Advantages and disadvantages of solutions as dosage forms

◎ Advantages ◎ Disadvantages
 Drug available
immediately for absorption
 Flexible dosing
 May be designed for any
route of administration
 No need to shake
container
 Facilitates swallowing in
difficult cases
 Drug stability often reduced in
solution
 Difficult to mask unpleasant
tastes
 Bulky, difficult to transport and
prone to container breakages
 Technical accuracy needed to
measure dose on administration
 Some drugs poorly soluble
 Measuring device needed for
administration

Solubility and
dissolution rate
 “
Solubility is defined in quantitative terms
as the concentration of solute in a
saturated solution at a certain
temperature, and in a qualitative way, it
can be defined as the spontaneous
interaction of two or more substances to
form a homogeneous molecular
dispersion

Let’s review some concepts

1 2 3
Solubility is an Attractive forces The intermolecular forces,
intrinsic material between atoms which are developed between
property that can be like molecules, are responsible
lead to the
altered only by for the physical state (solid,
chemical modification
formation of
molecules and liquid, or gas) of the substance
of the molecule under given conditions, such as
ions
temperature and pressure

4
5 6
When a solute dissolves,
the substance’s These forces must be This entails breaking the
intermolecular forces of overcome by forces solute–solute forces and
attraction (dipole–dipole of attraction between the solvent–solvent forces
or van der Waals forces, the solute and the to achieve the solute–
ion–dipole forces and solvent molecules. solvent attraction.
hydrogen bonding) 4

.
Dipole–dipole or van der Waals forces

Dipolar molecules frequently tend to align

themselves with other dipolar molecules so that
the negative pole of one molecule points toward
the positive pole of the other.
● Large groups of molecules may be
associated through these weak attractions,
known as dipole–dipole or van der Waals
forces.
 Hydrogen Bonding

Because of small
These size and large
Attractions include electrostatic field,
also occur ion– the hydrogen atom
Hydrogen
between can move in close bonding involves
dipole
polar and to an strongly
forces electronegative electronegative
nonpolar and atom, forming an atoms such as
molecules hydrogen electrostatic type oxygen, nitrogen,
and ions bonding of association, a and fluorine
hydrogen bond or
a hydrogen bridge

Factors affecting solubility

01 Temperature 02 polymorphism 03 pH
and solvation

04 Molecular 05 Particle size

structure of
solute
  Most chemicals absorb heat
when they are dissolved and

01 are said to have a positive

heat of solution, resulting in
increased solubility with an
increase in temperature.
 A few chemicals have a
negative heat of solution and
Temperature exhibit a decrease in
solubility with a rise in
temperature.

A brief about crystals and amorphous

state

• Crystalline materials: are those in

which the molecules are packed in
a defined order, and this same
order repeats over and over again
throughout the particle.
• Amorphous state: When a material
is in the solid state but the
molecules are not packed in a
repeating long-range ordered
fashion.
• Polymorphism: Is the phenomenon
in which the compound have the
same structure but differ in the
arrangement of molecules in the
crystal.
- Increasing the solubility of a
crystalline material, and hence its
rate of dissolution and bioavailability
can be achieved by using a
metastable polymorph (less stable
forms).
- The amorphous form slowly
02
convert to more stable crystalline
form, with an accompanying loss of
therapeutic effectiveness. Crystal characteristics:
-Thus unless adequate precaution polymorphism and
are taken to ensure the stability of solvation
the less stable more therapeutically
effective amorphous form of the drug
in dosage form, then unacceptable
variation in therapeutic effectiveness
may occur.

• Even a small change in

the molecular structure
03 of a compound can have
a marked effect on its
solubility in a given
liquid.
Molecular
structure of
solute
General guidelines relating solubility

1) “like dissolves like,” meaning a solvent having

a chemical structure most similar to that of the
intended solute will be most likely to dissolve it.
Thus, organic compounds are more soluble in
organic solvents than in water.

General guidelines relating solubility

2) Compounds may, however, be somewhat water

soluble if they contain polar groups capable of forming
hydrogen bonds with water.
◎ the greater the number of polar groups present, the
greater will likely be the organic compound’s
solubility in water.
◎ Polar groups include:
OH, CHO, COH, CHOH, CH2OH, COOH, NO2, CO,
NH2, and SO3H.

14
General guidelines relating solubility

3) The introduction of halogen atoms into a molecule

tends to decrease water solubility because of an
increase in the molecular weight of the compound
without a proportionate increase in polarity.

15

General guidelines relating solubility

4) An increase in the
molecular weight of an
organic compound without
a change in polarity
reduces solubility in water.

16
 General guidelines relating solubility

5) Most salts of monovalent cations, e.g., sodium,

potassium, and ammonium, are water soluble.
◎ divalent cations, e.g., calcium, magnesium, and
barium, usually form water-soluble compounds with
nitrate, acetate, and chloride anions but not with
carbonate, phosphate, or hydroxide anions
.

17

- The solubility of a pure

chemical substance at a
given temperature and
pressure is constant;
04 however, its rate of solution,
that is, the speed at which it
dissolves, depends on the
particle size of the substance
the state of subdivision
and the extent of agitation.
of the solute, and the -.
physical agitation
applied to the solution
as it dissolves
 - The finer the powder, the greater the surface area, which
comes in contact with the solvent, and the more rapid the
dissolving process.
- Also, the greater the agitation, the more unsaturated solvent
passes over the drug and the faster the formation of the
solution.

Henderson–Hasselbalch
relationship for a weak acid,
05
where [HA] is the concentration of pH
the nonionized weak acid and [A-]
is the concentration of its
conjugate base.
For a weak base, the equation is

where [B] is the concentration of the base

and [BH+] that of its conjugate acid.
pKa is the dissociation exponent for the
weak acid in each case.
 ● If the pH of a solution of either
a weakly acidic drug or a salt
of such a drug is reduced, then
the proportion of unionized
acid molecules in the solution
increases.
● Precipitation may occur,
therefore, because the
solubility of the unionized
species is less than that of the
ionized form.
● Conversely, in the case of
solutions of weakly basic drugs
or their salts, precipitation is
favored by an increase in pH.

● Many of the important organic medicinal agents

are either weak acids or weak bases, and their
solubility depends to a large measure on the pH
of the solvent.
● These drugs react either with strong acids or
strong bases to form water soluble salts.
 ● For instance, the weak bases, including many of
the alkaloids (atropine, codeine, and morphine),
antihistamines (diphenhydramine and
promethazine), local anesthetics (cocaine,
procaine, and tetracaine) are not very water
soluble, but they are soluble in dilute solutions of
acids.
● Pharmaceutical manufacturers have prepared
many acid salts of these organic bases to enable
the preparation of aqueous solutions.

Selection of proper solvent

Alcohol, glycerin, and
Clarity, low toxicity, propylene glycol are
viscosity, compatibility auxiliary solvent employed to
with other formulative augment the solvent action
ingredients, chemical of water or to contribute to a
inertness, palatability, product’s chemical or
odor, color, and In addition to the
physical stability
economy factors of
solubility and
For solutions to be taken pharmacist
orally, used intranasal, knowledge A number of fixed oils, such
ophthalmically, or as corn oil, cottonseed oil,
injected, water is the peanut oil, and sesame oil,
preferred solvent because are useful solvents,
it comes closer to particularly in the
meeting these criteria preparation of oleaginous
than other solvents injections.
 Determination of
solubility
The solubility of a The amount of
substance in a given solvent required
solvent may be to dissolve the
determined by amount of solute
preparing a saturated can be
solution of it at a determined by a
specific temperature simple
and by determining calculation.
by chemical analysis
the amount of
chemical dissolved in
a given weight of
solution

Solubility Expressions

• The solubility may then be expressed as grams

of solute dissolving in milliliters of solvent; for
example, “1 g of sodium chloride dissolves in
2.8 mL of water.”
• When the exact solubility has not been
determined, general expressions of relative
solubility may be used. These terms are defined
in the USP.
Solubility Expressions