SOLUBILIZATION TECHNIQUES
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The document discusses various solubilization techniques essential for enhancing the solubility of poorly soluble drugs, including co-solvency, complexation, salt formation, micronization, and selective adsorption. Each technique has its advantages and disadvantages, with specific methods recommended based on the nature of the drug and desired outcomes. Additionally, various examples of drugs utilizing these techniques are provided, along with references for further reading.
SOLUBILIZATION TECHNIQUES
- 2. Content: • 1. COSOLVENCY • 2.COMPLEXATION • 3. SALT FORMATION • 4.MICRONIZATION • 5.SELECTIVE ADSORPTION
- 3. Why solubilization techniques are needed? • Solubility is essential to a drug’s success. Most drugs are organic and will not go into an aqueous solution easily. • There are several different ways to enhance solubility, and the method of choice depends on the nature of the solute, the required degree of solubilization, and other formulation restrictions such as drug stability and compatibility with therapeutic use.
- 4. 1.Co-solvency: • definition : The solubility of a poorly water soluble drug can be increased frequently by the addition of a water miscible solvent in which the drug has good solubility and such technique is known as co-solvency. • Cosolvents are mixtures of water and one or more water miscible solvents used to create a solution with enhanced solubility for poorly soluble compounds . • Co-Solvents can increase the solubility of poorly soluble compounds several thousand times compared to the aqueous solubility of the drug alone. • Very high drug concentrations of poorly soluble compounds can be dissolved compared to other solubilization approaches.
- 5. Mechanism of co-solvency: Favours the dissolution of a non-polar solute Decreases intermolecular H-Bonding interactions of water Decreases the ability of water to “squeeze out” a non- polar organic solute Lower overall polarity than a purely aqueous system
- 6. Advantages: • Simple and rapid to formulate and produce. • Co-solvents may be combined with other solubilization techniques and pH adjustment to further increase solubility of poorly soluble compounds.
- 7. Disadvantages: • As with all excipients, the toxicity and tolerability related with the level of solvent administered has to be considered. • Uncontrolled precipitation occurs upon dilution with aqueous media. The precipitates may be amorphous or crystalline and can vary in size. • Many of the insoluble compounds shares works which are unsuited to co-solvents alone, particularly for intravenous administration. • This is because the drugs are extremely insoluble in water and do not readily redissolve after precipitation from the co- solvent mixture. • In these situations, there is a potential risk for embolism and local adverse effects at the injection site.
- 8. Commonly used Cosolvent • Glycerol • Propylene Glycol • PEG 400 • Dimethyl Sulfoxide • Dimethyl Acetamide • Ethanol • n-Octanol • Glycerol Cosolvents used in Drugs • Diazepam (Valium) -10 % ethanol and 40 % PG • Benzocaine(Aerbesol)- 70 % Ethanol
- 9. Co-solvent products: • Nimodipine Intravenous Injection (Nimotop®, Bayer) • Digoxin Elixir Pediatric (Lanoxin®,GSK)
- 10. 2.Complexation: • There are numerous examples in the literature of drugs whose solubility and hence bioavailability have been increased the use of cyclodextrins: they include piroxicam,itraconazole, indamethacin, pilocarpine, naproxen,hydrocortisone, diazepam and digitoxin. • The first product on the UK market containing a cyclodextrin is the poorly soluble antifungal itraconazole,which has been formulated as a liquid dosage form with the more soluble derivative of ^- cyclodextrin.
- 11. Two types of Complexation : Self association and Stacking Complexation • Stacking complexes are formed by the overlap of planar regions of aromatic molecules. Inclusion Complexation • inclusion complexes are formed by the insertion of the nonpolar region of one molecule into the cavity of another molecule (or group of molecules).
- 12. The mathematical description for the equilibrium constant of a 1:1 complex, K1:1 is defined by The equilibrium constant is also commonly referred to as the stability constant or the complexation constant.
- 13. Self association and Stacking Complexation Organic drug+water Nonpolar moieties are Squeezed out by strong water-water interaction force Forms aggregates Minimize the contact with water by aggregation of their Hydrocarbon moieties Large planar nonpolar regions Opposed by entropy Random arrangement Complexes stacked can be homogenous or mixed SELF ASSOCIATION COMPLEXATION
- 14. Examples of substances that interact in an aqueous media by stacking are, • Naphthalene • Pyrene • Benzoic acid • Methylene blue • Caffeine etc.
- 15. Inclusion Complex • Produced by the Inclusion of a nonpolar molecule or the nonpolar region of a molecule (Guest) into the nonpolar cavity of another molecule or group of molecules ( Host). • When the guest molecule enters the host molecule the contact between water and the nonpolar regions of both is reduced. • The most commonly used host molecules are the CYCLODEXTRINS.
- 16. Cyclodextrin • These cyclic oligomers of glucose are relatively soluble in water and have cavities large enough to accept common nonpolar portion of the drugs. • The characteristic nature and structure of Cyclodextrin makes its place in pharmaceutical excipients. • Cyclodextrins (CDs) can enhance apparent water solubility by forming dynamic, non-covalent, water-soluble inclusion complexes
- 17. The Natural Cyclodextrins • α-Cyclodextrin α-CD is of limited value due to low complexation efficiency with most drugs. • β-Cyclodextrin β-CD does not usually posses rather good complexation efficiency with drugs. However β-CD and its complexes have very limited aqueous solubility. • γ-Cyclodextrin γ-CD has frequently lower complexation efficiency than β-CD.
- 18. Complex formation: • Complexation of ketoprofen with Hydroxypropyl β-CD. The inclusion complex 0f KPF- 2 HPβ-CD could be formed spontaneously and lower temp is benefit to the formation. Hence, the solubility of KPF in aqueous solution increase. Example:
- 19. Advantages of - Cyclodextrine • It converts liquid drugs to microcrystalline powders. • Volatile component can be stabilized against losses through evaporation. • Molecules can be protect against oxidation. • It can be used for taste and smell masking. • Incompatible drug can be mixed together if one of them is protected by formation of Cyclodextrine complex. • Solubility in water as well as the rate of dissolution of poorly soluble drug can be increased.
- 20. Limitation of Complexation • These are very expensive materials. • In some cases when the complexing agent is too concentrated, the complex can precipitate out of solution as more complexing agent is added. • The sensitive nature of corneal epithelium precludes the use of certain cyclodextrins due to their toxicity. ▫ Ex-Jansen and coworkers found that dimethyl-b-cyclodextrin is toxic to the cornea and thus should not be used for corneal ophthalmic formulations • Natural cyclodextrins are not useful for parenteral drug delivery as they posess renal and cytotoxicity.some of the chemically modified Cyclodextrins are used. ▫ Ex: Hydroxypropyl and sulfobutyl ether derivatives. • β-Cyclodextrin is not useful for parenteral drug delivery. • limiting factor for the use of cyclodextrins is the ability of a drug to form a complex with the cyclodextrin internal cavity. The entrance to the cavity of cyclodextrins may have hydroxyl groups or bulky alkyl groups that may provide steric restrictions to the encapsulation of drugs
- 21. 3.Salt Formation: Why? • Salt formation is frequently performed on weak acidic or basic drugs • The ideal characteristics of a salt are that it is chemically stable, not hygroscopic, presents no processing problems, dissolves quickly from solid dosage forms (unless it is formed with the intent to delay dissolution) and exhibits good bioavailability.)
- 22. Selection Of Salt: • Weakly acidic drugs , a strong base salt is prepared such as the sodium and potassium salts of barbiturates and sulphonamides. • Weakly basic drugs , a strong acid salt is prepared like hydrochloride or sulphate salts of alkaloidal drugs (Atropine) • Size of the counter ion influence the solubility of salt forms of the drug. • Smaller the size of the counter ion , greater the solubility of salt • Novobiocin from its sodium salt , calcium salt and free acid form was found solubility in the ratio – 50:25:1
- 23. INORGANIC SALTS • Salts were found to have the systematic effect on the behaviour of aqueous solutions & were divided into kosmotropes (polar water-structure markers) or chaotropes (water-structure breakers). • kosmotrope:- A doubly charged ion (e.g So4-2) or an ion with a high charge density. (e.g. F-) was proposed to interact with the adjacent water molecules more strongly than would bulk water. • chaotrope :- a large ion with a single charge (e.g. ClO4- or SCN-) was proposed to interact with adjacent water molecules less strongly than would bulk water
- 24. Example of inorganic salt: • Caffeine solubility of Different salts have different effects on the solubility: Added NaClO4 or NaSCN increases the caffeine solubility, whereas added Na2SO4 or NaCl decreased it and added NaBr did not show any significant effect.
- 25. The solubility were also treated using the empirical Setschenow equation:- The k values are positive for salts that decrease solubility & negative for salt that increase solubility.
- 26. Examples of salts: • Many of the antibiotics administered i.v. are sodium salts. • Organic acid salt forms of basic drugs, such as amines, frequently have higher aqueous solubilities than their corresponding inorganic salts. • Solubilization does not always improve the taste. Eg: potassium salts frequently have an unpleasant taste and leave a metallic after taste. • N-Cyclohexylsulfate salts of several drugs have improved taste and enhanced solubility properties.
- 27. Advantages of Salt • It can be effectively applied for the solubilization of weak acids and bases . • Different salts(i.e. caffeine) of the same drug can also be used to generate crystals with different lattice energies and hence different solubilities. • dissolves quickly from solid dosage forms (unless it is formed with the intent to delay dissolution) and exhibits good bioavailability. • N-Cyclohexylsulfate salts of several drugs have improved taste and enhanced solubility properties.
- 28. Disadvantages of Salt • Solubilization does not always improve the taste. Eg: potassium salts frequently have an unpleasant taste and leave a metallic after taste. • Selection of an appropriate salt is difficult for desired solubility . • It is not feasible to form salts of neutral compounds. • Difficult to form salts of very weak bases/acids. • The salt may be hygroscopic , exhibit polymorphism or has poor processing characteristic. • Conversion of salt to free acid/base form of the drug on surface of solid dosage form that prevents or retards drug release .
- 29. 4.Micronisation: • It is a high energy particle size reduction technique that can convert coarse particles into particles of less than 5 μ in diameter. • Generally, desired in pharmaceutics is smaller than 1mm • By micronization we get uniform and narrow particle size distribution which is essential for developing uniform dosage form • griseofulvin, chloramfenicol, tetracycline salts shows 50% more absorption rate after micronizer.
- 30. • As micronization occurs surface area increases with decreasing particle size and solubility increases and observed solubility increased with decreasing particle size in accordance this equation :- • further decreases the particle radius (smaller than micron level)then it may decreases solubility because any changes on particle it may affect the static charge present on the particle and which may decreases the solubility
- 31. Techniques for Micronization: • Jet milling fluid energy mill or micronizer • Solid solution & eutectic mixtures • Microprecipitation & microcrystallization • Controlled crystallization • Supercritical fluid technology Supercritical fluid nucleation (SFN) Gas antisolvent recrystallization precipitation with compressed fluid antisolvent • Spray freezing in to liquid
- 32. RECENT WORK ON MICRONIZATION • Drug powder properties decisive for pulmonary use. • A small particle size, a good deagglomeration behaviour required. • Several anti-inflammatory drugs Beclomethasone dipropionate , Betamethasone-valerate , Triamcinolone acetonide, Prednisolone micronized by controlled crystallization without any milling processes
- 33. • Micronized purified flavonoid fraction for chronic venous insufficiency , venous ulcer and haerrorrhoids. • Improvement of dissolution rate of ARTEMISININ by supercritical fluid tech. and solid dispersion. • Enhancement of dissolution rate of poorly water soluble particle by spray freezing into liq. With atmospheric freeze – drying
- 34. Advantages: • Micronization will results in higher dissolution rates . • As there is reduction in the particle size it provides uniform distribution of the drugs in dosage form . • Micronization helps in decrease the dose of certain drugs because of increased absorption efficiency ,for eg.griseofulvin dose was reduced to half following micronization .
- 35. Disadvantages : The amorphous region are thermodynamically unstable and therefore susceptible to recrystallization on storage particularly in hot and humid condition .
- 36. 5.SELECTIVE ADSORPTION : • Highly active adsorbent inorganic clay like bentonite enhance dissolution rate of poorly water soluble drugs like ▫ griseofulvin ▫ indomethacin ▫ prednicolone • Rapid release due to: ▫ Weak physical bonding between adsorbent-adsorbate ▫ Hydration ▫ Swelling of clay in the aqueous media
- 37. Comparison among solubilization techniques: • Based on nature of drug molecules, site of action, structure of molecules appropriate solubilization technique is selected. • Salt formation has wide spectra in solubility enhancement from techniques which have been discussed.
- 38. If any query then please feel free to ask ………
- 39. References: • Vemula VR, Venkateshwarlu L., Lingala s., solubility enhancement technique. International Journal of Pharmaceutical sciences Review and Research, Vol. 5, Nov–Dec 2010; Article-007,42. • Pharmaceutics – The Science of Dosage Form Design Edited by M.E. Aulton • Encyclopedia of Pharmaceutical technology, Volume 3, Edited By James Swarbrick, 2458-2477 • Encyclopedia of pharmaceutical technology, vol. -3, p. no. 337-344. • Encyclopedia of pharmaceutical technology, vol. -14, page -: 207- 221. • Physical Pharmacy, Third edition, By Alfred Martin • The theory and practice of Industrial Pharmacy, By Leon Lachman • Solubility and related properties by Kenneth c. James. Pg – : 253 – 271. 1. : 253 – 271.
- 40. Thanks for your kind attention..