(JTES) Delving: Journal of Technology and Engineering Sciences “Mixed-Solvency” – A novel concept for solubilization of poorly
water-soluble drugs
Department of Pharmacy, Shri G.S. Institute of Technology and Science
Abstract- On the basis of a large number of solubilization experiments on poorly water-soluble
drugs, the author is of the opinion that hydrotropy is another type of cosolvency and all water soluble
substances whether liquids or solids may act as solubilizers for poorly water-soluble drugs. In the
present investigation, mixed-solvency concept has been utilized for solubility enhancement of poorly
water-soluble drug, salicylic acid (as model drug). Various blends containing so called hydrotropes
(urea and sodium citrate), cosolvents (glycerin, propylene glycol, PEG 300 and PEG 400) and water-
soluble solids (PEG 4000 and PEG 6000) were made to study the influence on solubility of salicylic
acid. Most of the blends were found to increase the solubility of salicylic acid synergistically. This
concept shall prove a boon in pharmaceutical field (and also in non-pharmaceutical fields viz.
chemical engineering etc.). In the present investigation, the mixed solvency concept has been
employed to analyze salicylic acid in the bulk drug sample precluding the use of organic solvents (a
way to green chemistry).

1. Introduction

cosolvency. This gave a new thought that like In the pharmaceutical analysis and formulation mixed-hydrotropy, a mixed-solvency concept development fields, it is most often required to may be tried to observe the effect on solubility increase the aqueous solubility of poorly water- of poorly water-soluble drugs. Therefore, soluble drugs. Most of the newly developed salicylic acid was selected as model poorly drug molecules are lipophillic in nature and water-soluble drug. The total concentration of poor solubility is one of the most difficult soubilizer(s) was kept constant (40 % w/v) in solubilizers were hydrotropes (urea, sodium cosolvents25-33 have been observed to enhance citrate), cosolvents (glycerin, propylene glycol, the aqueous solubilties of poorly water-soluble PEG 300, PEG 400) and water-soluble solids drugs. Maheshwari 10 has demonstrated the (PEG 4000, PEG 6000). Ten blends containing synergistic solubilizing capability due to four randomly selected solubilizers (each 10% mixed-hydrotropy concept. Same concept has w/v) were made to study the influence on been applied to analyze the poorly water- solubility of salicylic acid. The strength of each soluble drug, aceclofenac, titrimetrically, blend was 40 % w/v. Seven blends were found precluding the use of organic solvents. Author to increase the solubility of salicylic acid, has carried out a good amount of work on synergistically. This concept shall prove a boon in pharmaceutical field (and also in non- application of hydrotropy in titrimetric and spectrophotometric estimations of a large engineering, etc.). In the present investigation precluding the use of organic solvents. He is of employed to analyze salicylic acid in the bulk the opinion that hydrotopy is another type of (JTES) Delving: Journal of Technology and Engineering Sciences drug sample precluding the use of organic 2.Experimental Materials and Method
Salicylic acid (S. D. Fine Chemicals Limited, Mumbai) was procured from the market. All chemicals and solvents used were of analytical grade. Distilled water was used to prepare the Solubility determination
Solubilities of salicylic acid in distilled water, in solutions of individual solubilizers (40% w/v glycerin, 40% w/v propylene glycol, urea and 40% w/v sodium citrate and different blends (compositions are shown in Table 2) were determined at 28±1oC. All of the solutions saturated with salicylic acid were subjected to phenolphthalein solution as indicator. Blank Therefore, contributory solubility of salicylic acid in blend FH-FT-ST-UR = 4.280 % w/v. solubilities were determined(Table 1 and 2). Determination of additive or synergistic
contributory solubilties in cases of all blends effect on solubility in presence of blends
Analysis of salicylic acid bulk sample by
I.P. (1996) method34 : Accurately weighed
synergistic effect on solubility. The total strength of all solubilizers was 40% w/v dissolved in 50 ml of ethanol (95%) and was (constant) in all solubilizer systems containing titrated with sodium hydroxide solution (0.1 single solubilizer or combinations of four M) using phenol red solution as indicator. solubilizers (each solubilizer 10 % w/v). One Necessary blank determination was adjusted example for blend FH-FT-ST-UR (containing to get drug content (Table 3). Total three such determinations were performed by this method explained here. The solubility of salicylic acid Analysis of salicylic acid bulk sample by
in this blend was found to be 6.666% w/v proposed GL-TH-FH-SC method: In the
(Table 2). The contributory solubility based on contribution of individual solubilizer for blend weighed (0.3 g) salicylic acid bulk sample was FH-FT-ST-UR can be calculated a follows – solubilized in 25 ml of GL-TH-FH-SC blend (composition is shown in Table 2) in a conical flask by shaking for about 5 min and titrated with sodium hydroxide solution (0.1M) using phenolphthalein (JTES) Delving: Journal of Technology and Engineering Sciences Necessary correction was done by conducting solubilizer to give a concentrated solution (say blank determination and amount of salicylic 25%, 30% w/v etc.) to act as solubilizing acid was calculated (Table 3). Total three such system for development of liquid (solutions) determinations were performed by this method syrups or topical solutions or injections etc. Analysis of salicylic acid bulk sample by
other proposed methods:
FT-ST and TH-FH-UR-SC blends were 98.63, analysis, the drug content of salicylic acid bulk 98.44, 101.58, 101.18, 101.09 and 99.84, drug sample was determined using PG-TH-FT- respectively (Table 3). These values are very close to 100, indicating the accuracies of the proposed methods of analysis. Also, these values of the mean percent drug estimated are estimated (99.16) by a standard method of 3. Results and Discussions:
Indian pharmacopoeia, which confirms the was improvement in the solubility of salicylic Satisfactorily low values of standard deviation, acid in all solutions containing individual percent coefficient of variation and standard solubilizers. The greatest enhancement in error further validated the proposed analytical solubility was observed in case of 40% w/v sodium citrate solution and least in case of 40% w/v urea solution. Table 2 illustrates the formamide, methanol, chloroform and ethanol advantages of making blends of solubilizers. have been employed for solubilization of poorly water-soluble drugs to conduct their UR and GL-PG-ST-UR blends, all remaining titrimetric analysis. Drawbacks of organic seven blends showed more solubility than solvents include their higher costs, toxicities contributory (calculated) solubility. These and pollution. The present investigation results demonstrate the principle of mixed- focuses on the application of mixed-solvency concept to discourage the use of organic substances whether hydrotropes or solvents or water-soluble solids (like PEG 4000, PEG It is, thus, concluded that the proposed 6000 etc) can be combined randomly to give a titrimetric methods are new, simple, cost- desired solubility for a poorly water-soluble effective, safe, free from pollution and precise. Just like salicylic acid other poorly water- developing liquid (solutions) dosage forms, soluble drugs may be tried to get solubilized by blends of solubilizers can be employed to mixed-solvency concept to carryout their reduce the toxicities of solubilizers by reducing titrimetric analyses precluding the use of the individual concentration of solubilizers (instead of employing one solubilizer in higher concentration which may be toxic for same FH refers to PEG 400, FT refers to PEG 4000, solubility enhancement). Blends of water ST refers to PEG 6000, UR refers to urea, SC soluble substances (hydrotropes, cosolvents, refers to sodium citrate, TH refers to PEG 300, water soluble excipients etc.) can be made in PG refers to propylene glycol and GL refers to safe level of concentrations of individual (JTES) Delving: Journal of Technology and Engineering Sciences Table 2 - Observed solubilities and
contributory solubilities (calculated) of
[1] Maheshwari RK. Solubilization of ibuprofen salicylic acid in different blends
[2] Maheshwari RK. Analysis of frusemide by o. FH-FT-ST-UR
Table1-Solubilities of salicylic acid in individual
Solvent system
[3] Maheshwari RK. New application of spectrophotometric estimation of ketoprofen in tablet dosage form. The Pharma Review [4] Maheshwari RK. A novel application of hydrotropic solublization in the analysis of bulk samples of ketoprofen and salicylic acid. [5] Maheshwari RK. Novel application of spectrophotometric analysis of tinidazole in dosage form. Asian J Chem 2006; 18:640-4. (JTES) Delving: Journal of Technology and Engineering Sciences [6] Maheshwari RK. Application of hydrotropic solubilization in the analysis of aceclofenac. MA, El-Kamel A. Solubilization of etodolac for parenteral administration. Indian J Pharm spectrophotometric analysis of piroxicam in solid dosage form. Indian Drugs 2006; 8:683-5. [8] Maheshwari RK. A novel application of spectrophotometric estimation of frusemide in tablets. The Pharma Review 2006; 4:148-9. [18] Shah SP, Flanagan DR. Solubilization of [9] Maheshwari RK. Application of hydrotropic antihistamines in aqueous solution. J Pharm spectrophotometric estimation of norfloxacin in [19] Paruta AN, Irani SA. Solubility profiles tablets. Indian J Pharm Edu and Res 2006; mixtures-I. J Pharm Sci 1999; 55:1055-9. Clow CS, Serajuddin ATM. Optimization of spectrophotometric analysis of aceclofenac. The [21] Breon TL, Paruta AN. Solubility profiles [11] Maheshwari RK, Chaturvedi SC, Jain NK. for several barbiturates in hydroalcoholic phenomenon in spectrophotometric analysis of hydrochlorothiazide tablets. Indian drugs 2005; antipyrine and aminopyrine in hydroalcoholic [12] Maheshwari RK, Chaturvedi SC, Jain NK. Titrimetric analysis of aceclofenac in tablets solute structure on deviations from the log- using hydrotropic solubilization technique. glycol:water mixtures. J Pharm Sci 1991; Maheshwari RK, Khera C, Lovlekar A. Novel Extended Hildebrand solubility approach: solubility of theophylline in polar binary cosolvent solubilization of indomethacin. Acta [24] Williams NA, Amidon GL. Excess free [14] Darwish A, Florence AT, Saleh AM.
Effects of hydrotropic agents on the solubility, precipitation and protein binding of etoposide. J Ethanol-Propylene glycol-Water mixtures. J (JTES) Delving: Journal of Technology and Engineering Sciences [25] Paruta AN. Solubility of parabens in ethanol-water mixtures. J Pharm Sci 1969; [26] Kristiansen H, Nakano M, Nakano NI, Higuchi T. Effect of solvent composition on association between small organic species. J [27 ]Indian Pharmacopoeia, Controller of Table 3 - Analysis data of salicylic acid bulk drug sample with statistical evaluation (n=3)



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