Physicochemical, parameters in relation to biological activity || Pharma...

Introduction

The biological activity of a targeted drug molecule is solely dependent on its physicochemical characteristic essentially (NTS)

Nature &

Types of functional moieties

and also the Spatial arrangement of such group in the molecule

[Note: Spatial arrangement of atoms concern how different atomic particles and molecules are situated about in the space around the organic compound namely its carbon chain, each with their unique placement of atoms in 3-dimensional space]

Following introduction in the body

The drug must pass through many barriers before it reaches the site of action usually a receptor or cell.

How the drug is Transported

Distributed throughout the body compartment

Metabolic alteration

Excretion

Physiochemical or bio-distribution parameters

1. S Solubility
2. D Dissociation constant
3. H Hydrogen bonding
4. C Chelation
5. O Oxidation-Reduction potential &
6. S Surface activity

2. Physical Properties

1. Solubility
2. For most drugs the first step in the process of entering the body from a formulation is dissolution.

An important factor for oral absorption

S 1. Sufficient solubility

M 2. Membrane permeability

The measurement of aqueous solubility depends upon the following facts

(i) Buffer & ionic strength (salting out)

(ii) Polymorphism and purity of the sample

(iii) pH

(iv) Supersaturation

(v) Thermodynamic Vs Kinetic solubility

In certain sending homologous series of synthesized analogs, a correlation between bioactivity and length of alkyl chain has been observed For example

(i) in a series of esters 4- aminobenzoic acid, the length of the alkyl chain is proportional to local anesthetic activity.

(ii) in a series of alkylated resorcinol, the length of the alkyl chain is proportional to the antibacterial activity.

In ascending homologous series the physio-chemical property likes

Boiling points, Viscosity, Surface activity, Partition coefficient Increases whereas aqueous solubility decreases.

The point at which maximum bioactivity is found is called the cut off point. Carbon chain increases and antibacterial activity also increases due to the increase in partition coefficient.

2. Partition co-efficient

• The ability of a drug to dissolve in the lipid phase is referred to as lipophilicity.
• The highly water-soluble drug can not penetrate organs rich in lipids such as the brain and other neural tissue.
• [Influencing the drug reaches the site of action from the site of application.
• Since the blood distributes the drug they must penetrate and transverse many cells to reach the site of action.
• Partition coefficient can be defined as the equilibrium constant of drug concentration for a molecule in two phases.

• Since partition coefficients are difficult to measure in a living system they are usually determined in vitro using 1- octanol as a lipid phase and phosphate buffer of pH 7.4 as the aqueous phase.
• The Partition coefficient, P is dimensionless and its logarithm (logP) is widely used as the measure of lipophilicity.

The log P is measured by the following method-

(1) Shake flask method

• A weighed the amount of the substance shaken in a flask containing a measured amount of buffer pH-7.4 or water n-octanol.
• The amount of chemical in one or both the phase is determined by appropriate analytical technique and the partition coefficient is calculated.
• The method is tedious, time-consuming, messy, and smelly but is the only method that can be used in case of a very low log P-value.

(2) Chromatographic method (HPLC)

• Compounds with known log P values are injected into the C-18 reverse phase HPLC column to create a calibration curve, unknown compounds are then injected to predict log P.
• Disadvantage- retention time is linearly related to the partition coefficient for doubling of log P there is a ten-fold increase in the retention.
• This often requires different length columns to be used short ones for high log P and long ones for low values.

2.3 Ionization and pKa value

• Most of the drugs are either weak acids or bases and can exist in either ionized or unionized states.
• The ionization of the drug depends on its pKa and pH.
• The rate of drug absorption in the biological fluids is not proportional to the concentration of the drug at the absorption site but rather to the concentration of the absorbable form of the drug.
• For example - Aspirin in the stomach will be more than 99 percent unionized and hence it gets more readily absorbed in the stomach.
• Same way if we take barbituric acid and 5,5 unsubstituted barbituric acid, the latter has CNS depressant action and the former is inactive.
• This is because at the physiological action barbituric acid is a strong acid and 90 percent of exists in ionic form, so it can not penetrate the lipoidal membrane, But as 5,5 unsubstituted acids are weak acids only 50 percent exist in ionized form and it is capable of crossing the lipoidal membrane of the CNS.
• Acids can be divided into two type HA and BH+ on the basis of the ionic form HA acids include

Organic acid

enol

barbiturate

hydantoin

carboxylic acids

amides

imides

BH+ protonated amines

According to lewis acid-base theory

Those drugs in an ionized form will tend to distribute throughout the body more than the unionized molecule.

In general, drugs pass through the non-polar membrane of capillary walls, cell membrane, and blood brain barrier in unionized form.HA acid is the parent acid that will readily cross the membranes.

2.4 Hydrogen bonding

• Hydrogen bonding is a type of dipole-dipole interaction between non-bonding electron pairs of heteroatoms like N, S, O, and electron-deficient hydrogen atom in polar bonds such as Oh, NH F, etc.
• These are weak bonds (10 kcal/mol) and denoted as dotted lines.

Generally, hydrogen bonding is classified into two types.

1. Intermolecular hydrogen bonding
2. Intramolecular hydrogen bonding

1. Intermolecular hydrogen bonding

Hydrogen bonding occurs between two or more molecules.

2. Intramolecular hydrogen bonding

Hydrogen bonding occurs within the molecules

2.5 Surface activity

• A surfactant is defined as a material that can reduce the surface tension of water at a low concentration.
• These molecular aggregates are called miscelle, which entrap the drug molecule in their hydrophobic core; result in the retardation of the rate of absorption.
• At lower concentration the surfactant enhances the absorption rate; the same in higher concentration reduce the absorption rate.