Micellization and their pharmaceutical applications

micellization process and its applications in pharmaceuticals

1. Micellization and their Pharmaceutical Applications By Maria Shuaib

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

3. 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.

4. Micelle A micelle is an aggregate of surfactant molecules dispersed in a liquid colloid. The process of forming micelle is known as micellization.

5. I ntroduction 5 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

6. PHYSICOCHEMICAL BACKGROUND 6 cohesive forces between molecules down into liquid the intermolecular attractive forces is called surface tension

7. Micelle formation 7 Typical micelle is Spherical in structure which contain 50-100 monomers Number of monomers to form micelle is called as aggregation number

8. A micelle is an aggregate of monomer surfactant molecules dispersed in a liquid colloid. Hydrophilic "head" regions in contact with surrounding 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 8

9. 9 SAA bulk Concentration Surface excess Surface saturated with SAA Excess in the bulk Micelles ( colloidal aggregates )

10. Oil in water type Because of arrangement monomers micelle is capable to hold lipidic nature drug at centre

11. 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.

12. Factors affecting process of micelles formation Molecular wt. of monomer Aggregation no. Proportion of hydrophobic and hydrophilic chain length Preparation process CMC

13. Critical micelle concentration (CMC) 13 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.

14. 14 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

15. Determination of the CMC 15 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

16. 16 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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18. Factors Affecting CMC 18 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

19. 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.

20. 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)

21. 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

22. 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

23. 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.

24. 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

25. 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.

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

27. 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.

28. 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.

29. 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 & bioavailability Increased 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 units Improved bioavailability & reduce cytotoxicity

30. 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.

31. 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.

32. 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.

33. Conclusion 33 By using Phenomenon of micellization we improve solubility of API Considering factor of CMC we modify micelle size Shape & release profile

34. Conclusion Applying this knowledge in field of Pharmacy Improve API stability Maintain Bioavailability long period Research is continued in Targeted DDS (Cancer)

35. References 35 A. N. Martin, Martin's Physical Pharmacy and Pharmaceutical Sciences , 6 th edition, p. M.E. Aulton, Pharmaceutics science of dosage form design , 2 nd Edition, p. 88-89 Leon Lachman, The Theory and Practice of Industrial Pharmacy, 3 rd edition, p. 106 H.A. Liebereman, M.M. Rieger, G.S. Banker, Pharmaceutical Dosage Forms: Disperse Systems,2nd Edition , Vol.3, p. 216-220

36. 36 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 2 nd Edition, p.54-55 Online Reference http://www.biolinscientific.com/attension/applications/?card=AA8

37. 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

38. 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.