ASSIGNMENT:

PHARMACEUTIC-II
(PHYSICAL PHARMACY)
SUBMITTED BY:
AAMIR NAWAZ
SESSION:
(2020-2021)
2nd A
STUDENT ID:
BPD02201039
SUBBMITED TO:
DR. ASIF MEHMOOD SB
Assistance professor of pharmaceutics
________________________________________________________
FACULTY OF PHARMACY
THE UNIVERSITY OF LAHORE
LAHORE, PAKISTAN
 SOLUBILITY AND SOLUBILITY ENHANCEMENT
TECHNIQUES
SOLUBILITY:
Definition:
The term ‘‘solubility’’ is defined as maximum amount of solute that
can be dissolved in a given amount of solvent to form a homogenous
system at specified temperature’’.
o The solubility of drug is represented through various
concentration expressions such as parts, percentage, molarity,
volume fraction, mole fraction.
FACTOR AFFECTING SOLUBLIZATION:
 Particle size
 Temperature
 Pressure
 Molecular size
 Nature of solute
 Polarity
 Polymorphs
NEED FOR SOLUBILITY ENHANCEMENT:
There are variety of new drug and their derivatives are available but
less than 40% of lipophilic drugs candidates fail to reach market due
to poor bio-availability.
The lipophilic drug that reach market requires a high dose to attain
proper pharmacology action.
SOLUBILITY OF DRUG OCCUR DUE TO:
o Polarity of solvents, A polar solvent dissolves ionic solutes and
other polar substances.
o The ability of solute to form hydrogen bond with solvent.
o Also depends on the ratio of the polar to non-polar group of the
molecule.
 TECHNIQUES FOR SOLUBILITY ENHANCEMENT:
Various techniques have been using to attempt to improve solubility
and dissolution rates of poorly water-soluble drugs which includes as
followings:
1) Particle Size Reduction
 Conventional methods
 Micronization
 Nanosuspension
2) Hydrotropy
3) Co-solvencyz
4) Solubilization by surfactants
5) Solid dispersion
 The fusion (Hot melt) method
 The solvent (evaporating) method
 Dropping (Hot melt extrusion) method
6) pH adjustment
7) High pressure homogenization
8) Superficial fluid recrystallization
9) Sonocrystalization
10) Complexation
 Physical mixture
 Kneading method
 Co-precipitate
11)Spray Drying
12) Inclusion complex Formation-Based technique
13)Liquisolid technique
14)Micro-emulsion
15)Self-emulsifying drug delivery System
16)Neutralization
17)Cryogenic method
 Spray freezing onto cryogenic fluids
 Spray freezing into cryogenic liquids (SFL)
 Spray freezing into vapor over liquid (SFV/L)
  Ultra-rapid freezing (URF)
18)Polymeric alteration
19)Salt formation

1) PARTICAL SIZE REDUTION:

o The solubility of drug is often intrinsically related to drug

particle size as a particle becomes smaller, the surface area
increases.
o The larger surface area allows greater interaction with the
solvent which causes an increase in solubility.
TECHNIQUES OF PARTICAL SIZE REDUCTION:
a. Micronization
b. Nanosuspension
I) Micronization

 Micronization is another conventional technique for the

particle size reduction.
Micronization increases the
dissolution rate of drugs
through increased surface
area.
 Micronization of drugs is done
by milling techniques using jet
mill, rotor stator colloid mills
and so forth.
 These processes were applied
to griseofulvin, progesterone,
spironolactone, and
fenofibrate.

II) Nanosuspension
 The technology is applied to poorly soluble drugs that are
insoluble in both water and oils.
 A pharmaceutical nanosuspension is biphasic system
consisting of nano sized drug particles stabilized by
surfactants for either oral and topical use or parenteral and
pulmonary administration.
 The particle size distribution of the solid particles in
nanosuspension is usually less than one micron with an
average particle size ranging between 200 and 600 nm.

2) Hydrotropy

o Hydrotropy is a solubilisation process, whereby addition

of a large amount of second solute, results in an increase in
the aqueous solubility of existing solute.
o Concentrated aqueous hydroscopic solutions of sodium
benzoate, sodium acetate, sodium alginate, urea,
nicotinamide, sodium citrate, and sodium acetate have
been observed to enhance the aqueous solubilities of many
poorly soluble drugs.

3) CO-SOLVENCY
o The solubility of poorly soluble drugs in water can be
increased by mixing it with some water miscible solvent in
which the drug is rapidly soluble. This process is known as
co-solvency and the solvent use known as co-solvent.
o Co-solvent system works by reducing the interfacial
tension between the aqueous solution and hydrophobic
solute. It is also commonly referred to as solvent
blending. 
o Co-Solvency is one of the most popular approaches for
improving the solubility of poorly aqueous soluble drugs
in pharmaceutical liquid formulations. Cosolvents have
 hydrogen bond donor and/or acceptor groups as well as
small hydrocarbon regions. 
o Hydrophobic hydrocarbon regions interfere with waters
hydrogen bonding network, reducing the overall
intermolecular attraction of water. Consequently, reduces
the intermolecular attraction of water while the hydrogen
bond ensures water solubility.

4) SOLUBLIZATION BY SURFACTANT:

o Solubilization may be defined as the spontaneous dissolving of a

substance (solid, liquid, or gas) by reversible interaction with
the micelles of a surfactant in a solvent to form a
thermodynamically stable isotropic solution with reduced
thermodynamic activity of the solubilized material.
o Surfactants reduce surface tension and improve the dissolution
of lipophilic drugs in aqueous medium.
o Examples of poorly soluble compounds that use Micellar
solubilization are antidiabetic drugs, gliclazide, glyburide,
glimepiride, glipizide, repaglinide, pioglitazone, and
rosiglitazone.

5) SOLID DISPERSION:
o Solid dispersion as group of solid products consisting of at
least two different component, generally hydrophilic and
hydrophobic drug.
o The term solid dispersion refers to a group of solid products
consisting of at least two different components, generally a
hydrophilic matrix and a hydrophobic drug.
o The most commonly used hydrophilic carriers for solid
dispersions include polyvinylpyrrolidone (Povidone, PVP),
polyethylene glycols (PEGs), Plasdone-S630. Surfactants like
Tween-80, docusate sodium, Myrj-52, Pluronic-F68, and
 sodium lauryl sulphate (SLS) also find a place in the
formulation of solid dispersion.
a) The fusion (melt) method:

 In this method drug is dissolved in a suitable liquid solvent.

Then, the solution is incorporated directly into the melt of
polyethylene glycol obtainable below 70°c, without removing
the liquid solvent
 The melting method is the preparation of physical mixture of a
drug and a water-soluble carrier and heating it directly until it is
melted. The final solid mass is crushed, and sieved.
Appropriately this has undergone many modifications in
pouring the homogenous melt in the form of a thin layer onto a
stainless-steel plate and cooled by flowing air or water on the
opposite side of the plate. 

b) The solvent method:

 The solvent evaporation method consists of the solubilization of

the drug and carrier in a volatile solvent that is later
evaporated 17, 18. In this method the thermal decomposition of
drugs or carriers can be prevented, since organic solvent
evaporation occurs at low temperature
 Accurately weight amounts of active drug and carrier are
dissolved in minimum quantities of chloroform in around
bottom flask. The solvent is removed using a rotatory
evaporator.
 The obtained solid dispersion is transferred on to the aluminium
pan allowed to dry at room temperature

c) Dropping method:
  A solid of a melted drug-carrier mixture is pi petted and
then dropped onto a plate, where it solidifies into round
particles.
 The size and shape of the particles can be influenced by
factors such as the viscosity of the melt and the size of the
pipette. Because viscosity is highly temperature
dependent, it is very important to adjust the temperature
so that when the melt is dropped onto the plate it solidifies
to a spherical shape.

6) pH ADJUSTMENT:

o To access the solubility of this approach, the buffer capacity and

tolerability of the selected pH a of are important to consider.
o Solubilized excipients that increase environmental pH within the
dosage form to a range higher than pKa of weekly acidic drugs
increase the solubility of that drug, excipient that act as
alkalizing agents may increase the solubility of weekly basic
drugs.

7) HIGH PRESSURE HOMOGENIZATION:

o It has been used to prepare nanosuspension of many poorly

water-soluble drugs. In this method, the suspension of a drug
and surfactant is forced under pressure through a nanosized
aperture valve of high-pressure homogenizer.
o The principle of this method is based on cavitation in the
aqueous phase in this method, the cavitation forces within the
particle are sufficiently high to convert the drug microparticles
into nanoparticles.

8) SUPERFICIAL FLUID RECRYSTALIZATION:

o Those fluids are referred to as supercritical fluids which are
having temperature and pressure greater than its critical
 temperature so as they are acquire properties of both gas and
liquid carbon dioxide.
o As the drug gets solubilized within SCF they can be
recrystallized with reduced particle size of drug.

9) SONOCRYSTALISATION
o The novel approach for particle size reduction on the basis of
crystallization by using ultrasound is son crystallisation.
o Son crystallisation utilizes ultrasound power characterized by
frequency range of 20-100kHz for including crystallization.
o It is not only enhancing the nucleation rate but also an effective
means of size reduction and controlling size distribution of the
active pharmaceutical ingredients.
o Most applications use ultrasound in the range 20 kHz-5 MHz.

10)COMPLEXATION
o Complexation of drugs with cyclodextrins has been enhance
aqueous solubility and drug stability.
o Cyclodextrins of pharmaceutical relevance contain 6, 7 or 8
dextrose molecules bound in a 1, 4 configuration to form ring of
various diameters.
o The ring has a hydrophilic exterior and lipophilic core in which
approximately sized organic molecules can form noncovalent
inclusion complexes resulting in increased aqueous solubility
and chemical stability.
o Complexation relies on relatively weak forces such as London
forces, hydrogen bonding and hydrophobic interaction.

TECHNIQUE OF COMPLEXATION
1. Physical mixture:
 Active drug with suitable polymer in different ratios mixed in a
mortar for about one hour with constant trituration.
 The maximum is passed through sieve no.80 and stored in
desiccator over fused calcium chloride.
2. Kneading method:
 active drug with suitable polymer in different ratios is added to
the mortar and triturated with small quantity of ethanol to
prepare a slurry
 slowly the drug is incorporated into slurry with constant
trituration the prepared slurry rate is then air dried at 250 degree
for 24 hours.
 The resulting product is pulverized and passed through sieve
no.80 and stored in desiccator over fused calcium chloride.

3.Co-precipitate method:
o Active drug is dissolved in ethanol at room temperature and
suitable polymer is dissolved in distilled water.
o Different molar ratios of active drug and suitable polymers are
mixed respectively.
o The mixture is stirred at room temperature for 1 hour and the
solvent is evaporated the resultant mass is pulverized.
o And pass through sieve number 80 and stored in a desiccator
11) SPRAY DRYING:
o The solvent evaporation of drug and polymer solution in
different ratio is carried out by using spray dryer
o the solutions are prepared by dissolving drug in methanol and
polymer in distilled water and mixed both solution which
produces a clear solution.
o The solvent evaporated by using evaporator.
o The spray dried mixture of drug with polymer is obtained in 20
to 30 minutes.
 12) INCLUSION COMPLEX FORMATION-BASED
TECHNIQUE:
o inclusions complexes are formed by the insertion of the non-
polar molecules or the non-polar region of one molecule (known
as guest) into the cavity of another molecule or group of
molecules (known as host). EXA-cyclodextrin
o the cavity of 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.
TECHNIQUES OF INCLUSION COMPLEX METHOD:
i. Lyophilization or a freeze-drying technique:
 In order to get a porous amorphous powder with a high degree
of interaction between drug and CD.
 in this technique the solvent substance from the solution is
eliminated 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.
Limitations
 Use of specialized equipment.
 Time consuming process.
 Poor flowing powder product.

ii. Microwave irradiation method:

 This technique involves the microwave iridisation reaction
between drug and complexing agent using a microwave oven.

13)LIQUISOLID TECHNIQUE:

o where a liquid may be transformed into a free flowing readily

compressible and apparently dry powder by simple physical
blending with selected carrier and coating material.
o the liquid portion, which can be a liquid drug, a drug suspension
or a drug solution in suitable non-volatile liquid vehicles is
incorporated into the porous carrier material.
o once the carrier is saturated with liquid a liquid layer is formed
on the particle surface which is instantly adsorbed by the fine
coating particles.
o Thus, an apparently dry, free flowing and compressible powder
is obtained.
14) MICRO EMULSION:
o A micro emulsion is an optically clear pre- concentrate,
isotropic thermodynamically stable transparent system
containing a mixture of oil, hydrophilic surfactant and
hydrophilic solvent which dissolves a poorly water-soluble drug.
o Micro emulsion has been employed to increase the solubility of
many drug that are practically insoluble in water along with
incorporation of protein for oral as well as a percutaneous
/transdermal use.

15) SELF EMULSIFYING DRUG DELIVERY SYSTEM:

o it uses the concept of in situ formation of emulsion in the
gastrointestinal track.
o the mixture of oil surfactant, cosurfactant one or more
hydrophilic solvent and cosolvent form a transparent isotropic
solution that is known as the self-emulsifying drug delivery
system as a (SEDDS).
o The poorly soluble drug can be dissolved in a mixture of
surfactant oil which is weekly widely known as preconcentrate.

16) NEURARRALIZATION:

o Neutralization drug is added in alkaline solution like sodium

hydroxide ammonium hydroxide.
o Solution of beta cyclodextrin is then added to dissolve the joined
drug.
o the clear solution obtained after few second under vegetation is
neutralized using HCL solution until reaching the equivalence
point.
o at this moment the appearance of a white precipitate could
appreciated cross ponding to the formation of the inclusion
compound.
o The precipitate is then filter and dried.

17) CRYOGENIC METHOD:

o it is developed to enhance the d dissolution rate of drugs by
creating nanostructured amorphous drug particles with the high
degree of porosity at very low temperature conditions.
o 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) and the
composition of cryogenic liquid (hydro fluoroalkanes, N2, Ar,
O2 and organic solvents).

18) POLYMERIC ALTERATION

o Different crystalline forms of a drug that may have different
properties are known as polymorphs.
o Polymorphs may differ in physicochemical properties such as
physical and chemical stability, shelf-life, melting point, vapour
pressure, intrinsic solubility, dissolution rate, morphology,
density, and biological activities as well as bioavailability.
o Metastable crystalline polymorphs metastable forms are
associated with higher energy with increased surface area
subsequently solubility, bioavailability and efficiency.

19) SALT FORMATION:

o Dissolution rate of particular salt is usually different from that of
parent compound.
o Sodium and potassium salt of week acid dissolve more rapidly
than that of pure salt.
o Limitations of salt formation-
o Epigastric distress due to high alkalinity.
o Reactivity with atmospheric water and carbon dioxide lead to
precipitation.
o Patient compliance and commercilation.