Review On Solubility Enhancement Techniques - Ijpbs

Available Online throughwww.ijpbs.com (or) www.ijpbsonline.comThe melted mixture was then cooled and solidifiedrapidly in an ice bath under rigorous stirring. Thefinal solid mass was crushed, pulverized, andsieved which improve the solubility andbioavailability of drug. Limitation regarding thismethod is at high temperature many drug may getdegraded. [17]3. Hot melt extrusion: [HME]HME can be simply defined as the process offorming a new material (the extrudate) by forcingit through an orifice or die under controlledconditions, such as temperature, mixing, feed-rateand pressure. HME differs from simple extrusionin that, polymer, drug and excipients blends aremixed thoroughly in the molten state in thisprocess, needing no solvents for granulation. Themolten polymer serves as the thermal binder. [18]Advantage of HME [19]1. Improve the solubility and bioavailability ofpoorly soluble compounds.2. Processing in the absence of solvents andwater.3. Economical process with reduced productiontime, fewer processing steps, and a continuousoperation.4. Uniform dispersion of fine particle occurs.5. Good stability at varying pH and moisturelevels.6. Safe application in humans due to their nonswellable and water insoluble nature.Disadvantages:1. Not applicable to heat sensitive material.IJPBS Volume 3 Issue 3 JUL-SEPT 2013 462-4752. Limited number of available polymer.3. This method requires high energy input.HME are complex mixture of active drug andexcipient. The commonly use polymer in HME yl cellulose, Hydroxypropylmethylcellulose, Poly(dimethylamino ethyl methacrylateco- methacrylate ester), Ammonio-comethacrylatecopolymer.Application of HME: [20]1) Masking the bitter taste of an active s which increased drugsolubility and increased drug dissolution rate.3) Formulation of controlled release dosage forms(including implants).4) Formulation of targeted release dosage forms.4. Super Critical Fluid Method: (SCF)Super critical fluid is fluid which exists as singlefluid above its critical temperature andpressure.SCF shows the properties of both a liquidand a gas above its critical condition. It is safe,environmentally friendly, and economical. The lowoperating conditions (temperature and pressure)make SCFs attractive for pharmaceutical research.At near-critical temperatures, SCFs are highcompressible, allowing moderate changes inpressure to greatly alter the density and masstransport characteristics of a fluid that largelydetermine its solvent power. [23] Once the drugparticles are solubilised within SCF, they may bere-crystallized at greatly reduced particle sizes.Page465Figure 1: Phase diagram of super critical fluid study. [21]International Journal of Pharmacy and Biological Sciences (e-ISSN: 2230-7605)Int J Pharm Bio SciS.V.Kadam* et alwww.ijpbs.com or www.ijpbsonline.com

Available Online throughwww.ijpbs.com (or) www.ijpbsonline.comCarbon dioxide is the most commonly used SCFbecause it is chemically inert, non toxic and nonflammable. Other supercritical solvents includenitrous oxide, ethylene, propylene, propane, npentane, ethanol, ammonia, and water. [22, 23]LIQUISOLID METHOD:In liquisolid technique liquid may be transfer intofree flowing, readily compressible and apparentlydry powder by simple blending with selectedcarrier and coating material. [24] The liquidportion which can be liquid drug, drug suspensionor drug solution in a suitable non volatile liquidvehicle can be converted into acceptably flowingand compressible powders by blending withselected powder excipients. The acceptableflowing and compressible powder form of liquidmedication is liquisolid compact. The liquisolid isIJPBS Volume 3 Issue 3 JUL-SEPT 2013 462-475newer and promising approach because of simplemanufacturing process, low production coast, andapplicable for industry due to good flow andcompact property of liquisolid formulation. Whenthe drug dissolved in the liquid vehicle isincorporated into a carrier material which has aporous surface and closely matted fibers in itsinterior as cellulose, both absorption andadsorption take place; i.e. the liquid initiallyabsorbed in the interior of the particles iscaptured by its internal structure, and after thesaturation of this process, adsorption of the liquidonto the internal and external surfaces of theporous carrier particles occur. Then, the coatingmaterial having high adsorptive properties andlarge specific surface area gives the liquisolidsystem the desirable flow characteristics. [25]Figure 2: Comparison of wettability between conventional tablet and liquisolid compacts. [26]Classification of liquisolid system:Classification based on type of liquid medicationcontain there in;1. Powdered drug solutions.2. Powdered drug suspensions.3. Powdered liquid drugs.Classification based on technique use forformulation;1. Liquisolid compacts.2. Liquisolid MicrosystemsPage466The wettability of the compacts by the dissolutionmedia is one of the proposed mechanisms forexplaining the enhanced dissolution rate from theliquisolid compacts. Non-volatile solvent presentin the liquisolid system facilitates wetting of drugparticles by decreasing interfacial tensionbetween dissolution medium and tablet surface.Fig.2 Shows lower contact angle of liquisolidcompacts than the conventional tablets and thusimproved wettability. [27]International Journal of Pharmacy and Biological Sciences (e-ISSN: 2230-7605)Int J Pharm Bio SciS.V.Kadam* et alwww.ijpbs.com or www.ijpbsonline.com

Available Online throughwww.ijpbs.com (or) www.ijpbsonline.comComponentNon Volatile LiquidsCarrier MaterialsCoating MaterialsDisintegrantsGlidantLubricantRelease retardantmaterialIJPBS Volume 3 Issue 3 JUL-SEPT 2013 462-475Table 3: Components of Liquisolid System. [28]ExamplesPoly Ethylene Glycol 200, Poly Ethylene Glycol 300, Poly Ethylene Glycol 400,Glycerine, Propylene Glycol, fixed oils.Microcrystalline Cellulose PH 101, Microcrystalline Cellulose PH 200, Lactose,Methyl Cellulose, Ethyl Cellulose, Starch1500, Ethocel, Eudragit RL, Eudragit RS12, Hydroxy Propyl Methyl Cellulose K4M, Hydroxy Propyl Methyl CelluloseK100M, Xanthum Gum, Guar gumAerosil 200, Silica (Cab-O-Sil M5), Syloid 244FP, and Colloidal Silicon Dioxide.Sodium Starch Glycolate (Explotab, Primogel), Croscarmellose Sodium, CrossPolyvinyl Pyrrolidine, Pregelatized Starch.Talc.Magnesium Stearate.Eudragit RS, RL, Hydroxy Propyl Methyl Cellulose K100M, K15M, K4M.Advantages of liquisolid method: [29]1. Method improves the solubility andbioavailability of orally administered waterinsoluble or poorly soluble drugs.2. Method is applicable in industry.3. Useful for the formulation of oily drugs/liquiddrugs.4. By using different carrier and additives drugrelease can be modified like PVP, PEG 60000,Hydroxy Propyl Methyl Cellulose and Eudragit etc.5. A number of poorly soluble drugs can beformulated in to the system.6. Production cost is low compared to that ofpreparation of soft gelatin capsules7. This system is specifically for the powderedliquid medications.Disadvantages of liquid solid method:1) High solubility of drug in the non-volatile liquiddrugs for the improvement of dissolution rate andbioavailability.2) It requires recipients of high adsorptionproperties and high specific surface area.Page467CategoryAromatic anionicsAromatic cationicsAliphatics and linear anionics3) It is not applicable to high dose insoluble drugs( 100 mg).4) During compression sometimes liquid drug maybe squeezed out of the tablet result in improperhardness.HYDROTROPY METHOD:The term Hydrotropy was coined by Carl Neubergin 1916 but the practical implications wereintroduced as late as 1976 by Thoma andcoworkers. [30] In this method by adding largeamount of secondary solute increase the aqueoussolubility of water insoluble drug.Mechanism of action of Hydrotropes:Hydrotropes are the compounds having both ananionic group and a hydrophobic aromatic ring orring system. The hydrophilicity increase by anionicgroup and the ring system interacts with thesolute to be dissolved. [31] The mechanisminvolved in hydrotropy is related to complexationwhich involves interaction between lipophilicdrugs and the hydrotropic agents such as urea,nicotinamide, sodium alginate, sodium benzoateetc. [32]Table 4: Classification of hydrotropes. [33]ExampleSodium benzoate, Sodium salicylate, Sodium benzene sulphonate,Sodium benzene disulphonate, Sodium cinnamate.Para amino benzoic acid hydrochloride, Procaine hydrochloride,Caffeine.Sodium alkanoate.International Journal of Pharmacy and Biological Sciences (e-ISSN: 2230-7605)Int J Pharm Bio SciS.V.Kadam* et alwww.ijpbs.com or www.ijpbsonline.com

Available Online throughwww.ijpbs.com (or) www.ijpbsonline.comAdvantages of hydrotropy method:1. In the hydrotropy method solvent character isindependent of pH, has high selectivity and doesnot require emulsification.2. In this method simply mix the drug with thehydrotropes in water.3. It does not require chemical modification ofhydrophobic drugs, use of organic solvents, orpreparation of emulsion system.Mixed Hydrotropy:In mixed hydrotropy method the blends ofhydrotropes is use. in blends of hydrotrops thecombination of hydrotropes gives synergisticeffect on solubility of poorly water soluble drug .By reducing the concentration of individualhydrotropic agent we reduce the side effect ofhydrotropes. It is new, simple, cost-effective, safe,accurate, precise and environmental friendlymethod for the analysis (titrimetric andspectrophotometric) of poorly precluding the use of organic solvents. As examplein case of ketoprofen by using 1.25M sodiumcitrate increase the solubility of 180 fold ascompair to solubility in distilled water.Maheshwari and co-workers increased solubilityof Paracetamol using Urea and of aceclofenacIJPBS Volume 3 Issue 3 JUL-SEPT 2013 462-475using mixed hydrotropic phenomenon using Ureaand Sodium acetate. [34]Advantages of Mixed Hydrotropy method: [35]1. It may reduce the large total concentration ofhydrotropic agents necessary to produce modestincrease in solubility by employing combination ofagents in lower concentration.2. The use of hydrotropic solubilizers aspermeation enhancers.3. Application of mixed- hydrotropy to developinjection dosage forms of poorly water-solubledrugs.4. Application of hydrotropic solubilisation innanotechnology (by controlled precipitation).5. Application of hydrotropic solubilisation inextraction of active constituents from crude drugs(in pharmacognosy field).Application of hydrotropy in pharmacy:1. Preparation of dry syrups (for reconstitution) ofpoorly water-soluble drugs.2. Quantitative estimations of poorly watersoluble drugs by UV-Visible spectrophotometricanalysis precluding the use of organic solvents.3. Quantitative estimations of poorly watersoluble drugs by titrimetric analysis.Such asibuprofen, flurbiprofen.Page468Table 5: Solubility enhancement of poorly water soluble drug by using Hydrotropes.Drug nameHydrotropes useGlipizide [36]Sodium Benzoate, Sodium acetate, Sodium salicylatePacilitaxel [37]N N Diethyl Nicotinamide, N N Dimethyl BenzamideAmlodipine besylate [38]UreaChartreusin[39]Sodium Benzoate, Sodium trihydroxy BenzoateSONOCRYSTALLIZATION:Melt sonocrystallization is newer particleengineering technique. In this method by applyingultrasound energy in range of 20 to100 kHzcrystallization process achieve. [40] In pharmacyindustry ultra sound energy was introducedtraditionally to increase the solubility of sparinglysoluble drug. Ultrasound system use to influencethe initial nucleation stage of crystallisation. ion of particle. cavitation is animportant phenomenon of ultrasonication.[41] Insonocrysatllization the energy of ultrasound causerepeated compression and expansion. Afterseveral cycle the bubble forms, grows andcollapses. Due to bubble collapses the energyproduced .This energy was responsible forbreaking of particles. This results in highrepeatable and predictable crystallization.Applying Ultrasound to crystallization results in:a. Nucleation at the lowest level ofsupersaturationwherethe crystallizationInternational Journal of Pharmacy and Biological Sciences (e-ISSN: 2230-7605)Int J Pharm Bio SciS.V.Kadam* et alwww.ijpbs.com or www.ijpbsonline.com

Available Online throughwww.ijpbs.com (or) www.ijpbsonline.comovercomes the tendency of the compound to redissolve in the solution.b. Narrowing of the metastable zone width.c. Narrow particle size distribution.d. Decrease in the level of cooling necessary toachieve crystallization.IJPBS Volume 3 Issue 3 JUL-SEPT 2013 462-475e. Highly repeatable and predictable crystallizationf. Polymorph control.In 2012 Vikram Deshmukh and co-workers e. [42] Chaudhari and co-workers,2009, studied the process on Valdecoxib. [43]Page469Figure 3: Process of Sonocrystallization. [44].SELF EMULSIFYING SYSTEM:SEDDS or SMEDDS are the important method toimprove the solubility and bioavailability of poorlywater soluble drug. SEDDS are define as isotropicmixture natural or synthetic oils, solid or liquidsurfactant, or alternative, one or more hydrophilicsolvent and co-solvent/surfactant. [46] SEDDSstypically produce emulsions with a droplet sizebetween 100–300 nm while self-micro-emulsifyingdrug delivery systems (SMEDDSs) formtransparent micro-emulsions with a droplet size ofless than 50 nm. Upon mild agitation followed bydilution in aqueous media, such as GI fluids, thesesystems can form fine oil in water (o/w)emulsions or micro-emulsions (SMEDDS).Selfemulsifying formulations spread readily in the GItract, and the digestive motility of the stomachand the intestine provide the agitation necessaryfor self-emulsification. When compared withemulsions, which are sensitive and metastabledispersed forms, SEDDS are physically stableformulations that are easy to manufacture.Composition of SEDDS: [45]The composition of self emulsifying system issimple combination of drug, oils, surfactant and cosurfactant or co-solvent.The self-emulsifying process depends on:The nature of the oil and surfactantThe concentration of surfactantThe temperature at which self-emulsificationoccurs1. Oils:Oils can solubilise the lipophilic drug in a specificamount. Oil can facilitate self-emulsifying andincrease the fraction of lipophilic drug transportedvia the intestinal lymphatic system, increasingabsorption from GIT. Example; olive oil, oleic oil,sesame oil.2. Surfactant:Non-ionic surfactant with high hydrophiliclipophilic balances (HLB) value is used in theformulation of SEDDS. High HLB and hydrophilicityof surfactant assists the immediate formulation ofo/w droplets and rapid spreading of formulationin the aqueous media. Example; Tween, Labrasol,Labrafac CH 10, cremophore etc.3. Co-surfactant/ co-solvent:Dissolve large amount of hydrophilic surfactant orhydrophobic drugs in lipid phase. It increasesfluidity of the interfacial film. Example: ethlene,propylenecarbonatetetrahydrofurfuryl alcohol, Glycofurol etc.Mechanism of self emulsification:Self-emulsification takes place when the entropychange favouring dispersion is greater than theInternational Journal of Pharmacy and Biological Sciences (e-ISSN: 2230-7605)Int J Pharm Bio SciS.V.Kadam* et alwww.ijpbs.com or www.ijpbsonline.com

Available Online throughwww.ijpbs.com (or) www.ijpbsonline.comenergy required to increase the surface area ofthe dispersion. Free energy in the micro-emulsionformation is directly proportional to the energyIJPBS Volume 3 Issue 3 JUL-SEPT 2013 462-475require to create new surface between the twophases, and is given by the equation; [46]Where;G is the free energy associated with the process (ignoring the free energy of mixing)N is the number of droplets of radius r,S represents the interfacial energy.Page470The type of self emulsifying dosage form includesSelf emulsifying tablet, capsule, pellets, soliddispersion, powder ets. Method use forpreparation of self emulsifying system is meltgranulation, spray drying, capsule filling, and meltextrusion ets.Advantages of Self Emulsifying system:a. Improvement in oral bioavailabilityenabling reduction in dose.b. Ease of manufacturing and scale up.c. High drug loading efficiency.d. Protection of drugs from the gutenvironmente. More consistent and reproducible profile ofdrug absorption and blood time profile.Disadvantages of Self Emulsifying system:a. High surfactant concentration irritates theGIT.b. Chemical instability of drug and surfactant informulation.COMPLEXATION:Complexation is the association between two ormore molecules to form a non bonded entity witha well defined stochiometry. In Complexationrelatively weak forces such as London forces,hydrogen bonding and hydrophobic interactionsinvolved.Two type of complex available:1. Stacking complexes:It is driven by association of non polar area of drugand complexes agent this results in exclusion ofthe non polar area from contact with water,thereby reducing total energy of the system.Stacking can be homogeneous or mixed, butresults in clear solution.2. Inclusion complexes: [47]It is formed by the inserting the nonpolarmolecule or the nonpolar region of one moleculeinto the cavity of another molecule or group ofmolecules. There are no forces involved betweenthem and therefore there are no bond is alsocalled as no-bond complexes. Cyclodextrins are agroup of cyclic oligosaccharides obtained fromenzymatic degradation of starch. The three majorcyclodextrins α, ß, and γ-CD are composed of six,seven, and eight D-( ) -glucopyranose units.Cyclodextrins have a hydrophilic exterior and ahydrophobic internal cavity. Cyclodextrine andtheir derivatives commonly use in Complexation.They form complex with drug and improve thesolubility and bioavailability of poorly solubledrug.[48] Derivatives of R-cyclodextrin withincreased water solubility (e.g. hydroxypropyl-Rcyclodextrin HP-R-CD) are most commonly used inpharmaceutical formulation.The forces driving complexation were attributedto1. The exclusion of high energy water from thecavity,2. The release of ring strain particularly in the caseof -CD,3. Van Der Wal’s interactions,4. Hydrogen and hydrophobic bindings.Solid inclusion complexes can be prepared byusing following methods: [49]1 .Kneading method:This method is based on impregnating the CDswith little amount of water or hydro alcoholicsolutions to converted into a paste. The drug isthen added to the above paste and kneaded for aInternational Journal of Pharmacy and Biological Sciences (e-ISSN: 2230-7605)Int J Pharm Bio SciS.V.Kadam* et alwww.ijpbs.com or www.ijpbsonline.com

Available Online throughPage471www.ijpbs.com (or) www.ijpbsonline.comspecified time. The kneaded mixture is then driedand passed through sieve.2. Co-precipitation:In this method, in the solution of CDs the requiredamount of drug is added. The complex kept undermagnetic agitation with controlled processparameters. The complex is protected from thelight. The formed precipitate is separated byvacuum filtration and dried at room temperaturein order to avoid the loss of the structure waterfrom the inclusion complex. This method isapplicable to industry.3. Physical blending method:It is simple trituration method. In this method theCDs and drug are mixed together thoroughly bytrituration in a mortar and passes throughappropriate sieve to get the desired particle size inthe final product.4. Neutralization method:In this method precipitation of inclusioncompounds by neutralization technique take place.in this dissolve the drug in alkaline solutions likesodium/ammonium hydroxide and mix with anaqueous solution of CDs. The clear solution isobtained. This solution is neutralising underagitation using hydrochloric acid solution tillreaching the equivalence point. A whiteprecipitate is being formed at this moment. Thisprecipitate is filtered and dried.5. Milling/Co-grinding technique:By using this method a solid binary inclusioncompounds of drug and CD is prepared. In thismethod Drug and CDs are mixed intimately andthe physical mixture is introduced in an oscillatorymill and grinded for suitable time. Ball mill is alsouse for preparation of binary complex.6. Lyophilisation/ Freeze drying technique:Lyophilisation/ freeze drying technique isconsidered as a suitable technique to get aporous, amorphous po

Solubility affected by molecular size of particle. The solubility of the substance is decreased when molecules have higher molecular weight and higher molecular size because larger molecules are more difficult to surround with solvent molecules in order to solvate the substance. 4 Temperature: Solubility affected by temperature.