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
References Torchilin VP. Micellar nanocarriers:
pharmaceutical perspectives. Pharmaceutical Research 2007:24:1–16.
Chen H, Khemtong C, Yang X et al. Nanonization strategies for poorly water-soluble drugs. Drug Discovery Today 2011:16:354–60.