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

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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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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 theSolubilization can be defined as a the
preparation of a thermodynamicallypreparation of a thermodynamically
stable isotropic solution of astable isotropic solution of a
substance normally insoluble or verysubstance normally insoluble or very
slightly soluble in a given solvent byslightly soluble in a given solvent by
the introduction of an additionalthe 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 bonds
Valence 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 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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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, 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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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 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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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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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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