Definition of solubility
Solubility is the mass of solute that dissolves in a specific mass or volume of solvent at a given temperature. For example 1 gm of NaCl dissolves in 2.786ml of water at 25°C.

The solubility of drug is an important physicochemical property because it affects the bioavailability of the drug, the rate of drug release into the dissolution medium, and consequently,the therapeutic efficacy of the pharmaceutical product.

Solubility of a drug can be determined by two important ways:
1. intrinsic solubility of pure acid the solubility of a weakly acidic drug in and acidic media is known as intrinsic solubility of the drug. 2.Intrinsic solubility of pure base the solubility of weakly basic drug in an alkaline media is known as intrinsic solubility of the drug.

There are some importance of solubility, such as:  Dissolution  Bioavailability  Rate of drug release by diffusion  Therapeutic efficacy

How to improve solubility:  Addition of co-solvent eg, water, alcohol, glycerin.  Chemical modification of the drug  pH adjustment  Addition of surfactant eg, tween, span

Definition of dissociation or ionization constant (pKa)
pKa is a important determinant in the determination of solubility in preformulation. Definition:pKa is the pH of the medium at which 50% of the drug remain ionized and 50% of the drug remain unionized.

 Acidic

drug remains unionized in acidic media but readily ionized in basic condition  Basic drug remains unionized in basic media but readily ionized in acidic condition.

 Degree

the pH.

of ionization depends up on

 For

weakly acidic drug, the intrinsic solubility will be lowest when the pH of the media is 2 unit below its pKa value.  For a weakly basic drug, the intrinsic solubility will be lowest when the pH of the media is 2 unit above its pKa value.

for acidic drugs pKa ranges from 37.5 and for basic drugs pKa ranges from 7-11.

pKa Determination
Determination of the dissociation constant for a drug capable of ionization within a pH range of 1 to 10 is important since solubility, and consequently absorption, can be altered by orders of magnitude with changing pH.

The Henderson-Hasselbalch equation provides an estimate of the ionized and unionized drug concentration at a particular pH For acidic compounds: pH = pKa + log ([ionized drug]/[un-ionized drug]) For basic compounds: pH = pKa + log ([un-ionized drug]/[ionized drug]) pKa of a compound is thus a measure of drug un-ionized at a certain pH pKa = -log Ka , where Ka is the acidity or ionization constant of a weak acid. For a weak base, Ka = Kw/Kb, where Kw is the ionic product of water (Kw= [H3O+] x [OH-]) and Kb is the basicity or ionization constant of the weak

Definition of partition coefficient
It is the ratio of the concentration of an unionized drug distributed between an organic oil phase and the concentration of that unionized drug in aqueous phase.(K=Co/Cw) The value of partition co-efficient in between 1-3 is called the optimum level of absorption. It is denoted as logP= (1-3)

Importance of partition coefficient
 In

drug solubility  In tissue permeability  Absorption potential  Bio-availability  Plasma protein binding  Tissue distribution  Absorption in renal or hepatic layer

According to the biopharmaceutics classification system (BCS) the drugs are divided into 4 classes based on their partition co-efficient value or solubility and permeability:  Class 1:High permeability and high solubility  Class 2:High permeability and low solubility  Class 3:High solubility and low permeability  Class 4:Low solubility and low permeability

FDA center for drug evaluation and research gives also a classification of drug according to the partition co-efficient value of a drug:  Highly soluble: When the highest dosage strength of a drug substance is soluble in less than 250ml of water over a pH range of 1-7.5.  Highly permeable: When the extent of absorption in humans is determined to be more than 90% of an administered dose in comparison to an intravenous reference dose.

 Rapidly

dissolving: When more than 85% of the labeled amount of drug substance dissolves within 30 minutes using USP apparatus 1 or 2 in a volume of less than 900ml of buffer solution.

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