MICELLIZATION AND THEIR PHARMACEUTICAL APPLICATIONS

ByMaria Shuaib

Contents Introduction to micelles Process of micellization Factors affecting micellization Critical micelle concentration (CMC) Factors affecting CMC Determination of CMC Thermodynamic aspects Pharmaceutical applications

Micelle

A micelle is an electrically charged particle formed by an aggregate of

molecules, above a critical concentration and occurring in certain colloidal

electrolyte solutions, especially those of soaps and detergents.

Micelle

A micelle is an aggregate of surfactant

molecules dispersed in a liquid colloid.

The process of forming micelle is known as micellization.

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Introduction

In dilute solution Amphiphiles tend to reduce Surface tension

As concentration molecules of amphiphiles goes on increasing they disturb hydrogen structure, to minimize the disturbance molecules tend to form aggregate into a structure

Structure called as micelle and Amphiphilic molecule Surface Active Agent

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PHYSICOCHEMICAL BACKGROUND

cohesive forces between molecules down into liquid

the intermolecular attractive forces is called surface tension

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Micelle formation

•Typical micelle is Spherical in structure which contain 50-100 monomers •Number of monomers to form micelle is called as aggregation number

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• A micelle is an aggregate of monomer surfactant molecules dispersed in a liquid colloid.• Hydrophilic "head" regions in contact withsurrounding solvent, sequestering the hydrophobic tail regions in the micelle centre. (oil-in-water micelle). • Inverse micelles have the head groups at the centre with the tails extending out (water-in-oil micelle).

Micelle

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SAA bulk Concentration

Surface excess

Surface saturated with SAA

Excess in the bulk

Micelles( colloidal aggregates)

Oil in water type

Because of arrangement monomers micelle is capable to hold lipidic nature drug at centre

Water in oil type

In Reversed micelle at middle able to hold relatively large amounts of water in their interior. In that way, a "pocket" is formed which is particularly suited for the dissolution and transportation of polar solutes through a non polar solvent.

Factors affecting process of micelles formation

Molecular wt. of monomer Aggregation no. Proportion of hydrophobic and hydrophilic

chain length Preparation process CMC

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Critical micelle concentration (CMC)

The lowest concentration at which micelles first appear is called the critical concentration for micelle formation

The critical micelle concentration is the point at which surfactant molecules aggregate together in the liquid to form groups known as micelles.

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The critical micelle concentration of a surfactant indicates the point at which surface active properties are at an optimum and performance is maximised.

The CMC is the concentration above surfactant when micelles will form spontaneously.

Increase in concentration of surfactant beyond CMC change number size or shape but not provide increase in concentration of monomeric species

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Determination of the CMC

Micelles are formed at the critical micelle

concentration (CMC), which is detected as an inflection point in physical properties which are plotted as a function of concentration.

• surface tension, • Conductivity, • Turbidity, • Osmotic Pressure

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1. At very low concentrations of surfactant only slight change in surface tension is detected.

2. Additional surfactant decreases surface tension

3.Surface becomes fully loaded, no further change in surface tension.

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Factors Affecting CMC Structure of hydrophobic group. –length of hydrocarbon chain is

Micelle size CMC

Addition of Electrolyte Micelle Size CMC

Effect of Temperature up to cloud point Micelle Size CMC

Thermodynamic aspect

The formation of micelle can be understood using thermodynamics: micelles can form spontaneously

because of balance between entropy and enthalpy

For ionic surfactants, the solubility of a material will often be observed to undergo a sharp, discontinuous increase at some characteristic temperature, commonly referred to as the Krafft temperature, Tk.

A surfactant, when present at low concentrations in a system, adsorbs onto surfaces or interfaces significantly changing the surface or interfacial free energy

Primary reason of micelle formation is attainment of minimal free energy

Free energy change ∆G depend upon both Etropy,S and Enthlpy H at temperature T

∆G= ∆H-T∆S (T∆S is 90-95% value of ∆G)

Pharmaceutical Applications

Micelles are an important factor of pharmaceutical chemistry and have a

number of applications which give them great importance in delivering medicines to patients, or to specific locations within

the patient

Solubilization

Micelle can be used to increase the solubility of material that are normally insoluble or poorly soluble in dispersed

medium phenomenon called as solubilization

Solubilization

Solubilization 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 introduction of an additional amphiphilic component or

components.

Solubilization by micelles

The location of a solubilized molecule in a micelle is determined primarily by the chemical structure of the solubilizate.

Solubilization can occur at a number of different sites in a micelle

1. On the surface, at the micelle–solvent interface,

2. At the surface and between the hydrophilic head groups,

3. In the palisades layer, i.e., between the hydrophilic groups and the first few carbon atoms of the hydrophobic groups that comprises the outer regions of the micelle core.

4. More deeply in the palisades layer, and in the micelle inner core.

Hydrophilic drugs can be adsorbed on the surface of micelle

Drugs with intermediate Solubility should be located in intermediate positions within the micelle such as between the hydrophilic head group of Peo MicellesCompletely insoluble hydrophobic drugs may be located in the Inner Core of the micelle.

Examples

1. Polar alcohols are soluble in aqueous solution, so it located in solution / on surface of micelle.

2. Phenol are having polar –OH group and non polar benzene ring. In which –OH gr. Located in hydrophilic environment and benzene ring in hydrophobic environment, so it located at the surface and between the hydrophilic head groups.

3. Semi polar materials, such as fatty acids are usually located in the palisades layer, the depth of penetration depending on the ratio of polar to non-polar structures in the solubilisate molecule.

4. Non-polar additives such as hydrocarbons tend to be intimately associated with the hydrocarbon core of the micelle.

Example of improved solubility of drugs using polymeric micellar system

DRUG AMPHIPHILIC POLYMER COMENT

Camptothesin Pluronic p-105,d-tocopherol

Peg 1000 succinate

Increased micellar stability & bioavailabilityIncreased cytotoxicity

Docetaxel Polyethylene oxide-b-polystyrene oxide Increased solubility

Griseofulvin

Pacletaxel

EmBn (E-oxyethylene,B-oxybutylene)

N-octyl-o-sulfate chitosan

Solubilization independent of B block length, when it exceeds about 15B unitsImproved bioavailability & reduce cytotoxicity

Drug Protection

   Protection of drug molecules from degradation via hydrolysis or other physicochemical reactions — this

increases their shelf life, or prolongs their stability during use.

Targeted Drug Delivery

Micelles may have an increasingly important role as carriers of drug molecules to target sites, for example, delivering doxorubicin to a tumour.

Polymeric micelles, self-assembling nano-constructs of amphiphilic copolymers, are widely considered as convenient nano-carriers for a variety of applications, such as diagnostic imaging, and drug and gene delivery.

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Conclusion

By using Phenomenon of micellization we improve solubility of API

Considering factor of CMC we modify micelle size Shape & release profile

Conclusion

Applying this knowledge in field of Pharmacy Improve API stability Maintain Bioavailability long period Research is continued in Targeted DDS

(Cancer)

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References A. N. Martin, Martin's Physical Pharmacy and

Pharmaceutical Sciences, 6th edition, p. M.E. Aulton, Pharmaceutics science of

dosage form design, 2nd Edition, p. 88-89 Leon Lachman, The Theory and Practice of

Industrial Pharmacy, 3rd edition, p. 106 H.A. Liebereman, M.M. Rieger, G.S. Banker,

Pharmaceutical Dosage Forms: Disperse Systems,2nd Edition, Vol.3, p. 216-220

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Sanjay K. Jain, Vandana Soni, Benley’s Text Book of Pharmaceutics, p.68-74

Ram I. Mahato Pharmaceutical Dosage Forms and Drug Delivery,CRC press pharmacy education series, p.111-119

Nita K. Pandit & Robert R. Soltis, Introduction to the Pharmacetical Sciences 2nd Edition, p.54-55

Online Referencehttp://www.biolinscientific.com/attension/

applications/?card=AA8

References

Martins physical pharmacy & pharmacuetical sciences maryland USA lippincott williams & wilkins:2007 pg no. 469-97

Moroi y.micelles: theorotical &applied aspects springer international ed. New york:springer:2005 pg no.41-50

Jones mc ,leroux jc polymeric micelles: a new generation of colloidal drug carriers. Eur j pharm biopharm 1999 pg no.101-11

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