solubility enhancement and cosolvency by madhavi

“cosolvency and soluility enhancement” Pharmatech 2003, 160-166. They had developed simultaneous determination of sitagliptin phospate monohydrate and metformin by ultra performance liquid chromatographic (uplc)method.

1. Presented by:madhavee borade Uder guidance of: madhuri gite Shri r.d.bhakt college of pharmacy,jalna Review On:Solubility Enhancement & Cosolvancy

2. CONTENTS INTRODUCTION REVIEW LITERATURE METHOD OF SOLUBLITY ENHANCEMENT STUDY OF COSOLVENCY THEORY OF COSOLVENCY CONCLUSION REFERENCE

3. INTRODUCTION STUDY OF COSOLVENCY   DEFINITION: The solubility of weak electrolytes and nonpolar molecules can be increased by the addition of water-miscible solvents. This process is known as co-solvency or solvent blending, and the solvents used in combination to increase the solubility of the solute are called co-solvents. COSOLVENTS : Co solvents have some degree of hydrogen bond donating and or hydrogen bond accepting ability as well as small hydrocarbon regions. The resulting solution will have physical properties that are intermediate to that of the pure organic solvent and water through the reduction of water-water interaction Example: Ethanol , propylene glycol, glycerin, sorbitol and polyethylene glycol. Mechanism : 1) change the dielectric constant. DC of a good co-solvent : 25-80. 2 ) hydrogen bonding in two solvents

4. REVIEW LITERATURE 1 . S.K. dash et al(2012) [12 ] : solubility enhancement of poorly poorly water drugs. Crit Rev Ther Drug Carrier Syst. 2002; 19:553-585. 2. Chellos N.et al(2012) [13] : “ cosolvency and soluility enhancement” Pharmatech 2003, 160-166. They had developed simultaneous determination of sitagliptin phospate monohydrate and metformin by ultra performance liquid chromatographic ( uplc )method. the chromographic sepreation was achieved on aquity uplc BEH C8 100 X 2.1mm,1.7 m, colunm using a buffer consisting of 10 mM potassium dihydrogen phosphate and 2 nm hexane 1-sufonic acid sodiun , salt(PH adjusted to 5.50 with diluted phosphoric acid) and acetonitrile as organic solvent in a gradient program. The flow rate was 0.2 ml min-1 and the detection wavelength was 210nm.the limit of detection (LOD) was 0.2 and 0.06 g ml-1,respectively.the limit of quantification (LOD)was 0.7 and 0.2g ml-1,respectively.this method was validated with respect to linearity, accuracy,precision , specificity,and robustnes soluble drugs . . Crit Rev Ther Drug Carrier Syst. 2002; 19:553-585.

5. Properties of co-solvents co-solvent increases the solubility of a drugs. An ideal co-solvents should provide values of dielectric constant between 25 to 80. The most widely used system that will cover this range is a water. It should not cause toxicity or irritancy when administrated for oral or parental use.   Selection of co-solvent Some characteristics of co-solvent which are considered at selection: 1. Biocompatible 2. It must be non-toxic. Non-irritating. 3. It should be able to solubilize the drug in given solvent. 4. It should be able to cross the membrane. 5. does not have potential systemic effects.

6. Applications Ultimate role in solubility enhancement of poorly water soluble drugs. Improvement in absorption and bioavailability. Apart from increasing solubility, it have importance in improvement solubility of volatile constituents used to impart a desirable flavor and odour to the product. Solubility considerations at dosage form design.

7. Commonly used co-solvent Glycerol PEG400 Dimethyl Acetamide N- Octanol Glycerol Dimethyl Sulfoxide Propylene Glycol Co-solvent used in Drugs Diazepam Benzocaine

8. Advantages Simple and rapid to formulate and produce. Solvents may be combined with other solubilization techniques and and pH adjustment to further increase solubility of poorly soluble compounds. Disadvantage: As with all excipients, the toxicity and tolerability related with the level of solvent administer not 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 drug are extremely insoluble in water and do not readily re-dissolve after precipitation from the co-solvent mixture. In these situations there is potential risk for embolism and local adverse effects at the injection site.

9. SOLUBILITY ENHANCEMENT BY VARIOUS TECHNIQUES: AN OVERVIEW Descriptive term Part of solvent required per part of solute Very soluble < 1 Freely soluble 1-10 Soluble 10-30 Sparingly soluble 30-100 Slightly soluble 100-1000 Very slightly soluble 1000-10000 Practically insoluble >10000 Table : USP & BP Solubility criteria Descriptive term Part of solvent required per part of solute SOLUBILITY Solubility is the property of a solid, liquid, or gaseous chemical substances called solute to dissolve in a solid, liquid, or gaseous solvent to form a homogeneous solution of the maximum quantity of solute in a certain quantity of solvent at specified temperature and perssure .  

10. PROCESS OF SOLUBILISATION The process of solubilisation contains three steps: • The separation of the molecule of the solvent to provide space in the solvent for solute. • The breaking of intermolecular ionic bonds in the solute. • The interaction between the solvent and the solute molecule or ion

11. FACTORS AFFECTING SOLUBILISATION Particle size Temperature Pressure Molecular Size Polarity Polymorphs Nature of solute & solvent.

12. NEED FOR SOLUBILITY ENHANCEMENT Class I Class II High permeability   High solubility High permeability   Low solubility   Class III Class IV Low permeability   High solubility   Low permeability   Low solubility Fig 1: BCS classification

13. METHODS OF SOLUBILITY ENHANCEMENT • Particle Size Reduction Conventional methods Micronization Nano suspension • Hydrotropic • Co-solvency • Solubilization by Surfactants • Solid Dispersion The fusion (melt) method The solvent method Dropping method • pH adjustment • High Pressure Homogenization • Supercritical fluid recrystallization(SCF) • Sonocrystallisation  

14. • Complexion Physical Mixture Kneading method Co-precipitate method • Spray Drying • Inclusion Complex Formation-Based Techniques Kneading Method Lyophilization Freeze-Drying Technique Microwave Irradiation Method • Liquid solid technique • Micro-emulsion • Self-Emulsifying Drug Delivery Systems • Neutralization • Cryogenic Method Spray Freezing onto Cryogenic Fluids Spray Freezing into Cryogenic Liquids (SFL) Spray Freezing into Vapor over Liquid (SFV/L) Ultra-Rapid Freezing (URF) • Polymeric Alteration • Salt formation

15. CONCLUSION The various techniques enlisted in this article are used in combination for solubility enhancement of poorly water soluble drugs, but the solubility improvement mainly depends on the selection of proper method. The selection of suitable method for solubility enhancement is depends on drug properties like melting point, solubility, chemical nature, physical nature, pharmacokinetic behavior and so on. The article concludes that solubility of poorly water soluble drugs is an important concept to reach into systemic circulation to show its pharmacological response.   Solubility enhancement by co-solvent system gives new approaches for design and formulation of new dosage forms of poor aq. Soluble drugs. It also helps in improving : Bioavailability of drugs Stability of drugs

16. REFERENCES 1. Lachman L, Lieberman HA, The Theory and Practice of Industrial Pharmacy, CBS Publication & Distributors Pvt. Ltd. Special Indian Edition 2009: 221.   2. Sharma D, Soni M , Kumar S, Gupta GD, Solubility Enhancement-Eminent Role in Poorly Soluble Drugs, Research Journal of Pharmacy and Technology.2(2);April- June.2009:220-224.   3. Nikam SP, A Review: Increasing Solubility of Poorly Soluble Drugs, by Solid Dispersion Technique. Research Journal of Pharmacy and Technology.4(12);Dec.2011:1933-1940.   4. Chauhan NN, Patel NV, Suthar SJ, Patel JK, Patel MP. Micronization of BCS-II Drugs By Various Approaches For Solubility Enhancement-A Review. Research Journal of Pharmacy and Technology.5(8);Aug.2012:999-1005.   5. Pardhi D, Shivhare U, Suruse P, Chabra G. Lquid solid Technique For Solubility Enhancement of Poorly Water Soluble Drugs. Research Journal Pharmaceutical Dosage Forms and Technology.2(5);Sept-Oct.2010:314-322   6.Md. Sajid A, Choudhary V. Solubility Enhancement Methods With Importance of Hydrotropy. Journal of Drug Delivery and Therapeutics(6);2012:96-101..  

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