Solubility By Rahul Satapara

Solubility and Solubilization: 

Solubility and Solubilization Presented By :- Rahul satapara M.Pharm (Sem-1) 2011-12 Roll No.4 1

CONTENT: 

CONTENT Aim Of Studying Solubility Definition Of Solubility Types Of Solubility Mechanism Of Solubilization Factors Affecting Solubility Application of Solubility Reasons For Insolubilization Of Drugs Techniques for solubility Enhancement 9.Questions 10.Reference 2

AIM OF STUDING SOLUBILITY: 

AIM OF STUDING SOLUBILITY 1. The best solvent medium for a drug or combination of drugs. 2. Help in overcoming certain difficulties that arises in the preparation of pharmaceutical solution. 3. And further more, can serve as a standard test of purity. So, it is essential to study about solubility and solubilization characteristics 3

DEFINITIONS: 

DEFINITIONS Solubility is defined as the number of milliliters of solvent in which 1 gm of solute will dissolve. 4

TYPES OF SOLUBILITY: 

TYPES OF SOLUBILITY 5

Process of solubilisation: 

Process of solubilisation Step 1: Holes opens in the solvent Step2: Molecules of the solid breaks away from the bulk Step 3:The freed solid molecule is intergrated into the hole in the solvent 6

Mechanism Of Solubilization: 

Mechanism Of Solubilization Solubilization takes place by consideration of Polarity, Dielectric constant, Association, Salvation, Internal pressure, Acid-base reaction. 7

Factors Affecting Solubility: 

Factors Affecting Solubility COMMON ION EFFECT CRYSTAL STRUCTURE PARTICLE SIZE MOLECULER STRUCTURE ELECTROLYTES pH TEMPERATURE SOLUBILITY 8

Application Of Solubility : 

Application Of Solubility Solubility is of fundamental importance in a large number of scientific disciplines and practical applications , to the use of medicines , and the transport of pollutants . Solubility is represents a fundamental concept in fields of research such as chemistry, physics, food science, pharmaceutical, and biological sciences. 9

Application Of Solubility: 

Application Of Solubility The solubility of a substance becomes specially important in the pharmaceutical field because it often represents a major factor that controls the bioavailability of a drug substance. Solubility is commonly used to describe the substance, to indicate a substance's polarity , to help to distinguish it from other substances, and as a guide to applications of the substance. Solubility of a substance is useful when separating mixtures. 10

Application Of Solubility: 

Application Of Solubility Moreover, solubility and solubility-related properties can also provide important information regarding the structure of drug substances, and in their range of possible intermolecular interactions . For these reasons, a comprehensive knowledge of solubility is essential. 11

SOLUBILIZATION TECHNIQUES : 

SOLUBILIZATION TECHNIQUES MICRONIZATION pH CONTROL COSOLVENCY USE OF SURFACTANT SALT FORMATION SOLID SOLUTION SOLID DISPERSION POLYMORPHISM COMPLEXATION SOLUTE –SOLVENT COMPLEXATION SOLVENT DEPOSITION SELECTIVE ADSORPTION ON IN SOLUBLE CARRIERS FAST DISSOLVING PRODCUTS COMBINE TECHNIQUES a. Combining of pH & Complexation b. Combining of pH & Surfactants c. Combining of Co-solvents & Surfactants ADDUCTS AND CLATHRATES BY NANOSTRUCTURE HYDROTROPIC SOLUBILIZATION 12

MICRONIZATION: 

MICRONIZATION 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 13

Methods For Micronization: 

Methods For Micronization 1. Conventional Trituration and Grinding. -Ball milling -Jet milling 2. Super Critical Fluid Technique - RESS(RAPID EXPANSION OF SUPERCRITICAL SOLUTIONS) - GAS(GAS ANTISOLVENT RECRYSTALLIZATION ) - PCA(PRECIPITATION WITH COMPRESSED FLUID ANTISOLVENT ) - SEDS(SOLUTION ENHANCED DISPERSION WITH SCF ) 3. Fluid energy Micronization. 14

Methods For Micronization: 

Methods For Micronization 4 . Microemulsion. 5. Microprecipitation Or Microcrystallization. 6. Controlled Crystallization. 7. In vivo Micronisation 8. Spray Freez drying. 9. By ultrasonic waves. 15

Trituration And Grinding: 

Trituration And Grinding Jet milling Based on principle of impact and attrition. Not used for thermo labile drugs because heat generation and not give extreme reduction of the particle size Ball milling Fluid energy mill / Micronizer , High speed HAMMER MILL with Internal classifier, Vibration mills 16

Super Critical Fluid Technology: 

Super Critical Fluid Technology SUPERCRITICAL TECHNOLOGY SUPERVANES THE CLASSICAL METHODS?? Produces micronic & nanometric particles. Opportunities to produce & modify ALL TYPES. Continuous adjustable s olvent power. Process T imes greatly reduced, & no W astes . Enhanced solubilization power & its modulation. Large d iffusivities. Solvent less or organic solvent reduced operation. Control over the P article size distribution & morphology Safe, environmentally f riendly , economical. 17

Super Critical Fluid Technology: 

Super Critical Fluid Technology 18

Rapid Expansion of Supercritical Solution (RESS): 

Rapid Expansion of Supercritical Solution (RESS) RAPID EXPANSION SCF (RESS) Principle : Due to expansion , density & solubilising power of the SCF decreases dramatically, supersaturation & precipitation . 19

GAS ANTISOLVENT RECRYSTALLIZATION (GAS). : 

GAS ANTISOLVENT RECRYSTALLIZATION (GAS). Rapid crystallisation results by introducing the antisolvent gas( SF) into a solution containing dissolved solute The size distribution of precipitate depends on the rate of addition of the SCF 20

Precipitation With Compressed Fluid Antisolvent (PCA): 

Precipitation With Compressed Fluid Antisolvent (PCA) Same principle of GAS, but here liquid solution is spraying into the super- critical antisolvent. Because super-critical expanded solvent has a lower solvent strength than the pure solvent, the mixture becomes super-saturated resulting in the precipitation of the solute 21

SPRAY FREZING IN TO LIQUID: 

SPRAY FREZING IN TO LIQUID Stable protein microstructure particles can be produced by spray freezing into liquid N2 .protein crystals are dissolved in water and then delivered to 4.65 micrometer inner nozzle at 5000 psi, which was submerged below the surface of liquid N2. Then these frozen slurries were lyophilized in a lyophilizer with a condenser temp. Of -67˙c and pressure of 100 mToor 22

Other Techniqes Of Micronization: 

Other Techniqes Of Micronization MICROEMULSIONS MICROPRECIPITATION OR MICROCRYSTALLIZATION CONTROLLED CRYSTALLIZATION IN VIVO MICRONIZATION SPRAY FREEZE DRIYING 23

Resent Works on Micronization: 

Resent Works on Micronization 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. In situ micronization of Disodium chromoglycate for pulmonary delivery. 24

Resent Works on Micronization: 

Resent Works on Micronization Nanocrystals for stability and dissolution rate improvement of NIFEDIPINE. Griseofulvin and Ampicillin Micronisation by SCF with atomization. Micronisation of Insulin from halogenated alcohol using super critical carbon dioxide. 25

pH CONTROL: 

pH CONTROL The ionized form of the drug has responsible for solubility of drug. For weak acidic drugs, Lower pH Unionized form insoluble/ ppt. Higher pH ionized form more soluble drug. For weak basic drugs, Lower pH ionized form more soluble drug. Higher pH Unionized form insoluble/ ppt. 26

Handersson-Hasselbach Equations: 

Handersson-Hasselbach Equations For weak Acid, pH=pK a +log For weak Base, pH=pK a +log 27

Drugs showing improvement in solubility upon alteration in pH : 

Drugs showing improvement in solubility upon alteration in pH pH Solubility mg/ml 1.2 0.70 6.2 0.86 7.4 4.10 8.4 43.90 Weak acids : Nimesulide: practically insoluble in water but there is increase in solubility by increased in pH from 1.2 to 8.4 Same way for Aspirin, phenytoin, penicillin, cephalosporin, etc 28

Drugs showing improvement in solubility upon alteration in pH : 

Drugs showing improvement in solubility upon alteration in pH Weak bases : Similar increase in solubility of Levemopamil HCl by decreasing pH. Other examples; Morphine, Ephedrine, Itraconazole, Flavopiridol, etc. 29

Factors to be considered in selecting pH: 

Factors to be considered in selecting pH Selection of pH pH must not conflict with chemical stability Physiological compatibility Drug activity Drug absorption 30

Buffers used in pharmaceuticals: 

Buffers used in pharmaceuticals 31

COSOLVENCY: 

COSOLVENCY Definition: The addition of a water-miscible or partially miscible organic solvent (i.e. cosolvent to water) by which there is a increase solubility of a nonpolar drug . The technique is known as cosolvency 32

Mechanism of Co-solvents: 

Mechanism of Co-solvents They decrease water-water interaction, leads to decreases the ability of water to squeeze out” a non-polar organic solute in the cosolvent system . Cosolvent decrease intermolecular H-Bonding interactions of water, forming a new solvent system which has low polarity then purely water system. 33

Mechanism of Co-solvents: 

Mechanism of Co-solvents Aqueous solubilisation via cosolvency is dependent on both the solute and cosolvent physical properties . i.e solubilisation is directly related to the polarity of the drug and the polarity of the cosolvent . More nonpolar the cosolvent , the more nonpolar the cosolvent system , the better the solubilisation of a non-polar drug . 34

Commonly used Cosolvents : 

Commonly used Cosolvents Water Glycerol Propylene Glycol PEG 400 Dimethyl Sulfoxide Dimethyl Acetamide Ethanoln-Octanol Preparation containing 100 % cosolvent are not given IV. but it be acceptable for IM injection . For IV injection it must be diluted with sterile aqueous diluent 35

SOLUBILIZATION BY SURFACTANTS OR MICELLER SOLUBILIZATION: 

SOLUBILIZATION BY SURFACTANTS OR MICELLER SOLUBILIZATION Ideal Properties : Non-toxic Non-irritant Compatible with other ingredients Good solubilizing power Free from disagreeable odor and taste and be non-volatile 36

Types of surfectant: 

Types of surfectant 37

What is Micelles ?: 

What is Micelles ? In water as the concentration of surfactant increases above critical value, the molecule get associate into a soluble structure called as MICELLES. The CONCENTRATION at which they begin to form is called as CRITICAL MICELLE CONCENTRATION.(CMC) 38

Solubilization by Micelles: 

Solubilization by Micelles There are a number of possible loci of solubilization for a drug in a micelle, as represented in the following figure. 39

Types of Micelles: 

Types of Micelles Spherical Micelles : Lamellar Micelles (L) and Spherulite Micelles (M) : 40

Types of Micelles: 

Types of Micelles Reverse Micelles or Inverted Micelles Bilayed Structure Rod Shaped Micelles Hexagonal Micelles 41

SALT FORMATION : 

SALT FORMATION 42

A. Salt Formation: 

A. Salt Formation Salts were found to have the systematic effect on the behaviour of aqueous solutions & were divided into a. Kosmotropes (polar water-structure markers) b. Chaotropes (water-structure breakers). 43

PowerPoint Presentation: 

Determine need for Salt Form Measure solubility as a function of pH ACIDS BASES Prepare Sodium Salt Prepare Hydrochloride Salt Study physical properties as a function of temperature and humidity Study physical properties as a function of temperature and humidity DECISION TREE FOR SALT SELECTION 44

DECISION TREE FOR SALT SELECTION : 

DECISION TREE FOR SALT SELECTION Prepare Metallic Salts Prepare Mineral Acid Salts Characterize chemical stability Characterize chemical stability Prepare Organic Salts Prepare Organic Salts Test for absorption Test for absorption Select Salt form to commercialize 45

Hydrotropic effect: 

Hydrotropic effect Hydrotropic effect is taken as the increase of saturation solubility of a substance in water by the addition of organic salts or also non-electrolytes which of course must be physiologically compatible for pharmaceutical application. These hydrotropic substances are able to increase the number of hydrogen bridges in the water clusters . This makes the water more hydrophobic & a better solvent for non-polar drug . 46

Solid solution: 

Solid solution Mechanisms of enhancing the solubilization of poorly water soluble drug in solid solution Reduction Of Particle size. The resulting enhanced surface area produces higher dissolution rate & bioavailability Carrier material have solubilization effect on the drug. Carrier material enhances wettability & Dispersability. Formation of the metastable dispersions. 47

CLASSIFICATION OF SOLID SOLUTION: 

CLASSIFICATION OF SOLID SOLUTION 48

PowerPoint Presentation: 

CONTINUOUS SOLID SOLUTION In this type of solid solution the two components are miscible in the solid state in all proportion. DISCONTINUOUS SOLID SOLUTION In contrast to the continuous solid solution, there is only a limited solubility of a solute in a solid solvent in this group of solid solution 49

PowerPoint Presentation: 

SUBSTITUTIONAL INTERSTITIAL 50

SOLID DISPERSION: 

SOLID DISPERSION Classification of S.D. : -Simple eutectic mixture. -Solid solution. -Glass solution and glass suspension. -Amorphous precipitations in a crystalline carrier. -Compound or Complex formation. -Combinations of previous five types-- 51

Solid dispersion: 

Solid dispersion Methods of preparation of solid dispersion: Melting / fusion method. Solvent method. Melting-solvent method. (Encyclopedia of P T, VOL- 3, page 337) Cogrinding method. Kneading method. (C.A. VOL- 142, No: - 9. Feb- 28, 2005, 162219f) 52

Comparison: 

Comparison 53

POLYMORPHISM : 

POLYMORPHISM Definition: : Polymorphism is the ability of an element or compound to crystallize in more then one crystalline form. 54

PowerPoint Presentation: 

PSEUDOPOLYMORPHISM Stoichiometric type of adducts where the solvent molecule are incorporated into the crystalline lattice of the solid are called as the solvates and the trapped solvent as solvent of the crystallization. When the solvent in the association with the drug is water, the solvate is known as Hydrates. Anhydrous form Hydrates Solubility > Thermodynamically higher energy state They are already in interaction with water and therefore have less energy for crystal breakup for further interaction with water 55

Importance of polymorphism under solubilization and solubilized systems: 

Importance of polymorphism under solubilization and solubilized systems Different arrangement of molecules in the crystalline lattice Melting Point Heat Capacity Conductivity Bulk Density Hardness Morphology Hygroscopicity Dissolution rate Solubility 56

Effect of polymorphs on dissolution rate & oral absorption: 

Effect of polymorphs on dissolution rate & oral absorption Ch. Palmitate Ready for absorption Hydrolysis Intestinal esterase In vitro hydrolysis Pancreatin Significant hydrolysis of P-B Little hydrolysis of P-A P-B is more soluble than P-A. This solubility difference results in diff. in ester hydrolysis rate & ultimately diff in oral absorption. 57

COMPLEXATION (CYCLODEXTRINE): 

COMPLEXATION (CYCLODEXTRINE) Cyclodextrin are widely used in the pharmaceutical field owing their high aqueous solubility and ability to enhance solubility of poorly water soluble drugs The two types of complexation that are useful for increasing the solubility of drugs in aqueous media are Stacking and Inclusion 58

Types of complexation: 

Types of complexation Stacking complexes are formed by the overlap of planar regions of aromatic molecules. Inclusion complexes are formed by the insertion of the nonpolar region of one molecule into the cavity of another molecule (or group of molecules). 59

Self-Association and Stacking Complexation: 

Self-Association and Stacking Complexation Nonpolar moieties tend to be squeezed out of water by the strong hydrogen bonding interactions of the water. This causes some molecules to minimize the contact with water by aggregation of their hydrocarbon moieties. This aggregation is favored by large planar nonpolar regions in the molecule. Stacked complexes can be homogenous or mixed. The former is known as self-association and the later as complexation. Examples of substances that interact in an aqueous media by stacking are Naphthalene, benzoic acid, pyrene, methylene blue, caffeine etc. 60

Inclusion Complexes: 

Inclusion Complexes 61

WHAT ARE CYCLODEXTRINS USED FOR? : 

WHAT ARE CYCLODEXTRINS USED FOR? To increase aqueous solubility of drugs. To increase chemical stability of drugs. To enhance drug delivery to and through biological membranes. To increase physical stability of drugs. To convert liquid drugs to microcrystalline powders. To prevent drug-drug and drug-excipient interactions. To reduce local irritation after topical or oral administration. 62

SOLUTE –SOLVENT COMPLEXATION: 

SOLUTE –SOLVENT COMPLEXATION The association process of solute molecule to the solvent based on the “ DONOR –ACCEPTOR” mechanism In this process Lewis base donating loan pair of electron and lewis acid accepting loan pair electron. For as example iodine is lewis acid and it associate to lewis base like ether and carbonyl compound 63

SOLVENT DEPOSITION: 

SOLVENT DEPOSITION In this method, the poorly aqueous soluble drug such as nifedipine is dissolved in an organic solvent like alcohol and deposited on inert, hydrophilic, solid matrix such as starch or micro-crystalline cellulose by evaporation of solvent. 64

SELECTIVE ADSORPTION ON IN SOLUBLE CARRIERS: 

SELECTIVE ADSORPTION ON IN SOLUBLE CARRIERS A highly active adsorbent such as in organic clays like bentonite can enhance dissolution rate of poorly water soluble drugs such as griseofulvin, indomethacin and prednisone by maintaining the concentration gradient at its maximum. 65

FAST DISSOLVING PRODCUTS: 

FAST DISSOLVING PRODCUTS “ Fast dissolving system can be defined as a dosage form for oral administration , which when placed in the mouth disintegrates rapidly or dissolves and can be swallowed in the form of liquid.” 66

CHARACTERISTICS OF FAST DISSOLVING PRODUCTS: 

CHARACTERISTICS OF FAST DISSOLVING PRODUCTS Taste of the medicament T aste making of the drugs become critical to the patient compliance. Hygroscopicity: They need protection from humidity which calls for specialized product packaging. 67

PowerPoint Presentation: 

Friability: In order to allow fast dissolving tablets to dissolve in the mouth, they are made of either very porous or self-moulded matrices or compressed into tablets with very low compression force, which makes the tablet friable and/or brittle which are difficult to handle, often requiring specialized peel-off blister packing. 68

STEPS FOR PREPARATION OF THE FAST DISSOLVING PRODUCTS: : 

STEPS FOR PREPARATION OF THE FAST DISSOLVING PRODUCTS: 69

PATENTED TECHNOLOGIES: 

PATENTED TECHNOLOGIES 70

COMBINE TECHNIQES OF SOLUBILIZATION   : 

COMBINE TECHNIQES OF SOLUBILIZATION a. pH and complexation The effect of pH on solubilization by complexation will depend entirely on the given solute and ligand 71

PowerPoint Presentation: 

b. pH and Surfactants As we increase the concentration of surfactant ( Polysorbate 20 or 80) linear increase in solubility is seen for Flavopiridol . But, solubility increase is much greater at pH 4.3 than that at 8.4. Ex. Flavopridol 72

PowerPoint Presentation: 

c. combination of Cosolvents and Surfactants Glycerol has also been used with polysorbate 80 to improve the solubility of vitamin A. Example Gelucire 44/14 is a surface-active excipient that can solubilize poorly soluble drugs. Gelucire form micelles. 73

CLATHRATES: 

CLATHRATES Definition : A special type of inclusion compound in which the host molecules form a crystal lattice containing spaces into which guest molecules can fit.” The macrocyclic molecule is called the HOST. The small included molecule is the GUEST. The inclusion process gives rise to HOST-GUEST CHEMISTRY 74

NANOSTRUCTURE FORMATION : 

NANOSTRUCTURE FORMATION It is done by two method. CONTROLLED PRECIPITATION Controlled precipitation is a particle engineering technology that creates crystalline nanostructure drug particles with rapid dissolution rates 2. ULTRA RAPID FREEZING Ultra-rapid freezing is a novel, cryogenic technology that creates nanostructured drug particles with greatly enhanced surface area. 75

HYDROTROPIC SOLUBILIZATION: 

HYDROTROPIC SOLUBILIZATION Hydrotropy is a solubilization process whereby addition of large amoumt of a second solute result in an increase in the aqueous solubility of a sparingly soluble solute. eg.Nicotinamide, Vitamin B3 76

STUDY QUESTIONS : 

STUDY QUESTIONS What is solubilization? Why should we go for solubilization? Why are cyclodextrins better than organic solvents? Describe the different methods of preparation of drug–cyclodextrin complexes. 2003 Explain Solubilization using combination of pH and complexation. Describe solubility principle. Why compounds are insoluble ? What is solubilization ? Describe factor affecting solubility & dissolution. Why we should go for solubilization ? 77

PowerPoint Presentation: 

REFERENCES Encyclopedia of Pharmaceutical technology, Volume 3, Edited By James Swarbrick Encyclopedia of Pharmaceutical technology, Volume 18, Edited By James Swarbrick Advanced pharmaceutical solids Vol 110 edited by Jeans . T.Carstenson Pharmaceutics: The science of dosage form design, edited by Aulton . Physical Pharmacy, Third edition, By Alfred Martin The theory and practice of Industrial Pharmacy, By Leon Lachman The Science and Pharmacy practice Remington vol:1 Indian Journal of Pharmaceutical Science, May-June, 2006, 301-307 Drug development and Industrial pharmacy.2007,39(8), 856-873 Biopharmaceutics and Pharmacokinetics a treatise by D.M.Brahmankar , second edition, page no 349 to 359 www.SCOLR.com www.wikipedia.com Thank You… www.pharmscitech.org 78

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QUESTIONS…….???? 79

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Thank You… 80

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