AReview on Novel Solubility Enhancement Technique Hydrotrophy Introduction: The hydrotropic agent may also use of organic solvent so that a simpleaccurate, novel, safe & precise method developed for estimation of poorlysoluble drug. The aqueous solubility of drug is the main big problem inpharmaceutical industry; almost 70% drugs suffer from poor solubility. Solubilityis defined in quantitative term as concentration of solute in concentratedsolution at a certain temperature and in quantitative way it can be defined asa spontaneous interaction of two or more substances to from a homogenousmolecular dispersion. The solubility of asubstance fundamentally depends on the physical and chemical properties of thesolute and solvent as well as on temperature, pressure and the pH of thesolution. Increasing the aqueous solubility of insoluble and poorly solubledrug is major importance1. Maheshwari et al (2008) evaluate an experiment using hydrotropic solubilizingtechnique to enhance the aqueous solubility of poorly water soluble drug. Theyhave various organic solvent like methanol, chloroform, dimethyl-formide &ethanol for the solubilization of poorly water soluble drug2.

 Problems with poor solubility:·       Reduce drugefficiency. ·       Reducedabsorption of drug.·       May cause sideeffects.  1.   Hydrotropicagent: Neubergwas first proposed the term Hydrotrophy in 19163.Hydrotrope is aclass of amphiphilic molecules they increase the aqueous solubility of organiccompound4.

In the presence of large quantity of solute to enhance theaqueous solubility another solute5.Hydrotropic agents are ionicorganic salt to increase or decrease the aqueous solubility of solute, severalsalts are ionic they mostly soluble in water which have “salting in” of nonelectrolytes called “hydrotropic salts” a phenomenon also known as”hydrotropism”.                                            Fig.1. Structureof hydrotropic agent   They don’t have anycolloidal properties but increase aqueous solubility through weak interactionof organic salts and hydrotropic agents 6-7.The Hydrotropes solubilizationtechnique refer to the ability of a concentrated solution of chemicalcomposition to increase the aqueous solubility of another composition through asparingly soluble organic composition also called hydrotropic technique. Themost popular example of hydrotropic agent is urea, Sodium benzoate,sodium salicylate, nicotinamide, urea, sodium ascorbate, sodium acetate, sodiumcitrate, niacenamide; N-dimethylurea8-26.Hydrotropicagents have hydrophobic and hydrophilic properties27.

                         Table1. Expression forapproximate solubility28-32. Descriptive term Relative amount of solute to dissolve 1 part of solute   Very soluble                                           <1   Freely soluble                                          1-10   Soluble                                          10-30   Sparingly soluble                                          30-100   Slightly soluble                                         100-1000  Very slightly soluble                                         1000-10000  Practically insoluble                                          >10000  Preparation ofhydrotrpes: hydrotropicagent produced by sulfonation of an aromatic hydrocarbon e.g. – Toluene, Xylene,or cumene.

Sulfonic acid neutralized by using an appropriate base e.g. –NaoH to reduce the Hydrotropes & Sulfonate. The hydrotropic agents are”pure” compound. It produces and transport in either aqueous solution at 30-60%level of activity or in granular solid at 90-95% level of activity. Thegranular solid which includes sodium sulfate and w’ater. Granular Hydrotropesproducts are produced by spray drying which include source control and dust collection.Hydrotropic agents are manufactured for consumer/professional and industrialuse & they don’t used as derivatives33.

Characteristicof hydrotropic agents: The following characteristic of hydrotropic agent are-       i.           Hydrotropes practically soluble inwater.    ii.

           Hydrotropic agents are ecofriendly andsafe. iii.           Hydrotropes are easily available. iv.           Hydrotropes are non-toxic -reactive.     v.           Hydrotropes is a class of amphiphilicmolecules.

They increase the solubility of organic compounds. vi.           Hydrotropes do not reduce in anytemperature, dissolve in water.vii.           Hydrotropes are highly selectivity of solvent34.

  Measurethe solubility:Solubilitydetermination of solid in liquid by using following steps-1.   Preparationof saturated solution: solubility indicates the maximum amount of a substance can be dissolve in asolvent at given temperature also called saturated solution. Solubility ismeasure either in g/100g of solvent or no of moles /L of the solution.2.   Analysisof saturated solution: The saturated solutions areprepared and its analysis carried out to check solubility. Solubility dependson the nature of solute & accuracy of method employed.The following methods involve in theanalysis of saturated solution-                                          i.           Evaporation method.

                                       ii.           Volumetric method.                                    iii.           Gravimetric method.                                    iv.           Instrumental method35-37.Enhancement ratio insolubility were determine by following formula-Ø Enhancementratio   =  Solubility of drug in hydrotropicsolution%           Solubility of drug indistilled water Hydrotropicsolubilization: Hydrotrophy is a solubilization processwhich addition of large amount of solute to increase the aqueous solubility ofanother solute.

Solubilization can be defined as a preparation ofthermodynamically stable isotropic solution of a substance normally insolubleor slightly soluble in a given solvent by introduction of an additionalcomponent or components or by suitable methods38-41.Processof solubilization: Solubility is the important parameterdesired concentration of drug. The following factors affect the solubility ofdrug such as temperature, nature of solvent, nature of solute, particle size,molecular size, pressure etc. The following steps involve in the process ofsolubilization-Ø Solubilizationprocess involves the breaking of inter-ionic of intermolecular bond in solute.Ø  Separation of solvent molecules to providespace for the solute in solvent.Ø Interactionbetween solvent and the solute molecule or ion5-9.

Hydrotropescontain both properties hydrophobic and hydrophilic. Hydrotropes have smallhydrophobic fraction in compression with surfactant14.thehydrophobic and hydrophilic properties of hydrotrpes affect the efficiency ofhydrotropic solubilization42.      Mechanismof Hydrotrophy: Every hydrotropic agent has selectiveability to a particular component in mixture. They increase the solubilityafter addition of hydrotrpes in aqueous phase but on subsequent increasing theconcentration of hydrotropic agent. The minimum hydrotrpes concentration termedas the critical concentration hydrotrpes which required hydrotrpes in aqueousphase43-46. Hydrotropic agent consists of hydrophilic andhydrophobic such as surfactant but spontaneous self-aggregation caused byhydrophobic surfactant2. Hydrotropic agent also called couplingagent.

The addition of hydrotrpes to turbid liquid through relatively highcontent cause transport liquid because of phase transaction47.Themechanism of Hydrotrophy involved following steps-1.   Self-aggregationpotential: Self aggregation of hydrotrpes molecules formed byaggregates.

The aggregates depend on the amphiphilic properties and nature ofsolute. It also attract the molecules inside the aqueous phase48-50.Hydrotropicagent interact with solute to formed a complex and the complex have higheraqueous solubility. These outcomes evolved from fluorescence emission method51.Hydrotrpes may act as bridging agent by reducing Gibbs energy to increaseaqueous solubility of solute52.

Finally the structure of hydrotrpesaround the dry molecules is a true key of understanding the origin of selfaggregation potential53. 2.   Structurebreaker & structure maker: changing the structureof solvent through alerting the ability of changing in structure formation ofintro-molecule H-bonding.

  Hydrotrpes play a vital role inhydrotrophy solubilization like an   electrostatic force of the donor and acceptor molecule. They also calledstructure breaker and structure maker54-55. Solutes are capable forboth hydrogen donor and acceptor helps to increase the solubility56.  3.    Ability to form micelles likestructure: This mechanism is   based on the self aggregation of hydrotropicagent with solute80. The solute formed the micelles by exhibit selfaggregation of hydrotrpes like alkyl benzene sulfonate, and alkyl sulfates. Improvesolubility of riboflavin (via self association) through aromatic anionichydrotrpes e.g.

nicotinamide57. Hydrotropic solubilizationtechnique: The following solubilization techniquesare – 1.    Physical modification-                               i.           Particlesize reduction: The solubilization of drug depends uponthe particle size of drug. The larger particle size has larger surface areacreate greater interaction with solvent and increase the solubility of drug.

Particlesize reduction can be achieved by following method.·       Micronization: Inthis method increasing thedissolution rate of drug through surface area. ·       InMicronization of drug involved following steps milling technique using jetmill, rator stator colloid mills etc.·       Micronizationis not suitable for drug have a high dose no because it does not change thesaturation solubility of drug58-60.                             ii.

           Soliddispersion: It is a group of solid product containstwo different components like hydrophobic and hydrophilic. Preparation of soliddispersion involves solvent or co-precipitation method. In guest soluteaddition with solid carrier solvent as dissolve in common volatile liquid solidsuch as alcohol. The liquid solvent is removed by evaporation under reduce pressure by freeze drying whichresulting in amorphous precipitation of guest in crystalline carrier whichsolubilize rapidly e.g. Amorphous sulfathiazole in crystalline urea61-62.                         iii.           Nanosuspension: Nano suspension technique is applied forpoorly soluble drug that are insoluble in water and oils.

Nano suspension hasbiphasic system contain Nano sized drug particle stabilize by surfactant. Thefollowing method involve in nanosuspension… ·       Precipitationtechnique.·       Mediamilling. ·       Highpressure homogenization.·       Combinedprecipitation & homogenization63-65.2.    Chemical modification:                              i.

           ChangingpH:For organic solute that are ionizable changing the pH of the system is simplestand most effective means of increasing aqueous solubility.·       Changeof pH by 1 fold increase solubility by 10 fold.                            ii.           Useof buffer: The pH of solute measured by buffer of potentialfor precipitation on dilution pH alteration occur that decrease solubility.·       Ifone pH unit change it that decrease ionization of drug and solubility decreaseby 10 fold66-67.

                         iii.           Complexation:The ability to formation of molecules inclusion complexes through beta cyclodextrin with hydrophilic drug has poor aqueous solubility e.g.barbiturates benzodiazeoine68.

                         iv.           Saltformation: Salts have improved solubility in compression tothe original drug e.g.

alkali metal salts of acidic drug like penicillin69-70.3.    Miscellaneous method:                              i.           Supercritical fluid (SCF) 71-72.                            ii.           Inclusion complex formationtechnique73.

                         iii.           Micellar solubilization. Other solubilization technique:1.    Saltingin.2.

    Saltingout.3.    Co-solvency.4.

    Micellarsolubilization.5.    Hydrotrophy74-75.

Featuresof Hydrotropes:Ø Hydrotropesincrease unprecedented solubilization.Ø Hydrotropicagent very high selectivity.Ø Easyrecovery of solute from solution.Ø Economical& cost effective.Ø Absenceof emulation.

Ø Absenceof hazard present in other solvent used in extracted separation76.Advantageof hydrotropic solubilization: Ø Hydrotropicsolubilization technique is superior to other solubilization method likeMicellar solubilization salting in and co-solvency because solvent independentof pH has high selectivity.Ø Hydrotropicsolubilization only require for mixing the drug with hydrtope in water.Ø  It does not require chemical modification ofhydrophobic drug use of organic solvent or preparation of emulsion system77.

Applicationof solubilization:Ø Itused for solubility enhancement. Ø Hydrotropicsolvent used to enhance the permeation.Ø Itis used for extraction.Ø Preparationof injection of poorly water soluble drug.

Ø Hydrotropesused in the preparation of dry syrup of poorly water soluble drug. Ø Itis used in suppositories for fast release of poorly water soluble drug.Ø Quantitativeestimation of poorly water soluble drug by UV-visible spectrophotometricanalysis titrimetric analysis precluding the use of organic solvent78-79.



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