SOLUBILIZATION & METHOD OF SOLUBILIZATION

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SOLUBILITY It can be defined quantitatively as the conc. of solute

in a saturated solution at a certain temperature, and qualitatively as the spontaneous interaction of two or more substances to form a homogenous molecular dispersion It can also be defined as the molecular dispersion of solute in the solvent.

Importance of solubility: It is an important physico-chemical property of the

drug, It is an important parameter to achieve desired

concentration in systemic circulation . Solubility behavior of the drug is a one of the

important aspects of preformulation testing for poorly soluble drug

EXPRESSION FOR APPROXIMATE SOLUBILITY

Descriptive terms Relative amounts of solvents to dissolve 1 part of solute

Very soluble Less than 1

Freely soluble From 1-10

Soluble From 10-30

Sparingly soluble From 30-100

Slightly soluble From 100-1000

Very slightly soluble From 1000-10,000

Insoluble or practically insoluble

More than 10,000

PROBLEMS WITH POOR SOLUBILITY: Reduced drug efficiency Reduced absorption of drug May cause side effects

SOLUBILIZATION It can be defined as the preparation of a

thermodynamically stable isotropic solution of a substance normally insoluble or very slightly soluble in a given solvent by the addition of component or components or by any suitable methods

PROCESS OF SOLUBILIZATION1) Breaking of inter-ionic or inter–molecular

bonds in the solute2) Separation of solute molecules to provide

space for the solute3) Interaction between the solvent and solute

molecule or ion a) Molecules of solids break away from bulkb) Separation of solvent molecules c) Freed solid molecules is integrated into the

holes of solvent molecule

SOLUBILIZATION TECHNIQUES- CO-SOLVENCY

Substances like weak electrolytes and non-polar molecules are poorly soluble in water .

The solubility of these substances can be enhanced by the addition of water miscible solvents in which the drug has good solubility.

This process of improving solubility is called as co-solvency and the solvents used are known as co-solvents.

This technique is mainly used in the formulation of parenterals.

Commonly used co-solvents are Ethanol, Sorbitol, Glycerin, Polyethylene glycol, propylene glycol etc.

The solubilizing effect by co-solvency is depends on the polarity of the drug with respect to solvent and co-solvent. That means more non-polar the solute the greater is the solubilization achieved by the added solvents

• Mechanism responsible for solubility enhancement through co-solvency is by reducing the interfacial tension the predominantly aqueous solution and hydrophobic solutes and reduces the contact angle between the solid and liquid• Co-solvents increases the solubility by reducing the difference between the polarity of the drug and water sustem Ex. For co-solvency The solubility of diazepam can be increased by using 10% ethanol and 40% propylene glycol. Phenobarbitone is relatively insoluble in water but it solubility can be increased by using mixture of solvents like water, alcohol and glycerin

ADDITION OF SURFACTANTS

Surfactants are very useful as absorption enhancers and enhance both dissolution rate as well as permeability of the drug .

Surfactants act by reducing the surface tension and forms colloidal aggregates known as micelles. Micelles are formed at CMC .

Ability of a surfactant solution to dissolve or solubilise water insoluble materials starts at CMC and increases with increase in conc. of micelles .

Lipophilic surfactants with HLB value higher than 15 are best solubilising agents Concentration of surfactant must be controlled very less conc.

Improper solubilization very high conc. Affect on bioavailability

SOLID DISPERSION TECHNIQUE It is the dispersion of one or more active ingredients

in an inert carrier or matrix in solid state prepared by fusion or melting-solvent method.

It is the dispersion of a drug or drugs in solid diluent or diluents. Solid dispersions may also be called “ solid state dispersions”. Solid dispersion provides particle size reduction and increased rates of dissolution

Various systems of solid dispersions:1) Simple eutectic mixtures 2) Solid solutions 3) Glass solution and glass suspension 4) Amorphous precipitation of drug in crystalline carrier5) Compound or complex formation between drug and

carrier6) Any combination among the above

COMPLEXATION

It is reversible association of a substrate and ligand molecule.

The most common complexing ligands are cyclodextrins, caffeine, urea, polyethylene glycol, N methylglucamide.

cyclodextrin are unique since they increase the water solubility of poorly soluble drugs by fitting them into the hydrophobic cavity of the cyclodextrin molecule.

These cyclodextrins have the ability to form molecular inclusion complexes with hydrophobic drugs having poor aqueous solubility.

CHANGING TEMPERATURE The solubility of a solute or solid in a liquid is

dependent on temperature, nature of solute and nature of solvent

∆Hs( heat of solution) represents the heat released or absorbed when a mole of solute is dissolved in a large amount of solvent

If the solution process is endothermic, increase in temperature increases the solubility of the solute

And if the solution process is exothermic, increase in temperature decreases the solubility of the solute

HYDROTROPHY Addition of large amount of a second solute results in an

increase in the aqueous solubility of another solute. Concentrated aqueous hydrotropic solutions of sodium

benzoate, sodium salicylate, urea, nicotinamide, sodium citrate and sodium acetate have been observed to enhance the aqueous solubilities of many poorly water-soluble drugs.

Advantages:

1. Hydrotropy is suggested to be superior to other Solubilization method, such as miscibility, micellar Solubilization, cosolvency and salting in, because the solvent character is independent of pH, has high selectivity and does not require emulsification

2. It only requires mixing the drug with the hydrotrope in water.

3. It does not require chemical modification of hydrophobic drugs, use of organic solvents, or preparation of emulsion system

Drug Hydrotropic agent

Riboflavin ProcaineHCl , PABAHCl , CinchocaineHCl , Resorcinol, Pyrogallol

Chartreusin Sodium benzoate, Sodium p hydroxybenzoate , Sodium m- hydroxybenzoate , Sodium o- hydroxybenzoate , Sodium 2,4-dihydroxybenzoate, Sodium 2,5-dihydroxybenzoate, Sodium 2,6-dihydroxybenzoate, Sodium 2,4, 6-trihydroxybenzoate

Diazepam, Medazepam , Oxazepam , Nitrazepam , Clonazepam

Sodium salicylate

SOLID STATE MANIPULATIONS Polymorphic modifications Solubility of each form depends upon the ability of

the molecules to escape from the crystal to solvent. The stable form posses the lower free energy at a

particular temperature and therefore has the lower solubility or escaping tendency where as the meta stable forms posses higher free energy hence has higher solubility.

About fifty to hundred percent increase in the dissolution rate can be achieved through polymorphic modifications.

Examples: Chloramphenicol palmitate (form B) Methyl prednisolone (form 2)

Chlor tetracycline (form B)

NON CRYSTALLINE SOLUTES (AMORPHOUS)

As the term implies they will not contain internal crystal lattice structure.

These are thermodynamically unstable. Amorphous solid forms give faster dissolution rates

and higher solubility than polymorphic modifications. Eg : Novobiocin Thus, the order for dissolution of different solid forms of

drug is Amorphous > Metastable >Stable

SOLVATES (PSEUDO POLYMORPHISM )  The recrystallization of many drug substances

from solution will results in the formation of solids containing solvent molecules as an integral part of their crystal structure. Majority of these crystalline materials referred as pseudo polymorphs, contain stoichiometric amount of solvent.

Anhydrates > hydrates Organic solvates > organic non-

solvates Enhances the solubility of drug markedly. Examples: Pentanol solvates of fludrocortisone

Chloroform solvates of griseofulvin Cephalexin hydrate

Salt formation Salts have improved solubility and dissolution characteristics in comparison to the original drug. Alkali metal salts of acidic drugs like penicillin and strong acid salts of basic drugs like atropine are water-soluble than the parent drug.

Precipitation: In this method, the poorly aqueous soluble drug is dissolved in a suitable organic solvent followed by its rapid mixing with a non-solvent to effect precipitation of drug in nano size particles. The product so prepared is also called as hydrosol. Ex. Cyclosporine

Other techniques •Micronization •Nanonisation• Supercritical Fluid Recrystallization• Spray freezing into liquid and lyophilization •Evaporative precipitation into aqueous solution •Use of precipitation inhibitors•Selective Adsorption on Insoluble Carriers •Solvent Deposition• Drug derivatisation

Conclusion The aqueous solubility of drug is often a limiting factor in developing most desirable dosage form. A highly solubilized formulation is highly desired to minimize dissolution limited absorption .Often, these early stage formulations become the backbone for the later stage commercial formulations. But still there has been a lot of research going on in this topic and many newer and advanced methods are used to enhance the solubility of the drug.