SOLUTION
Waters
Six USP Monographs:
► Purified Water, USP
►
--Less than 0.001% total solids—
--Intended for oral and topical dosage forms
--Prepared by
1.
2.
3.
Distillation
Ion-exchange
Reverse Osmosis
Waters
► Water for Injection, USP
--Prepared by distillation or RO
--Total Solids not more than 1mg/100 ml
--Use within 24 hours
--Free from pyrogens (bacterial byproduct)
--Intended for injections which are to be sterilized
after manufacture
Waters
Sterile Waters—Four grades
1. Sterile Water for Injection, USP
--Package less than or equal to 1 liter
--Single use only
2. Sterile Water for Irrigation, USP
--Package in larger containers, Single use
--Type I—Highly resistant borosilicate glass
--Type II—Treated soda-lime glass
3. Bacteriostatic Water for Injection, USP
--Sterile
--Contains antimicrobial agents which must be stated on label—
toxicity issues
--Preserve in single-dose or multi-dose vials (30 ml)
--Not for seniors or newborns
4. Sterile Water for Inhalation, USP
►
--Distillation or RO
--No antimicrobial agent
SOLUBILITY OF GASES IN LIQUIDS
• What is solubility of a gas in
liquids?
– The solubility of a gas in a
liquid is the concentration of
the dissolved gas when it is in
equilibrium with some of the
pure gas above the solution.
• The solubility of a gas in liquids
depend on:
– Pressure,
– Temperature
– Presence of salt
– Chemical reactions that the
gas sometimes undergoes
with the solvent.
EffECT OF PRESSURE ON THE SOLUBILITY OF A GAS
• The effect of pressure on solubility of gas is expressed by Henry’s law.
• In a very dilute solution at constant temperature, the concentration of
dissolved gas is proportional to the partial pressure of the gas above the
solution at equilibrium.
• The relationship between the solubility of a gas with pressure is expressed
by the following equation.
c = kP
• c is the concentration (M) of the dissolved gas
• P is the pressure of the gas over the solution
• k is a constant (mol/L•atm) that depends only on temperature.
Limitations of Henry’s Law:
It applies closely to gases with nearly ideal behavior. Thus
Henry’s law is applicable:
 At moderate temperature and pressure
 If the solubility of the gas in the solvent is low.
 If the gas does not react with the solvent to form a
new species
PRESSURE ON THE SOLUBILITY OF A GAS
– Solubility
of
a
gas
increases directly as the
pressure
of
the
gas
increases and that the
solubility
of
the
gas
decreases as the pressure
of the gas decreases.
gas volume is reduced;
pressure (concentration!)
increases; more collisions
occur with liquid surface
PRESSURE ON THE SOLUBILITY OF A GAS
• Example:
– “When the stopper is removed from an
effervescent solution, the gas escapes
violently because of the release of pressure.
– Carbonated beverages provide the best
example of this phenomena. All carbonated
beverages are bottled under pressure to
increase the carbon dioxide dissolved in
solution.
– When the bottle is opened, the pressure
above the solution decreases. As a result,
the solution effervesces and some of the
carbon dioxide bubbles off”.
TEMPERATURE EFFECT ON THE SOLUBILITY OF A
GAS
• As the temperature increases the solubility of
most gas decreases, owing to greater tendency
of gas to expand.
• “This gas solubility relationship can be
remembered if you think about what happens to
a carbonated beverages as it stands around
for awhile at room temperature. The taste is
very "flat" since more of the "tangy" carbon
dioxide bubbles have escaped.
• Boiled water also tastes "flat" because all of the
oxygen gas has been removed by heating”.
• More gas is present in a solution with a lower
temperature compared to a solution with a
higher temperature.
TEMPERATURE EFFECT ON THE SOLUBILITY
OF A GAS
– Pharmacist should exercise caution in opening
containers of gaseous solutions in warm climates and
under conditions of elevated temperature.
– For example, a vessel containing a gaseous solutions
or a liquid with a high vapor pressure, such as ethyl
nitrite, should be immersed in ice or cold water for
some time to reduce the temperature and pressure of
the gas before opening.
SALTING OUT
• It is the phenomenon when gases are
liberated from solutions in which they are
dissolved by the introduction of electrolyte
such as sodium chloride.
– This effect can be demonstrated by adding a small
amount of salt to a carbonated solution.
EFFECT OF CHEMICAL REACTION
• Gases such as hydrogen chloride, ammonia,
and carbon dioxide show deviation from
Henry’s law as a result of chemical reaction
between the gas and solvent, which usually
result in increase in solubility.
– For example, hydrogen chloride is about 10,000
times more soluble in water than is oxygen.
SOLUBILITY OF LIQUIDS IN LIQUID
SOLUBILITY OF LIQUIDS IN LIQUIDS
• Examples
hydroalcoholic
spirits and elixir.
MISCIBILITY OF LIQUIDS IN LIQUIDS
• Complete miscibility
• Partial miscibility
MISCIBILITY OF LIQUIDS IN LIQUIDS
• Complete miscibility
• Partial miscibility
• Binary
• Ternary systems
BINARY LIQUID-LIQUID SYSTEMS
TERNARY SYSTEMS
• What is ternary system?
• How ternary system increases solubility?
SOLUBILITY OF SOLIDS IN LIQUIDS
SOLUBILITY OF SOLIDS IN LIQUIDS
SOLUBILITY OF A SOLID IN AN IDEAL
SOLUTION
EFFECT OF pH ON THE SOLUBILITY
• Effect of pH on the solubility of solids in liquids
• Effect of pH on the solubility of acidic drugs
• Effect of pH on the solubility of basic drugs
SUMMARY OF THE EFFECT OF PH ON
SOLUBILITY
Log solubility (µmol/L)
B- + HA = HB + A-
pH
EFFECT OF PARTICLE SIZE ON
SOLUBILITY
► The size and shape of small particles, those in the
micrometer range, can affect solubility.
► A micronized drug will have an increase in solubility over
a drug that is not micronized.
► Breaking the bonds in the crystal lattice by micronization
will reduce the energy required to separate the solute
from itself, consequently, increase solubility.
Factors Affecting Solubility:
Temperature
► Temperature
is a principal factor that
influences the equilibrium solubility.
► When a solid solute dissolves, it takes in
energy to break apart the crystal lattice
structure and separate it into ions or
molecules.
► The solvent (water) takes in energy to
break apart its hydrogen bonds to allow
the solute to come in contact with
adjacent molecules of water.
Factors Affecting Solubility: Temperature
► The nearly exponential rise or
fall of temperature with
solubility is related to the
exchange of energy that
occurs
during
solution
formation.
► Most
substances
are
endothermic, absorbing heat
in the process of dissolution.
► A
few substances, such as
calcium
hydroxide,
are
exothermic and give off heat
in the process of dissolution.
Factors Affecting Solubility:
Ionization
► Ionization of solute generally increases solubility
 Strong Electrolytes: Solutes that are completely ionized
include strong acids and bases and inorganic and
organic salts, which are soluble in water.
 The polar nature attracts the ions and forms a solution.
 Weak electrolytes: Weak acids and bases with high
molecular weight are not soluble in water.
Balanced Solubility
hydrophilic....................water loving
lipophobic.....................lipid hating
lipophilic.......................lipid loving
hydrophobic..................water hating
► It is important to note that a majority of agents possess the
property of balanced solubility, that is, most drugs have some
degree of solubility in both aqueous and lipid media.
► This is because there is a need for drugs to move through both
aqueous (plasma, extracellular fluid, cytoplasm, etc.) and lipid
media (biologic membranes) in the biological system.
► Hence,
solubility of drugs should be viewed as being on a
continuum between high lipophilicity on one end of the spectrum
and high hydrophilicity on the other.
Solubility curves
► A
Solubility (g/100g water)
curve drawn between solubility and temperature is
termed solubility curve.
 Continuous solubility curve: Continuous solubility curve
shows the continuous increase in the solubility of the
solute with the increase in temperature.
 Discontinuous solubility curve: discontinuous solubility
curve shows a sudden change in the solubility of the
solute with the increase in temperature.
NaNO3
CaCl2.6H2O
CaCl2.2H2O
CaCl2.4H2O
Temperature 0C
SOLUBILITY AND SOLUBILIZATION
WHAT IS SOLUBILIZATION AND WHY?
• Solubilization is the process of dissolving a chemical in a
solvent and commonly referred to the process that enhance
intrinsic solubility of the chemical.
• Many drug substances are not soluble in water or a large
amount of water is needed to solubilize a single dose of the
drug.
• Consider a drug that has a solubility of 5mcg/l, the dose is 500
mg. How much water do you need to solubilize a single dose
of the drug?
• Since we cannot solubilize this drug with 100,000 liter water,
we have to use other agents to solubilize the drug.
SOLUBILIZATION
• The dissolving process involves a consideration of the relative
strength of intermolecular attractive forces.
• A solute will dissolve in a solvent if the solute-solvent forces of
attraction are great enough to overcome the solute-solute and
solvent-solvent forces of attraction.
• A solute will not dissolve if the solute-solvent forces of attraction are
weaker than individual solute and solvent intermolecular attractions.
STRATEGIES TO ENHANCE SOLUBILITY
• Many drug substances are very poorly soluble in water.
• In order to formulate as solution dosage forms, their
solubility has to be increased by one of the following
methods.
• Salt formation
• Solubilization through pH control
• Hydrotropy
• Change in physical form
• Cosolvancy
• Use of surfactants
• Complexation
SOLUBILIZATION BY SALT FORMATION
• The solubility of weakly acidic or basic drugs can be
increased by forming salts.
• Salt forms easily dissolve in water by the ion- dipole
interactions.
• Most salts of organic compounds can be formed by
addition or removal of a proton to form an ionized
drug species which is then neutralized with a counter
ion.
• Propranolol HCl, for example, is prepared by addition
of a proton to form propranolol-HCl which is then
neutralized with a chloride anion to form the salt.
• Similarly salts can be formed by reacting weak acids
and strong bases. e.g. Phenobarbital sodium is the
salt of a weakly acidic drug, phenobarbital.
Example: Salt Forms of Drugs
Solubilization through pH Control
► The solubility of a drug can be increased or
decrease exponentially with pH alteration.
► The degree and extent of precipitation will
depend on the ability of a formulation to
resist pH change when diluted.
► Use of buffer will aid in reducing the risk of
precipitation up dilution.
SOLUBILIZATION BY HYDROTROPY
• When the aqueous solubility of a drug substance is
increased by adding additives, the phenomenon is
called hydrotropy.
• The effect of hydrotropy is either due to a weak
interaction between the solute and the additive, or due
to a change in the solvent properties because of the
additive.
• For example: the solubility of benzoic acid and caffeine
can be increased by adding sodium benzoate.
• Similarly sodium acetate increases the solubility of
theophylline.
SOLUBILIZATION BY CHANGING PHYSICAL STATE
• Sometimes by physical modifications of the
drug substances, solubility can be enhanced.
• For example, a freeze dried product or a finer
product may have more solubility than a
coarse product.
• Micronization reduces particle size and
increases dissolution.
• Because of micronization, more and more of
particle will be available for interaction with
water
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SOLUBILIZATION BY COSOLVENCY
• Cosolvency is a phenomenon where a
solute is more soluble in a mixture of
solvents than in one solvent alone.
• Cosolvents are organic compounds that are
substantially miscible with water.
• Cosolvents reduce the cohesive interactions
of water, so that it is less effective in
squeezing out nonpolar solutes from
solution.
• The combination of the hydrogen-bonding
group and the hydrocarbon group makes
the cosolvent part polar and part nonpolar.
• This property enables the cosolvent to be
miscible with water, which is polar, and with
many water-immiscible solutes that are
nonpolar.
SOLUBILIZATION BY COSOLVENCY
• As an example, nitrocellulose is sparingly soluble in alcohol
and ether but is fairly soluble in an alcohol - ether mixture.
• Cosolvents are generally liquids, but, there are solids which
have been used as cosolvents.
• For example, sugars and high molecular weight hydrophilic
polymers, such as polyethylene glycol (PEG) and
polyvinylpyrrolidone (PVP), both of which are solids in their
pure state, can be used as cosolvent.
Co-Solvent Example
► Valium (Diazepam) Injection 5mg/mL
 40% Propylene Glycol
 10% Alcohol
 5% Na Benzoate/Benzoic Acid
 1.5% Benzyl Alcohol
 QS Purified Water
► Diazepam – crystalline, insoluble in water
► Inject at rate < 1mL/min to avoid venous thrombosis, phlebitis,
irritation
► Do not mix with other solution or drug in IV or infusion
SOLUBILIZATION BY USE OF SURFACTANTS
• Surfactant molecules are amphiphiles that are
characterized by two distinct regions: polar and
noploar.
• The polar region of a surfactant orient to the polar
side of an interface and nonpoplar region orient to
nonpolar side.
• These properties of surfactants are exploited to
increase solubility of poorly soluble drugs.
• Solubility of a hydrophobic drug can be increased my
means of micellar solubilization.
• Hydrophobic drugs can be entrapped in the micelles
and reduce contact with water.
The Cleansing Action of Soap
SOLUBILIZATION BY USE OF SURFACTANTS
• What are micelles?
• When surfactants are in a
liquid
medium
at
low
concentration,
surfactant
molecules stay separated from
each other.
• As
we
increase
the
concentration,
surfactants
start to aggregate over a
certain concentration range
and these aggregates are
called micelles.
• The concentration at which
micelles are formed called
critical micelle concentration
Surfactants in water
Surfactants in oil
SOLUBILIZATION BY COMPLEXATION
inclusion complexes
Chemical structure and
molecular geometry of
cyclodextrins
Chemical structure and molecular
geometry of cyclodextrins
DRUG-CYCLODEXTRIN COMPLEXATION
• Cyclodextrins are donut shaped molecules; inner side of the
donut is hydrophobic and outer side is hydrophilic.
• A hydrophobic drug may easily fit into the hydrophobic cavity
of cyclodextrin
Drug
Drug
1:1 Complex
Drug
Drug
1:2 Complex
2:1 Complex