Importance: Solubility is an important preformulation property that affects the performance of a drug molecule. Solubility plays an important role during
formulation development. Bioavailability of tablets and capsules depend on solubility and dissolution rate
of the drug. Orally administered drug has to first dissolve in gastrointestinal fluid before it can be absorbed. Dissolved drug then passes through the
intestinal membrane and enters into blood. Solubility studies in nonaqueous solvents are important for development of
analytical methods, crystallization method and formulation development of soluble oral or Parenteral formulations.
About 40 of drug molecules fail to come into the market because of poor aqueous solubility.
Determination: Solubility of a drug is determined using shake flask method.
Preformulation solubility studies are carried out in distilled water, 0.9 NaCl isotonic solvent, 0.01 M HCl, 0.1 M HCl, 0.1 M NaOH all at room temperature
and at 37 degree centigrade. Solubility studies are also carried out in fasted state simulating intestinal
fluid the fed state simulated intestinal fluid. The effect of temperature and pH on solubility of drug is also studied.
If a drug is having poor solubility and dissolution rate, limited solubilization experiments are carried out using co solvency micellar solubilization
complexationsolid dispersions salt formation principles. This information will be useful for the formulation scientist to formulate his dosage form.
Example: Diclofenac is converted into diclofenac sodium to increase its aqueous solubility and dissolution rate.
Example: Nimesulide is complexed with beta cyclo dextrin to increase its aqueous solubility, dissolution rate and bioavailability.
2. Dissolution Rate: Concept: The process by which a drug goes into a solvent to form a solution is
called dissolution. The speed of dissolution is called dissolution rate. For
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Sir C.R.R College of Pharmaceutical Sciences, Eluru, Andhra Pradesh, India
example salt dissolves fast in water when compared with sugar.
Importance: Orally administered drug has to first dissolve in gastrointestinal fluid before it can be absorbed. Dissolved drug then passes through the
intestinal membrane and enters into blood circulation.
Dissolution rate speed of dissolving of drug particles depend on several physico chemical properties like chemical form, crystal habit, particle size,
solubility, surface area and wetting properties. Dissolution experiments help to identify the solvate polymorph complex solid dispersions solvent
deposited systems salt forms having high dissolution rates. The fast dissolving forms will be used by the formulation scientist to develop tablets.
Example: Diclofenac is converted into diclofenac sodium to increase its aqueous solubility and dissolution rate.
Example: Nimesulide is complexed with beta cyclo dextrin to increase its aqueous solubility, dissolution rate and bioavailability.
Example: Generally solid dispersions of drugs in hydrophilic carriers have good dissolution rate and oral bioavailability.
Determination: Dissolution studies are carried out using official dissolution testing apparatus.
3. Dissociation Coefficient pKa : Concept: Most of the drugs are weak acids or weak bases. The dissociation
coefficient is a measure of the drugs ability to ionize in water. The extent of ionization of a drug depends on its dissociation coefficient value and pH of the
solvent.
The Henderson – Hasselbalch equation can be used to calculate the extent of ionization of a drug at a particular pH value.
For weak acids, pH = pK
a
+ Log [ionized formunionized form]
For weak bases, pH = pK
a
+ Log [unionized formionized form]
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Sir C.R.R College of Pharmaceutical Sciences, Eluru, Andhra Pradesh, India
Importance: Ionized drug molecules have more water solubility but less tissue permeability. Unionized drug molecules have less water solubility but more
tissue permeability. This is because unionized molecules are more lipophillic and can easily cross biological membranes.
Gastrointestinal tract exposes the drug molecule to a wide range of pH values. Information on pKa value allows understanding the behavior of ionizable drug
molecule, under different pH conditions. For example a weakly acidic drug with a pK
a
value greater than three remains unionized in stomach pH is 1 and is ionized in intestine. Hence we can predict
that this drug is going to be rapidly absorbed in the stomach. Due to large surface area of the intestine this drug will be absorbed from the intestine also.
Determination: pK
a
values of a drug can be determined by potentiometric method or by spectral shifts in UVVisible spectroscopy. Buffers, temperature,
ionic strength and co solvents affect the pK
a
value and should be controlled during pK
a
experiments.
4. Partition coefficient: Concept: It indicates the lipophillic nature of a drug molecule and its ability to
cross biological membranes. It is given by the equation: P = K
ow
= C
o
C
w
P = Partition coefficient of drug between n octanol and water C
o
= Concentration of drug in octanol C
w
= Concentration of drug in pH 7.4 buffer
Importance: The lipophillic nature of a drug molecule is expressed in terms of P and Log P values. Higher log P values indicate that the drug is more
lipophillic in nature. For example, Log P value of diclofenac is 4.0 and
Log P value of ibuprofen is 3.65. If a drug is highly lipophillic, it will easily cross biological membranes in the
body. A
small log P value indicates that the drug is hydrophilic in nature, it will
have good water solubility but it will not easily cross biological membranes. A
higher log P value indicates that the drug is strongly lipophillic. It has poor
aqueous solubility, but once it goes into solution in G.I fluids, it enters into the biological membrane and stays there only. It will not go into the blood. This
drug gets accumulated in the membrane.
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Sir C.R.R College of Pharmaceutical Sciences, Eluru, Andhra Pradesh, India
Hence a drug should have
optimum hydrophilic and lipophillic nature. It
should dissolve easily in G.I fluids and pass through biological membrane easily. A
log P value of two is considered optimal for good bioavailability. Determination: It is determined by shaking the drug between octanol and pH
7.4 buffer until equilibrium is achieved. The two layers are separated and assayed for drug content.
5. Permeability: Concept: The ability of a drug molecule to cross biological membranes is