It is an important physicochemical property of a drug substance, especially in an aqueous system such as,

1.Disintegration of drug substance 2.Dissolution of drug substance 3.Absorption of drug substance 4.Protein binding of drug substance 5.Distribution of drug substance 6.Therapeutic efficacy or bioavailability 7.Selection of route of administration

Relation in between solubility and particle size

The particle size and surface area of a drug exposed to a medium can affected actual solubility, can calculated by the following equation: solubility =log S S0 where S solubility of the small particles S0 solubility of the large particles

Modification
If the solubility of the drug substance is less then desirable, must be given to improve its solubility. The methods is mainly depend upon the chemical nature of the drug and the type of drug and the type of drug product. 1.Chemical modification of drug into salt or ester forms is frequently used to increase solubility 2.Solubilization : a general means of increasing solubility is the addition of a co-solvent to the

Modification
The solubility of poorly soluble nonelectrolytes can often be improved by the addition of cosolvents such as ethanol, propylene glycol, glycerin. Mechanism of cosolvent: These cosolvents solubilize drug molecules by disrupting the hydrophobic interactions of water at the nonpolar solute or water interface. Note: The more nonpolar solute, greater is the Solubilization achieved by cosolvent as compare to the more polar solute.

Modification
E.g. : Hydrocartisone (more polar) and Hydrcartisone 21-haptanoate (polar) in presence of Propylene glycol-water mixture (cosolvent). Some poorly soluble drugs can be solubilized in miceller solution such as 0.01M Tween 20 or molecular complexes with caffeine. Temperature : the heat of solution ( Hs), represent the heat released or absorbed when a mole of solute is dissolved in a large quantity of solvent. Most commonly, the solution process is

Solubility measurement
Analytical methods that are particularly useful for solubility measurement include HPLC, UV spectroscopy, fluorescence spectroscopy and gas chromatography.

pKa Determinations
The negative logarithm of the acid dissociation constant, Ka. Its also known as Dissociation constants. This is important because the extent of ionization has a major effect on the formulation and pharmacokinetic parameters of the drug. The amount of dissociation or ionization is highly dependent on the pH of the medium containing the drug. In formulation, often the vehicle is adjusted to a certain pH to obtain a certain level of ionization of the drug for solubility and

pKa Determinations
In the pharmacokinetic area, the extent of ionization of a drug has a strong effect on its extent of absorption, distribution, and elimination. Dissociation constant, or pKa, is usually determined by potentiometric titration. The Henderson Hasselbalach equation provides an estimate of the ionized and un-ionized drug concentration at a perticular pH . For acidic compounds: pH = pKa + log [ionized drug ]

pKa Determinations
For basic compounds: pH = pKa + log [unionized drug ] [ionized drug] pKa value can be determined by a variety of analytic methods. Buffer, ionic strength, and cosolvent affect the pKa value and should be controlled for these determinations. The preferred method is the detection of spectral shifts by ultraviolet (UV) or visible spectroscopy

Partition Coefficient

A partition- (P) or distribution coefficient (D) is the ratio of concentrations of a compound or solute in the two phases of a mixture of two immiscible solvents at equilibrium. The partition coefficient is a ratio of concentrations of un-ionized compound between the two solutions. Po/w= C equilibrium
oil

C water

To measure the partition coefficient of ionizable solutes, the pH of the aqueous phase is adjusted such that the predominant form of the compound is un-ionized. The

Applications
Pharmacology A drug's distribution coefficient strongly

affects how easily the drug can reach its intended target in the body, and how long it will remain in the body in an active form. Pharmacokinetics pharmacokinetics means that what the body does to a drug, the partition coefficient has a strong influence on ADME properties (A bsorption, Distribution, Metabolism, and E xcretion) of the drug.

Applications
Pharmacodynamics Pharmacodynamics means that what a drug

does to the body, the hydrophobic effect is the major driving force for the binding of drugs to their receptor targets.[5][6] On the other hand, hydrophobic drugs tend to be more toxic because they in general are retained longer, have a wider distribution within the body (e.g., intracellular), are somewhat less binding to proteins, and finally are often extensively metabolized. In some cases the metabolites may be chemically reactive. Hence it is advisable to make the

Measurement

Shake flask (or tube) method HPLC determination

Measurement

Thank you.

Thank you

Thank you