Solubilization by raghavendra kumar

05/01/2305/01/23 SOLUBILIZATION OF NON-ELECTROSOLUBILIZATION OF NON-ELECTROLYTESLYTES

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SOLUBILIZATION OF NON-ELECTROLYTES

GUIDED BY:A.M.SUDHAKAR BABU SIR,

PRINCIPAL& HODDEPARTMENT OF PHARMACEUTICS

A.M.REDDY MEMORIAL COLLEGE OF PHARMACYPresented by:

RAGHAVENDRA KUMAR GUNDA


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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 Solubilization can be defined as a the preparation of a thermodynamically preparation of a thermodynamically stable isotropic solution of a stable isotropic solution of a substance normally insoluble or very substance normally insoluble or very slightly soluble in a given solvent by slightly soluble in a given solvent by the introduction of an additional the introduction of an additional component or componentscomponent or components


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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 bondsValence Bonds· Electrovalent Bond· Covalent Bond· Homo-polar Bond· Ionic Bond· Heteropolar Bond


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SOLUTE RELATED SOLVENT RELATED ENVIRONMENT RELATED FORMULATION RELATED

SOLUTE RELATEDNature of solute – Size, Shape and surface areaPhysicochemical properties- melting point, heat of fusion, molar volume& pKaPhysical forms- Salt, crystalline state, &polymorphism

SOLVENT RELATED•Nature of the solvent •Polarity •pH of the medium•volume of solvent

ENVIRONMENT RELATED PRESSURE TEMPERATURE

FORMULATION RELATEDOther ingredients


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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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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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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

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 Use of CHAOTROPIC AGENTS


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HYDROTROPHY METHOD

GRAPH 2

GRAPH 1


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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, Testosterone17- 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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Structure of some hydrotropes: (A)N,N-diethylnicotinamide ; (B) N-picolylnicotinamide ;

(B)(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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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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Application of ultrasonic wavesSolubility 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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REFERENCES:1>Solubility enhancement of hydrophobic drugs using synergistically interacting cyclodextrins and cosolvent Praveen Chaudhari1,*, Pramodkumar Sharma2, Nilesh Barhate1, Parag Kulkarni1 and Chetan Mistry12> TECHNIQUES OF SOLUBILIZATION BY Samuel H. Yalkowsky3> Encyclopedia of Pharmaceutical technology Vol 3 4> Essentials of Physical Pharmacy – subramanyam5> Biopharmaceutics and pharmacokinetics -Brahmankar.6> Enhancement of solubility of valdecoxib by Solid Dispersion Techniques – research paper By Modi1, P Tayade2 7> Pharmaceutical white papers –solubilization8> Martin’s physical pharmacy fifth edition9>Solubility of Nonelectrolytes in Water: A Thermodynamic and Quantum Chemical Approach based on Dihydroxynaphthalene Derivatives By Christian Machon, Ingfried Zimmermann10>SOLUBILITY ENHANCEMENT TECHNIQUES WITH SPECIAL EMPHASIS ON HYDROTROPHYPURWA JAIN*, ACHHRISH GOEL, SHWETA SHARMA, MEGHAL PARMAR11>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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13>Enhancement of Solubility: A Pharmaceutical OverviewBehera A. L.*1, Sahoo S. K.2 and Patil S. V.314>Solubility Improvement of Drugs using N-Methyl PyrrolidoneRitesh Sanghvi,1,4 Ryuichi Narazaki,2 Stephen G. Machatha,3 and Samuel H. Yalkowsky115>Hydrotropic Solubilization of Poorly Water-Soluble DrugsJI YOUNG KIM,1 SUNGWON KIM,1 MICHELLE PAPP,1 KINAM PARK,1,2 RODOLFO PINAL116>FACTORS DETERMINING SOL UBILITY AMONGNON-ELECTROL YTES*BY JOEL H. HILDEBRAND17>Determination of Aqueous Solubility by Heating and Equilibration:A Technical Note by Thorsteinn Loftsson1 and Dagný Hreinsdóttir118>Oral Delivery of Poorly Soluble DrugsBy Michael Hite, Lead Research Associate, Stephen Turner19>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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Education

Solubilization by raghavendra kumar