Thermodynamics and solubility of tadalafil in diethylene glycol monoethyl ether + water co-solvent mixtures at (298.15 to 333.15) K Faiyaz Shakeel a,b, ⁎, Nazrul Haq a,b , Mahmoud El-Badry b,c , Fars K. Alanazi b , Ibrahim A. Alsarra a,b a Center of Excellence in Biotechnology Research (CEBR), College of Science, King Saud University, P.O. Box 2460, Riyadh 11451, Saudi Arabia b Department of Pharmaceutics, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia c Department of Pharmaceutics, College of Pharmacy, Assiut University, Assiut, Egypt abstract article info Article history: Received 2 April 2014 Received in revised form 18 May 2014 Accepted 10 June 2014 Available online 21 June 2014 Keywords: Apelblat model Solubility Tadalafil Thermodynamics Transcutol Temperature dependent solubility data of tadalafil (TDL) in diethylene glycol monoethyl ether (Transcutol) + water co-solvent mixtures are not available in literature. Therefore, the aim of present study was to determine the temperature dependent solubility data of crystalline TDL in mono-solvents and various Transcutol + water co-solvent mixtures from 298.15 to 333.15 K at atmospheric pressure. The experimental solubilities of crystalline TDL were measured using the shake flask method. The experimental solubilities were correlated with the Apelblat model. The solubilities of crystalline TDL were regressed by Apelblat equation with a relative deviation in the range of 0.02 to 6.81% in all co-solvent mixtures investigated at 298.15 to 333.15 K. The root mean square devia- tions were observed in the range of 0.013 to 0.058. However, the correlation coefficients were observed in the range of 0.996 to 0.999. The solubility of crystalline TDL was found to be increased with increase in temperature and mass fraction of Transcutol in co-solvent mixtures. The mole fraction solubility of crystalline TDL was ob- served highest in pure Transcutol (8.76 × 10 -3 at 298.15 K) as compared to water (5.74 × 10 -7 at 298.15 K). Around 15,263 fold enhancements in solubility of crystalline TDL in Transcutol were observed as compared to its aqueous solubility at 298.15 K. The dissolution of TDL in most of the co-solvent mixtures was assumed to be non-spontaneous, endothermic and an entropy driven process. Overall, the results of these studies indicated that Transcutol could be used as a co-solvent in formulation development especially in terms of liquid dosage forms of crystalline TDL. © 2014 Elsevier B.V. All rights reserved. 1. Introduction Chemically, tadalafil (TDL) is hydro-2-methyl-6-[3,4-(meth- ylenedioxy)phenyl] pyrazino-[1′ ,2′ :1,6]pyrido[3,4-b]indole-1,4- dionepyrazino[1′,2′:1,6]pyrido[3,4-b]indole-1,4-dione (Fig. 1) [1]. It is a white crystalline powder with molecular formula and molar mass of C 22 H 19 N 3 O 4 and 389.40 g mol -1 , respectively [1,2]. It is commercially available as almond shaped tablets with strength ranging from 2.5 to 20 mg. It is a recently approved drug and is recommended for the treatment of erectile dysfunction (impotency) [1–4]. It is practically insoluble in water (18.2 μg mL -1 at 32 °C), sparingly soluble in some co-solvents such as propylene glycol (PG) (2.89 mg mL -1 at 32 °C) and ethanol (2.75 mg mL -1 at 32 °C) and soluble in polyethylene glycol-400 (PEG-400) (20.18 mg mL -1 at 32 °C) [5]. Currently, its highest solubility has been reported in PEG-400 (20.18 mg mL -1 at 32 °C) [5]. Therefore, it is very important to search an alternate co- solvent that could be able to enhance the aqueous solubility of TDL suf- ficiently. The solubility/solubility parameter of drugs is an important physicochemical parameter which has tremendous applications in drug development/drug discovery processes [6–8]. The selection of a suitable co-solvent and its solubilizing capacity has great impact on the process efficiency during pre-formulations studies and formulation development [6]. Co-solvent approach is an error free approach which is the common method for solubility and stability enhancement of drugs in an aqueous vehicle [7]. The poor solubility of TDL in water is the main barrier for its formulation development especially in terms of parenteral/liquid dosage forms [2–5]. The solubility and dissolution of TDL have been enhanced by various approaches such as co-crystal ap- proach [9], solid dispersion [10,11], cyclodextrin complexation [4], transdermal formulation [5] and microporous silica [3]. Chemically, Transcutol is a diethylene glycol monoethyl ether and its molecular for- mula and molar mass are C 6 H 14 O 3 and 134.17 g mol -1 , respectively [12–14]. Recently, the potential of Transcutol as a co-solvent has been proven in enhancing the solubility of paracetamol in water [12]. How- ever, it has not been investigated for solubility enhancement of TDL. The modified Apelblat model is the commonly used model for solubility prediction of both polar and nonpolar solutes [8,12,15,16]. The solubil- ity of TDL in Transcutol + water co-solvent mixtures at 298.15 to Journal of Molecular Liquids 197 (2014) 334–338 ⁎ Corresponding author at: Center of Excellence in Biotechnology Research (CEBR), College of Science, King Saud University, P.O. Box 2460, Riyadh 11451, Saudi Arabia and Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia. Tel.:+966 537507318. E-mail address: faiyazs@fastmail.fm (F. Shakeel). http://dx.doi.org/10.1016/j.molliq.2014.06.010 0167-7322/© 2014 Elsevier B.V. All rights reserved. Contents lists available at ScienceDirect Journal of Molecular Liquids journal homepage: www.elsevier.com/locate/molliq