solubility and solubilization

Presented by:
K. Sindhu
16031S0312
M. Pharm; Pharmaceutics
CPS- IST,JNTUH

 INTRODUCTION
 FACTORS AFFECTING SOLUBILITY
 PROCESS OF SOLUBILIZATION
 TECHNIQUES OF SOLUBILITY ENHANCEMENT
 SOLUBILIZATION BY CO-SOLVENCY
 SOLUBILIZATION BY USE OF SURFACTANTS
 SOLUBILIZATION BY COMPLEXATION
 SOLID STATE MANIPULATION
 CONCLUSION
 REFERENCES

 The term ‘solubility’ is defined as maximum amount of
solute that can be dissolved in a given amount of solvent.
 It is represented through various concentration terms such
as parts, percentage, molarity, molality, mole fraction,
volume fraction etc
 Solute is the substance being
dissolved – powder
 Solvent is the dissolving agent –
water

 Solubility can also be
defined quantitatively as
well as qualitatively
 Quantitatively it is
defined as the
concentration of the
solute in a saturated
solution at a certain
temperature
 Qualitatively it may be
defined as the
spontaneous interaction
of two or more
substances to form a
homogenous molecular
dispersion

• Solubility is one of the important parameter to achieve
desired concentration of drug in systemic circulation
for achieving required pharmacological response
• Most of the drugs(>40%) belongs to BCS class II
(low solubility and high permeability). As for BCS
class II drugs rate limiting step is drug release from the
dosage form and solubility in the gastric fluid, so
increasing the solubility in turn increases the
bioavailability for BCS class II drugs

 Particle size
 Molecular size
 Temperature
 Pressure
 Nature of solute and solvent
 Polarity

SOLUBILIZATION: Solubilization can be defined as a
preparation of thermodynamically stable isotropic solution
of a substance normally insoluble or slightly soluble in a
given solvent by introduction of an additional component
or components

Step 1 Step2 Step 3
Holes open in the
solvent
Molecules of the solid
breaks away from
the bulk
The freed solid
molecule is integrated
into the hole in the
solvent

• Solubility improvement techniques can be categorized
into physical modification, chemical modifications of
the drug substance, and other techniques.
• Physical Modifications —Particle size reduction like
micronization and nano-suspension, modification of
the crystal habit like polymorphs, amorphous form and
co-crystallization, drug dispersion in carriers like
eutectic mixtures, solid dispersions and solid solutions.

• Chemical Modifications —Change of pH, use of buffer,
drug derivatization, complexation, and salt formation.
• Miscellaneous Methods —Supercritical fluid process,
use of adjuvants like surfactants, solubilizers, co-solvents,
hydrotropy etc .

• Substances like weak electrolytes and non-polar
molecules are poorly soluble in water
• The solubility of these substances can be enhanced by
the addition of water miscible solvents in which the
drug has good solubility
• This process of improving solubility is called as co-
solvency and the solvents used are known as co-
solvents
• This technique is mainly used in the formulation of
parenterals.

• Commonly used co-solvents are Ethanol, Sorbitol, Glycerin,
Polyethylene glycol, propylene glycol etc
• The solubilizing effect by co-solvency depends on the polarity
of the drug with respect to solvent and co-solvent. That means
more non-polar the solute the greater is the solubilization
achieved by the added solvents

• Mechanism responsible for solubility enhancement
through co-solvency is by reducing the interfacial tension
predominantly between the aqueous solution and
hydrophobic solutes and reducing the contact angle
between the solid and liquid
• Co-solvents increases the solubility by reducing the
difference between the polarity of the drug and water
system
Ex. For co-solvency
The solubility of Diazepam can be increased by using
10% ethanol and 40% propylene glycol
 Phenobarbitone is relatively insoluble in water but its
solubility can be increased by using mixture of solvents
like water, alcohol and glycerin

• Surfactants are termed as surface-active agents also
wetting agents, emulsifying agents or suspending
agents depending on its properties and use
• Surface-active agents are substances which, at low
concentrations, adsorb onto the surfaces or interfaces
of a system and alter the surface or interfacial free
energy and the surface or interfacial tension

• Therefore, they are soluble in both organic solvents and
water, so they called amphiphilic.
• Surfactants are monomers, it has a characteristic structure
possessing both hydrophobic groups / non-polar regions
(their "tails") usually contain a C12–C18 hydrocarbon chain
and hydrophilic groups / Polar Regions(their heads)
Hydrophobic
tail
Hydrophilic head

• The functional groups such as alcoholic (-OH),
carboxylic acid (-COOH), sulphate (-SO4) & quaternary
ammonium(NH4
+) contribute to hydrophilic portion
• Alkyl chains contribute to lipophilic nature of
molecules
• The polar end is oriented towards the water and the non
polar end is projected upwards to space

Surfactants can work in three different ways:
Roll-up, Emulsification and Solubilization
(a)Roll-up mechanism: The surfactant lowers the
oil/solution and fabric/solution interfacial tensions and
in this way lifts the stain of the fabric
(b)Emulsification: The surfactant lowers the oil/solution
interfacial tension and makes easy emulsification of the
oil
(c)Solubilization : Through interaction with the micelles
of a surfactant in a solvent (water), a substance
spontaneously dissolves to form a stable and clear
solution.

Fig. Surfactant mechanism of action in stain removal from
fabric

• Surfactants can be classified based on charge groups
present in their head
• A nonionic surfactant do not have any charge groups over
its head
• The head of an ionic surfactant carries a net charge. If the
charge is negative, the surfactant is more specifically called
anionic and if the charge is positive, it is called cationic
• If a surfactant contains a head with two oppositely charged
groups, it is termed zwitter ion

(a)Anionic surfactants:
In solution, the head is negatively charged. These surfactants
are the most widely used type of surfactant for preparing
shampoos because of its excellent cleaning properties and
high hair conditioning effects. Anionic surfactants are
particularly effective at oil cleaning and oil/clay suspension.

•The most commonly used anionic surfactants are alkyl
sulphates, alkyl ethoxylate sulphates and soaps. Most of the
anionic surfactants are carboxylates , sulfates and sulfonate
ions
• The straight chain is a saturated /unsaturated C12-C18
aliphatic group. The water solubility potential of the
surfactant is determined by the presence of double bonds

(b) Cationic Surfactants:
In solution, the head of the cationic surfactant is
positively charged. Cationic surfactants are quaternary
ammonium compounds and they are mostly used for
their disinfectant and preservative properties as they
have good bactericidal properties. They are used on skin
for cleansing wounds or burns. Mostly used cationic
surfactants are cetrimide which has tetradecyl trimethyl
ammonium bromide with minimum amount of dodecyl
and hexadecyl compounds

(c) Non-Ionic Surfactants:
• Those surfactants do not have any electrical charge, which
makes them resistant to water hardness deactivation
• They are less irritant than other anionic or cationic surfactants
• The hydrophilic part contains the polyoxyethylene
,polyoxypropylene or polyol derivatives
• The hydrophobic part contains saturated or unsaturated fatty
acids or fatty alcohols They are excellent grease/oil removers
and emulsifiers.

The non ionic surfactant can be classified as
• Polyol esters ,
• polyoxyethylene esters ,
• poloxamers
 The Polyol esters includes glycol and glycerol esters and
sorbitan derivatives
Polyoxyethylene esters includes polyethylene glycol
(PEG 40,PEG -50 ,PEG- 55).
The most commonly used non-ionic surfactants are esters
of fatty Alcohols

(d) Amphoteric Surfactants:
• These surfactants are very mild, making them particularly
suited for use in personal care preparations over sensitive
skins
• They can be anionic (negatively charged), cationic
(positively charged) or non-ionic (no charge) in solution,
depending on the acidity or pH of the water
• These surfactants may contain two charged groups of
different sign, Where the positive charge is almost always
ammonium but the source of the negative charge may vary
(carboxylate, sulphate, sulphonate)

• These surfactants have excellent dermatological properties.
They are frequently used in shampoos and other cosmetic
products, and also in hand, dishwashing liquids because of
their high foaming properties

Solubilization by Micelles
•When a surfactant is placed in water it forms micelles at
concentrations above its critical micelle concentration(CMC)
• In a micelle, the hydrophobic tails flock to the interior in
order to minimize their contact with water, and the hydrophilic
heads remain on the outer surface in order to maximize their
contact with water .

• Critical micellar concentration is the concentration at which
the monomeric surfactant molecules associates into small
aggregates called micelles
• Diluting the surfactant solution to below the CMC causes the
micelles to disperse or break up into single or non
associated surfactant molecules
• Micelles are not static aggregates but dissociate, regroup and
reassosciate rapidly
• There is a dynamic equilibrium between single surfactant
molecules and micelles
• The shape of micelles in dilute surfactant solutions
is approximately spherical.

• At surfactant concentrations above the CMC the
solubility increases linearly with the concentration of
surfactant, indicating that solubilization is related to
micellization
• The lower the CMC value and higher the aggregation
number , the more stable are the micelles

1. On the surface, at the micelle–solvent interface
2. At the surface and between the hydrophilic head groups
3. In the palisade layer, i.e., between the hydrophilic groups
and the first few carbon atoms of the hydrophobic groups that
comprises the outer regions of the micelle core
4. More deeply in the palisade layer, and in the micelle inner
core.

Examples
1. Polar alcohols are soluble in aqueous solution, so it is located
in solution / on surface of micelle
2. Phenol is having polar –OH group and non polar benzene
ring. In which –OH is Located in hydrophilic environment and
benzene ring in hydrophobic environment, so it is located at the
surface and between the hydrophilic head groups
3. Semi polar materials, such as fatty acids are usually located in
the palisades layer, the depth of penetration depending on the
ratio of polar to non-polar structures in the solubilisate molecule
4. Non-polar additives such as hydrocarbons tend to be
intimately associated with the hydrocarbon core of the micelle

Pharmaceutical Examples of
Solubilization
• The solubilization of phenolic compounds such as cresol,
chlorocresol, chloroxylenol and thymol with soap to form
clear solutions for use in disinfection
• Solubilized solutions of iodine in non-ionic surfactant
micelles (iodophors) for use in instrument sterilization
• Solubilization of drugs (for example, steroids and water
insoluble vitamins), and essential oils by non-ionic
surfactants (usually polysorbates or polyoxyethylene
sorbitan esters of fatty acids)

• It is reversible association of a substrate and ligand molecule
• The most common complexing ligands are cyclodextrins,
caffeine, urea, polyethylene glycol, N -methyl glucamide
• Cyclodextrins are unique since they increase the water
solubility of poorly soluble drugs by fitting them into the
hydrophobic cavity of the cyclodextrin molecule
• These cyclodextrins have the ability to form molecular
inclusion complexes with hydrophobic drugs having poor
aqueous solubility.

These are formed by the insertion of the nonpolar molecule
or the nonpolar region of one molecule into the cavity of
another molecule or group of molecules. 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.
Hydrphobic
Hydrophillic

• Complexation of drugs with cyclodextrins has been used to
enhance aqueous solubility and drug stability.
• Cyclodextrins of pharmaceutical relevance contain 6, 7 or 8
dextrose molecules (α, β, γ-cyclodextrin) bound in a 1,4-
configuration to form rings of various diameters.
• The ring has a hydrophilic exterior and lipophilic core in
which appropriately sized organic molecules can form non
covalent inclusion complexes resulting in increased aqueous
solubility and chemical stability.
• Complexation relies on relatively weak forces such as
London forces, hydrogen bonding and hydrophobic
interactions.

PHYSICAL MIXTURE:
Active drug with suitable polymer in different ratios is mixed in
a mortar for about one hour with constant trituration. The
mixture is passed through sieve no. 80 and stored in dessicator
over fused calcium chloride.

KNEADING METHOD:
• Active drug with suitable polymer in different ratios is
added to mortar and triturated with small quantity of
ethanol to prepare a slurry
• The prepared slurry is then air dried at 250c for
24hours
• The resultant product is pulverized and passed through
sieve number.80 and stored in dessicator over fused
calcium chloride

CO-PRECIPITATE METHOD:
• Active drug is dissolved in ethanol at room temperature and
suitable polymer is dissolved in distilled water
• Different molar ratios of active drug and suitable polymers are
mixed respectively
• The mixture is stirred at room temperature for 1hour and
solvent is evaporated. The resultant mass is pulverized and
passed through sieve number .80 and stored in dessicator.

• Manipulation or modification of solid state to exist in more
than one form as solid
• The different solid state modifications are found to exhibit
different physicochemical properties
• By making use of these differences between
physicochemical properties of various solid states,
pharmaceutical scientists have been started to optimize drug
delivery
• So there has been great deal of interest in the thermodynamic
and biopharmaceutical properties of solid state modifications
of drugs.

 Homogenous solid
phases
A) Crystalline forms
B) Non crystalline forms
 Heterogenous solid
phase
A) Solvates
B) Retardation of phase
transformation
C) Racemates- enantiomers
D) Drug dispersion in matrix
Eutectics
Solid dispersions
Glass dispersions
Complexes

• Polymorphism is often characterized as the ability of a
drug substance to exist as two or more crystalline
phases that have different arrangements and/or
conformations of the molecules in the crystal lattice
• Solubility of each form depends upon the ability of the
molecules to escape from the crystal to solvents
•The stable from process the lower free energy at a
particular temperature and therefore has the lower
solubility or escaping tendency where as the metastable
forms possess higher free energy hence has higher
solubility

About 50% to 100% increase in the dissolution rate
can be achieved through polymorphic modifications.
Ex. Chloramphenicol palmitate (form B) , Methyl
prednisolone (form 2), chlortetracyclin (form B).

•Amorphous solids consist of disordered arrangements
of molecules and do not possess a distinguishable
crystal lattice
•As the term implies they will not contain internal
crystal lattice structure. These are thermodynamically
unstable
•Amorphous solid forms give faster dissolution rates
and higher solubilities than polymorphic modifications
E.g. Novobiocin
•Thus, the order for dissolution of different solid forms
of a drug is
Amorphous > Metastable > stable

The recrystallization of many drug substances from
solution will results in the formation of solids
containing solvent molecules as an integral part of their
crystal structure. Majority of these crystalline materials
referred as pseudo polymorphs, contain stoichiometric
amount of solvent.
Anhydrates > hydrates
Organic solvates > organic non-solvates
Enhances the solubility of drug markedly.
Examples: Pentanol solvates of fludrocortisone
Chloroform solvates of griseofulvin
Cephalexin hydrate

 PVP, pectin, acacia, gelatin, methylcellulose, carboxy
methyl cellulose, surfactants retard phase
transformation.
 These materials retard phase transformation by;
Inhibiting crystal growth by absorbing on to the
surface of nucleated crystals or by Increasing viscosity
which in tern retard the diffusion control process of
crystallization
 The retardation has improved physical stability of
amorphous drugs by inhibiting drug crystallization or
by minimizing molecular mobility

 The racemates and enantiomeric forms of a compound
differ in their solubility. The difference in solubility
can be substantial. Enantiomers are found to be five
times more soluble than the racemic compounds. Trace
amounts of racemates can alter the solubility of drug
which in turn results in dosage form. Enantiomeric
systems are known to exhibit three types of phase
behaviour. They can form racemic mixtures , racemic
compounds and racemic solid solutions

 The term solid dispersion is applied to those systems in
which the dispersion of one or more active ingredients
in a carrier solvent or matrix (hydrophobic), where the
active ingredients could exist in amorphous states
 Solid dispersions represent a useful pharmaceutical
technique for increasing the dissolution, absorption and
therapeutic efficacy of drugs in dosage forms
 The most commonly used hydrophilic carriers for solid
dispersions include polyvinyl pyrrolidine, polyethylene
glycols, Plasdone-S630, Tween-80, Docussate sodium,
Myrj-52, Pluronic-F68 and Sodium Lauryl Sulphate

 Examples:
1. Polyvinyl Glycols:- Oxazepam, Nifedipine, Ketoprofen
2. Polyvinyl pyrrolidine:- Hydrochlorthiazide, Valdecoxib
3. Maltodextrins:- Pyroxicam solid dispersions

 The physical mixture of a drug and a water-soluble
carrier was heated directly until it is melted
 The melted mixture was then cooled and solidified
rapidly in an ice bath under rigorous stirring
 The final solid mass was crushed, pulverized, and
sieved, which can be compressed into tablets with the
help of tableting agents
 The melting point of a binary system is dependent
upon its composition, i.e., the selection of the carrier
and the weight fraction of the drug in the system.

 The first step is to dissolve both the drug and the
carrier in a common solvent and then evaporate the
solvent under vacuum to produce a solid solution
 This enabled them to produce a solid solution of the
highly lipophilic β-carotene in the highly water soluble
carrier polyvinyl pyrrolidine
 Many investigators studied solid dispersion of
Meloxicam15, Naproxen and Nimesulide using solvent
evaporation technique

2. Solvent evaporation method:
Drug + vehicle ( both soluble in solvent)
organic solvent
solution
evaporate the solvent
co-precipitates
dosage forms

 Hot melt extrusion of miscible components results in
amorphous solid solution formation, whereas
extrusion of an immiscible component leads to
amorphous drug dispersed in crystalline excipient
 The process has been useful in the preparation of solid
dispersions in a single step.

 When two materials are completely miscible in their
molten state, they will solidify to form a eutectic
mixture
 At the eutectic composition, both drug and carrier exist
In finely devised state, which results in higher surface
area and enhanced dissolution rate of drug
 The process of eutectic formation may cause the drug
to crystallize in a metastable state
 Urea and Succinic acid have been found to form simple
eutectic with a wide variety of drugs.

 When solid solution is a homogenous and transparent
and brittle systems it is called glass dispersion
 Carriers that form glass structures are citric acid, urea,
polyvinyl pyrrolidine etc
 Drug substance and carrier can be both in glassy state.
Total solubility, partial solubility, or total immiscibility
can be observed
 This type of system is very sensitive to temperature
and moisture and crystallizations are often observed
after long storage

 Mechanisms suggested for enhanced solubility and
rapid dissolution of molecules are as follows:
1. 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.
2. When solid solution is exposed to the dissolution
fluid, the soluble carrier dissolves rapidly leaving the
insoluble drug at almost molecular level

• Solubility of the drug is the most important factor that
controls the formulation of the drug as well as.
Therapeutic efficacy of the drug, hence the most
critical factor in the formulation development.
• The various techniques described above alone or in
combination can be used to enhance the solubility of
the drug
• Because of solubility problem of many drugs the
bioavailability of them gets affected and hence
solubility enhancement becomes necessary.

1. International journal of pharmaceutical sciences
review and research,vol5,issue1, Varun Raj Vemula,
article007 nov-dec2010.
2. Journal of drug delivery & therapeutics 2012,Md.Ali
sajid.
3. International journal of drug development research,
vol3, issue2, apr-jun2011
4. International journal of pharmaceutical research &
bio-science.
5. Encyclopedia of solubilization and solubility.
6. www.google.com

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