PRESENTED BY:

K.SAI VANI

256213886014M.PHARM (PHARMACEUTICS)

GUIDED BY:

Mrs. Yasmin Begum

M.pharm

DEFINITION:

The term ‘solubility’ is defined as maximum amount of

solute that can be dissolved in a given amount solvent.

Solute is the substance being

dissolved – powder

Solvent is the dissolving agent –

water

Solubility can also be defined quantitatively as well as qualitatively.

Quantitatively it is defined as the concentration of the solute

in a saturated solution at a certain temparature.

Qualitatively it may be defined as the spontaneous

interaction of two or more substances to form a homogenous molecular dispersion.

A saturated solution is one in which the solute is in equilibrium with solvent.

The solubility of drug is represented through various concentration expression such as parts,percentage,molarity,molality,volume fraction,mole fraction

Solubility is one of the important parameters to achieve desired

concentration of drug in systemic circulation for achieving required

pharmacological response.

These poorly water soluble drugs having slow drug absorption leads to

inadequate and variable bioavailability and gastrointestinal mucosal

toxicity.

Most of the drugs(>40%) belongs to BCS class II (low solubility and

high permeability).

As for BCS class II drugs rate limiting step is drug release from the

dosage form and solubility in the gastric fluid, so increasing the solubility

in turn increases the bioavailability for BCS class II drugs.

Solubility improvement techniques can be categorizedinto physical modification, chemical modifications of thedrug substance, and other techniques.

Physical Modifications —Particle size reduction likemicronization and nano-suspension, modification of thecrystal habit like polymorphs, amorphous form and co-crystallization, drug dispersion in carriers like eutecticmixtures, solid dispersions and solid solutions.

Chemical Modifications —Change of pH, use of buffer,derivatization, complexation, and salt formation.

Miscellaneous Methods —Supercritical fluid process, useof adjuvant like surfactant, solubilizers,cosolvency,hydrotropy etc.

Step 1 Step2 Step 3

Holes open in the

solventMolecules of the solid

breaks away from

the bulk

The freed solid

molecule is integrated

into the hole in the

solvent

MICELLAR SOLUBILIZATION:

Micellar solubilizatiion:

Surfactants can lower surface tension & improve the

dissolution of lipophilic drugs in the aqueous medium.

When the concentration of surfactants exceeds their

critical micelle concentration (CMC, which is in a

range of 0.05-0.10% for most surfactants), micelle

formation occurs,entrapping the drugs within the

micelles.

This process is known as micellisation and generally

results in enhanced solubility of poorly soluble drugs.

Micellar solubilization is a powerful alternative fordissolving hydrophobic drugs in aqueousenvironments.

Surfactants are known to play a vital role in manyprocesses of interest in both fundamental and appliedscience.

One important property of surfactants is the formationof colloidal-sized clusters in solutions, known asmicelles, which have particular significance inpharmacy because of their ability to increase thesolubility of sparingly soluble substances in water

Micelles are known to have an anisotropic water

distribution within their structure

Micellar systems can solubilize poorly soluble drugs and

thus increase their bioavailability

Surfactants are amphiphilic molecules composed of a

hydrophilic or polar moiety known as head and a hydrophobic

or nonpolar moiety known as tail.

The surfactant head can be charged (anionic or cationic),

dipolar (zwitterionic), or non-charged (nonionic).

Ex: SDS, DTAB, Ethylene oxide, dioctanoyl phosphatidyl

choline etc.

The surfactant tail is usually a long chain hydrocarbon residue

and less often a halogenated or oxygenated hydrocarbon or

siloxane chain.

A surfactant, when present at low concentrations in a system,

adsorbs onto surfaces or interfaces significantly changing the

surface or interfacial free energy

Surfactants usually act to reduce the interfacial free energy,

although there are occasions when they are used to increase it.

When surfactant molecules are dissolved in water at

concentrations above the critical micelle concentration (cmc),

they form aggregates known as micelles.

In a micelle, the hydrophobic tails flock to the interior in order

to minimize their contact with water, and the hydrophilic heads

remain on the outer surface in order to maximize their contact

with water.

The micellization process in water results from a delicate balance of intermolecular forces, including hydrophobic, steric, electrostatic, hydrogen bonding, and van der Waals interactions.

The determination of a surfactant cmc can be made by use of several physical properties, such as surface tension(γ), conductivity (κ) – in case of ionic surfactants, osmotic pressure (π), detergency, etc.

When these properties are plotted as a function of surfactant concentration (or its logarithm, in case of surface tension), a sharp break can be observed in the curves obtained evidencing the formation of micelles at that point

Another important parameter that characterizes micelles is the

aggregation number, Nag, that corresponds to the average

number of surfactant monomers in each micelle of a micellar

solution.

Micelles are labile entities formed by the noncovalent

aggregation of individual surfactant monomers. Therefore, they

can be spherical, cylindrical, or planar (discs or bilayers).

Micelle shape and size can be controlled by changing the

surfactant chemical structure as well as by varying solution

conditions such as temperature, overall surfactant

concentration, surfactant composition (in the case of mixed

surfactant systems), ionic strength and pH

An important property of micelles that has particular significance in pharmacy is their ability to increase the solubility of sparingly soluble substances in water.

Solubilization can be defined as the spontaneous dissolving of a substance by reversible interaction with the micelles of a surfactant in water to form a thermodynamically stable isotropic solution with reduced thermodynamic activity of the solubilized material.

From the thermodynamic point of view, the solubilization canbe considered as a normal partitioning of the drug between twophases, micelle and aqueous, and the standard free energy ofsolubilization (ΔGS º) can be represented by the followingexpression

ΔGS º= -RTlnP

where R is the universal constant of the gases, T is theabsolute temperature, and P is the partition coefficient betweenthe micelle and the aqueous phase.

Usually, the solubilization of a molecule by a surfactant can beevaluated based on two descriptors that are the molarsolubilization capacity, χ, and the micelle water partitioncoefficient, P

The χ value is defined as the number of moles of the solute

(drug) that can be solubilized by one mol of micellar surfactant,

and characterizes the ability of the surfactant to solubilize the

drug.

Where Stot is the total drug solubility, SW is the water drug

solubility, Csurf is the molar concentration of surfactant in

solution, and cmc is the critical micelle concentration.

The micelle-water partition coefficient is the ratio of drug

concentration in the micelle to the drug concentration in water

for a particular surfactant concentration, as follows:

Combining Equations we can relate the two solubility descriptors. Accordingly, for a given surfactant concentration

As can be seen, P is related to the water solubility of thecompound, in contrary to χ . In order to eliminate thedependence of P on the surfactant concentration, a molarmicelle-water partition coefficient (PM), corresponding to thepartition coefficient when Csurf = 1 M, can be defined asfollows

The lower is the cmc value of a given surfactant, the more stable are the micelles.

Hydrophilic drugs can be adsorbed on the surface of the micelle.

Drugs with intermediate Solubility should be located in intermediate positions within the micelle such as between the hydrophilic head group of Peo Micelles

In the Palisade Layer between the hydrophilic group and the first few carbon atoms of the hydrophobic group , that is the outer core.

Completely insoluble hydrophobic drugs may be located in the Inner Core of the micelle.

Examples of poorly soluble compounds that

use micellar solubilization are

Anti-diabetic drugs,

Gliclazide,

Glipizide,

Gluburide,

Glimepride,

Repaglinide,

Pioglitazone,and

Rosiglitazone.

INTRODUCTION:

The term Hydrotropic agent was first introduced by Neuberg(1916)

to designate anionic organic salts.

Hydrotropy is defined as a solubilisation process where by addition

of a large amount of second solute results in an increase in the

aqueous solubility of another solute and the chemicals which are

used in hydrotropy are called hydrotropes.

Ex: sodium benzoate, urea, sodium salicylate, ibuprofen sodium etc.

The chemical structure of the conventional Neuberg’s hydrotropic

salts consists of two essential parts, an anionic group and a

hydrotropic aromatic ring or ring system.

Hydrotropic agents are ionic organic salts.

Additives or salts that increase solubility in given solvent are

said to “salt in” the solute & those salts that decrease solubility

“salt out ” the solute.

Several salts with large anions or cations that are themselves

very soluble in water result in “salting in” of non electrolytes

called “hydrotropic salts” a phenomenon known as

“hydrotropism”.

Hydrotropic solutions do not show colloidal properties and

involve a weak interaction between the hydrotropic agent and

solute.

A hydrotrope is a compound that solubilises

hydrophobic compounds in aqueous solutions.

Typically, hydrotropes consist of a hydrophilic part and

a hydrophobic part, but hydrophobic part is too small

to cause self aggregation.

Hydrotropes do not have a critical concentration above

which self aggregation 'suddenly' starts to occur.

Ex: Paracetamol with urea as hydrotropic agent.

The more is the concentration of hydrotrope, more is the aqueous solubility

of poorly water-soluble drugs. Distilled water was used in making

hydrotropic solutions.

To select suitable hydrotropes for various poorly water soluble drugs

following method is used.(approx solubility can be determined)

25ml of H2O/Hydrotropic soln 50ml beaker Gross weight was

noted.(1)

Gross weight is same operation is Add drug and shake

noted (2) continued till excess

drug remain undissolved.

From the difference in two readings, solubility was determined.

Hydrotropic solubilisation study of various

poorly water soluble drugs:

DRUG HYDROTROPIC AGENT

Cefprozil Potassium acetate, Potassium

citrate, Sodium acetate, Sodium

citrate, Urea

Hydrochlorothiazide Sodium acetate, urea

Paracetamol, Diclofenac

sodium

urea

Theophylline Sodium salicylate

Salicylic acid Ibuprofen sodium, sodium

salicylate

Furesamide Ibuprofen sodium

Chlorpropamide,

Gatifloxacin

Ibuprofen sodium

Nifedipine Sodium salicylate

ketoprofen Urea, sodium salicylate.

The determination of interference of hydrotropic agents inthe spectrophotometric estimation of the standardsolutions of drugs were determined in distilled water aloneand in the presence of the maximum concentration of thehydrotropic agent employed for spectrophotometricanalysis.

The absorbances were recorded against respective reagent blanks at appropriate wavelengths

Enhancement ratios can be determined by the formula

Enhancement ratio = solubility in hydrotropic solution/ solubility in distilled water.

Hydrotropy is suggested to be superior to other

solubilization method, such as miscibility, micellar

solubilization, co solvency and salting in, because the

solvent character is independent of pH, has high

selectivity and does not require emulsification

It only requires mixing the drug with the hydrotrope in

water.

It does not require chemical modification of

hydrophobic drugs, use of organic solvents, or

preparation of emulsion system

Mixed hydrotropic solubilization technique is the

phenomenon to increase the solubility of poorly water-

soluble drugs in the blends of hydrotropic agents which

may give miraculous synergistic enhancement effect on

solubility of poorly water soluble drugs.

Utilization of it in the formulation of dosage forms of

water insoluble drugs and to reduce concentration of

individual hydrotropic agent to minimize the side

effects.

It may reduce the large total concentration of hydrotropic

agents necessary to produce modest increase in solubility by

employing combination of agents in lower concentration.

It is new, simple, cost-effective, safe, accurate, precise and

environmental friendly method for the analysis (titrimetric

and spectrophotometric) of poorly water-soluble drugs

titrimetric and spectrophotometric precluding the use of

organic solvents.

It precludes the use of organic solvents and thus avoids the

problem of residual toxicity, error due to volatility,

pollution, cost etc

Quantitative estimations of poorly watersoluble drugs

by UV-Visible spectrophotometric analysis precluding

the use of organic solvents.

Quantitative estimations of poorly watersoluble drugs

by titrimetric analysis.such as ibuprofen, flurbiprofen

and naproxen using sodium benzoate[29] .

Preparation of hydrotropic solid dispersions of poorly

water-soluble drugs precluding the use of organic

solvents. Such as felodipine[30] using poly ethylene

glycol 6000 and poly-vinyl alcohol.

Preparation of injection of poorly water soluble drugs.

The use of hydrotropic solubilizers as permeation enhancers.

The use of hydrotropy to give fast release of poorly water-

soluble drugs from the suppositories.

Application of mixed- hydrotropy to develop injection dosage

forms of poorly water-soluble drugs.

Application of hydrotropic solubilization in nanotechnology

(by controlled precipitation).

Application of hydrotropic solubilization in extraction of active

constituents from crude drugs (in pharmacognosy field).

Hydrotropic solutions can also be tried to develop the

dissolution fluids to carry out the dissolution studies of dosage

forms of poorly water soluble drugs.

Solubility of the drug is the most important factor that controls the formulation of the drug as well as. Therapeutic efficacy of the drug, hence the most critical factor in the formulation development.

The various techniques described above alone or in combination can be used to enhance the solubility of the drug

Because of solubility problem of many drugs the bioavailability of them gets affected and hence solubility enhancement becomes necessary.

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Journal of drug delivery & therapeutics

2012,Md.Ali sajid.

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research, vol3, issue2, apr-jun2011

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