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SOLUBILITY ENHANCEMENT TECHNIQUES
Compiled by:
Priyanka D. Dabir
Assistant Professor
Department of Pharmaceutics
Gokhale Education Society’s
Sir Dr. M.S. Gosavi College Of Pharmaceutical
Education & Research, Nashik-422005
Solubility
• Solubility is defined in quantitative terms as the concentration of the solute in a
saturated solution at a certain temperature and in qualitative terms, it may be
defined as the spontaneous interaction of two or more substances to form a
homogeneous molecular dispersion.
• A saturated solution is one in which the solute is in equilibrium with the solvent.
The solubility of a drug may be expressed as parts, percentage, molarity,
molality, volume fraction, and mole fraction.
• Drug solubility is the maximum concentration of the drug solute dissolved in the
solvent under specific condition of temperature, pH and pressure.
• The drug solubility in saturated solution is a static property where as the drug
dissolution rate is a dynamic property that relates more closely to the
bioavailability rate.
• Poorly water soluble drug present significant challenges during dosage form
designing due to their inadequate solubilization in digestive fluids and hence
solubility enhancement becomes necessary. It is now possible that to increase
the solubility of drug with the help of various techniques as mentioned:
Particle size reduction:
The bioavailability intrinsically related to drug particle size. By reducing
particle size, increased surface area improves the dissolution properties.
Particle size reduction can be achieved by micronization and
nanosuspension. Each technique utilizes different equipments for reduction
of the particle size.
1. Micronization
In micronization the solubility of drug is often intrinsically related to
drug particle size. By reducing the particle size, the increased
surface area improves the dissolution properties of the drug.
Micronization of drugs is done by 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.
2. Nanosuspension
Nanosuspension is another technique which is sub-micron colloidal
dispersion of pure particles of drug, which are stabilised by
surfactants. Nanosuspensions are produced by homogenization and
wet milling process.
• Advantages:
1. Liquid forms can be rapidly developed for early stage testing
(pre-clinical) that can be converted into solids for later clinical
development.
2. Typically, low excipient to drug ratios is required.
3. Formulations are generally well tolerated provided that strong
surfactants are not required for stabilisation.
• Disadvantages:
1. Due to the high surface charge on discrete small particles,
there is a strong tendency for particle agglomeration.
2. Developing a solid dosage form with a high pay load without
encouraging agglomeration may be technically challenging.
3. Technically, development of sterile intravenous formulations is
even more challenging.
Modification of the crystal habit
• Modification of the crystal habit Polymorphism is the ability of an element or
compound to crystallize in more then one crystalline form.
• Different polymorphs of drugs are chemically identical, but they exhibit
different physicochemical properties including solubility, melting point,
density, texture, stability etc.
• Broadly polymorphs can be classified as enantiotropes and monotropes
based on thermodynamic properties.
Drug dispersion in carriers
• The solid dispersion approach to reduce particle size and
therefore increase the dissolution rate and absorption of drugs
was first recognised in 1961.
• The term “solid dispersions” refers to the dispersion of one or
more active ingredients in an inert carrier in a solid state,
frequently prepared by the melting (fusion) method, solvent
method, or fusion solvent-method.
• Novel additional preparation techniques have included rapid
precipitation by freeze drying and using supercritical fluids
and spray drying , often in the presence of amorphous
hydrophilic polymers and also using methods such as melt
extrusion.
Complex formation
• Complexation is the association between two or more molecules to form a
nonbonded entity with a well defined stichiometry. Complexation relies on
relatively weak forces such as London forces, hydrogen bonding and
hydrophobic interaction.
• In aqueous solutions, cyclodextrins are able to form inclusion complexes
with many drugs by taking up the drug molecule or some lipophilic moiety of
the molecule, into the central cavity.
• No covalent bonds are formed or broken during complex formation, and the
drug molecules in complex are in rapid equilibrium with free molecules in
the solution.
• The driving forces for the complex formation include release of enthalpy rich
water molecules from the cavity, hydrogen bonding, Vander Waals
interaction, charge transfer interaction etc.
• The physicochemical properties of free cyclodextrin molecule differ from
those in complex. The stoichiometry of the complexes formed and the
numerical value of their stability constants can be determined by observing
the changes in physicochemical properties like solubility, chemical reactivity,
UV/VIS absorbance etc.
• By physical observation amongst all above solutions, 1M: 3.0M
solution of Nepafenac with SBE-β-CD was found to be clear after
sonication for 1 hr.
Solubilization by surfactants or solubilizing agents
• Microemulsions and Self microemulsifying drug delivery system
• Microemulsions have been employed to increase the solubility of many
drugs that are practically insoluble in water, along with incorporation of
proteins for oral, parenteral, as well as percutaneous / transdermal use.
• A microemulsion is an optically clear pre-concentrate containing a mixture of
oil, hydrophilic surfactant and hydrophilic solvent which dissolves a poorly
water soluble drug. Upon contact with water, the formulations
spontaneously disperse (or ‘self emulsifies’) to form a very clear emulsion of
exceedingly small and uniform oil droplets containing the solubilized poorly
soluble drug.
• A self microemulsifying drug delivery system (SMEDDS) is an anhydrous
system of microemulsions. It is composed of oil, surfactant and cosurfactant
and has the ability to form o/w microemulsion when dispersed in aqueous
phase under gentle agitation.
• The agitation required for the self-emulsification comes from stomach and
intestinal motility.
Co-crystallisation
• The new approach available for the enhancement of drug
solubility is through the application of the cocrystals, it is also
referred as molecular complexes.
• If the solvent is an integral part of the network structure and
forms at least two component crystals, then it may be termed
as co-crystal.
• If the solvent does not participate directly in the network itself,
as in open framework structures, then it is termed as clathrate
(inclusion complex).
• 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 are more stable, particularly as the co-crystallizing
agents are solids at room temperature.
Cosolvency
• Co-solvents are mixtures of water and one or more water miscible
solvents used to create a solution with enhanced solubility for poorly
soluble compounds.
• Historically, this is one of the most widely used techniques because
it is simple to produce and evaluate.
• Examples of solvents used in co-solvent mixtures are PEG 300,
propylene glycol or ethanol.
• Advantages: Simple and rapid to formulate and produce.
• Disadvantages: As with all excipients, the toxicity and tolerability
related with the level of solvent administered has to be considered
and uncontrolled precipitation occurs upon dilution with aqueous
media. The precipitates may be amorphous or crystalline and can
vary in size.
Hydrotrophy
• Hydrotrophy is a solubilisation process whereby addition of a large
amount of second solute results in an increase in the aqueous
solubility of another solute. Solute consists of alkali metal salts of
various organic acids.
• Hydrotropic agents are ionic organic salts. Additives or salts that
increase solubility in given solvent are said to “salt in” the solute and
those salts that decrease solubility “salt out” the solute.
• Advantages of hydrotropic solubilization technique:
• Hydrotropy is suggested to be superior to other solubilization
method, such as miscibility, micellar solubilization, cosolvency and
salting in, because the solvent character is independent of pH, has
high selectivity and does not require emulsification.
• It only requires mixing the drug with the hydrotrope in water and
does not require chemical modification of hydrophobic drugs, use of
organic solvents, or preparation of emulsion system.
REFERENCES:
• Chavan D.V., Waghmare P.V., Chinchole A.S., Bhusnure O.G., Usnale
S.V. Solubility Enhancing Methods for Poorly Soluble Drugs: A Review.
Int. Res J Pharm. App Sci., 2013, 3(2):190-203.
• Khan N. A. and Durakshan M. Cyclodextrin: An Overview. International
Journal of Bioassays, 2013, 02 (06):858-865.
• Anjana. M. N., Nair S.C., Jipnomon J. An Updated Review of
Cyclodextrins –An Enabling Technology for Challenging Pharmaceutical
Formulations. Int J Pharm Pharm Sci., 2013, 5(3): 54-58.
• Tirunagari M., Mehveen N., Qureshi M.F., Sultana J.P., Tirunagari V.
Solubility Enhancement of Flurbiprofen Using Different Solubilization
Techniques . Int J Pharm Pharm Sci., 2012, 4:97-100.
• Kulkarni S., Gupta S.P., Upmanyu N., Tonpay S. D., Solubility
Enhancement of Ophthalmic Indomethacin. J. Chem. Pharm. Res.,
2011, 3(4): 280-284.
• Wagh D. G., Shahi S.R., Dabir P. D., Deore S.V., Solubility
Enhancement of Nepafenac Using Different Solubilizers. Euro. J of
Pharm. Med. Res, 2016; 3(2); 181-185.

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Solubility enhancement techniques

  • 1. SOLUBILITY ENHANCEMENT TECHNIQUES Compiled by: Priyanka D. Dabir Assistant Professor Department of Pharmaceutics Gokhale Education Society’s Sir Dr. M.S. Gosavi College Of Pharmaceutical Education & Research, Nashik-422005
  • 2. Solubility • Solubility is defined in quantitative terms as the concentration of the solute in a saturated solution at a certain temperature and in qualitative terms, it may be defined as the spontaneous interaction of two or more substances to form a homogeneous molecular dispersion. • A saturated solution is one in which the solute is in equilibrium with the solvent. The solubility of a drug may be expressed as parts, percentage, molarity, molality, volume fraction, and mole fraction. • Drug solubility is the maximum concentration of the drug solute dissolved in the solvent under specific condition of temperature, pH and pressure. • The drug solubility in saturated solution is a static property where as the drug dissolution rate is a dynamic property that relates more closely to the bioavailability rate. • Poorly water soluble drug present significant challenges during dosage form designing due to their inadequate solubilization in digestive fluids and hence solubility enhancement becomes necessary. It is now possible that to increase the solubility of drug with the help of various techniques as mentioned:
  • 3.
  • 4. Particle size reduction: The bioavailability intrinsically related to drug particle size. By reducing particle size, increased surface area improves the dissolution properties. Particle size reduction can be achieved by micronization and nanosuspension. Each technique utilizes different equipments for reduction of the particle size. 1. Micronization In micronization the solubility of drug is often intrinsically related to drug particle size. By reducing the particle size, the increased surface area improves the dissolution properties of the drug. Micronization of drugs is done by 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. 2. Nanosuspension Nanosuspension is another technique which is sub-micron colloidal dispersion of pure particles of drug, which are stabilised by surfactants. Nanosuspensions are produced by homogenization and wet milling process.
  • 5. • Advantages: 1. Liquid forms can be rapidly developed for early stage testing (pre-clinical) that can be converted into solids for later clinical development. 2. Typically, low excipient to drug ratios is required. 3. Formulations are generally well tolerated provided that strong surfactants are not required for stabilisation. • Disadvantages: 1. Due to the high surface charge on discrete small particles, there is a strong tendency for particle agglomeration. 2. Developing a solid dosage form with a high pay load without encouraging agglomeration may be technically challenging. 3. Technically, development of sterile intravenous formulations is even more challenging.
  • 6. Modification of the crystal habit • Modification of the crystal habit Polymorphism is the ability of an element or compound to crystallize in more then one crystalline form. • Different polymorphs of drugs are chemically identical, but they exhibit different physicochemical properties including solubility, melting point, density, texture, stability etc. • Broadly polymorphs can be classified as enantiotropes and monotropes based on thermodynamic properties.
  • 7. Drug dispersion in carriers • The solid dispersion approach to reduce particle size and therefore increase the dissolution rate and absorption of drugs was first recognised in 1961. • The term “solid dispersions” refers to the dispersion of one or more active ingredients in an inert carrier in a solid state, frequently prepared by the melting (fusion) method, solvent method, or fusion solvent-method. • Novel additional preparation techniques have included rapid precipitation by freeze drying and using supercritical fluids and spray drying , often in the presence of amorphous hydrophilic polymers and also using methods such as melt extrusion.
  • 8. Complex formation • Complexation is the association between two or more molecules to form a nonbonded entity with a well defined stichiometry. Complexation relies on relatively weak forces such as London forces, hydrogen bonding and hydrophobic interaction. • In aqueous solutions, cyclodextrins are able to form inclusion complexes with many drugs by taking up the drug molecule or some lipophilic moiety of the molecule, into the central cavity. • No covalent bonds are formed or broken during complex formation, and the drug molecules in complex are in rapid equilibrium with free molecules in the solution. • The driving forces for the complex formation include release of enthalpy rich water molecules from the cavity, hydrogen bonding, Vander Waals interaction, charge transfer interaction etc. • The physicochemical properties of free cyclodextrin molecule differ from those in complex. The stoichiometry of the complexes formed and the numerical value of their stability constants can be determined by observing the changes in physicochemical properties like solubility, chemical reactivity, UV/VIS absorbance etc.
  • 9. • By physical observation amongst all above solutions, 1M: 3.0M solution of Nepafenac with SBE-β-CD was found to be clear after sonication for 1 hr.
  • 10. Solubilization by surfactants or solubilizing agents • Microemulsions and Self microemulsifying drug delivery system • Microemulsions have been employed to increase the solubility of many drugs that are practically insoluble in water, along with incorporation of proteins for oral, parenteral, as well as percutaneous / transdermal use. • A microemulsion is an optically clear pre-concentrate containing a mixture of oil, hydrophilic surfactant and hydrophilic solvent which dissolves a poorly water soluble drug. Upon contact with water, the formulations spontaneously disperse (or ‘self emulsifies’) to form a very clear emulsion of exceedingly small and uniform oil droplets containing the solubilized poorly soluble drug. • A self microemulsifying drug delivery system (SMEDDS) is an anhydrous system of microemulsions. It is composed of oil, surfactant and cosurfactant and has the ability to form o/w microemulsion when dispersed in aqueous phase under gentle agitation. • The agitation required for the self-emulsification comes from stomach and intestinal motility.
  • 11.
  • 12. Co-crystallisation • The new approach available for the enhancement of drug solubility is through the application of the cocrystals, it is also referred as molecular complexes. • If the solvent is an integral part of the network structure and forms at least two component crystals, then it may be termed as co-crystal. • If the solvent does not participate directly in the network itself, as in open framework structures, then it is termed as clathrate (inclusion complex). • 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 are more stable, particularly as the co-crystallizing agents are solids at room temperature.
  • 13. Cosolvency • Co-solvents are mixtures of water and one or more water miscible solvents used to create a solution with enhanced solubility for poorly soluble compounds. • Historically, this is one of the most widely used techniques because it is simple to produce and evaluate. • Examples of solvents used in co-solvent mixtures are PEG 300, propylene glycol or ethanol. • Advantages: Simple and rapid to formulate and produce. • Disadvantages: As with all excipients, the toxicity and tolerability related with the level of solvent administered has to be considered and uncontrolled precipitation occurs upon dilution with aqueous media. The precipitates may be amorphous or crystalline and can vary in size.
  • 14. Hydrotrophy • Hydrotrophy is a solubilisation process whereby addition of a large amount of second solute results in an increase in the aqueous solubility of another solute. Solute consists of alkali metal salts of various organic acids. • Hydrotropic agents are ionic organic salts. Additives or salts that increase solubility in given solvent are said to “salt in” the solute and those salts that decrease solubility “salt out” the solute. • Advantages of hydrotropic solubilization technique: • Hydrotropy is suggested to be superior to other solubilization method, such as miscibility, micellar solubilization, cosolvency and salting in, because the solvent character is independent of pH, has high selectivity and does not require emulsification. • It only requires mixing the drug with the hydrotrope in water and does not require chemical modification of hydrophobic drugs, use of organic solvents, or preparation of emulsion system.
  • 15. REFERENCES: • Chavan D.V., Waghmare P.V., Chinchole A.S., Bhusnure O.G., Usnale S.V. Solubility Enhancing Methods for Poorly Soluble Drugs: A Review. Int. Res J Pharm. App Sci., 2013, 3(2):190-203. • Khan N. A. and Durakshan M. Cyclodextrin: An Overview. International Journal of Bioassays, 2013, 02 (06):858-865. • Anjana. M. N., Nair S.C., Jipnomon J. An Updated Review of Cyclodextrins –An Enabling Technology for Challenging Pharmaceutical Formulations. Int J Pharm Pharm Sci., 2013, 5(3): 54-58. • Tirunagari M., Mehveen N., Qureshi M.F., Sultana J.P., Tirunagari V. Solubility Enhancement of Flurbiprofen Using Different Solubilization Techniques . Int J Pharm Pharm Sci., 2012, 4:97-100. • Kulkarni S., Gupta S.P., Upmanyu N., Tonpay S. D., Solubility Enhancement of Ophthalmic Indomethacin. J. Chem. Pharm. Res., 2011, 3(4): 280-284. • Wagh D. G., Shahi S.R., Dabir P. D., Deore S.V., Solubility Enhancement of Nepafenac Using Different Solubilizers. Euro. J of Pharm. Med. Res, 2016; 3(2); 181-185.