solubility, dissociation or ionization constant, partition coefficient in preformulation

7/27/2019 Solubility, Dissociation or Ionization Constant, Partition Coefficient in Preformulation

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DETERMINATIONOFSOLUBILITY,

DISSOCIATIONORIONIZATION

CONSTANT, PARTITIONCOEFFICIENTIN

PREFORMULATION


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Definition of solubility

Solubility is the mass of solute thatdissolves in a specific mass orvolume of solvent at a given

temperature. For example 1 gm ofNaCl dissolves in 2.786ml of water at25C.


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The solubility of drug is an

important physicochemicalproperty because it affects thebioavailability of the drug, the rateof drug release into the dissolution

medium, and consequently,thetherapeutic efficacy of thepharmaceutical product.


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Solubility of a drug can be

determined by two importantways:

1. intrinsic solubility of pure acid

the solubility of a weakly acidic drug in andacidic media is known as intrinsic solubilityof the drug.

2.Intrinsic solubility of pure base

the solubility of weakly basic drug in analkaline media is known as intrinsicsolubility of the drug.


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There are some importance of

solubility, such as:

Dissolution

Bioavailability

Rate of drug release by diffusion

Therapeutic efficacy


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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


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Definition of dissociation orionization constant (pKa)

pKa is a important determinant in thedetermination of solubility inpreformulation.

Definition:pKa is the pH of themedium at which 50% of the drugremain ionized and 50% of the drug

remain unionized.


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Acidic drug remains unionized inacidic media but readily ionized in

basic conditionBasic drug remains unionized inbasic media but readily ionized in

acidic condition.


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Degree of ionization depends up onthe pH.

for acidic drugs pKa ranges from 3-7.5 and for basic drugs pKa ranges from7-11.

For weakly acidic drug, the intrinsicsolubility will be lowest when the pHof the media is 2 unit below its pKavalue.

For a weakly basic drug, theintrinsic solubility will be lowest

when the pH of the media is 2 unitabove its pKa value.


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pKa Determination

Determination of the dissociationconstant for a drug capable ofionization within a pH range of 1to 10 is important since solubility,

and consequently absorption, canbe altered by orders of magnitudewith changing pH.


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The Henderson-Hasselbalch equationprovides an estimate of the ionized and un-ionized drug concentration at a particular

pHFor acidic compounds:pH = pKa + log ([ionized drug]/[un-ionized

drug])For basic compounds:

pH = pKa + log ([un-ionized drug]/[ionizeddrug])

pKa of a compound is thus a measure ofdrug un-ionized at a certain pH

pKa = -log Ka , where Ka is the acidity orionization 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


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Definition of partition co-efficient

It is the ratio of the concentrationof an unionized drug distributed

between an organic oil phase and

the concentration of that unionizeddrug in aqueous phase.(K=Co/Cw)

The value of partition co-efficient

in between 1-3 is called theoptimum level of absorption. It is

denoted as logP= (1-3)


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Importance of partition co-efficient

In drug solubility

In tissue permeability

Absorption potential

Bio-availability

Plasma protein binding

Tissue distribution

Absorption in renal or hepaticlayer


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According to the biopharmaceutics

classification system (BCS) the drugs

are divided into 4 classes based ontheir partition co-efficient value or

solubility and permeability:

Class 1:High permeability and highsolubility

Class 2:High permeability and lowsolubility

Class 3:High solubility and lowpermeability

Class 4:Low solubility and lowpermeability


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FDA center for drug evaluation andresearch gives also a classification

of drug according to the partitionco-efficient value of a drug:Highly soluble: When the highestdosage strength of a drug

substance is soluble in less than250ml of water over a pH rangeof 1-7.5.

Highly permeable: When the

extent of absorption in humans isdetermined to be more than 90%of an administered dose incomparison to an intravenous

reference dose.


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Rapidly dissolving: When morethan 85% of the labeled amount

of drug substance dissolveswithin 30 minutes using USPapparatus 1 or 2 in a volume of

less than 900ml of buffersolution.

solubility, dissociation or ionization constant, partition coefficient in preformulation

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