solubilityenhancingtechnique2 by Kuldeep

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A SEMINAR ON SOLUBILITY ENHANCING TECHNIQUES :

A SEMINAR ON SOLUBILITY ENHANCING TECHNIQUES Pesented by Kuldeep Saikia Dibrugarh University Department of Pharmaceutical Sciences

Introduction:

Introduction Therapeutic effectiveness of a drug depends upon the bioavailability and ultimately upon the solubility of drug molecules. Solubility is one of the important parameter to achieve desired concentration of drug in systemic circulation for pharmacological response to be shown. The objective of this chapter is to consider the use of solubility enhancing techniques in altering apparent solubility. Solubility: The maximum amount of solute dissolved in a given solvent under standard conditions of temperature, pressure and pH is called as solubility. This process is called as solubilization. 2

Factors affecting solubility:

Factors affecting solubility 3

Techniques for solubility enhancement :

Techniques for solubility enhancement 4 Physical modification Particle size reduction Modification of crystal habit Drug dispersion in carrier Complexetion Slubilization by surfactants

Continued..:

Continued.. 5 Chemical modification Co- crystalization Salt formation Cosolvency Hydro trophy Use of soluble prodrug Nanotechnology approach

PARTICLE SIZE REDUCTION: MICRONIZATION: Micronisation increases the dissolution rate of drugs through increased surface area . Conventional methods of particle size reduction > comminution and spray drying, > milling techniques using jet mill, rotor stator, colloid mills etc. Micronization is not suitable for drugs having a high dose number because it does not change the saturation solubility of the drug. :

PARTICLE SIZE REDUCTION : MICRONIZATION: Micronisation increases the dissolution rate of drugs through increased surface area . Conventional methods of particle size reduction > comminution and spray drying, > milling techniques using jet mill, rotor stator, colloid mills etc. Micronization is not suitable for drugs having a high dose number because it does not change the saturation solubility of the drug. 6 PHYSICAL METHOD

NANOSUSPENSION: Nanosuspensions are sub-micron colloidal dispersion of pure particles of drug, which are stabilized by surfactants. > increase in dissolution rate due to larger surface area. Techniques for production of nanosuspension a) Homogenization: by >conventional homogenizers > sonicators > high shear fluid processors b) Wet milling: Active drug in the presence of surfactant is defragmented by milling. :

NANOSUSPENSION: Nanosuspensions are sub-micron colloidal dispersion of pure particles of drug, which are stabilized by surfactants. > increase in dissolution rate due to larger surface area. Techniques for production of nanosuspension a) Homogenization : by >conventional homogenizers > sonicators > high shear fluid processors b) Wet milling: Active drug in the presence of surfactant is defragmented by milling. 7

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8 Supercritical fluid process : do A SCF exists as a single phase above its critical temperature ( Tc ) and pressure (Pc) exist as intermediate between those of pure liquid and gas. Basic techniques in SCF technology: >Rapid expansion of super critical solution >Gas antisolvent recrystalization >Precipitation with compressed fluid antisolvent >Solution enhanced dispersion by super critical fluid

Sonocrytalization: do :

Sonocrytalization : do 9 Ultrasound acts on a liquid or melt mixtures causing cavitations and extreme molecular motion, which divides the drop of material into number of micro drops of narrow size range. One of the mechanical effects cause by ultrasonification is disaggregation or deagglomeration of the particle assembling.

Modification of the crystal habit: Polymorphism is the ability of an element or compound to crystallize in more then one crystalline form. Polymorphs can be classified in to two types based on thermodynamics properties 1. enantiotropes 2. monotropes. Metastable forms are associated with higher energy and thus higher solubility. Dissolution order of different solid forms- Amorphous > Metastable polymorph > Stable polymorph :

Modification of the crystal habit: Polymorphism is the ability of an element or compound to crystallize in more then one crystalline form. Polymorphs can be classified in to two types based on thermodynamics properties 1. enantiotropes 2. monotropes . Metastable forms are associated with higher energy and thus higher solubility. Dissolution order of different solid forms- Amorphous > Metastable polymorph > Stable polymorph 10

Drug dispersion in carriers: The term “solid dispersions” refers to the dispersion of one or more active ingredients in an inert carrier in a solid state. The most commonly used hydrophilic carriers for solid dispersions include: polyvinylpyrrolidone,polyethylene glycols,Plasdone. Example: etoposide, glyburide, itraconazole. Solid dispersions are prepared by following methods: :

Drug dispersion in carriers: The term “solid dispersions” refers to the dispersion of one or more active ingredients in an inert carrier in a solid state. The most commonly used hydrophilic carriers for solid dispersions include: polyvinylpyrrolidone,polyethylene glycols,Plasdone . Example: etoposide , glyburide , itraconazole . Solid dispersions are prepared by following methods: 11 >hot-melt method >Solvent evaporation method >Hot-melt extrusion >Melting solvent method

Complxetion: Complexation is the association between two or more molecules to form a nonbonded entity with a well defined stoichiometry. Complexation relies on relatively weak forces such as london forces, hydrogen bonding and hydrophobic interactions. Factors affecting complexation: 1. Steric effects 2. Electronic effects a. Effect of proximity of charge to CD cavity b. Effect of charge density c. Effect of charge state of CD and drug 3. Temperature, additives and cosolvent effects :

Complxetion : Complexation is the association between two or more molecules to form a nonbonded entity with a well defined stoichiometry . Complexation relies on relatively weak forces such as london forces, hydrogen bonding and hydrophobic interactions. Factors affecting complexation: 1. Steric effects 2. Electronic effects a. Effect of proximity of charge to CD cavity b. Effect of charge density c. Effect of charge state of CD and drug 3. Temperature, additives and cosolvent effects 12

Types of complexes: >Staching complexation >Inclusion complexation Staching complexation: Staching complexes are formed by the overlap of the planar regions of aromatic molecules. Stached complexes can be homogeneous or mixed. Compounds that forms staching complexes are:- Nicotinamide, Anthracene, Pyrene, Methylene blue, Benzoic acid, Salicylic acid, Ferulic acid, Gentisic acid, Purine, Theobromine, Caffeine, and Naphthalene etc. :

Types of complexes: >Staching complexation >Inclusion complexation Staching complexation: Staching complexes are formed by the overlap of the planar regions of aromatic molecules. Stached complexes can be homogeneous or mixed. Compounds that forms staching complexes are:- Nicotinamide , Anthracene , Pyrene , Methylene blue, Benzoic acid, Salicylic acid, Ferulic acid, Gentisic acid, Purine , Theobromine , Caffeine, and Naphthalene etc. 13

Inclusion complexes: Inclusion complexes are formed by the insertion of the nonpolar molecule or the nonpolar region of one molecule (known as guest) into the cavity of another molecule or group of molecules. Inclusion complexes formed by Cyclodextrins, other types of molecular complexes also have been used to increase the solubility. Approaches for making Inclusion complexes: :

Inclusion complexes: Inclusion complexes are formed by the insertion of the nonpolar molecule or the nonpolar region of one molecule (known as guest) into the cavity of another molecule or group of molecules. Inclusion complexes formed by Cyclodextrins , other types of molecular complexes also have been used to increase the solubility. Approaches for making Inclusion complexes: 14 >Physical blending method >Kneading method >Co-precipitation technique >Solution/ solvent evaporation method >Neutralization precipitation method

Solubilazation by surfactants: Surfactants (surface-active-agents) , are substance which at low concentration ,adsorb onto the surface or interface of a system &alter the surface or interfacial free energy &alter the surface or interfacial tension , thus facilitate the solubilisation. Microemulsion: A microemulsion is an optically clear mixture of oil, hydrophilic surfactant and hydrophilic solvent. Upon contact with water, the formulations spontaneously disperse to form a very clear emulsion of exceedingly small and uniform oil droplets containing the solubilized poorly soluble drug. :

Solubilazation by surfactants: Surfactants (surface-active-agents) , are substance which at low concentration ,adsorb onto the surface or interface of a system &alter the surface or interfacial free energy &alter the surface or interfacial tension , thus facilitate the solubilisation . Microemulsion : A microemulsion is an optically clear mixture of oil, hydrophilic surfactant and hydrophilic solvent. Upon contact with water, the formulations spontaneously disperse to form a very clear emulsion of exceedingly small and uniform oil droplets containing the solubilized poorly soluble drug. 15

Self emulsifying drug delivery system: Self-emulsifying drug delivery systems (SEDDS) are mixtures of oils and surfactants, ideally isotropic, sometimes including co solvents, which emulsify under conditions of gentle agitation. The self-emulsification process is specific to the nature of the oil/surfactant pair, surfactant concentration, oil/surfactant ratio and temperature at which self-emulsification occurs. :

Self emulsifying drug delivery system: Self-emulsifying drug delivery systems (SEDDS) are mixtures of oils and surfactants, ideally isotropic, sometimes including co solvents, which emulsify under conditions of gentle agitation. The self-emulsification process is specific to the nature of the oil/surfactant pair, surfactant concentration, oil/surfactant ratio and temperature at which self-emulsification occurs. 16

Co-crystalization: A co-crystal may be defined as a crystalline material that consists of two or more molecular (and electrically neutral) species held together by non-covalent forces. Co crystals can be prepared by evaporation of a heteromeric solution or by grinding the components together. Another technique for the preparation of co-crystals includes sublimation, growth from the melt, and slurry preparation. :

Co- crystalization : A co-crystal may be defined as a crystalline material that consists of two or more molecular (and electrically neutral) species held together by non-covalent forces. Co crystals can be prepared by evaporation of a heteromeric solution or by grinding the components together. Another technique for the preparation of co-crystals includes sublimation, growth from the melt, and slurry preparation. 17 CHEMICAL METHOD

Salt formation: Salt formation is the most common and effective method of increasing solubility and dissolution rates of acidic and basic drugs. Primary or essential criteria for the selection of a particular form of salt: :

Salt formation: Salt formation is the most common and effective method of increasing solubility and dissolution rates of acidic and basic drugs. Primary or essential criteria for the selection of a particular form of salt: 18 > Aqueous solubility measured at various pH values. >High degree of crystallinity . >Low hygroscopicity , which gives consistent performance. >Optimal chemical and solid-state stability under accelerated conditions.

Cosolvancy: Cosolvents are water-miscible organic solvents used to increase the solubility of poorly water-soluble substances or to enhance the chemical stability of a drug. It is also commonly referred to as solvent blending. Most cosolvents their hydrophilic hydrogen bonding groups ensure water miscibility while their hydrophobic hydrocarbon regions interfere with water hydrogen bonding network, reducing the overall intermolecular attraction of water, by disrupting waters self-association. Examples of cosolvents used for formulation: Propylene glycol, Ethyl alcohol, Glycerine, Polyethylene glycol, Dimethyl sulfoxide , Ethyl acetate etc. :

Cosolvancy : Cosolvents are water-miscible organic solvents used to increase the solubility of poorly water-soluble substances or to enhance the chemical stability of a drug. It is also commonly referred to as solvent blending. Most cosolvents their hydrophilic hydrogen bonding groups ensure water miscibility while their hydrophobic hydrocarbon regions interfere with water hydrogen bonding network, reducing the overall intermolecular attraction of water, by disrupting waters self-association. Examples of cosolvents used for formulation: Propylene glycol, Ethyl alcohol, Glycerine , Polyethylene glycol, Dimethyl sulfoxide , Ethyl acetate etc. 19

Hydrotrophy: Hydrotrophy designate the increase in solubility in water due to the presence of large amount of additives. The mechanism - related to complexation involving a weak interaction between the hydrotrophic agents (sodium benzoate, sodium acetate, sodium alginate, and urea) and the solute. Example: Solubilisation of Theophylline with sodium acetate and sodium alginate.:

Hydrotrophy : Hydrotrophy designate the increase in solubility in water due to the presence of large amount of additives. The mechanism - related to complexation involving a weak interaction between the hydrotrophic agents (sodium benzoate, sodium acetate, sodium alginate, and urea) and the solute. Example: Solubilisation of Theophylline with sodium acetate and sodium alginate. 20

Use of soluble prodrug: Prodrug is a compound that must under go bioconversion before existing its pharmacological effect. The term prodrug refers to a drug with a covalently bound to the inactive moiety (promoiety) that provides the desired pharmaceutical properties, where the promoiety must be removed upon administration to regenerate the parent drug. Eg:Clindamycin2phosphate, chloramphenicol palmitate. :

Use of soluble prodrug : Prodrug is a compound that must under go bioconversion before existing its pharmacological effect. The term prodrug refers to a drug with a covalently bound to the inactive moiety ( promoiety ) that provides the desired pharmaceutical properties, where the promoiety must be removed upon administration to regenerate the parent drug. Eg:Clindamycin2phosphate, chloramphenicol palmitate . 21

Nanotechnology approach: do A nanocrystal is a crystalline material with dimensions measured in nanometers; a nanoparticle with a structure that is mostly crystalline. Nanocrystallization is thought to be a universal method that can be applied to any drug. Approaches for making nanocrytals: :

Nanotechnology approach: do A nanocrystal is a crystalline material with dimensions measured in nanometers; a nanoparticle with a structure that is mostly crystalline. Nanocrystallization is thought to be a universal method that can be applied to any drug. Approaches for making nanocrytals : 22 >Milling >High pressure homogenization > Cryso -vacuum method > Nanomorphs > Dissocudes > Nanoedge technology > Nanocrystal technology > Crititech technology

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23 CONCLUSION

References: 1) Leon Lachman; Herberta.Lieberman; Joseph L.Kanig The Theory And Practise Of Industrial Pharmacy . 3rd edition,pp 458. 2) Encyclopedia of pharma technology , pp2466 3) Alfred Martin.Physical Pharmacy , fourth edition, pp 212. 4) Solubility, From Wikipedia, the free encyclopedia. Retrieved from http://en.wikipedia.org/wiki/Solubility 5) Spray drying From Wikipedia, the free encyclopedia. Retrieved from http://en.wikipedia.org :

References: 1) Leon Lachman ; Herberta.Lieberman ; Joseph L.Kanig The Theory And Practise Of Industrial Pharmacy . 3 rd edition,pp 458. 2) Encyclopedia of pharma technology , pp2466 3) Alfred Martin.Physical Pharmacy , fourth edition, pp 212. 4) Solubility, From Wikipedia, the free encyclopedia. Retrieved from http://en.wikipedia.org/wiki/Solubility 5) Spray drying From Wikipedia, the free encyclopedia. Retrieved from http://en.wikipedia.org 24

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