µÀÑInternational Journal of Drug Development & Research | April-June 2011 | Vol. 3 | Issue 2 | ISSN 0975-9344 | Available online http://www.ijddr.in Covered in Official Product of Elsevier, The Netherlands ©2010 IJDDR HYDROTROPY: A PROMISING TOOL FOR SOLUBILITY ENHANCEMENT: A REVIEW Kapadiya Nidhi1, Singhvi Indrajeet1, Mehta Khushboo1, Karwani Gauri1 and Dhrubo Jyoti Sen2 2 Pacific College of Pharmacy, Pacific Hills, Udaipur-313002, Rajasthan, India Department of Pharmaceutical Chemistry, Shri Sarvajanik Pharmacy College, Gujarat Technological University, Arvind Baug, Mehsana-384001, Gujarat, India Abstract The study on solubility yields information about the structure and intermolecular forces of drugs. Use of the solubility characteristics action in and bioavailability, pharmacological Copyright © 2010 IJDDR, Kapadiya Nidhi et al. This is an open access paper distributed under the copyright agreement with Serials Publication, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 1 Review Paper Covered in Official Product of Elsevier, The Netherlands solubility enhancement of various poorly soluble compounds is a challenging task for researchers and pharmaceutical scientists. Hydrotropy is one of the solubility enhancement techniques which enhance solubility to many folds with use of hydrotropes like sodium benzoate, sodium citrate, urea, niacinamide etc. and have many advantages like; it does not require chemical modification of hydrophobic drugs, use of organic solvents, or preparation of emulsion system etc. Article History:-----------------------Date of Submission:24-03-2011 Date of Acceptance: 12-04-2011 Conflict of Interest: NIL Source of Support: NONE INTRODUCTION The term hydrotropic agent was first introduced by Neuberg (1916) to designate anionic organic salts Key words: Hydrotropy, enhancement. How to Cite this Paper: Kapadiya Nidhi, Singhvi Indrajeet, Mehta Khushboo, Karwani Gauri and DhruboJyoti Sen “Hydrotropy: A Promising tool for solubility Enhancement”, Int J. Drug Dev. & Res., April-June 2011, 3(2): 26-33 *Corresponding author, Mailing address: Kapadiya Nidhi, Email:
[email protected] Hydrotropes, Solubility, Solubility which, at high concentrations, considerably increase the aqueous solubility of poorly soluble solutes[1].Hydrotropy is a solubilization phenomenon whereby addition of large amount of second solute results in an increase in the aqueous solubility of another solute. However, the term has been used in the literature to designate non-micelle-forming substances, either liquids or solids, organic or inorganic, compounds. capable The of solubilizing structure insoluble of the chemical conventional Neuberg’s hydrotropic salts (proto-type, sodium benzoate) consists generally of two essential Int. J. Drug Dev. & Res., April-June 2011, 3 (2): 26-33 Covered in Scopus & Embase, Elsevier 26 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. topically and orally administered solutions. There are many techniques which are used to enhance the aqueous solubility. If exact solubilities are not known. Due to advanced research & development. J. The anionic group is obviously involved in bringing about high aqueous solubility.000 Review Paper Covered in Official Product of Elsevier.Kapadiya Nidhi et al: Hydrotropy: A Promising tool for solubility Enhancement parts. Solubility is one of the important parameter to achieve desired concentration of drug in systemic circulation for pharmacological response to be shown[5]. and physical forms of drugs. Hydrotropic agents are ionic organic salts. Hydrotropic solutions do not show colloidal properties and involve a weak interaction between the hydrotropic agent and solute[3]. NEED OF SOLUBILITY Therapeutic effectiveness of a drug depends upon the bioavailability and ultimately upon the solubility of drug molecules. shape and surface area physicochemical properties of drugs. The Netherlands minor effect on the phenomenon[2]. Descriptive terms Very soluble Freely soluble Soluble Sparingly soluble Slightly soluble Very slightly soluble Insoluble or practically insoluble Relative amounts of solvents to dissolve 1 part of solute Less than 1 From 1-10 From 10-30 From 30-100 From 100-1000 From 1000-10. General parameters affecting solubility are particle size. The basic aim of the further formulation & development section is to make that drug available at proper site of action within optimum dose[6]. The ability to increase aqueous solubility can thus be a valuable aid to increase efficiency and/or reduce side effects for certain drugs. planarity of the hydrophobic part has been emphasized as an important factor in the mechanism of hydrotropic solubilization. Solute consists of alkali metal salts of various organic acids. & Res. Elsevier . It can also be defined quantitatively as well as qualitatively. The study on solubility yields information about the structure and intermolecular forces of drugs. pH of the medium. Several salts with large anions or cations that are themselves very soluble in water result in “salting in” of non electrolytes called “hydrotropic salts” a phenomenon known as “hydrotropism”. solvents. The pharmacopoeia lists solubility in terms of dissolve 1g of solute..000 More than 10. an anionic group and a hydrophobic aromatic ring or ring system. which is a prerequisite for a hydrotropic substance. The lipophilic drug that reaches market requires a high dose to attain proper pharmacological action. This is true for parenterally. The type of anion or metal ion appeared to have a Table 1: Expression for approximate solubility[4]. 3 (2): 26-33 Covered in Scopus & Embase. April-June 2011. Drug efficacy can be severely limited by poor aqueous solubility and some drugs also show side effects due to their poor solubility. the pharmacopoeia provides general terms to describe a given range. But more than 40% of lipophilic drug candidates fail to reach market due to poor bioavailability. temperature and use of surfactants[3]. Solubility enhancement of various poorly soluble compounds is a challenging task for researchers and pharmaceutical scientists. there are varieties of new drugs & their derivatives are available. MECHANISM OF SOLUBILITY The term ‘solubility’ is defined as maximum amount of solute that can be dissolved in a given amount of solvent. even though these drugs might exhibit potential pharmacodynamic activities. These descriptive terms are listed in (Table 1). Solubility is one of the important parameter to achieve desired concentration of drug in systemic circulation for pharmacological response to be shown[2]. Drug Dev. On the other hand. Quantitatively it is defined as the 27 Int. Typically. Twenty five ml of distilled water/hydrotropic solution was taken in a 50 ml glass bottle and gross weight (including the cap) was noted. following method (an approximate solubility determination method) was used. 2 M sodium salicylate (2 M SS). When drug got dissolved. Then.. 10 M urea (10 M UR) and 1. Review Paper Covered in Official Product of Elsevier. Distilled water was used in making hydrotropic solutions. & Res. The bottle was shaken vigorously (by hand). In qualitative terms. IR analysis revealed that there was no complexation/interaction between paracetamol and urea. unless a solubilisate has been added. the separation of the molecules of the solvent to provide space in the solvent for the solute. Instead. SD was evaluated for dissolution rate and a marked increase in dissolution rate was observed with SD.Kapadiya Nidhi et al: Hydrotropy: A Promising tool for solubility Enhancement concentration of the solute in a saturated solution at a certain temperature. Step2 Step 3 Holes open in the solvent Molecules of the solid breaks away from the bulk The freed solid molecule is integrated into the hole in the solvent MECHANISM OF HYDROTROPE ACTION[2] A hydrotrope is a compound that solubilises hydrophobic compounds in aqueous solutions. solubility may be defined as the spontaneous interaction of two or more substances to form a homogenous molecular dispersion. many hydrotropes do not seem to selfaggregate at all.25 M SC) were employed as hydrotropic solutions. However. SELECTION OF HYDROTROPES FOR POORLY WATER-SOLUBLE DRUGS[11] It is evident from the literature survey that more is the concentration of hydrotrope. Hydrotropes do not have a critical concentration above which selfaggregation 'suddenly' starts to occur. more drugs (few mg by visual observation) were transferred to the bottle and again the bottle was shaken vigorously. Paracetamol syrups prepared with urea showed good chemical stabilities. Same operation was repeated till some excess drug remained undissolved (after constant vigorous shaking for 10 minutes). A saturated solution is one in which the PROCESS OF SOLUBILISATION[5] The process of solubilisation involves the breaking of inter-ionic or intermolecular bonds in the solute. 2 M niacinamide (2 M NM). J. Elsevier 28 . The Netherlands solute is in equilibrium with the Step 1 solvent[7-9]. Maheshwari et al[10]. Drug Dev. In order to select suitable hydrotropes (for sufficient enhancement in solubility) for various poorly watersoluble drugs. gradually increasing aggregation size. some hydrotropes aggregate in a step-wise self-aggregation process. Int. April-June 2011. highly concentrated solutions of hydrotropic agents were used in the present investigation. Therefore. interaction between the solvent and the solute molecule or ion. more is the aqueous solubility of poorly water-soluble drugs. a poorly water-soluble drug by use of concentrated solution of urea (a hydrotropic agent). hydrotropes consist of a hydrophilic part and a hydrophobic part (like surfactants) but the hydrophobic part is generally too small to cause spontaneous self-aggregation. 3 (2): 26-33 Covered in Scopus & Embase. 2 M sodium benzoate (2 M SB). This hydrotropic phenomenon was employed to prepare solid dispersion (SD) and syrup of paracetamol. enhanced the aqueous solubility of paracetamol.25 M sodium citrate (1. few mg (by visual observation) of fine powder of drug was transferred to the bottle. 4 M sodium acetate (4 M SA). The Netherlands Then. again gross weight was noted. urea Urea Sodium salicylate Ibuprofen sodium. J. Jayakumar C. a sparingly water‐soluble keratolytic drug. sodium citrate Urea analysis obtained by the Indian Pharmacopoeial method. When the determined solubility enhancement ratio was at least 5. 2) Analysis of saturated solution : Once the saturated solution is prepared its analysis is carried out to check the solubility. an approximate solubility was determined and solubility enhancement hydrotropic solution/solubility in distilled water) were calculated for all selected drugs for all six hydrotropic solutions. a) Evaporation method b) Volumetric method c) Gravimetric method d) Instrumental method DETERMINATION OF INTERFERENCE OF HYDROTROPIC DRUGS [11] A UV-Visible recording spectrophotometer with 1 cm matched silica cells was employed for For spectrophotometric determinations.0 M calcium disodium edentate solution as compared to the solubility in distilled water. Sampada Sinha[23] were developed titrimetric analysis method to solubilize the slightly water soluble topical antifungal drug. Sodium citrate.Titrimetric analysis method employed for determining equilibrium solubility at 29 Int. Deepak Kumar K. 3 (2): 26-33 Covered in Scopus & Embase. AGENTS IN THE SPECTROPHOTOMETRIC ESTIMATION OF TO MEASURE THE Review Paper Covered in Official Product of Elsevier. Nesakumar D. The absorbances were recorded against respective reagent blanks at appropriate wavelengths.Kapadiya Nidhi et al: Hydrotropy: A Promising tool for solubility Enhancement Table 2: Hydrotropic Solubilisation Study of Various Poorly Water-Soluble Drugs [12-22] Drug Cefprozil Hydrochlorothiazide Paracetamol. There was more than 15 fold enhancement in aqueous solubility of benzoic acid in 1. & Res. gatifloxacin nifedipine ketoprofen Cefadroxil Hydrotropic agent Potassium acetate. April-June 2011. Elsevier . It depends upon the nature of the solute and accuracy of the method employed. Solubility is measured either in grams per 100 g of solvent (g/100 g) or number of moles per 1 L of the solution. METHODS SOLUBILITY[24] To determine solubility of solids in liquids following two steps are used 1) Preparation of saturated solution: Solubility indicates the maximum amount of a substance that can be dissolved in a solvent at a given temperature. Potassium citrate.0 M calcium disodium edetate solution. such hydrotropic solution was selected for that drug. Diclofenac sodium Theophylline Salicylic acid Furesamide Chlorpropamide. Nagendra Gandhi N[15] were performed titrimetric estimation has been developed using 2 M sodium salicylate as a hydrotropic solubilizing agent for the quantitative determination of theophylline in bulk.. Urea Sodium acetate. Following methods are used for analysis. There was more than a 18‐fold enhancement in aqueous solubility of theophylline in 2 M sodium salicylate solution. Such a solution is called saturated. sodium salicylate Ibuprofen sodium Ibuprofen sodium Sodium salicylate Urea. From the difference in two ratios readings (solubility (of in weight). benzoic acid by 1. Mithun Singh Rajput. The results of analysis obtained by the proposed method are comparable with the results of determination of interference of hydrotropic agents in the spectrophotometric estimation of the standard solutions of drugs were determined in distilled water alone and in the presence of the maximum concentration of the hydrotropic agent employed for spectrophotometric analysis. R K Maheshwari. Sodium acetate. Drug Dev. utilization of it in the formulation of dosage forms of water insoluble drugs and to reduce concentration of individual hydrotropic agent to minimize the side effects (in place of using a large concentration of one hydrotrope a blend of.5M) was employed as solubilizing agent to solubilize the poorly water-soluble drug. Brahm Prakash Gupta. because the solvent character is independent of pH. Ornidazole shows its maximum absorbance at 320 nm and Beer’s law was obeyed in concentration range of 5-25 mcg/ml. micellar solubilization. which may give miraculous synergistic enhancement effect on solubility of poorly water soluble drugs. April-June 2011. Kumar. 5 hydrotropes can be employed in 1/5th concentrations reducing their individual toxicities[27]. The Netherlands investigate that hydrotropic solution of 8M urea has been employed as solubilizing agent to solubilization poorly water soluble drug Pseudoephedrine Sulphate.4 nm and 289. say. in tablet dosage form.99% in sodium acetate and urea respectively. There were more than 55 and 70 fold enhancements in the solubility of hydrochlorothiazide increases in 2 M sodium acetate and 8 M Urea solution as compared to solubilities in distilled water. in the present investigation. It only requires mixing the drug with the hydrotrope in water. Veena Nair. ADVANTAGES SOLUBILIZATION OF HYDROTROPIC TECHNIQUE[2] Spectrophotometric method using 2 M sodium acetate and 8 M Urea solution as hydrotropic solubilizing agent for the quantitative determination of poorly water‐soluble hydrochlorothiazide in tablet dosage form.1nm. use of organic solvents. and thus no interference in the estimation was seen. Enhancement ratios in agents. Mithun S Rajput[28] were developed a novel.74 and 99. 13. Mukesh C.999) in urea with mean recovery 98. Sharma[25] were Review Paper Covered in Official Product of Elsevier. & Res. Sodium acetate and urea did not show any absorbance above 240 nm.999) in sodium acetate and 5 to 25 µg/ml (r2= 0. Beer's law was obeyed in the concentration range of 4–20 µg/ml. containing a blend of 30% w/v urea. Navneet Thakur. Hydrochlorothiazide shows maximum absorbance at 272 nm. There was more than 570-fold enhancement in aqueous solubility of ketoprofen in mixed hydrotropic solution as compared with the solubility in distilled water precluding the use of organic solvents. d. s. Drug Dev. has high selectivity and does not require emulsification 2. Bishnoi. Ruchi Jain. safe and sensitive method of spectrophotometric estimation in the ultraviolet region using a mixed hydrotropic solution. 3.6% w/v sodium acetate and 11. Nilesh Jain. K. Desloratidine resulting solutions were measured at 274. or preparation of emulsion system. a poorly water soluble drug. MIXED HYDROTROPY Mixed hydrotropic solubilization technique is the phenomenon to increase the solubility of poorly water-soluble drugs in the blends of hydrotropic Int. Elsevier 30 .. 1. murali krishna[26] . Hydrotropy is suggested to be superior to other solubilization method. R. ornidazole from fine powder of its tablets for spectrophotometric determination. co solvency and salting in. Jitendra Banweer and Surendra Jain[13] were developed solubilities were determined by following formula Enhancement ratio = Solubility in hydrotropic solution÷ Solubility in distilled water Smita Sharma. such as miscibility. J. Maheshwari.Kapadiya Nidhi et al: Hydrotropy: A Promising tool for solubility Enhancement room temperature. Hydrochlorothiazide is obeyed Beer’s law in the concentration range of 10 t0 50µg/ml (r2= 0. Desloratidine. from fine powder of its tablet dosage form for spectrophotometric region. It does not require chemical modification of hydrophobic drugs.8% w/v sodium citrate for the quantitative determination of ketoprofen. hydrotropic solution of ibuprofen sodium (0. 3 (2): 26-33 Covered in Scopus & Embase. R. shows determination absorbance in at ultraviolet Pseudoephedrine maximum Sulphate. Santosh Tambe. accurate. 11.such as ibuprofen. All these agents do not show absorbance above 245 nm and hence do not interfere with absorbance of Cefprozil (λmax‐ 280 nm). It may reduce the large total concentration of hydrotropic agents necessary to produce modest increase in solubility by employing poly-ethylene glycol 6000 and poly-vinyl alcohol.0M). It precludes the use of organic solvents and thus avoids the problem of residual toxicity. error due to volatility. Rupali Shinde. Hydrotropic solutions can also be tried to develop the dissolution fluids to carry out the dissolution studies of dosage forms of poorly water-soluble drugs CONCLUSION By this Study we can conclude that. Santosh Bhalerao. Sodium citrate (1. formulation. development of different dosage form of different drugs and for quantitative analysis. 2. 2. These include Potassium acetate (6. 3. The use of hydrotropy to give fast release of poorly water-soluble drugs from the suppositories. It is new. precise and environmental friendly method for the drugs analysis titrimetric and (titrimetric and spectrophotometric) of poorly water-soluble spectrophotometric precluding the use of organic solvents. 4. Solubility is the most important physical characteristic of a drug for its oral bioavailability.25M) and Urea (10. Hydrotropy is defined as a solubilisation process whereby addition of a large amount of second solute results in an increase in the aqueous solubility of another solute and the chemicals which are used in hydrotropy are called Review Paper Covered in Official Product of Elsevier.Kapadiya Nidhi et al: Hydrotropy: A Promising tool for solubility Enhancement ADVANTAGES OF MIXED HYDROTROPIC SOLUBILIZATION[2] 1. & Res. precluding the use of organic solvents. Preparation of dry syrups (for reconstitution) of poorly water-soluble drugs. Elsevier . 9. safe. 8. Quantitative estimations of poorly watersoluble drugs by titrimetric analysis. 10. Preparation of injection of poorly water soluble drugs. flurbiprofen and naproxen using sodium benzoate[29] . Application of hydrotropic solubilization in nanotechnology (by controlled precipitation). The use of hydrotropic solubilizers as permeation enhancers. Lalit Gupta[12] were employed Estimation Conventional Spectrophotometric (Method I) and Area Under Curve Method (Method II) for quantitation of Cefprozil by using five different hydrotropic agents. 3. metronidazole and salicylic acid using sodium benzoate and sodium citrate. 6. Potassium citrate (1. Solubility can be enhanced by many techniques among them hydrotropy is of very much importance. Sodium acetate (4. Quantitative estimations of poorly watersoluble drugs by UV-Visible spectrophotometric analysis precluding the use of organic solvents. Such as tinidazole.0M). cost-effective.. cost etc. 5.hydrotropy to develop injection dosage forms of poorly water-soluble drugs. April-June 2011. Vikas Pareek. 12. Preparation of hydrotropic solid dispersions of poorly water-soluble drugs precluding the use of organic solvents. 7. Application of hydrotropic solubilization in extraction of active constituents from crude drugs (in pharmacognosy field). Application of mixed. Drug Dev. simple. pollution.5M). The Netherlands 31 combination of agents in lower concentration.0M). Preparation of topical solutions of poorly water-soluble drugs. Such as felodipine[30] using Int. 3 (2): 26-33 Covered in Scopus & Embase. J. NOVEL PHARMACEUTICAL APPLICATIONS OF HYDROTROPIC SOLUBILIZATION IN VARIOUS FIELDS OF PHARMACY[02] 1. Ethiraj T. 7.net. New Delhi. Novel spectrophotometric estimation of frusemide phenomenon.. Pareek V. Ali N. Sengottuvel T. Pathodiya G. Indian Pharmacist 2006.) In: “Remington’s Pharmaceutical sciences. 2(3): 1114. 2. 61-62. Biochem J. Mack Publishing Company. 12. 3. 20. Martin A. Quantitative analysis of theophylline bulk sample using sodium salicylate hydrotrope. Banweer J. 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