods like micronization, nanonization, and production of nanosuspensions. Other techniques covered are drug dispersion in carriers through solid solutions, eutectic mixtures and solid dispersions. It also discusses solubilization using surfactants, complexation, and chemical modifications. The techniques discussed aim to improve drug dissolution rates and oral absorption of class II drugs limited by solubility.

1. Solubilization Techniques
Presented by
(Dr) Kahnu Charan Panigrahi
Asst. Professor, Research Scholar,
Roland Institute of Pharmaceutical Sciences,
(Affiliated to BPUT)
Web of Science Researcher ID: AAK-3095-2020

2. Introduction
For the drugs exhibiting low solubility
but reasonable membrane permeability,
which are categorised as BCS class II, the
rate-limiting process of absorption is the
drug dissolution step.
 Formulation plays a major role in
determining the rate and extent of
absorption of such drugs from the
gastrointestinal tract.

4. Techniques to improve solubility
I. Physical Modifications
• A. Crystal Modification
• a. Metastable Polymorphs
• b. Salt formation
• C. Co-crystal formation
• B. Particle size reduction
• a. Micronization
• b. Nanonization
• C. Drug dispersion in carriers
• a. Eutectic mixtures
• b. Solid dispersions
• c. Solid solutions
• D. Complexation
• a. Use of complexing agents
• E. Solubilization by surfactants
• a. Microemulsions
• b. Self microemulsifying drug delivery systems
• II. Chemical Modifications

5. Crystal Modification
Metastable polymorphs
Polymorphism in crystalline solids is defined as
materials with the same chemical composition, but
different lattice structures and/or different
molecular conformations. The vast majority of
drugs can crystallize 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
higher than that of a thermodynamically more
stable polymorph.

6. Although the utilization of metastable polymorphs is one
of the effective approaches to enhance the dissolution
rate of a drug, the metastable forms eventually
transform to the thermodynamically stable form.
It is necessary to monitor the polymorphic transformation
during both manufacturing and storage of dosage
forms to ensure reproducible bioavailability after oral
administration.
Such a transformation of metastable to stable form can
be inhibited by dehydrating the molecule environment
or by adding viscosity building macromolecules such as
PVP, CMC, Pectin or gelatin that prevent such a
conversion by adsorbing on to the structure of crystal.

7. Salt formation
• In the pharmaceutical industry, salt formation approach is
commonly used for an ionizable drug to increase solubility
and dissolution rate.
• The counter ion containing salt changes the pH at 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 corresponding free forms.
• The solubility of haloperidol mesylate was significantly
higher than that of its hydrochloride salt at a lower pH
range.
• The aqueous solubility of a moderately soluble
hydrochloride salt for a basic drug is sometimes reduced in
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.

8. Cocrystal formation
• Definition
• The term ‘cocrystal’ is meant to define
[a] crystalline phase wherein at least two components
of the crystal interact by hydrogen bonding and
possibly by other noncovalent interactions rather than
by ion pairing or without transfer of hydrogen ion.
• The primary difference is the physical state of the pure
isolated compound. If one component is liquid at room
temperature, the crystals are referred to as solvates; if
both components are solids at room temperature, the
products are referred to as cocrystals”.
Pharmaceutical co-crystals can be defined as crystalline
materials comprised of an API and one or more unique
co-crystal formers, which are solids at room
temperature.

9. • Co-crystal formation may be rationalised by
consideration of the hydrogen bond donors
and acceptors of the materials that are to be
co-crystallized and how they might interact.

10. • In recent years, much attention has been drawn to cocrystal for
improving the dissolution rate of poorly water-soluble drugs.
• Cocrystal is broadly defined as crystalline materials comprised of
at least two different components.
• 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 cocrystal.
• Generally, pKa is one of the reliable indicators for distinguishing
between salts and cocrystals and molecular complexes.
• The molecular complexes can be defined as a cocrystal when the
pKa is less than 0. 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.

11. • There have been several studies demonstrating the enhanced
dissolution rate and oral bioavailability by cocrystal
formation.
• AMG-517 (Amgen) is a potent and selective VR1 antagonist.
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 showed a higher
dissolution rate in fasted state simulated intestinal fluid, and
9.4-fold enhancement in AUC0–∞ 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.

12. Particle size reduction
Micronization
Particle size reduction approach is widely used to
increase dissolution rate.
The dissolution rate of a drug proportionally
increases with increasing surface area of drug
particles.
The decrease of diffusion layer thickness by
reducing particle size, particularly down to < 5
µm, would result in accelerated dissolution.
Thus, the increased surface area and the
decreased diffusion layer thickness would lead to
an enhanced dissolution rate of the drug.

13.  The common method to obtain micronized drug particles is
mechanical pulverization 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.
 The thermal stress which may occur during comminution and
spray drying is also a concern when processing thermosensitive
or unstable active compounds.

14. Nanonization
• Nanotechnology will be used to improve drugs
that have poor solubility.
• Nanotechnology broadly refers to the study
and use of materials and structures at the
nanoscale level of approximately 100 nm or
less .
• For many new chemical entities with very low
solubility, oral bioavailability enhancement by
micronization is not sufficient because
micronized product has the tendency to
agglomerate, which leads to decreased
effective surface area for dissolution, and the
next step taken was nanonisation.

15. Nanosuspension
• Nanosuspensions are submicron colloidal dispersion of
pure particles of drug that are stabilized by surfactants.
• The advantages offered by nanosuspension is an
increased dissolution rate due to a larger exposed
surface area.
• The recent techniques widely used to form
nanosuspensions are
1.Homogenization
2. Wet milling
3. Sonocrystallization,
4.Super critical fluid technology
5. Spray drying.

16. Homogenization
• The suspension is forced under pressure through a
valve that has a nano aperture.
• This causes bubbles of water to form, which collapse
as they come out of the valves.
• This mechanism cracks the particles.
• Three types of homogenizers are commonly used
for particle size reduction in the pharmaceutical and
biotechnology industries:
1. Conventional homogenizers
2. Sonicators
3. High-shear fluid processors.

17. Wet Milling
• Active drug in the presence of surfactant is
defragmented
by milling.
• Drying of nanosuspensions can be done by
lyophilization or spray drying.
• The nanosuspension approach has been
employed for drugs including
Tarazepide
Atovaquone,
Amphotericin B
Paclitaxel
Bupravaquone.

18. Sonocrystallization
• Sonocrystallization utilizes ultrasound power
characterized by a frequency range of 20–100 kHz
for inducing crystallization.
• Most applications use ultrasound in the range of
20 kHz to 5 MHz to reduce the particle size.

19. Supercritical Fluid Process
• In the supercritical fluid (SCF) process, micronization
is
done by the supercritical fluid.
• Supercritical fluids are fluids whose temperature and
pressure are greater than their critical temperature
(Tc) and critical pressure (Tp).
• An SCF is highly compressible, which allows moderate
changes in pressure to greatly alter the density and
mass
transport characteristics that largely determine its
solvent
power.
• The SCF process can create nanoparticulate
suspensions of particles 5–2,000 nm in diameter.

20. Spray drying
• Spray drying is a commonly used method for drying a
liquid feed through a hot gas.
• Typically, this hot gas is air, but sensitive materials such as
pharmaceuticals and solvents like ethanol require oxygen-
free drying, and nitrogen gas is used instead.
• The liquid feed varies depending on the material being
dried. This method of drying is a one-step, rapid process.
• Spray drying of the poorly water-soluble salicylic acid
dispersed in acacia solutions resulted in as much as a 50%
improvement in its solubility.

21. Nanocrystals
• Particle size reduction to nano-meter range (<1 µm) is an attractive
approach for poorly water-soluble drugs.
• In addition to these factors, an increase in the saturation solubility is also
expected by reducing the particle size to less than 1 µm.
• The nanocrystal formulations are commonly produced by wet-milling with
beads, high-pressure homogenization, or controlled Precipitation.
• 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
technologies.
• 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.

22. Nanomorphs
• Nanomorph technology converts drug substances with low water solubility
from a coarse crystalline state into amorphous nanoparticles to enhance
their dissolution.
• A suspension of drug substance in solvent is fed into a chamber, where it is
rapidly mixed with another solvent.
• Immediately the drug substance suspension is converted into a true
molecular solution.
• The admixture of an aqueous solution of a polymer induces precipitation of
the drug substance.
• The polymer keeps the drug substance particles in their nanoparticulate
state and prevents them from aggregation or growth.
• Water-redispersable dry powders can be obtained from the nanosized
dispersion by conventional methods (e.g., spray drying).
• Using this technology, a coarse, crystalline drug substance is transformed
into a nanodispersed amorphous state without any physical milling or
grinding
procedures.
• It leads to the preparation of amorphous nanoparticles.

23. Drug Dispersion in Carriers
A. Solid Solutions
• solid solution, mixture of two crystalline solids that coexist as a new
crystalline solid, or crystal lattice.
• The mixing can be accomplished by combining the two solids when they
have been melted into liquids at high temperatures and then cooling the
result to form the new solid.
• It is a binary system comprising of a solid solute molecularly dispersed in a
solid solvent.
• Since the two components crystallize together in a homogenous one phase
system, solid solutions are also called as molecular dispersions or mixed
crystals.
• Because of reduction in particle size to the molecular level, solid solutions
show greater aqueous solubility and faster dissolution than eutectics and
solid dispersions.
• They are generally prepared by fusion method whereby a physical mixture
of solute and solvent are melted together followed by rapid solidification.
• Such systems prepared by fusion are called as melts
• Eg. Griseofulvin-succinic acid

24. • If the diameter of the solvent molecules is less
than 60 % of diameter of solvent molecules or
its volume is less than 20% of volume of
solvent molecules, the solute molecules can
be accommodated within the intermolecular
spaces of solvent molecules.
• Eg. Digitoxin-PEG 6000
Mechanism
When the binary mixture is exposed to water,
the soluble carrier dissolves rapidly leaving the
insoluble drug in a state of microcrystalline
dispersion of very fine particles.

25. Eutectic Mixture
• These systems are prepared by a fusion method.
• Eutectic melts differ from solid solutions in that the
fused melt of solute and solvent show complete
miscibility but negligible solid–solid solubility (i.e.,
such systems are basically an intimately blended
physical mixture of two crystalline components).
• When the binary mixture is exposed to water, the
soluble carrier dissolves rapidly leaving the insoluble
drug in a state of microcrystalline dispersion of very
fine particles.
• Examples of eutectic mixtures include paracetamol–
urea, griseofulvin–urea, and griseofulvin–succinic
acid.

26. • Sekiguchi and co-workers suggested that submicron
particle size reduction could be achieved through
eutectic formation between a poorly soluble drug and a
rapidly soluble carrier and reported one of the earliest
techniques used.
• As an example, significant improvement in the
dissolution rate of chloramphenicol was obtained when
incorporated in a eutectic mixture with urea.
• The soluble carrier dissolves rapidly leaving the insoluble
drug in a state of microcrystalline dispersion consisting of
extremely fine particles.
• The advantage with solid solutions and eutectics is that
they are melts, are easy to prepare, and are economical
because no solvent is used. Some limitations are that it
cannot be applied to drugs that fail to crystallize from the
mixed melt, thermolabile drugs, and carriers such as
succinic acid that decompose at their melting points.

27. Solid dispersions
• An important prerequisite for the manufacture of a
solid dispersion is that both the drug and the carrier
are dissolved in a common volatile solvent such as
alcohol.
• The liquid solvent can be removed by various
methods like by spray-drying, freeze-drying or
evaporation under reduced pressure which results in
amorphous precipitation of guest in a crystalline
carrier.
• Here the drug is precipitated in an amorphous form.
• These techniques have problems such as negative
effects of the solvents on the environment and high
cost of production.

28. D. Complexation:
• Complexation is the reversible association between two or more
molecules to form a non-bonded entity.
• Complexation relies on relatively weak forces such as vanderwaal
forces, hydrogen bonding and hydrophobic interactions.
Inclusion Complexation:
• Inclusion complexes are formed by the insertion of the nonpolar
molecule or the nonpolar region of one molecule (known as guest)
into the cavity of another molecule or group of molecules (known as
host).
• The most commonly used host molecules are cyclodextrins.
• Cyclodextrins are non-reducing, crystalline, water soluble, cyclic,
oligosaccharides.
• Cyclodextrins consist of glucose monomers arranged in a donut shape
ring.

29. • Three naturally occurring CDs are α-Cyclodextrin, β-
Cyclodextrin, and γ- Cyclodextrin.
• The internal surface of cavity is hydrophobic and
external is hydrophilic, this is due to the arrangement
of hydroxyl group within the molecule.

30. Solubilization by surfactants
• Surfactants are molecules with distinct polar and nonpolar
regions. Most surfactants consist of a hydrocarbon segment
connected to a polar group.
• The presence of surfactants may lower the surface tension
and increase the solubility of the drug.
Microemulsion:
• A microemulsion is a four-component system composed of
external phase, internal phase, surfactant and co-
surfactant.
• The addition of surfactant, which is predominately soluble
in the internal phase unlike the co-surfactant, results in the
formation of an optically clear, isotropic,
thermodynamically stable emulsion.
• It is termed as microemulsion because of the internal phase
is <0.1 micron droplet diameter.

31. • The formation of microemulsion is spontaneous and does
not involve the input of external energy.
• The surfactant and the cosurfactant form a mixed film at the
interface, which contributes to the stability of the
microemulsion.
• Non-ionic surfactants, such as Tweens (polysorbates) and
Labrafil (Polyoxyethylated oleic glycerides), with high
hyrophile-lipophile balances are often used to ensure
immediate formation of oil-in-water droplets during
production.
• Advantages of microemulsion over coarse emulsion, It’s
ease of preparation due to spontaneous formation,
thermodynamic stability, transparent and elegant
appearance, enhanced penetration through the biological
membranes, increased bioavailability and less inter- and
intra-individual variability in drug pharmacokinetics.

32. Self-emulsification
• In recent years, self-emulsification drug delivery
systems (SEDDS) have been utilized to enhance
the oral bioavailability of poorly water-soluble
drugs, especially for highly lipophilic drugs.
• Self-emulsification formulations are isotropic
mixtures of oil, surfactant, cosolvent, and
solubilized drug.
• These formulations can rapidly form oil in water
(w/o) fine emulsions when dispersed in aqueous
phase under mild agitation.
• SEDDS are additionally classified into self-
microemulsification drug delivery systems
(SMEDDS) and self-nanoemulsification drug

33. • The rapid emulsification of these formulations in
the gastrointestinal tract can provide both
improved oral bioavailability and a reproducible
plasma concentration profile.
• The droplet size of the emulsion would influence
the extent of absorption of the orally administered
drugs. Neoral®, a cyclosporin SNEDDS formulation,
is a good example of the effectiveness of the
utilization of droplets of a smaller size.
• Neoral® showed increased Cmax and AUC
compared with Sandimmune®, a coarse SMEDDS
formulation, in human.

35. B. CHEMICAL MODIFICATIONS
Derivatization:
 It is a technique used in chemistry which transforms
a chemical compound into a product of similar
chemical structure, called derivative.
 Derivatives have different solubility as that of
adduct.

36. drug derivatization or prodrug concept
DEFINITION:
 Prodrug are pharmacologically inactive compounds that result from
transient chemical modifications of a biologically active species and are
designed to convert to biologically active species in vivo by a predictable
mechanism.
As per IUPAC
Prodrug is defined as any compound that undergoes bio-transformation
before exhibiting its pharmacological effects.
CHARACTERISTICS:
• Low oral absorption properties
• Lack of site specificity
• Chemical instability
• Toxicity
• Bad taste
36

37. • Bad odour
37
• Bad odour
• Pain at application site
 ADVANTAGES Advantages of prodrugs can be classified on the following
basis:

38. DISADVANTAGES
• The inert carrier generated following cleavage of prodrug
may also transform into a toxic metabolite.
• During activation prodrug might consume a vital cell
constituent such as glutathione leading to it’s depletion.
38

39. The Drug derivatization Concept:
39
A derivative of a known, active drug (D) can be capped to
furnish a prodrug (PD).
The PD enhances delivery characteristics and/or therapeutic
value of the drug by transforming into the active drug via an
enzymatic or a chemical process to remove the cap P at the site
of action to regenerate D.

40. Following is a partial list of examples of prodrugs
that have been marketed successfully
 Antiviral/anticancer agents: Alkyl aminocarboxyl derivatives of 5-
fluorouracil,ancitabine, 5-fluorpdeoxyuridine, acyclovir (Zovirax), valacyclovir,,
methotrexate
 Central Nervous System (CNS) agents: Lopiazepate, oxazepam,
lorazepam, nipecotic acid, L-Dopa, phenytoin
 Ophthalmic drugs: Pilocarpine, adrenalone, and propranolol (Ketoxime).
 Anti-infectives: Mecillinam, cycloserine, alfonsfalin, mebendazole,
polyoxins, ara-A, and Spectrobid (becampicillin)
 Cardiovascular agents: Pivopril, captopril, pindolol, and amino acid
derivatives of prazosin.
 Anti-inflammatory agents: aspirin, niflumic acid, loxoprofen, diclofenac,
sulindac, N-alkyllactame esters of indomethacin, and piroxicam.
 Antiallergy agents: Terbutaline, bambuterol, and albuterol.
40

41. Enhancement of solubility and dissolution rate of Drug
Parent Drug Prodrug with enhanced solubility
Chlorphenicol Sodium succinate ester
Tocopherols Sodium succinate ester
Corticosteroids 21-sodium succinates, 21-phosphate
esters
Testosterone Phosphate ester
Menthol Β-Glucoside
Sulfanilamide Glucosyl sulfanilamide
Tetracycline Tetralysine
Diazepam L-lysine ester
Metronidazole Amino acid ester