Solubility Enhancement

Modern Pharmaceutics
Dr. Kailas Mali
Professor in Pharmaceutics,
Adarsh College of Pharmacy, Vita
Solubility Enhancement
Techniques

1. Concept of solubility and dissolution.
2. Factors affecting solubility.
3. Factors affecting dissolution.
4. Techniques of solubility / dissolution enhancement.
Contents

Dissolution
● It is a process in which a solid substance
solubilizes in a given solvent i.e. mass
transfer from the solid surface to the liquid
phase.
● Dissolution is kinetic process, and is
quantified by its rate.
● Rate of dissolution: It is the amount of drug
substance that goes in solution per unit
time under standardized conditions of
liquid/solid interface, temperature and
solvent composition.
Introduction
Solubility
● It is a process in which maximum amount of
solute dissolved in a given solvent under
standard conditions of temp, pressure and
pH.
● Solubility is a characteristic property of a
specific solute–solvent combination, and
different substances have greatly differing
solubilities.
● Quantifies the dynamic equilibrium state
achieved when the rate of dissolution
equals the rate of precipitation

Process of Solubilisation
● 1: A single solute molecule is removed from
the crystal lattice; energy is required in this
step to overcome solute-solute interactions
in the solid state.
● Step 2: A void is created within the solvent
to accommodate the solute molecule.
Although this step also requires energy, it is
likely to be considerably lower than the
energy required in step 1.
● Step 3: The solute molecule inserts into the
solvent, forming solute-solvent interactions.
Simplistically, if the energy released from
the solute-solvent interactions (i.e., step 3)
is greater than the energy required for steps
1 and 2, solubility is favored.

Forces and Bonds
● Like dissolves in like. The type of
intermolecular forces and bonds vary
among each molecule. The chances of
solubility between two unlike substances
are more challengeable than the like
substances.
Pressure
● Gaseous substances are much influenced
than solids and liquids by pressure. When
the partial pressure of gas increases, the
chance of its solubility is also increased.
Physical and chemical properties of drug
Factors affecting solubility
Temperature
● By changing the temperature we can
increase the soluble property of a solute.
Generally, water dissolves solutes at 20° C
or 100° C. Sparingly soluble solid or liquid
substances can be dissolved completely by
increasing the temperature. But in the case
of gaseous substance, temperature
inversely influences solubility i.e. as the
temperature increases gases expand and
escapes from their solvent.

Rate of solution
● Particle size
● Temperature
● Amount of solute dissolved
● Stirring
Factors affecting solubility
● Nature of solute
● Nature of solvent
● Molecular size
● Polarity
● Polymorphism
● pH of solvent
● pka of drug
● Rate of solution

● Low aqueous solubility is the major problem
encountered with formulation development
of new chemical entities.
● Any drug to be absorbed must be present in
the form of an aqueous solution at the site
of absorption.
● The negative effect of compounds with low
solubility include poor absorption and
bioavailability, insufficient solubility for IV
dosing, development challenges leading to
increasing the development cost and time,
burden shifted to patient (frequent high-
dose administration)
Importance of Solubility
● Therapeutic effectiveness of a drug
depends upon bioavailability and ultimately
upon the solubility of drug molecules.
● Solubility is one of the important parameter
to achieve desired concentration of drug in
systemic circulation for pharmacological
response to be shown.
● Currently only 8% of new drug candidates
have both high solubility and high
permeability and nearly 40% of the new
chemical entities currently being discovered
are poorly water soluble.
● More than one-third of the drugs listed in
the US pharmacopoeia fall into the poorly
water soluble category.

Factors affecting dissolution
● Physical characteristics of dosage form.
● Wettability of dosage unit.
● Penetration ability of media.
● The swelling process.
● The disintegration and deaggregation of
dosage form.
Dissolution

Chemical Modifications
● Change of pH, use of buffer, derivatization,
complexation, and salt formation.
Miscellaneous Methods
● Supercritical fluid process, use of adjuvant
like surfactant, solubilizers, cosolvency,
hydrotrophy, and novel excipients.
Techniques of Solubility Enhancement
Physical Modifications
● Particle size reduction like micronization
and nanosuspension.
● Modification of the crystal habit like
polymorphs, amorphous form and
cocrystallization.
● Drug dispersion in carriers like eutectic
mixtures, solid dispersions, solid solutions
and cryogenic techniques.

Use of Surfactants
● Surfactants are amphiphilic in nature i.e.
composed of hydrophilic as well as
lipophilic portions. These molecules have
been widely used as solubility enhancers
(solubilizers).
● This method is commonly known as
micellar solubilization since they form
micelles, which are association aggregates
of surfactant molecule.
● Surfactants reduces interfacial tension
between solute and solvent.
● Promotes wetting of particles.
● Tweens, spans, polyoxyetylene glycerides,
polyoxyetylene stearates and Poloxamers.

● The surfactants like polyoxy ethylene
surfactants for ex. Brij 35 or sugar esters
like sorbitan monooleate (Span 80), cationic
or anionic like alkyltrimethylammonium
bromide and sodium dodecyl sulphate or
zwitter ionic such as phospholipids like
lecithin are used as surfactants to prepare
microemulsions.
Microemulsions
● A Micro emulsion is an optically clear,
isotropic, thermo dynamically stable
translucent system which contains a
mixture of oil, Hydrophilic surfactant and
hydrophilic solvent in which the poorly water
soluble drug dissolves.
● When comes in contact with water the
formulation is spontaneously disperse or
self emulsified to form a very clear
emulsion of exceedingly small as well as
uniform oil droplets containing the
solubilized poorly soluble drug.

● The ease of emulsification could be
associated with the ease of water
penetrating into the various liquids
crystalline or gel phases formed on the
surface of the droplet.
● Systems are thermodynamically stable.
● Large quantity of surfactants irritates GIT.
● Problem of chemical instability.
Self- Emulsifying Drug Delivery System
● A SE or SME system is the concept of in situ
formation of emulsion in the GIT.
● Contains mixture of oil, surfactant, co-
surfactant, one or more hydrophilic solvents
and co-solvent forms a transparent
isotropic solution in the absence of external
phase (water).
● It forms fine o/w emulsions or micro-
emulsions spontaneously upon dilution by
the aqueous phase in the GIT and is used
for improving lipophillic drug dissolution
and absorption.

pH Adjustment
● Adjustment of micro-environmental pH to
modify the ionization behavior is the
simplest and most commonly used method
to increase the water solubility behavior.
● Therfore as per the pH partition hypothesis
and Handerson- Hesselbatch equation,
ionization of a compound is dependent on
the pH of media and pKa of drug.
● Also the change in the ionic compound can
result to in –situ salt formation. Therefore
this salt formation is infeasible for
unionized compounds. The formed salts
may also converse to respective acid or
base forms in GIT.

● Nanoparticle technology is an approach for
improving the solubility of drugs that are
less soluble in water, namely BCS class II
and class IV drugs.
● The reduction in particle size affects the
kinetic solubility of a compound.
● This is because a reduction in size to <1
mm increases the pressure of the solvation,
which increases solubility and also disrupts
the interaction of the solute, which
facilitates solubilization.
● Reduction in particle size to <1 μm
significantly increases the saturation
solubility.
Particle Size reduction
● Drug solubility can be increased by reducing
particle size, as drug solubility is intrinsically
related to drug particle size. If the particle
size decreases, the surface area of the drug
with a volume ratio increases.
● A greater surface area allows greater
interaction with the solvent, which increases
solubility.
● There are two principal approaches to
reducing particle size: micronization and
nanonization.
● Drug particles in the submicron range,
referred to as nanoparticles, are <1 μm in
size.

● The thermal stress which may occur during
comminution and spray drying is also a
concern when processing thermosensitive
or unstable active compounds.
● Using traditional approaches for nearly
insoluble drugs may not be able to enhance
the solubility up to desired level.
● Conventional methods of particle size
reduction, such as comminution and spray
drying, rely upon mechanical stress to
disaggregate the active compound.
● Particle size reduction is thus permitting an
efficient, reproducible, and economic means
of solubility enhancement.
● However, the mechanical forces inherent to
comminution, such as milling and grinding,
often impart significant amounts of physical
stress upon the drug product which may
induce degradation.

Ball Milling
● Ball milling, metal powder is placed in a
container with heavy balls.
● The powder is then processed with high
mechanical energy from the balls, which
rotate at high speed.
● There are several types of particle size
reduction by milling: low-energy tumbling
mill, vibrating ball mill, planetary ball mill,
high-energy ball mill, and attrition ball mill.
● Griseofulvin, progesterone, spironolactone
diosmin, and fenofibrate.
Micronization
● It is another conventional technique for the
particle size reduction.
● Micronization increases the dissolution rate
of drugs through increased surface area, it
does not increase equilibrium solubility.
● Decreasing the particle size of these drugs,
which cause increase in surface area,
improve their rate of dissolution.
● Micronization of drugs is done by milling
techniques using jet mill, rotor stator colloid
mills and so forth micronization is not
suitable for drugs having a high dose
number because it does not change the
saturation solubility of the drug

Mechanochemical synthesis
● Is based on the repetition of welding and
deformation from the reactant mixture.
● The starting material is stoichiometrically
mixed and processed by grinding.
● When grinding, chemical reactions occur on
the surface layer between the substrate and
the reagent so that the chemical reaction
uses only low temperatures.
● The nanoparticles produced will be
dispersed in the salt matrix and
subsequently washed using a good solvent
and dried at 105°C for 12 h.
Micronization
Advantages
● The micronization is used to increased
surface area for dissolution
● Micronization increases the dissolution rate
of drugs through increased surface area.
Disadvantages
● It does not increase equilibrium solubility
● Micronization is not suitable for drugs
having a high dose number because it does
not change the saturation solubility of the
drug.

● Tarazepide, atovaquone, amphotericin B,
paclitaxel, and buparvaquone.
● Advantages: Increased dissolution rate is
due to larger surface area exposed while
absence of Ostwald ripening is due to the
uniform and narrow particle size range
obtained, which eliminates the
concentration gradient factor
● Disadvantages: The major concern related
to particle size reduction is the eventual
conversion of the high-energy polymorph to
a low-energy crystalline form, which may not
be therapeutically active one.
Nanosuspension
● Nanosuspensions are sub-micron colloidal
dispersion of pure particles of drug which
are stabilized by surfactants.
● Homogenization and wet milling- Active
drug in the presence of surfactant is
defragmented by milling.
● Spraying of a drug solution in a volatile
organic solvent into a heated aqueous
solution. Rapid solvent evaporation
produces drug precipitation in the presence
of surfactants.
● Drying of nanosuspensions can be done by
lyophilization or spray drying.

Media Milling
● Using high-shear media mills.
● The milling chamber charged with milling
media, water, drug, and stabilizer is rotated
at a very high-shear rate under controlled
temperatures for several days (at least 2–7
days).
● The milling medium is composed of glass,
Zirconium oxide, or highly cross-linked
polystyrene resin.
● High energy shear forces are generated as a
result of the impaction of the milling media
with the drug resulting into breaking of
microparticulate drug to nanosized
particles.
Nanosuspension Methods
Precipitation
● drug is dissolved in a solvent, which is then
added to antisolvent to precipitate the
crystals.
● It is simple and low cost equipments.
● The drug needs to be soluble in at least one
solvent and this solvent needs to be
miscible with antisolvent.
● Not applicable to drugs, which are
simultaneously poorly soluble in aqueous
and nonaqueous media.

Combined Precipitation and Homogenization
● The precipitated drug nanoparticles have a
tendency to continue crystal growth to the
size of microcrystals.
● They need to be processed with high-energy
forces (homogenisation).
● They are in completely amorphous, partially
amorphous or completely crystalline forms
which create problems in long term stability
as well as in bioavailability, so the
precipitated particle suspension is
subsequently homogenized which preserve
the particle size obtained after the
precipitation step.
High Pressure Homogenization
● The suspension of a drug and surfactant is
forced under pressure through a nanosized
aperture valve of a high pressure
homogenizer.
● The principle of this method is based on
cavitation in the aqueous phase.
● The cavitations forces within the particles
are sufficiently high to convert the drug
microparticles into nanoparticles.
● The concern with this method is the need
for small sample particles before loading
and the fact that many cycles of
homogenization are required.

Drug nanocrystal
● They are composed of 100% drug without
carriers and typically stabilized with
surfactants or polymeric steric stabilizers.
● A dispersion of drug nanocrystals in an
outer liquid medium and stabilized by
surface active agents is so-called
nanosuspensions. The dispersion medium
can be water, aqueous, or non-aqueous
media, e.g. liquid PEG and oils.
● The nanosuspensions can be used to
formulate compounds that are insoluble in
both water and oil.
Nanonization
● Use of materials and structures at the
nanoscale level of approximately 100 nm or
less.
● It is alternate to micronization because
micronized product has the tendency to
agglomerate, which leads to decrease
effective surface area for dissolution.
● There are different techniques used for
nanonization of drug including wet milling,
homogenization, emulsification solvent
evaporation technique, pear milling, and
spray drying.

● The polymer keeps the drug substance
particles in their nanoparticulate state and
prevents them from aggregation or growth.
● Water-redispersible dry powders can be
obtained from the nanosized dispersion
rather than by conventional methods (e.g.,
spray drying).
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.

Polymorphs
● Polymorphism is the ability of drug moiety
to exist in more than one crystalline form.
● Polymorphs are different crystalline forms
of the drug that may have different
physicochemical properties and biological
activities such as shelf life, melting point,
vapor pressure, solubility, morphology,
density, bioavailability, and efficacy.
● Metastable forms are associated with
higher energy and increased surface area
lead to increase solubility, bioavailability and
efficacy.
● β-polymorph chloramphenicol palmitate.
C] Modification of the crystal habit
Crystal engineering
● The approach of crystal engineering offers a
potentially fruitful method for improvement
in solubility, dissolution rate, and finally
bioavailability of hydrophobic drugs by
polymorphs, Hydrates/solvates method.
● These techniques are developed for
controlled crystallization of drugs to
produce high purity powders with well-
defined properties as particle size, shape,
etc., leading to stable and robust
pharmaceutical products.

● Controlling the crystallization process,
amorphous or meta stable forms of drugs
possessing high free energy can be forcibly
created.
● They offer the advantage of higher solubility
but suffer from stability issues unless
stabilizers intended to inhibit crystal growth
are incorporated in the formulation.
Manipulation of solid state
● Crystalline to amorphous form.
● Polymorphism (existence of a drug
substance in multiple crystalline forms) can
cause variations in melting point, density,
stability and drug solubility.
● Drug that have the highest order of
crystallinity is the most stable form, exists
in multiple polymorphic forms, i.e. with the
least amount of free energy, and,
consequently, possesses the highest
melting point and the least solubility.

● When solvent in association with the drug is
water, the solvate is known as hydrate and
thus have less energy for crystal breakup
when compared to anhydrous forms.
● For example, the antidiabetic drug
glibenclamide has been isolated as pentane
and toluene solvates which exhibited higher
solubility and dissolution rate than the non-
solvated polymorphs.
Hydrates/solvates
● The stoichiometric type of molecular
adducts, in which solvent molecules are
incorporated in the crystal lattice of solid is
called as solvates.
● The solvates can exist in different
crystalline forms and called as
pseudopolymorphs and this phenomenon is
called as pseudopolymorphism.

Significance
● It narrows the metastable zone width,
● Narrows the distribution of particle size,
● Minimizes the level of cooling process for
achieving the crystallization,
● The process is highly repeatable as well as
predictable.
● Controls the polymorphs.
● Technology: Ultrasound Mediated
Amorphous to Crystalline Transition
(UMAX) and Dispersive Crystallization with
Ultrasound (DISCUS
Sono Crystallization
● It is the process in which the application of
ultrasound energy to modify the nucleation
of crystallization.
● The energy of ultrasound leads to
compression as well as expansion.
● After completion of some cycles it forms a
bubbles and grows then it collapse.
● This collapse of formed bubbles gives the
energy to enhance the nucleation process
which leads to a highly repeatable as well as
predictable crystallization process.

Solid dispersion
● Refers to a group of solid products
consisting of at least two different
components, generally a hydrophilic matrix
and a hydrophobic drug.
● The matrix can be either crystalline or
amorphous. The drug can be dispersed
molecularly, in amorphous particles or
crystalline particles.
● Therefore, based on their molecular
rearrangement, six different types of solid
dispersions can be distinguished as a result
fine particles formed have shown promising
bioavailability of poorly water-soluble drugs.
Drug dispersion in carriers
Eutectic mixtures
● Eutectic mixtures are formed when the drug
and polymer are miscible in their molten
state, but on cooling, they crystallize as two
distinct components with negligible
miscibility.
● Both drug and carrier exist in the finely
divided state, which results in the higher
surface area and enhanced the dissolution
rate of the drug, for example, sulfathiazole-
urea mixture.

Hot-melt extrusion method
● Melt extrusion of miscible components
results in amorphous solid solution
formation, whereas extrusion of an
immiscible component leads to amorphous
drug dispersed in the crystalline excipient.
Mechanism responsible for solubility
enhancement from solid dispersion
● Reduced Particle Size
● Drug in amorphous state
● Particles with high porosity
● Particles with improved wettability
Solvent evaporation method
● Both the drug and the carrier dissolved in a
common solvent and then evaporate the
solvent under vacuum to produce a solid
solution.
● Advantages: The thermal decomposition of
drugs or carriers can be prevented because
of the relatively low temperatures required
for the evaporation of organic solvents
● Disadvantages: They are expensive,
ecological, and difficult to find common and
removable solvents and difficulty of
reproducing crystal form.

Disadvantages of solid dispersion
● Instability due to moisture and temperature.
● Several systems have shown changes in
crystalline and a decrease in dissolution
rate with aging.
● Some solid dispersion may not lend them to
easy handling because of tackiness.
Advantages of solid dispersion
● Results in particles with reduced particle
size, and thus, the surface area is increased
leads to increase dissolution rate
● Wettability is improved.
● Particles in solid dispersions have a higher
degree of porosity as a result; solid
dispersion particles accelerate the drug
release profile which depends on the carrier
properties
● Drugs are presented as supersaturated
solutions which are considered to be
metastable polymorphic form.

● According to the extent of miscibility of the
two components, solid solutions are the
continuous or discontinuous type.
● In continuous solid solutions, the two
components are miscible in the solid state
in all proportions.
● The components that are immiscible at
intermediate composition, but miscible at
extremes of the composition are referred to
as discontinuous solid solutions.
● Digitoxin, methyl testosterone,
prednisolone acetate, and hydrocortisone
acetate in the matrix of polyethylene
glycol (PEG) 6000.
Solid solution
● In amorphous solid solution the drug is
molecularly dispersed in the carrier matrix,
its effective surface area is significantly
higher, and hence, the dissolution rate is
increased.
● The physical stability of amorphous drugs
increased due to inhibiting drug
crystallization by minimizing molecular
mobility.
● Crystalline solid solution may result when a
crystalline drug is trapped within a
crystalline polymeric carrier.

● This causes some molecules to minimize
the contact with water by aggregation of
their hydrocarbon moieties.
● This aggregation is favored by large planar
non-polar regions in the molecule.
● Stached complexes can be homogeneous
or mixed. The former is known as self-
association and latter as complexation.
● Nicotinamide, anthracene, pyrene,
methylene blue, benzoic acid, salicylic
acid, ferulic acid, gentisic acid, purine,
theobromine, caffeine, and naphthalene,
etc. form staching complexes.
Complexation
● Complexation is the association between
two or more molecules to form a non-
bonded entity with a well-defined
stoichiometry.
● Complexation relies on relatively weak
forces such as London forces, hydrogen
bonding, and hydrophobic interactions.
Staching complexation
● Staching complexes are formed by the
overlap of the planar regions of aromatic
molecules.
● Non-polar moieties tend to be squeezed out
of the water by the strong hydrogen bonding
interactions of water.

● In cyclodextrin inclusion usually only one
guest molecule interacts with the cavity of a
cyclodextrin molecule to become entrapped
and form a stable association.
● The internal surface of the cavity is
hydrophobic and external is hydrophilic; this
is due to the arrangement of hydroxyl group
within the molecule.
● Molecules or functional groups of
molecules, those are less hydrophilic than
water, can be included in the cyclodextrin
cavity in the presence of water.
● Rofecoxib, celecoxib, clofibrate,
melarsoprol, taxol, cyclosporine.
Inclusion complexation
● Formed by the insertion of the nonpolar
molecule or the non-polar region of one
molecule (guest) into the cavity of another
molecule or group of molecules (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 non-
polar regions of the host and the guest is
reduced.
● The most commonly used host molecules
are cyclodextrins.

Co-precipitate method
● Different molar ratios of active drug are
dissolved in ethanol at room temperature,
and suitable polymers are mixed,
respectively.
● The mixture is stirred at room temperature
for 1 h, and the solvent is evaporated.
● The resultant mass is pulverized and
passed through sieve No. 80 and stored in
desiccators.
Manufacturing techniques
Kneading method
● An active drug with the suitable polymer in
different ratios is added to the mortar and
triturated with small quantity of ethanol to
prepare slurry.
● Slowly, the drug is incorporated into the
slurry with constant trituration.
● The prepared slurry is then air dried at 25°C
for 24 h.
● The resultant product is pulverized and
passed through sieve No. 80 and stored in
desiccator over fused calcium chloride.

● The solvent system from the solution is
eliminated through a primary freezing and
subsequent drying of the solution
containing both drug and CD at reduced
pressure.
● Thermolabile substances can be
successfully made into complex form by
this method.
● It is considered as an alternative to solvent
evaporation method, which involves
molecular mixing of drug and carrier in a
common solvent.
Spray drying
● The solvent evaporation of drug and
polymer solution in the different ratio is
carried out using spray dryer.
● The solutions are prepared by dissolving the
drug in methanol and polymer in distilled
water and mix both solutions, which
produces a clear solution.
● Then solution is spray dried.
Lyophilization/freeze-drying technique
● This is a suitable method to get a porous,
amorphous powder with a high degree of
interaction between drug and CD.

● The precipitate so obtained is separated
using Whatman filter paper, and dried in
vacuum oven at 40°C for 48 h.
Microwave irradiation method
● This technique involves irradiation reaction
between drug and complexing agent in a
microwave oven.
● The drug and CD in definite molar ratio are
dissolved in a mixture of water and organic
solvent in a round bottom flask.
● The mixture is reacted for 1-2 min at 60°C in
the oven.
● After the reaction completes, adequate
amount of solvent mixture is added to the
above reaction mixture to remove the
residual, uncomplexed free drug and CD.

● Advantages: Increased drug solubility;
increased stability against thermolysis,
photolysis, or hydrolysis; good organoleptic
properties; and increased tabletability.
● Disadvantages: Formed salt can transform
into its nonionic state from hydrolysis
reaction or disproportionation.
Disproportionation can change the
physicochemical aspect of active drug
compounds which result in decreased
solubility of drugs.
Salt formation
● Salt formation is a neutralization reaction
between acids and bases.
● It is used for drugs that can be ionized so
that solubility increases.
● Salt is formed by the transfer of protons
from acids to bases.
● Acidic and basic drugs are converted into
respective salt forms, e.g., aspirin,
theophylline, and barbiturates.
● Alkali metal salts of acidic drugs such as
penicillins and strong acid salts of basic
drugs such as atropine are water soluble
than parent drugs.

● When salt is formed, the components in the
crystal lattice are in an ionized state, the
cocrystal component is in a neutral state,
and it interacts through nonionic
interactions.
● Cocrystals consist of API with a neutral
guest compound termed cocrystallization
formers (coformers) in the same crystal
lattice.
● Coformers: Citric acid, glutamic acid, gallic
acid, ascorbic acid, histidine, glycine,
nicotinamide, valine, tyrosine, urea, and
saccharine) and nutraceuticals (e.g., p-
coumaric acid, quercetin, pterostilbene, and
saccharine.
Co-crystallization
● It is a molecular complexation process to
form co-crystals.
● A co-crystal may be defined as crystalline
material that consists of two or more
molecular species with a stoichiometric
ratio at room temperature held together by
non-covalent bonds usually hydrogen
bonds.
● Cocrystallization produces new crystalline
shapes that are often superior to each
separate component.
● Cocrystals have increased drug solubility
because of the lower lattice energy and
higher affinity of the solvent.

Advantages
● It is an alternative to salt formation,
particularly for neutral compounds.
● Cocrystallization has the potential to be
applied to API under acidic, basic, and
nonionized molecules.
● Storage age of the API can be extended by
using cocrystals in pharmaceutical
products.
Disadvantage
● Cocrystal formation is not guaranteed.
● Fluoxetine hydrochloride formed cocrystals
with succinic acid.
Co-crystallization Methods
● Solution evaporation, solid-state co-grinding
(without or with solvent), co-melting, co-
sublimation, and co-heating.
● Sophisticated techniques: Cocrystallization
by extrusion; sonococrystallization;
cocrystallization from suspensions;
electrochemically induced cocrystallization;
cocrystallization from supercritical fluids;
cocrystallization by laser irradiation; freeze-
drying cocrystallization; spray drying
cocrystallization; and cocrystallization from
polymers, ionization, and polymer gels.

Advantages
● Increase solubility is a low risk of failure of
formulation, and it does not require
complicated formulation equipment.
Disadvantages
● Tolerability and toxicity due to the use of
nonphysiological pH.
● Drugs in formulations with pH adjustment
can become difficult to dissolve and settle
when diluting in aqueous media or can
cause embolism if given intravenously.
● The drug is also less stable under water
conditions, as hydrolysis or other
degradation can increase
pH adjustment
● By this method, the hydrophobic molecule
can be protonated (base) or deprotonated
(acid) and be dissolved in water by applying
a pH change.
● Ionizable compounds that are stable and
soluble after pH adjustment are best suited.
● The poorly water-soluble repaglinide is
formulated with meglumine as a pH
modifier.
● Most intravenous formulations contain
lactic acid as a pH modifier to increase
solubility.
● Aspirin effervescent tablets.

● Cosolvents
Co-solvency
● Cosolvents are mixtures of water and/or
more water miscible solvent used to create
a solution with enhanced solubility for
poorly soluble compounds, e.g., PEG 300,
propylene glycol, or ethanol, PVA, PVP,
Poloxamer 407, etc.
● Dimethyl sulfoxide and dimethylacetamide
have been widely used as cosolvent
because of their large solubilization
capacity of poorly soluble drugs and their
relatively low toxicity.
● Simple and rapid to formulate and produce.
● Excipients toxicity and tolerability.

Advantages
● Better than miscibility, micellar
solubilization, cosolvency, and salting in,
because the solvent character is
independent of pH.
● Has high selectivity and does not require
emulsification or organic solvents or
chemical modification. It only requires
mixing the drug with the hydrotrope in
water.
Disadvantage
● Gather alone in solution.
● Eg: Ketoprofen, aceclofenac, salicylic acid,
cefixime, tinidazole, frusemide, and
amoxicillin
Hydrotrophy
● Increase in the aqueous solubility of BCS
Class II drugs by the addition of alkali metal
salts of various organic acids.
● Improves solubility by complexation
involving a weak interaction between drug
an the hydrotropic agents.
● Hydrotropes are organic amphiphilic
molecules (sodium benzoate, sodium
salicylate, urea, nicotinamide, sodium citrate
and sodium acetate) with similar structural
features to surfactants.
● In hydrotropic drug solubilization the
hydrotrope concentrates the drug
molecules.

● Also acceptable solution stability to provide
an appropriate product shelf life and the
ability to rapidly convert to the
pharmacologically active parent drug. In
addition, the promoieties must also prove to
be nontoxic.
● Water soluble prodrugs of steroids such as
sodium hemisuccinate esters and sodium
phosphate esters represent the successful
examples for the use of prodrugs of poorly
soluble drugs for intravenous (IV)
administration.
Prodrug
● A prodrug is a drug molecule which is a
covalently bound to a pharmacologically
inactive moiety also known as promoiety
with the aim to overcome on the various
physicochemical and biopharmaceutical
limitations of the parent drug.
● It is an key objective when applying into a
class II or IV poorly soluble drug with
respect to solubility enhancement.
● Perticullarly, a prodrug should possess an
adequate solubility to be formulated into a
solution for IV administration.

● When supercritical CO2 is used as solvent,
matrix and drug are dissolved and sprayed
through a nozzle, into an expansion vessel
with lower pressure and particles are
immediately formed.
● Create nanoparticulate suspensions of
particles 5–2,000nm in diameter.
● Methods: Precipitation with compressed
antisolvent process (PCA), solution
enhanced dispersion by SCF (SEDS),
supercritical antisolvent processes (SAS),
rapid expansion of supercritical solutions
(RESS), gas anti solvent recrystallization
(GAS), and aerosol supercritical extraction
system (ASES)
Supercritical Fluid Technique
● Supercritical fluids are fluids whose
temperature and pressure are greater than
its critical temperature (Tc) and critical
pressure (Tp), allowing it to assume the
properties of both a liquid and a gas.
● At near-critical temperatures, SCFs, are
highly compressible allowing moderate
changes in pressure to greatly alter the
density and mass transport characteristics
of the fluid that largely determine its solvent
power.
● SCF methods are mostly applied with CO2,
which is used either as a solvent for drug
and matrix or as an antisolvent.

● Spray Freezing onto Cryogenic Fluids
● Spray Freezing into Cryogenic Liquids
● Spray Freezing into Vapor over Liquid
● Ultra-Rapid Freezing
Cryogenic Techniques
● Creates nanostructured amorphous drug
particles with high degree of porosity at very
low temperature conditions.
● Cryogenic inventions can be defined by the
type of injection device (capillary, rotary,
pneumatic, and ultrasonic nozzle), location of
nozzle (above or under the liquid level), and
the composition of cryogenic liquid
(hydrofluoroalkanes, N2, Ar ,O2, and organic
solvents).
● Dry powder can be obtained by various drying
processes like spray freeze drying,
atmospheric freeze drying, vacuum freeze
drying, and lyophilisation.

Thank you
Professor in Pharmaceutics,
Adarsh College of Pharmacy, Vita, Sangli
415311
drkailasmali4u@gmail.com
+91 955 252 7353

Solubility Enhancement

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