Physical pharmaceutics
Module 1
Introduction
• Quantitatively:-
• Solubility is defined as the concentration of solute in a saturated solution at the
particular temperature.
• Qualitatively:-
• It can be defines as the spontaneous interaction of two or more substances to
form a homogenous molecular dispersion.
• It is important for the pharmacist to understand the concept of solubility as it
is a key parameter affecting the formulation of the dosage forms . Some of the
phenomena which make solubility an important criterion are:-
• 1. Choice of solvent for the liquid formulation.
• 2. Dissolution of drugs.
• 3. Bioavailability of drugs. The drug has to dissolve before it has been
absorbed.
Definitions related to solubility
• Solute:- It is component which is dissolved in solvent, present in less amount in solution.
• Solvent:- It is component in which solute is dissolved, present in more amount than solute
in the solution.
• Solution:- It is the mixture of two or more components that forms a homogenous mixture.
• Saturated solution:- It is a solution when solute is dissolved up to maximum limit of
solubility at any given temperature and pressure. It cannot dissolve any more quantity of
solute.
• Unsaturated solution:- It is a solution in which dissolved solute is in a concentration
below the required amount necessary for the complete saturation at a definite temperature.
• Supersaturated solution:- It is solution which contains more of the dissolved solute
than it would normally contain in a saturated state at a definite temperature . The
recrystallization of the excess dissolved solute in a supersaturated solution can be initiated by
the addition of a tiny crystal of solute.
Solubility expression
• The solubility of a drug may be expressed in terms of ways. The United States Pharmacopeia
describes the solubility of drugs as parts of solvent required for one part solute. Solubility is
also quantitatively expressed in terms of molarity, molality, and percentage. The USP
describes solubility using the seven groups listed in (table 1.0). The European Pharmacopoeia
lists six categories.
• Table 1.0 Solubility Definitions in the United States Pharmacopeia
• Description forms Parts of solvent Solubility range
required (mg/ ml)
Very soluble <1 >1000
Freely soluble From 1 to 10 100-1000
Soluble From 10 to 30 33-100
Sparingly soluble From 30 to 100 10-33
Slightly soluble From 100 to 1000 1-10
Very slightly soluble From 1000-10,000 0.1-1
Practically insoluble >10,000 <0.1
Quantitative expressions
• Molarity:- It is defined as no. of moles of solute dissolved per liter of the
solution. It is denoted by ‘M’.
• Molality:-It is defined as no. of moles of solute dissolved per kg of
solvent. It is denoted by ‘m’.
• Normality:- It is defined as no. of gram equivalent of solute dissolved/
present per liter of solution. It is denoted by ‘N’.
• Percentage concentration:-
• %w/w = mass of solute/mass of solution * 100
• %v/v = volume of solute/volume of solution *100
• %w/v = mass of solute/ volume of solution*100
• Parts per million:- It is defined as number of moles of a component
divided by total number of moles in solution.
Mechanism Of Solute Solvent Interaction
• A good solvent is selected on the principle of the “Like dissolves like” ; that is , a
solute dissolves best in the solvent with similar chemical properties. Thus, there
might be two rules of selecting a good solvent.
• 1. Polar solutes dissolve in polar solvents.
• 2. Nonpolar solutes dissolve in non polar solvents.
• The forces of attraction between solute and the solvent is a important parameter
which plays role in order to dissolve solute in the solvent. Thus, three types of force
of attractions may occur between solute and the solvent molecule viz. X-Y, Y-Y and X-
Y. There is one condition may take place out of the three conditions which are
described as under;
. If X-X>>X-Y, this condition describes that the affinity of solvent molecule
for its own kind of molecule is greater than its affinity for solute
molecules. For example, benzene is almost completely insoluble in water
because of the strong attraction force between solvent-solvent molecules.
• If Y-Y>>X-X, this describes that solvent will not be able to break the binding
forces between solute molecules. For example sodium chloride does not
dissolve in benzene because sodium chloride molecules are held together
by strong electrovalent forces which cannot be broken by the benzene. A
highly polar solvent such as water is required to overcome this attraction
between the solute molecules.
• If X-Y>>X-X OR Y-Y, this describes that the attraction force between the
solvent molecules and the solute molecules is greater than either between
own solvent molecules or between own solute molecules. The condition
may arise when all the three forces are of thw same order. In all the cases
the resultant is formation of solution.
Classification of solvents
• Based on dielectric constant:-
• Polar solvent:- water, glycols, methyl & ethyl alcohol. The mechanism of
polar solvent mainly depend on high dielectric constant.
• Non polar solvent:- e.g. Hexane. The mechanism of non polar solvent
depend on weak van der Waals forces.
• Semi polar solvent :- e.g. Alcohol. They act as intermediate solvents to
induce the miscibility of polar and nonpolar liquids.
• The polarity of the solvent varies on the dielectric constant. It increases with
the increase in dielectric constant. The solvents having dielectric constant
value of below 15 are generally considered as non polar. The polar solvents
can further classified into sub-groups; Protic and aprotic solvents. Protic
solvents (water, ethanol, methanol etc.) solvate anions through hydrogen
bond whereas aprotic solvents ( DMSO, DMF, acetone etc.) solvate cations.
Solvation
• Solvation is the phenomenon in which solvent interacts strongly with the
molecules or ions of solute which leads to stabilization of the solute species in
the solution. In the solvated state, an ion in a solution is surrounded or
completed by solvent molecules.
• For example, in order to dissolve sodium chloride, the Na+ and Cl- ions must
break free from the crystal- lattice structure of the solid. When the ions are in
solution they are surrounded by water molecules, and the ions are said to be
solvated, or dissolved in aqueous solution.
• H2O is a polar solvent which has negatively and positively charged regions. The
charged regions are attracted to ions with opposite charge. Hence, the positively
charged regions of water molecules are attracted to Na+ ions. When similar
water molecules surround in ions in the crystal, the sum of the attractive forces
between the water molecules and the anions in the crystal. The water molecules
forms a shell of solvation around the ions and the water surrounded ions can
break away from the crystal and the ions have become solvated by water
molecules.
Factors affecting solubility
• Solubility is a primary physiological factor which is considered in preparing
pharmaceutical solutions of various types of drugs. The choice of solvent
is very important which must comply with the required solubility and
biocompatibility. It is always defined as solute dissolved in a solvent at a
particular temperature and pressure. When both solute and solvent are
liquid, the term is called miscibility if miscible or immiscibility if not
miscible. Factors:-
• (a) Temperature:- Solubility of a solute is a function of
temperature. Most of the substances are endothermic and absorbs heat in
the process of dissolution. Thus, increase in temperature during the
dissolution of such solutes results in increase in the solubility. The
exothermic substances such as calcium hydroxide and sodium carbenicillin
give off heat in the process of dissolution and hence the solubility of such
substances decreases with increase in temperature.
(B) Molecular structure of solute
• A small change in the molecular structure of a compound can have a
marked effect on its solubility in a given liquid. For example , the
introduction of a hydrophilic hydroxyl group can produce a large
improvement in water solubility, as evidenced by more than 100-fold
difference in the solubilities of phenol and benzene. Another example of
increase in solubility is found when weak acid is converted its sodium salt
as in case of salicylic acid when converted to its sodium salt and their
solubilities are 1:550 and 1:1 respectively.
• Some parent drugs turn to less soluble by the esterification which can be
exploited for masking the bitter taste. For example, conversion of bitter
taste soluble Chloramphenicol palmitate, used in pediatric suspension.
• Similarly, erythromycin propionate is less soluble than erythromycin which
can protect the drug from degradation in gut and increase in absorption of
the drug from gastrointestinal tract.
Nature of solvent
• As discussed about the nature of solvent is very important to dissolve the
solute. The statement says that “ Like dissolves like” means thereby polar
solute dissolves in polar solvent and vice-versa. The technique of
cosolvancy is exploited to enhance the aqueous solubility of poorly
soluble solute by addition of water miscible cosolvent in which the solute
is highly soluble. For example ethanol, propylene glycol and other glycols.
A very nice example is metronidazole which is soluble in the quantity of
1000mg in 10ml, but if a cosolvent is added its aqeuous solubilty is
enhanced by five fold.
