SOLUBILIZATION BY RAGHAVENDRA KUMAR

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various stabilization techniques for the solubility enhancement for poorly soluble agents, Non-Electrolytes

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2/9/2016 SOLUBILIZATION OF NON-ELECTROLYTES 1 SOLUBILIZATION OF NON-ELECTROLYTES GUIDED BY: A.M.SUDHAKAR BABU SIR, PRINCIPAL& HOD DEPARTMENT OF PHARMACEUTICS A.M.REDDY MEMORIAL COLLEGE OF PHARMACY Presented by: RAGHAVENDRA KUMAR GUNDA

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2/9/2016 SOLUBILIZATION OF NON-ELECTROLYTES 3 SOLUBILIZATION OF NON-ELECTROLYTES

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2/9/2016 SOLUBILIZATION OF NON-ELECTROLYTES 4 DEFINITION:- The term ‘solubility’ is defined as maximum amount of solute that can be dissolved in a given amount of solvent. It can also be defined quantitatively as well as qualitatively. Quantitatively it is defined as the concentration of the solute in a saturated solution at a certain temperature. In qualitative terms, solubility may be defined as the spontaneous interaction of two or more substances to form a homogenous molecular dispersion. A saturated solution is one in which the solute is in equilibrium with the solvent. Spontaneous passage of poorly water soluble solute molecules into an aqueous solution of surfactant is termed as SOLUBILISATION. Solubilization can be defined as a 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 component or components

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2/9/2016 SOLUBILIZATION OF NON-ELECTROLYTES 5 Intramolecular forces · Dipole-dipole interaction (Keesome interactions) · Dipole- induced dipole interaction (Debye interactions) · Induced-dipole interaction-Induced-dipole interaction(London dispersion forces) · Ion-dipole interaction · Hydrogen bonds Valence Bonds · Electrovalent Bond · Covalent Bond · Homo-polar Bond · Ionic Bond · Heteropolar Bond

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2/9/2016 SOLUBILIZATION OF NON-ELECTROLYTES 6 Factors influencing solubility of Drugs SOLUTE RELATED SOLVENT RELATED ENVIRONMENT RELATED FORMULATION RELATED SOLUTE RELATED Nature of solute – Size, Shape and surface area Physicochemical properties- melting point, heat of fusion, molar volume& pKa Physical forms- Salt, crystalline state, &polymorphism SOLVENT RELATED Nature of the solvent Polarity pH of the medium volume of solvent ENVIRONMENT RELATED PRESSURE TEMPERATURE FORMULATION RELATED Other ingredients

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2/9/2016 SOLUBILIZATION OF NON-ELECTROLYTES 7 PARTICLE SIZE ses SURFACE AREA ses SOLUBILITY ses Upto some particular critical point due presence of electrical charge PHYSICOCHEMICAL PROPERTIES- The melting point molar heat of fusion, entropy of fusion molar volume . PHYSICAL FORMS OF DRUGS – Amorphous >metastable >stable forms >Anhydrous >hydrates Solvent Nature of Solute Examples of Drugs Dosage forms Water (Polar) Non electrolytes Dextrose i.v. injection Oil (non polar) Non polar Progesteron Oil injection DIPOLE MOVEMENT HYDROGEN BONDING

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2/9/2016 SOLUBILIZATION OF NON-ELECTROLYTES 8 Un ionised dissociation constant Ionised Acidic drugs: pH = pKa + log S- S0/ S0 Where pKa = dissociation constant of drug Basic drugs: pH = pKa + log S0/S- S0 S0 = solubility of unionised form, moles/litre, S =overall solubility of drug,moles/litre . Cosolvents Ethanol, propylene glycol, glycerine, PEG 300, and PEG 400 For the mfg of Liquid Orals, Parenterals, Semi-Solid preparations Benzyl alcohol, dimethyl sulphoxide(DMSO), Dimethyl acetamide(DMA) Dimethyl formamide(DMF) As Supplementary Solvents TEMPERATURE positive hit of solution, a rise in temperature leads to an increase in solubility of solid ex KNO3 liberation of heat then an increase in temperature leads to decrease in solubility ex (CH3COO)2 Ca

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2/9/2016 SOLUBILIZATION OF NON-ELECTROLYTES 9 SURFACTANTS enhance the solubility of poorly water-soluble drugs due to the formation of micelles Ex: Solubility of procaine is enhancing by 25% in aqueous buffer METHODS FOR ENHANCING THE SOLUBILITY OF DRUGS Use of co-solvent HYDROTROPHYMETHOD Change in dielectric constant of solvent Chemical modification of the drug Complexation Methods (inclusion complex or clathrates) Alteration of pH of solvent Use of surfactactants Use of hydrates or solvates Use of Soluble prodrug Application of ultrasonic waves Solid dispersion method: Spherical crystallization solubility enhancement of hydrophobic drugs using synergistically interacting cyclodextrins and cosolvent U se of CHAOTROPIC AGENTS

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2/9/2016 SOLUBILIZATION OF NON-ELECTROLYTES 10 HYDROTROPHY METHOD GRAPH 2 GRAPH 1

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2/9/2016 SOLUBILIZATION OF NON-ELECTROLYTES 11 Hydrotropic solubilization study of various poorly water-soluble drugs[48-68] Drug Hydrotropic agent Riboflavin ProcaineHCl, PABAHCl, CinchocaineHCl, Resorcinol, Pyrogallol Chartreusin Sodium benzoate, Sodium p-hydroxybenzoate, Sodium m-hydroxybenzoate, Sodium o-hydroxybenzoate, Sodium 2,4-dihydroxybenzoate, Sodium 2,5-dihydroxybenzoate, Sodium 2,6-dihydroxybenzoate, Sodium 2,4, 6-trihydroxybenzoate Diazepam, Medazepam, Oxazepam, Nitrazepam, Clonazepam Sodium salicylate Theophylline, Hydrocortisone, Prednisolone, Phenacetin Sodium benzoate, Sodium o-hydroxybenzoate, Sodium m-hydroxybenzoate, Sodium p-hydroxybenzoate, Sodium 2,4-dihydroxy benzoate, Sodium 2,5-dihydroxybenzoate, Sodium 2,6-dihydroxybenzoate, Sodium 3,4-dihydroxybenzoate, Sodium 3,5-dihydroxybenzoate, Sodium 3,4,5 –trihydroxybenzoate Progesterone, Testosterone 17- b Estradiol, Diazepam and Griseofulvin Nicotinamide, Isonicotinamide, Nipecotamide,N-methylnicotinamide, N, N-dimethylnicotinamide Paracetamol Sodium salicylate, Sodium glycinate, Sodium gentisate, Nicotinamide Saquinavir Nicotinamide, Ascorbic acid, Dimethyl urea, Resorcinol Benzoic acid, Salicylic acid Urea, Methyl Urea, 1-3-dimethyl urea Rofecoxib, celecoxib, melocoxib Nicotinamide, Sodium benzoate, Sodium salicylate Riboflavin Nicotinamide Temazepam Sodium salicylate, Nicotinamide Ibuprofen Sodium salt of Ibuprofen

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2/9/2016 SOLUBILIZATION OF NON-ELECTROLYTES 12 Structure of some hydrotropes: N,N-diethylnicotinamide ; (B) N-picolylnicotinamide ; (C) N-allylnicotinamide ; (D) sodium salicylate [47] . Nifedipine Urea, Methyl urea, Ehhyl urea, Butyl urea, icotinamide, N-methyl nicotinamide, N, N-dimethyl nicotinamide Ketoprofen Sodium benzoate, Sodium o-hydroxybenzoate, Nicotinamide, Sodium m-hydroxybenzoate, Sodium ascorbate, Sodium 2,5-dihydroxybenzoate icam Sodium ascorbate, Sodium benzoate, Sodium o-hydroxybenzoate, Sodium m-hydroxybenzoate, Sodium 2,5-dihydroxybenzoate Carbamazepine Sodium salicylate, Sodium benzoate

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2/9/2016 SOLUBILIZATION OF NON-ELECTROLYTES 13 Se the Concentration of Co-Solvent se Dielectric constant of the solvent Due to hydrogen bonding Se solubility of hydrophobic molecules The energy required to separate two oppositely charged bodies is inversely proportional to the dielectric constant of the medium. Chemical modification of the drug : By addition of polar groups like carboxylic acids, ketones and amines can increase solubility by increasing hydrogen bonding and the interaction with water . Complexation Methods (inclusion complex or clathrates) Betacyclodextrins solubilise water insoluble drugs. HYDROXYL PROPYL METHYL CELLULOSE(HPMC) relies on relatively weak force such as London forces, hydrogen bonding and hydrophobic interactions N-Methyl Pyrrolidone(NMP ) for drugs like Phenobarbital, Griseofulvin, Phenytoin, Ketoprofen, Estrone, Testosterone, Ibuprofen, Amiodarone ; Carbendazim, 2-Phenoxypropionic acid (PPA) and Benzoylphenyl urea derivative

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2/9/2016 SOLUBILIZATION OF NON-ELECTROLYTES 14 Application of ultrasonic waves Solubility increases by use o ultrasonic vibrators. A n oscillator of high frequency(100-500KHz) is use and device is known as Pohlman whistle. Solubility Enhancement of Hydrophobic Drugs using Synergistically interacting Cyclodextrins and Co-Solvent Loftsson et al. reported that addition of polyethylene glycol or ethanol in an aqueous solution of CD reduced the solubility of ibuprofen . Pitha and Hishino reported that the solubility of testosterone with hydroxypropyl- cyclodextrin (Hp--CD) is 10,000-fold lower in 80% ethanol than in water. The reason behind this was that the cosolvent may act by competing with the drug for entry into the CD cavity or by reducing solvent polarity Poloxamer-188 is one of the commercial grades of poloxamers, which are water-soluble, non-ionic, surface active copolymers. The polyoxyethylene segment of poloxamer- 188 is relatively hydrophilic, while the polyoxypropylene segment is relatively hydrophobic. It has been used in pharmaceutical formulations, primarily as emulsifying and solubilizing agents. It has the ability to form a clear solution or gel in aqueous media, thus solubilizing many water-insoluble compounds by the formation of micelles SOLUBILIZATION OF PARTICULATE PROTEINS AND NONELECTROLYTES BY CHAOTROPIC AGENTS* Chaotropic ions (those ions which favor the transfer of Apolar groups to water) provide a highly effective means for the resolution of membranes and multi-component enzymes and for increasing the water solubility of particulate proteins and nonelectrolytes. The action of chaotropic agents is related to their effect on the structure and lipophilicity of water.

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2/9/2016 SOLUBILIZATION OF NON-ELECTROLYTES 16 REFERENCES: 1>Solubility enhancement of hydrophobic drugs using synergistically interacting cyclodextrins and cosolvent Praveen Chaudhari1,*, Pramodkumar Sharma2, Nilesh Barhate1, Parag Kulkarni1 and Chetan Mistry1 2> TECHNIQUES OF SOLUBILIZATION BY Samuel H. Yalkowsky 3> Encyclopedia of Pharmaceutical technology Vol 3 4> Essentials of Physical Pharmacy – subramanyam 5> Biopharmaceutics and pharmacokinetics -Brahmankar. 6> Enhancement of solubility of valdecoxib by Solid Dispersion Techniques – research paper By Modi1, P Tayade2 7> Pharmaceutical white papers –solubilization 8> Martin’s physical pharmacy fifth edition 9>Solubility of Nonelectrolytes in Water: A Thermodynamic and Quantum Chemical Approach based on Dihydroxynaphthalene Derivatives By Christian Machon, Ingfried Zimmermann 10>SOLUBILITY ENHANCEMENT TECHNIQUES WITH SPECIAL EMPHASIS ON HYDROTROPHY PURWA JAIN*, ACHHRISH GOEL, SHWETA SHARMA, MEGHAL PARMAR 11>ENHANCEMENT OF SOLUBILITY AND DISSOLUTION RATE: AN OVERVIEW P. S Mohanachandran1*, P. G Sindhumol1 and T. S Kiran 2 12>Determination of Aqueous Solubility by Heating and Equilibration: A Technical Note Thorsteinn Loftsson1 and Dagný Hreinsdóttir1

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2/9/2016 SOLUBILIZATION OF NON-ELECTROLYTES 17 13>Enhancement of Solubility: A Pharmaceutical Overview Behera A. L.*1, Sahoo S. K.2 and Patil S. V.3 14>Solubility Improvement of Drugs using N-Methyl Pyrrolidone Ritesh Sanghvi,1,4 Ryuichi Narazaki,2 Stephen G. Machatha,3 and Samuel H. Yalkowsky1 15>Hydrotropic Solubilization of Poorly Water-Soluble Drugs JI YOUNG KIM,1 SUNGWON KIM,1 MICHELLE PAPP,1 KINAM PARK,1,2 RODOLFO PINAL1 16>FACTORS DETERMINING SOL UBILITY AMONG NON-ELECTROL YTES* BY JOEL H. HILDEBRAND 17>Determination of Aqueous Solubility by Heating and Equilibration: A Technical Note by Thorsteinn Loftsson1 and Dagný Hreinsdóttir1 18>Oral Delivery of Poorly Soluble Drugs By Michael Hite, Lead Research Associate, Stephen Turner 19>Solubilization of Poorly Soluble Drugs: A Review by Anil J Shinde 20>ABSORPTION AND DRUG DEVELOPMENT BY ALEX AVDEEF 21>ORAL DRUG ABSORPTION BY JENNIFER B. DRESSMAN

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2/9/2016 SOLUBILIZATION OF NON-ELECTROLYTES 18 THAN.....Q

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