This document provides information about solubility and techniques to enhance drug solubility. It defines solubility qualitatively as the spontaneous interaction between substances to form a homogeneous mixture, and quantitatively as the maximum concentration of a solute that can dissolve in a solvent at a given temperature. Poor solubility is a major challenge for drug development. Several techniques are described to improve solubility, including reducing particle size, solid dispersions, complexation, and use of surfactants. Factors like temperature, pressure, and surface area can also impact solubility. Proper characterization of solubility is important for applications in pharmaceutical sciences.

1. 1
Solubility
Dr.Zulcaif Ahmad
Pharm.D , MPhil Pharmaceutics (Scholar)

2. CONTENS:
 Introduction
 Importance of solubility
 Need of Improving Solubility
 Techniques of Solubility Enhancement
 Types of solubility
 Factors Affecting solubility
 Advantages And Disadvantages
 Applications
 Conclusions
 References

3. INTRODICTION
 SOLUBILITY:
1. Qualitative Terms:
Solubility is defined as, “the spontaneous interactions of two
or more substances to form a homogenous molecular dispersion”.
2. Quantitative Terms:
Solubility is defined as, “ the concentration of a solute in a
saturated solution at a constant temperature”.

4. Importance Of Solubility
 Therapeutic effectiveness of a drug depends upon the bioavailability
and ulimately upon the solubility of drug molecule.
 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
permeability.
 Nearly 40% of the new chemical entities currently being discovered are
poorly water soluble.

5. Need For Solubility Enhancement
 There are variety of new drugs & derivatives are available. But less than
40% of lipophilic drugs candidates fail to reach market due to
poor bioavailability, even though these drugs might exhibit
pharmaco -dynamic activities.
 The lipophilic drug that reaches market requires a high dose to
attain proper pharmacological action.
 The basic aim of Further formulation & development is to make that
drug available at proper site of action within optimum dose.

6. Process of Solubilization

7. Techniques Of Solubility Enhancement
1. Physical Modifications:
A).Particle size reduction
a. Micronization b. Sonocrystalisation
c. Nanosuspension d. Supercritical fluid process (substance at a
temperature and pressure above its critical point)
B). Modification of crystal habit
a. Polymorphs
b. Pseudopolymorphs (different crystal types are the result of hydration or solvation)
C). Drug dispersion in carriers
a. Eutectic mixtures (A mixture of two or more substances which melts at the lowest freezing point)
b. Solid dispersion
D). Solubilization by Surfactants
a. Microemulsions

8.  II. Chemical Modifications
a. Change in PH
b. Use of buffer
c. Derivatization (transforms a chemical compound into a product)
• III. Other Methods
a. Co- crystalisation (crystalline structure composed of at least two components)
b. Co-solvency (solvent that in conjunction with another solvent can dissolve a solute).
c. Solubilizing agents
d. Solvent disposition
e. Selective absorption on insoluble carrier
f. Using soluble prodrug

9. A. Partical Size Reduction:
 Particle size reduction can be achieved by :
a. Micronization
b. nanosuspension
c. supercritical fluid process
1. Micronization:
Micronization increases the dissolution rate of drugs through
increased surface area.
2. nanosuspension:
A pharmaceutical nanosuspension is biphasic system consisting of
nano size drug particles stabilized by surfactants for either oral and
topical use or parenteral and pulmonary administration.

10. Other techniques for reduction of particle size
1. Sonocrystallisation
2. Supercritical fluid process
1. Sonocrystallisation:
o The novel approach for partical size reduction on the basis
of crystallisation by using ultra sound is sonocrystallisation.
o Sonocrystallisation utillizes ultrasound power for
introducing crystallisation.
2. Supercritical fluid process:
o Novel nanosizing and solublization technology whose
application has increased particle size reduction via
supercritical fluid (SCF) process.
o A SCF can be defined as, “ dense non condensable fluid”.

11. B. Drug Dispersion In Carrier:
The term solid dispersions refers to the dispersion of one or more
active ingredients in an inert carrier on a solid state, frequently
prepared by the:
1. Hotmelt method
2. Solvent evaporation method
3. Hotmelt extrusion method

12. D. Complexation:
Complexation is the reversible association between two or more molecules to
form a non bonded entity with a well defined Stiochiometry.
There are many types of complexing agents and a partial list can be found in
table.

13. E. Solubilization by surfactants
 Surfactants are molecules with distinct polar and non polar regions. Most
surfactants consists of a hydrocarbon segment connected to a polar group.
The polar group can be anionic, cationic, zwitter ionic or non ionic.
 Non ionic surfactants, such as Tweens (polysorbates) and Labrafil
(polyethylated oleic glycerides), with high hydrophilic-Lipophilic balances
are often used to ensure immediate immediate formation of oil-in-water
droplets during production.
B. CHEMICAL MODIFICATION:
1). By Change of PH:
2)Use of Buffer :
Change of pH by 1 fold increase solubility by 10 fold
If it changes by one pH unit, that decreases ionization of drug and
solubility decreases by 10 fold.

14.  Derivatization:
It is a technique used in chemistry which transforms a chemical compound
into a product of similar chemical structure, called derivative.
III. Other Methods:
1. Co-Crystallization:
A co-crystallization may be defined as, “ a crystalline material
that consist of two or more molecular ( and electrically neutral) species
held together by non-covalent bond.
2. Cosolvency:
The solubilization of drugs in co-solvents in an another
techniques for improving the solubility of poorly soluble drug.
3. Hydrotrophy :
Hydrotrophy designate to increase in solubility in water due to
the presence f large amount of additives.

15. 4. Solubilizing agents:
The solubility of poorly soluble drug can also be improved by
various solubilizing materials.
5. Solvent dep0sition:
In this method, the poorly soluble drug as Nifedipine is dissolved
in an organic solvent like Alcohol and deposited on an inert,
hydrophylic, solid matrix such as starch or microcrystalline cellulose
and evaporation of solvent is done.
6. Selective adsorption on insoluble carriers:
A highly active adsorbent such as inorganic clays like Bentonite
can enhance the dissolution rate of poorly water-soluble drugs such as
Griseofulvin, indomethasin and prednisone by maintaining the
cocentration gradient at its maximum.

16. 7. Use of soluble prodrug:
The most common prodrug strategy involves the incorporation
of polar or ionizable moiety into the parent compound to improve
aqueous solubility.
Example:
Prodrug of established drugs has been successfully used to improve
water solubility of corticosteroids benzodiazepines.
8. Functional polymer Technology:
Functional polymer enhances the dissolution rate of poorly
soluble drugs by avoiding the lattice energy of the drug crystal, which
the main barrier to Rapid dissolution in aqueous media.

17. .TYPES OF SOLUTIONS:
Saturated:
Solvent holds as much solute as is possible at
that temperature.
Dissolved solute is in dynamic equilibrium
with solid solute particles.
Unsaturated:
Less than the amount of the solute for that
temperature is dissolved in the solvent.

18. Supersaturated:
solvent holds more solute than is normally possible at that
temperature.
These solutions are unstable; crystallization can usually be stimulates
by adding a “seed crystal” or scratching the side of flask.

19. 1). The nature of the solute and solvent.
• when two substances are similar they can dissolve in each other.
-polar solute dissolve in polar solvents
- non polar solutes tends to dissolve in non polar.
“Like dissolves Like”
-two liquids dissolve in each other because their molecule are a like in
polarity.
2). Temperature:
Temperature affecting the solubility as the solution is formed.
-when the temperature drops while you mix the solute and solvent,
raising the temperature will increase the solubility.
- If the temperature stays neutral , the temperature will have minimal
or insignificant effect either way.

20. 3). Pressure:
when the pressure is increased over the solvent, the solubility of the
gas is increased.
“Henry’s Law: Solubility of the gas is directly proportional to the
partial pressure of the gas above the liquid.
4). Surface Area:
Dissolving solutes happen in the surface area of the solvent.
Speed up the process by increasing the surface area.
The greater the surface area per unit mass, the quicker it will dissolve.

21. Advantages
1. Enhanced bioavailability can be obtained as compared
to the conventional tablets.
2. Greater drug surface area is exposed to the dissolution
medium.
3. Production cost is low compared to the soft gelatin
capsules.
4. These liquisolid systems formulate into immediate
release or sustained or controlled released dosage
forms.
5. This principle governs or administers the mechanism of
drug delivery from liquisolid systems of powdered drug
solutions and t is mainly responsible for the improved
dissolution profiles exhibited by this preparation.

22. Disadvantages
1. The liquisolid systems have low drug loading capacities and they
require higher solubility of the drug in non volatile liquid vehicles.
2. To maintain acceptable flowability and compatibility for liquisolid
powder formulation high levels of carriers and coating materials are
require and that in turn will increase the weight of each tablet above I
gm which is very difficult to swallow.
3. It requires more efficient excipients which have higher adsorbent
capacities which provides faster drug release with a smaller tablet
size to improve liquisolid formulations.

23. Application Of Solubility
 Solubility is fundamental importance in a large number
of scientific disciplines and practical applications, to the
use of medicines, and the transport of pollutents.
 Solubility is represents a fundamental concept in fields of
research such as chemistry, physics, food science,
pharmaceutical and biological sciences.
 The solubility of a substance becomes specially important
in the pharmaceutical field because it often represents a
major factor that controls the bioavailability of a drug
substance.

24. Conclusion
 A drug administered in the solution immediately available for
absorption,
 Solubility is a most important parameter for the oral
bioavailability of poorly soluble drugs,
 Dissolution of drugs is the rate determining step for oral
absorption of poorly water soluble drugs, which can
subsequently affect the in vivo absorption of drug.
 Currently only 8% of new drug candidates have both high
solubility and permeability.
 Because of solubility problem of many drugs the
bioavailability of them gets affected afected and hence
solubility enhancement becomes necessary.
 It is now possible that to increase the solubility of poorly
soluble drugs with the help of various techniques.

25.  When we talk about the mixing of two or more substances
together in solution we must consider solubility.
 Solubility may be defined as the maximum concentration of a
substance that may be completely dissolved in a given solvent
at a given temperature and pressure.
 When both solute and solvent are liquids, the term miscibility
rather than solubility may be used to describe the affinity
between the liquids.
 The solubility of a substance may be described in a variety of
ways.
 The USP/NF generally expresses the solubility in terms of the
volume of solvent required to dissolve 1 gram of the drug at a
specified temperature.

27. Phase Solubility Analysis
 Phase solubility analysis is the quantitative
determination of the purity of a substance through the
application of precise solubility measurements.
 Steps to Determine the Solubility
 Control temperature and pressure
 Add a quantity of solid to the solvent in the excess of
what will dissolve
 Let the system come to the equilibrium
 Use the specific assay to determine how much of the
substance is in solution (i.e., concentration of the
saturated solution)

28. The standard solubility method consists of
six distinct steps:
 Mixing, in a series of separate system, increasing
quantities of material with measured, fixed amount of
solvent
 Establishment of equilibrium for each system at identical
constant temperature and pressures;
 Separation of the solid phase from the solution;
 Determination of the concentration of the material
dissolved in the various solution;
 Plotting the concentration of the dissolved material per
unit of solvent (y-axis or solution composition) against
the weight of material per unit of solvent (x-axis or
system composition); and
 Extrapolation and calculation.

30. Solvent
 Prior to conducting the phase solubility experiment,
various solvents or solvent systems are evaluated in
order to select a solvent or solvent system that is
suited for the phase solubility analysis. The proper
solvent or solvent system has following
characteristics:
 Sufficient volatility to be evaporated under vacuum,
but not so volatile that it cannot be accurately
transferred or accurately weighed.
 In general, suitable solvents for phase solubility have
boiling points between 60°C and 150 °C.

31.  Does not adversely affect the test, compound, i.e.,
causing degradation or precipitate formation.
 Has known purity and composition.
 The test compound has solubility of about 10-20
mg/ml in the solvent or solvent system. However,
solvents that solubilize the drug substance at
concentration greater than 20 mg/ml can be used.

32. Apparatus
 Constant Temperature Bath
 Ampoules
 Solubility Flasks
 Constant Temperature Bath
 Use a constant temperature bath that is capable of
maintaining the temperature within ± 0.1 ̊ and that is
equipped with horizontal shaft capable of rotating at
approximately 25 rpm. The shaft is equipped with clamps
to hold the Ampoules. Alternatively, the bath may
contain suitable vibrator, capable of agitating the
ampoules at 100 to 120 vibrations per second, and
equipped with the shaft and suitable clamps to hold the
ampoules.

33.  Ampoules
 Use 15 ml ampoules of the type shown in the
accompanying illustration. Other containers may be
used provided that they are leak proof and otherwise
suitable.
 Ampoule (left) and Solubility Flask (right) used in
Phase Solubility Analysis.
 Solubility Flasks
 Use solubility flasks of the type shown in the
accompanying illustration

35. Procedure
 System Composition
 Weigh accurately, in g, not less than 7 scrupulously
cleaned 15 - ml ampoules. Weigh accurately, in g,
increasingly larger amount of test substance into each of
the ampoules. The weight of the test substance is selected
so that the first ampoule contain slightly less material
than will go into solution in 5 ml of the selected solvent,
the second ampoule contain slightly more material, and
each subsequent ampoule contains increasingly more
material than meets the indicated solubility. Transfer 5.0
ml of the solvent to each of the ampoules, cool in a dry
ice-acetone mixture, and seal, using the double-jet air-
gas burner and taking care to save all the glass.

36.  Allow the ampoules and their content to come to
room temperature, and weigh the individual sealed
ampoules with the corresponding glass fragment.
Calculate the system composition, in mg per g, for
each ample by the formula:
 Csystem (mg/g) = 1000 x (W2 – W1) / (W3 – W2)
 In which W1 is the weight of the ample plus test
substance, W2 is the weight of the empty ample, and
W3 is the weight of ample plus test substance,
solvent, and separated glass.

37. Equilibration
 The time required for equilibration varies with the
substance, the method of mixing (rotation or vibration),
and the temperature. Normally, equilibrium is obtained
more rapidly by the vibration method (1 to 7 days) than
by the rotational method (7 to 14 days). In order to
determine whether equilibration has being effected, one
ample, that is, the next to the last in the series, may be
warmed to 40 ̊ to produce a super-saturated solution.
Equilibration is assured if the solubility obtained on the
super-saturated solution falls in line with the test
specimens that approach equilibrium from an under
saturated solution.

38.  Solution Composition
 After equilibration, place the ampoules vertically in a
rack in the constant temperature bath, with the necks of
the ampoules above the water level, and allow the
contents to settle. Open the ampoules, and remove a
portion greater than to 2 ml from each by means of a
pipette equipped with a small pledged of cotton mem-
brane or other suitable filter. Transfer a 20 ml aliquot of
clear solution from each ample to a marked, tarred
solubility flask, and weigh each flask plus its solution to
obtain the weigh of the solution. Cool the flasks in a dry-
ice acetone bath, and then evaporate the solvent in
vacuum.

39.  Gradually increase the temperature to a temperature
consistent with the stability of the compound, and
dry the residue to constant weight. Calculate the
solution composition, in mg per g, by the for- mula:
 C (mg/g) =1000 x (F3-F1)/F2-F3)
 In which F1 is the weight of the flask plus residue, F2
is the weight of the solubility flask, and F3 is the
weight of the flask plus solution.

40.  Calculation
 For each portion of the test substance taken, plot the
solution composition as the ordinate and the system
composition as the abscissa. As shown in the
accompanying diagram, the points for those containers,
frequently only one, that represent a true solution fall on
a straight line (AB) with a slope of 1, passing through the
origin; the points corresponding to saturated solution fall
on another straight line (BC), the slope, S, of which
represent weight fraction of impurity or impurities
present in the test substance. Failure of points to fall on a
straight line indicates that equilibrium has not been
achieved.

42.  A curve indicates the material under test may be a
solid solution. Calculate the percentage purity of the
test substance by the formula:
 Purity (%) =100-100S
 The slope, S, may be calculate graphically or by least-
squares treatment for best fit of the experimental
values to a straight line.

44. References
1. International journal of pharma PROFESSIONAL’s Research Review
SOLUBILITY ENHANCEMENT TECHNIQUES WITH SPECIAL EN
HYDRROTRPHY-Volume 1, issue 1, july 2010available at www.ijppronline.com
2. SOLUBILITY ENHANCEMENT TECHNIQUES-Volume 5, issue 1, November-
December 2010;Article-007 available at www.pharmainfo.net
3. Journal of Global Pharma Technology TECHNIQUES TO SOLUBILITY OF
POORLY SOLUBLE DRUGS:A REVIEW available at www.jgpt.com
4. PHARMACIE GLOBALE- INTERNATIONAL JOURNAL OF COMPRIHENSIVE
PHARMACY-REVIEW ON SOLUBILITY ENHANCEMENT TECHNIQUES FOR
HYDROPHOBIC DRUGS available at www.pharmacle.globale.info
5. International Journal of pharmTech Research vol.2, No.3, pp2007-2015, july-
sept 2010, solubility Enhancement of poorly water soluble Drug by Solid
Dispersion Techniques