In the present investigation, mixed-solvency approach has been applied for the enhancement of aqueous solubility of a poorly water- soluble drug, zaltoprofen (selected as a model drug), by making blends (keeping total concentrations 40% w/v, constant) of selected water-soluble substances from among the hydrotropes (urea, sodium benzoate, sodium citrate, nicotinamide); water-soluble solids (PEG-4000, PEG-6000); and co-solvents (propylene glycol, glycerine, PEG-200, PEG-400, PEG-600). Aqueous solubility of drug in case of selected blends (12 blends) ranged from 9.091 ± 0.011？mg/ml–43.055 ± 0.14？mg/ml (as compared to the solubility in distilled water 0.072 ± 0.012？mg/ml). The enhancement in the solubility of drug in a mixed solvent containing 10% sodium citrate, 5% sodium benzoate and 25 % S cosolvent (25% S cosolvent contains PEG200, PEG 400, PEG600, Glycerine and Propylene glycol) was more than 600 fold. This proved a synergistic enhancement in solubility of a poorly water-soluble drug due to mixed cosolvent effect. Each solubilized product was characterized by ultraviolet and infrared techniques. Various properties of solution such as pH, viscosity, specific gravity and surface tension were studied. The developed formulation was studied for physical and chemical stability. This mixed solvency shall prove definitely a boon for pharmaceutical industries for the development of dosage form of poorly water soluble drugs. 1. Introduction Formulation has numerous benefits in drug discovery and development. It enables efficacy, toxicity, and pharmacokinetic (PK) studies. Formulation can improve oral bioavailability, shorten onset of a therapeutic effect, enhance stability of drugs, and reduce dosing frequency. More consistent dosing can be achieved by reducing food effect through formulation. Formulation can reduce side effects (i.e., decreasing tissue irritation and improving taste) [1–3]. An intramuscular (IM) medication is given by needle into the muscle. It can be a solution, oil, or suspension. Drugs in aqueous solution are rapidly absorbed. However, very slow constant absorption can be obtained if the drug is administered in oil or suspended in other repository vehicles. Solubility may also be enhanced by altering the pH and using cosolvents but excess amount of these agents may have adverse effects. The vehicle should contain a minimum amount and low concentration of the co-solvent to reduce viscosity and toxicity effects [3–6]. To significantly enhance the solubility of semipolar drugs, high concentrations of non-aqueous cosolvents may be required [7].
References
[1]
S. Neervannan, “Preclinical formulations for discovery and toxicology: physicochemical challenges,” Expert Opinion on Drug Metabolism and Toxicology, vol. 2, no. 5, pp. 715–731, 2006.
[2]
P. Simamora, S. Pinsuwan, J. M. Alvarez, P. B. Myrdal, and S. H. Yalkowsky, “Effect of pH on injection phlebitis,” Journal of Pharmaceutical Sciences, vol. 84, no. 4, pp. 520–522, 1995.
[3]
Y. C. Lee, P. D. Zocharski, and B. Samas, “An intravenous formulation decision tree for discovery compound formulation development,” International Journal of Pharmaceutics, vol. 253, no. 1-2, pp. 111–119, 2003.
[4]
S. Sweetana and M. J. Akers, “Solubility principles and practices for parenteral drug dosage form development,” PDA Journal of Pharmaceutical Science and Technology, vol. 50, no. 5, pp. 330–342, 1996.
[5]
R. G. Strickley, “Solubilizing excipients in oral and injectable formulations,” Pharmaceutical Research, vol. 21, no. 2, pp. 201–230, 2004.
[6]
S. H. Yalkowsky and T. J. Roseman, “Solubilization of drugs by co-solvents,” in Techniques of Solubilization of Drugs, S. H. Yalkowsky, Ed., pp. 91–134, Marcel Dekker, New York, NY, USA, 1981.
[7]
P. L. Gould, M. Goodman, and P. A. Hanson, “Investigation of the solubility relationships of polar, semi-polar and non-polar drugs in mixed co-solvent systems,” International Journal of Pharmaceutics, vol. 19, no. 2, pp. 149–159, 1984.
[8]
R. K. Maheshwari, “Analysis of frusemide by application of hydrotropic solublization phenomenon,” Indian Pharmacist, vol. 4, pp. 555–558, 2005.
[9]
R. K. Maheshwari, “New application of hydrotropic solublization in the spectrophotometric estimation of ketoprofen in tablet dosage form,” Pharma Review, vol. 3, pp. 123–125, 2005.
[10]
R. K. Maheshwari, “A novel application of hydrotropic solubilization in the analysis of bulk samples of ketoprofen and salicylic acid,” Asian Journal of Chemistry, vol. 18, no. 1, pp. 393–396, 2006.
[11]
R. K. Maheshwari, “Novel application of hydrotropic solubilization in the spectrophotometric analysis of tinidazole in dosage form,” Asian Journal of Chemistry, vol. 18, no. 1, pp. 640–644, 2006.
[12]
R. K. Maheshwari, “Application of hydrotropic solubilization in the analysis of aceclofenac drug,” Asian Journal of Chemistry, vol. 18, no. 2, pp. 1572–1574, 2006.
[13]
R. K. Maheshwari, “Solubilization of ibuprofen by mixed solvency approach,” The Indian Pharmacist, vol. 8, no. 87, pp. 81–84, 2009.
[14]
R. K. Maheshwari, “Potentiation of solvent character by mixed solvency concept: a novel concept of solubilization,” Journal of Pharmceutical Research, vol. 3, no. 2, pp. 411–413, 2010.
[15]
R. K. Maheshwari, S. C. Chaturvedi, and N. K. Jain, “Application of hydrotropic solubilization phenomenon in spectrophotometric analysis of hydrochlorothiazide tablets,” Indian Drugs, vol. 42, pp. 541–544, 2005.
[16]
R. K. Maheshwari, S. C. Chaturvedi, and N. K. Jain, “Titrimetric analysis of aceclofenac in tablets using hydrotropic solubilization technique,” Indian Drugs, vol. 43, pp. 516–518, 2006.
[17]
R. K. Maheshwari, S. R. Bishnoi, and D. Kumar, “Spectrophotometric analysis of hydrochlorothiazide tablets using chlorpheniramine maleate as hydrotropic solubilizing agent,” Asian Journal of Chemistry, vol. 20, no. 8, pp. 6594–6596, 2008.
[18]
R. K. Maheshwari, “Application of hydrotropic solubilization phenomenon in spectrophotometric estimation of norfloxacin in tablets,” Indian Journal of Pharmaceutical Education and Research, vol. 40, pp. 237–240, 2006.
[19]
R. K. Maheshwari, “Novel application of hydrotropic solubilization in the spectrophotometric analysis of piroxicam in solid dosage form,” Indian Drugs, vol. 8, pp. 683–685, 2006.
[20]
K. B. Aher, G. B. Bhavar, H. P. Joshi, and S. R. Chaudhari, “Economical spectrophotometric method for estimation of zaltoprofen in pharmaceutical formulations,” Pharmaceutical Methods, vol. 2, no. 2, pp. 152–156, 2011.
[21]
R. K. Maheshwari, “Spectrophotometric determination of cefixime in tablets by hydrotropic solubilization phenomenon,” The Indian Pharmacist, vol. 4, pp. 63–68, 2005.
[22]
R. K. Maheshwari and M. Singh, “Quantitative determination of ketoprofen bulk drug using sodium salt of aspirin as hydrotropic solubilizing agent,” Asian Journal of Chemistry, vol. 20, no. 6, pp. 4922–4924, 2008.
[23]
A. K. Jain, “Solubilization of indomethacin using hydrotropes for aqueous injection,” European Journal of Pharmceutics and Biopharmaceutics, vol. 68, no. 3, pp. 701–714, 2008.
[24]
S. Agrawal, S. S. Pancholi, N. K. Jain, and G. P. Agrawal, “Hydrotropic solubilization of nimesulide for parenteral administration,” International Journal of Pharmaceutics, vol. 274, no. 1-2, pp. 149–155, 2004.
[25]
R. K. Maheshwari and R. Shilpkar, “Formulation development and evaluation of injection of poorly soluble drug using mixed solvency concept,” International Journal of Pharmacy and Biological Science, vol. 3, no. 1, pp. 179–189, 2012.
[26]
R. K. Maheshwari, “‘Mixed-Solvency’-a novel concept for solubilization of poorly water- soluble drugs,” Delving Journal, vol. l, no. 1, pp. 39–43, 2009.
[27]
“The minister of health labour and welfare,” Japanese Pharmacopoeia, vol. 15, pp. 1242–1243, 2006.
[28]
J. Dicosta and S. Khan, “Calculation for aceclofenac injection using hydrotropic solubilization technique,” International Journal of Pharmaceutical Science and Health Care, vol. 1, no. 1, pp. 9–22, 2011.
[29]
A. Martin, Solubility and Distribution Phenomena, Physical Pharmacy and Pharmaceutical Sciences, vol. 4, Lippincott Williams and Wilikins, New York, NY, USA, 2006.
[30]
A. M. Saleh, A. A. Badwan, and L. K. El Khordagui, “A study of hydrotropic salts, cyclohexanol and water systems,” International Journal of Pharmaceutics, vol. 17, no. 1, pp. 115–119, 1983.
