Methods of solubility enhancements
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This document discusses various methods for enhancing the solubility of poorly soluble drugs, which is important for improving their bioavailability. It describes solubility and defines it qualitatively and quantitatively. It then explains the need for and categories of solubility enhancement techniques, including physical modifications, chemical modifications, and miscellaneous methods. Some key physical modification techniques discussed are particle size reduction through micronization and nanosuspensions, modifying the crystal habit through polymorphism, and using drug carriers like solid dispersions and cryogenic techniques. Chemical modification techniques include changing the pH, complexation, salt formation, and neutralization. Miscellaneous methods include microemulsions, use of adjuvants like surfactants, and cosolvency.
Methods of solubility enhancements
- 2. What is SOLUBILITY ??? • Solubility is defined in two terms- 1.Qualitative term- It can be defined as the spontaneous interaction of two or more substances to form a homogenous solution. 2.Quntitative term- It can be defined as the concentration of solute in saturated solution at given temperature.
- 3. Solubility as per IP
- 4. What is SOLUBILITY ENHANCEMENT • Unfortunately, many drugs are not sufficiently soluble in water and aqueous. Drug solubility must be increased by the inclusion of other solvents and chemicals, that process is called solubility enhancement. • And the chemical or solvent which is used to increase solubility is called solubility enhancer. • The nature of solubility enhancer is depends on the drug molecule and the route of administration, as well as the intended patient population.
- 5. WHY SOLUBILITY IS IMPORTANT • The solubility of poorly water soluble drugs is an important concept to reach into systemic circulation to show its pharmacological response. • The solubility improvement mainly depends on the selection of proper method.The selection of suitable method for solubility enhancement is depends on drug properties like melting point, solubility, chemical nature, physical nature, pharmacokinetic behavior. • We can increase solubility of drug by EnhancementTechniques.
- 6. SOLUBILITY ENHANCEMENT TECHNIQUES • Solubility enhancement techniques can be categorized in to three types which are given below- i. Physical Modifications ii. Chemical Modifications iii. Miscellaneous Methods
- 7. PHYSICAL MODIFICATIONS • Particle size reduction 1. micronization 2. nanosuspension • Modification of the crystal habit 1. polymorphs 2. amorphous form • Drug dispersion in carriers 1. eutectic mixtures 2. cryogenic techniques 3. solid dispersion
- 8. CHEMICAL MODIFICATIONS • Change of pH • Use of buffer • Neutralization • Complexation • Salt formation
- 9. MISCELLANEOUS METHODS • Supercritical fluid process • Sonocrystalization • Micro-emulsion • Use of adjuvant • Surfactant • Solubilizers • Cosolvency • Hydrotrophy
- 11. PARTICAL SIZE REDUCTION • The solubility of drug is often intrinsically related to drug particle size; as a particle become smaller, the surface area to vol. ratio increases.The larger surface area allows greater interaction with the solvent which causes an increase in solubility. By reducing particle size, increased surface area improves the dissolution properties. Micronization • Micronization is another conventional technique for the particle size reduction. Micronization increases the dissolution rate of drugs through increased surface area; by decreasing particle size, it does not increase equilibrium solubility. • Micronization of drugs is done by milling techniques using jet mill, rotor stator colloid mills and so forth micronization is not suitable for drugs having a high dose number because it does not change the saturation solubility of the drug.
- 12. Nanosuspension • This technology is applied to poorly soluble drugs that are insoluble in both water and oils. • A pharmaceutical nanosuspension is biphasic systems consisting of nano sized drug particles stabilized by surfactants for either oral and topical use or parenteral and pulmonary administration. • The particle size distribution of the solid particles in nanosuspensions is usually less than one micron with an average particle size ranging between 200 and 600 nm.
- 13. MODIFICATIONS OF THE CRYSTAL HABIT Polymorphs • Different crystalline forms of a drug that may have different properties are known as Polymorphs. • Polymorphs may differ in physicochemical properties such as physical and chemical stability, shelf-life, melting point, vapor pressure, intrinsic solubility, dissolution rate, morphology, density and biological activities as well as bioavailability. • Amongst the stable, unstable and metastable crystalline polymorphs, metastable forms are associated with higher energy with increased surface area, subsequently solubility, bioavailability and efficacy. • With regard to bioavailability, it is preferable to change drug from crystal forms into metastable or amorphous forms. However, the possibility of a conversion of the high energy amorphous or metastable polymorph into a low energy crystal form having low solubility cannot be ruled out during manufacture and storage. • It is preferable to develop the most thermodynamically stable polymorph of the drug to assure reproducible bioavailability of the product over its shelf-life under a variety of real-world storage conditions.
- 14. Drug dispersion in carriers Solid Dispersion The fusion(melt) method: • Accurately weighed amounts of carrier(s) are placed in an aluminum pan on a hot plate and liquefy, with constant stirring, at a temperature of about 60°C. • An accurately weighed amount of active drug is incorporated into the melted carrier(s) with stirring to ensure homogeneity. • The mixture is heated until a clear homogeneous melt is obtained.The pan isthen removed from the hot plate and allowed to cool at room temperature. The solvent method: • Accurately weighed amounts of active drug and carrier(s) are dissolved in minimum quantities of chloroform in a round-bottom flask. • The solvent is removed using a rotary evaporator.The obtained solid dispersion is transferred on to the aluminum pan and allowed to dry at room temperature.
- 15. Dropping method: • A solid dispersion of a melted drug-carrier mixture is pipetted and then dropped onto a plate, where it solidifies into round particles. • The size and shape of the particles can be influenced by factors such as the viscosity of the melt and the size of the pipette. • Because viscosity is highly temperature dependent, it is very important to adjust the temperature so that when the melt is dropped onto the plate it solidifies to a globular shape.
- 16. CryogenicTechniques Spray Freezing ontoCryogenicFluids: • Briggs and Maxwell invented the process of spray freezing onto cryogenic fluids. In this technique, the drug and the carrier (mannitol, maltose, lactose, inositol, or dextran) were dissolved in water and atomized above the surface of a boiling agitated fluorocarbon refrigerant. Sonication probe can be placed in the stirred refrigerant to enhance the dispersion of the aqueous solution. Spray Freezing intoCryogenic Liquids (SFL): • The SFL particle engineering technology has been used to produce amorphous nanostructured aggregates of drug powder with high surface area and good wettability. • It incorporates direct liquid-liquid impingement between the automatized feed solution and cryogenic liquid to provide intense atomization into microdroplets and consequently significantly faster freezing rates.The frozen particles are then lyophilized to obtain dry and free-flowing micronized powders.
- 17. Spray Freezing intoVapor over Liquid(SFV/L): • Freezing of drug solutions in cryogenic fluid vapours and subsequent removal of frozen solvent produces fine drug particles with high wettability. • During SFV/L the atomized droplets typically start to freeze in the vapour phase before they contact the cryogenic liquid.As the solvent freezes, the drug becomes supersaturated in the unfrozen regions of the atomized droplet, so fine drug particles may nucleate and grow. Ultra-Rapid Freezing (URF): • Ultra-rapid freezing is a novel cryogenic technology that creates nanostructured drug particles with greatly enhanced surface area and desired surface morphology by using solid cryogenic substances.Application of drugs solution to the solid surface of cryogenic substrate leads to instantaneous freezing and subsequent lyophilization (for removal of solvent) forms micronized drug powder with improved solubility. Ultra rapid freezing hinders the phase separation and the crystallization of the pharmaceutical ingredients leading to intimately mixed, amorphous drug-carrier solid dispersions, and solidsolutions
- 19. Change of pH • Poor water soluble drug may potentially dissolve in water by applying a pH change. • Toaccess the solubility of this approach, the buffer capacity and tolerability of the selected pH are important to consider. • Solubilized excipients that increase environmental pH within the dosage form to a range higher than pKa of weekly acidic drugs increase the solubility of that drug, those excipients that act as alkalizing agents may increase the solubility of weekly basic drugs.
- 20. COMPLEXATION Physical Mixture: • Active drug with suitable polymer in different ratios mixed in a mortar for about one hour with constant trituration.The mixture is passed through sieve no. 80 and stored in dessicator over fused calcium chloride.
- 21. Co-precipitate Method: • Active drug is dissolved in ethanol at room temperature and suitable polymer is dissolved in distilled water. • Different molar ratios of active drug and suitable polymers are mixed respectively.The mixture is stirred at room temperature for one hourand the solvent is evaporated. • The resultant mass is pulverized and passed through sieve no. 80 and stored in a desiccators.
- 22. SALT FORMATION • Dissolution rate of particular salt is usually different from that of parent compound. Sodium and potassium salt of weak acid dissolve more rapidly than that of pure salt. • Limitation of salt formation includes epigastric distress due to high alkalinity, reactivity with atmospheric water and carbon dioxide leads to precipitation, patient amenableness and commercilation.
- 23. NEUTRALIZATION • Drug is added in alkaline solution like sodium hydroxide, ammonium hydroxide. • A solution of β- Cyclodextrin is then added to dissolve the joined drug.The clear solution obtained after few seconds under agitation is neutralized using HCl solution until reaching the equivalence point. • At this moment, the appearance of a white precipitate could be appreciated, corresponding to the formation of the inclusion compound.The precipitate is then filtered and dried.
- 25. SONOCRYSTALIZATION • Recrystallization of poorly soluble materials using liquid solvents and antisolvents has also been employed successfully to reduce particle size. • The novel approach for particle size reduction on the basis of crystallization by using ultrasound is Sonocrystallization. • Sonocrystallization utilizes ultrasound power characterised by a frequency range of 20–100 kHz for inducing crystallization. It’s not only enhances the nucleation rate but also an effective means of size reduction and controlling size distribution of the active pharmaceutical ingredients. • Most applications use ultrasound in the range 20 kHz-5 MHz.
- 26. MICRO-EMULSION • A micro emulsion is an optically clear pre-concentrate, isotropic, thermo dynamically stable transparent (or translucent) system, 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 to form a very clear emulsion of exceedingly small and uniform oil droplets containing the solubilized poorly soluble drug. • Micro-emulsions 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.
- 27. USE OFADJUVANT Surfactants • Surfactants are molecules with distinct polar and nonpolar regions. • Most surfactants consist of a hydrocarbon segment connected to a polar group. The polar group can be anionic, cationic, zwitterionic or nonionic. • When small polar molecules are added they can accumulate in the hydrophobic core of the micelles. This process of solubilization is very significant in industrial and natural processes. • The addition of surfactants may decrease the surface tension and increase the solubility of the drug within an organic solvent. • The use of surfactants to improve the dissolution performance of poorly soluble drug products is possibly the fundamental, chief, and the oldest method. • Surfactants are the agents which reduces surface tension and enhance the dissolution of lipophilic drugs in aqueous medium.The surfactants are also used to stabilize drug suspensions.
- 28. • When the concentration of surfactants more than their critical micelle concentration (which is in the range of 0.05–0.10% for most surfactants), micelle formation occurs which entrap the drugs within the micelles.This is known as micellization and generally results in enhanced solubility of poorly soluble drugs. Hydrotropy • Hydrotropy is a solubilization phenomenon whereby addition of large amount of a second solute results in an increase in the aqueous solubility of existing solute. • Concentrated aqueous hydrotropic solutions of sodium benzoate, sodium salicylate, urea, nicotinamide, sodium citrate, and sodium acetate have been observed to enhance the aqueous solubilities of many poorly water- soluble drugs.
- 29. Cosolvency • The solubility of poorly soluble drugs in water can be increased by mixing it with some water miscible solvent in which the drug is readily soluble.This process is known as cosolvency and the solvent used in combination are known as cosolvent. • Cosolvent system works by reducing the interfacial tension between the aqueous solution and hydrophobic solute. It is also commonly known as solvent blending. • There is a dramatic change in the solubility of drugs by addition of organic co-solvent into the water. The cosolvents are having hydrogen acceptor or donor groups with a small hydrocarbon region. • The hydrophobic hydrocarbon region usually interferes with the hydrogen bonding network of water which consequently reduces the intermolecular attraction of water while the hydrophilic hydrogen bonds ensures water solubility.
- 30. REFERENCES • Savjani KT,GajjarAK, Savjani JK, Drug solubility: Importanceand EnhancementTechniques. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3399483/ • Aulton ME,Taylor K,Aulton’s Pharmaceautics-The Design and Manufacture of Medicines, Churchill Livingstone ELSEVIER, Fourth Edition • Lachman L, Lieberman HA,TheTheory and Practice of IndustrialPharmacy, CBS Publication & Distributors Pvt. Ltd. Special Indian Edition 2009. • MartinA, Sinko PJ,Martin’s Physical Pharmacy & PharmaceauticalSciences, Sixth Edition.
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