Significant Increase in the Solubility of Celecoxib in Presence of … · solubility data of CLX in...

Pharmaceutical Sciences 2020 26(4) 423-433doi1034172PS202048httpspstbzmedacir

Research Article

Significant Increase in the Solubility of Celecoxib in Presence of Some Deep Eutectic Solvents as Novel Sustainable Solvents and the Thermodynamic Analysis of These Systems

Corresponding Author Masumeh Mokhtarpour E-mail masomeh64_myahoocomcopy2020 The Author(s) This is an open access article and applies the Creative Commons Attribution License (httpcreativecommonsorglicensesby-nc40) which permits unrestricted use distribution and reproduction in any medium as long as the original authors and source are cited

AbstractBackground Deep eutectic solvents (DESs) exist a wide variety of potential and existing applications Based on the fact that the choline chloride (ChCl) is a complex B vitamin and widely used as food additive the choline-based DESs are generically regarded as being harmless and non-toxic In this regard the low aqueous solubility of celecoxib (CLX) have been increased by use of DESs as neoteric class of solvents at T = (29815 to 31315) K Methods DESs were prepared by combination of the ChClEG U and G with the molar ratios 12 and ChClMA with 11 The shake flask method was used to measure the solubility of CLX in the aqueous DESs solutions at different temperaturesResults The solubility of the CLX increased with increasing the weight fraction of DESs The observed solubility data was subjected to evaluate the relative performance of a number of models including Apelblat Yalkowsky and JouybanndashAcree models for their correlation efficacy Moreover the apparent dissolution enthalpy entropy and Gibbs free energy were obtained from the experimental solubility valuesConclusion It was found that the solubility data was satisfactorily fitted using the mentioned models at different temperatures The dissolution process of CLX in the studied solvent mixtures within investigated temperature range was endothermic and the driving mechanism is the positive entropy

Article Info

Article HistoryReceived 30 January 2020Accepted 9 June 2020ePublished 25 December 2020

Keywords-Deep eutectic solvent-Solubility-Celecoxib-JouybanndashAcree model-Dissolution thermodynamics

Hemayat Shekaari1 Masumeh Mokhtarpour1 Fereshteh Mokhtarpour1 Saeid Faraji1 Fleming Martinez2 Mohammed Taghi Zafarani-Moattar1 1Department of Physical Chemistry University of Tabriz Tabriz Iran2Grupo de Investigaciones Farmaceacuteutico-Fisicoquiacutemicas Departamento de Farmacia Facultad de Ciencias Universidad Nacional de Colombia Bogotaacute Colombia

IntroductionCelecoxib (CLX) (Figure 1) or 4-[5-(4-Methylphenyl)-3-(trifluoromethyl) pyrazol-1- yl] benzene sulfonamide is a COX-2 selective nonsteroidal anti-inflammatory drug (NSAID) and it is used clinically to treat pain and inflammation and rheumatoid arthritis12

Figure 1 Chemical structure of CLX

However CLX is a lipophilic drug with a slow dissolution rate and very poor water solubility (about 3 μgmL) which could limit the efficacy of its formulation in dry powder for inhalation It should be mentioned that water solubility of CLX should be increased because poor solubility is a persistent challenge in drug discovery which represents the most frequent causes of limited bioavailability34 The solubilization of drugs in co-solvents is employed for enhancing the solubility of low intrinsic water soluble drugs Additionally it is well-known that an organic co-solvent or ionic liquids (ILs) as co-solvent can improve the solubility of drugs5-8 But ILs are expensive sometimes highly toxic poor biodegradable and barely biocompatible whereas volatile organic solvents are a class of chemical solvents in the environment that can cause severe health problems9 By contrast deep eutectic solvents (DESs) have lower costs and environmental impacts Secondly the synthesis methods of IL and DES are different While DES

Shekaari et al

424 | Pharmaceutical Sciences 2020 26(4) 423-433

are prepared by simply mixing the components without waste and no purification step of the solvent is required Preparation of ILs is difficult and costly Finally ILs are organic salts that are wholly composed of ions DES are the result of complexation between a hydrogen bond acceptor (HBA) and a hydrogen bond donor (HBD) whose interactions involve mostly hydrogen bonds1011 The current work represents a continuation of our systematic study on drugs solubility and related properties12-18 and to develop the application of DESs as novel co-solvents in pharmaceutical science the CLX was used for investigation of its solubility in four DESs (ChClurea malonic acid ethylene glycol and glycerol) using UV spectrophotometry and shake flask method for drug quantification at T = (29815 to 31315) K For correlation of the experimental solubility data of CLX in these solvents the Apelblat19 Yalkowsky20 and JouybanndashAcree2122 models were used Comparison and discussion of the solubility and used equations were carried out Additionally we evaluated the apparent thermodynamic properties of the systems by using the experimental solubility data and Vanrsquot Hoff equation23

Materials and MethodsMaterialsCelecoxib (099 mass fraction purity) was obtained from Zahravi pharmaceutical company (Tabriz Iran) Urea malonic acid ethylene glycol glycerol and choline chloride extra pure and absolute ethanol (was used for dilution of the samples prior to spectrophotometric analysis) were purchased from Merck (Germany) All chemicals were used as received without further purification The description of the materials has been comprehensively collected in Table 1

Preparation of DESsThe DESs were prepared by weighing choline chloride (ChCl) as hydrogen bonding acceptor (HBA) with urea malonic acid ethylene glycol and glycerol as hydrogen bonding donors with mole ratios of 12 11 12 and 12 respectively10 using an electronic balance with a

precision of plusmn10-4 g (AW 220 GR220 Shimadzu Japan) After continuous stirring for about 1 h at 35315 K a homogeneous colorless liquid was obtained Finally the mixture was allowed to cool down to room temperature naturally Water content was analyzed by applying the KarlndashFisher titration technique (method TitroLine KF) for the prepared DESs and it has been used for calculation of concentrations Some of the thermophysical properties of these solvents as measured in this study and these findings are similar to those reported by other researchers they are listed in Table 2

Apparatus and procedureDensity measurement Density and speed of sound measurements of neat DESs were made with an accuracy of plusmn 4times10-3 kg∙m-3 and plusmn1 m∙s-1 using a vibrating-tube densimeter (Anton Paar DSA 5000 densimeter and speed of sound analyzer Austria) The densimeter is calibrated with dry air and water as reference fluid Furthermore the speed of sound of samples is measured using a propagation time method

Solubility determinationThere are various methodological approaches for solubilization studies reported in the literature24 In this study for solubility measurement the shake flask method was chosen In order to measure the solubility of drug in the aqueous solutions of DESs an excess amount of drug with 5 g of solvent was poured to a glass tube The electrical heating plates with magnetic stirring and thermostat control (ED Julabo Co Germany temperature variation plusmn 01 K) were used to heat the mixtures (solid + liquid) Then the samples were placed in water bath thermostat until equilibrium is reached (for 3 days) Samples were centrifuged for 15 min to remove the solid phase (D-7200 Tuttlingen Hettich Co USA) in addition the undissolved crystals was removed by filtration at isothermal condition through a membrane filters (Duraporereg membrane filters type HV 045 microm Millipore MA USA) A certain

Table 1 The sources and some properties of the materials

Chemical name Provenance Molar mass (gmol-1) CAS No Mass fraction (purity)Celecoxib Zahravi Pharmaceutical Co (Tabriz Iran) 38137 - gt099Choline Chloride Merck 13962 67-48-1 gt099Urea Merck 6006 57-13-6 gt099Malonic Acid Merck 10406 141-82-2 gt099Ethylene glycol Merck 6209 107-21-1 gt099Glycerol Merck 9209 56-81-5 gt099

Table 2 Some properties of DESs used in the article at 29815 K 863 hPa

DES designation Molar ratio Water content ρ g∙cm-3(exp) ρ g∙cm-3(Lit) u m∙s-1(exp)ChCl U 100200 lt003 1193926 1197925 206227ChCl MA 100100 lt001 1251470 1250010 196269ChCl EG 100200 lt001 1115551 111607210 190920ChCl G 100200 lt006 1186358 117696310 201242

Standard uncertainties (u) for each variables are u (ρ) = 0004 gcm-3 u (u) = 1 m∙s-1 u (T) = 10-2 K u (p) = 10 hPaStandard uncertainty (u) for DESs composition was estimated to be less than 005 molar ratio

Solubility of Celecoxib in Deep Eutectic Solvents

Pharmaceutical Sciences 2020 26(4) 423-433 | 425

amount of solution depending on temperature and composition was taken and diluted with a certain amount of ethanolwater mixtures The concentration of the drug was measured using double beam spectrophotometers model T80 UV-vis spectrometer PG instruments UK The λmax (wavelength of maximum absorption) for CLX was at 254 nm A calibration curve was required to calculate the drug concentration in the samples Data points represent the average of triplicate samples each from triplicate independent experimental tissues The aqueous solubility of CLX in terms of mole fraction x1 in CLX (1) + water (2) + DESs (3) systems are calculated by using of Eq (1)

where Mi and wi denote the molar mass and mass fractions of i component in the saturated solution respectively25-28

Modeling of the solubility dataTo correlate the obtained solubility data the Apelblat and Yalkowsky equations at dilute region while Jouyban-Acree model for full concentration range were used respectively

The modified Apelblat equationThe modified Apelblat equation corresponds to the following expression and the assumption of this equation is that the enthalpy of a solution is directly proportional to the temperature1929

where T is the absolute temperature and A B and C are three parameters obtained by fitting the experimental solubility data Eq (2) is used to correlate the solubility of CLX in every aqueous solutions The parameters A B and C were evaluated by using a non-linear optimization method

Yalkowsky equationThe simplest model to predict and correlate drug solubility in co-solvent mixtures is the one based on the algebraic rule of mixing in binary mixtures takes the following form where x1-mix and x1-water are the total solute solubilities

in the (co-solvent + water) mixture and in pure water respectively σ is the co-solvent solubilization power for the particular co-solvent-solute system and w3 is the weight fraction of the co-solvent in the aqueous mixture

Jouyban-Acree modelThe Jouyban-Acree model as a precise mathematical model can be used to correlate the solubility with respect to temperature and co-solvent composition3031 Its basic form to calculate the solubility of a solute in a binary solvent mixture is32

where Xm is the mole fraction solubility of the solute in solvent mixture w1 and w2 the weight fractions of solvents 1 and 2 in the absence of the solute X1 and X2 the mole fraction solubilities in neat solvents 1 and 2 respectively and Ji the solventndashsolvent and solutendashsolvent interaction parameters for each binary solvent system Two data points of solubilities in mono-solvent systems at every temperature should have measured in order to obtain the model parametersThe evaluation of the accuracy and applicability of the mentioned models are studied by the average relative deviation percent (ARD) This calculation can be done using the following equation33

Eq (1)

Eq (2)

Eq (3)

Eq (4)

Eq (5)

where expix cal

ix and N are experimental and calculated solubility mole fraction and the number of experimental data respectively

Thermodynamic properties of the drug dissolutionThe experimental solubility data of the investigated drug was plotted versus the temperature to calculate the thermodynamic properties of dissolution This process gives us a deep insight into the microscopic mechanisms in the solution processes by thermodynamic properties of solvation In this regard the modified Vanrsquot Hoff equation was applied to calculate the ΔHo

soln of CLX in the studied mixtures The mean harmonic temperature (Thm) is considered as

Eq (6)

where N is the number of experimental temperatures The calculated Thm value was 30555 K within the temperature range (from 29815 K to 31315 K) in this work In the present case by plotting ln x versus (1T ndash 1Thm) the values

Shekaari et al


ΔHosoln

of and Gibbs free energy change (ΔGosoln) of

dissolution can be obtained from the slope and the intercept34 Moreover the values of entropy (ΔHo

soln-ΔGosoln

Thm) are calculated as ΔSosoln Furthermore the following

equations can be used to compare the relative contributions to the dissolution Gibbs energy by enthalpy (ζH) and entropy (ζTS) toward the processes of CLX dissolution

Eq (7)

Eq (8)

Results and DiscussionSolubility of CLX in aqueous solutions of DESsThe results of the CLX solubility in terms of mole fraction x1 at different weight fraction of co-solvent and temperature ranges from 29815 to 31315 K is presented in Tables 3 and 4 and shown graphically in Figure 2

The results show that the solubility of CLX in aqueous DESs solutions enhanced with the rising of DESs weight fraction and temperature However the increasing extent of solubility differs in the studied co-solvents At same temperature the mole fraction solubility is highest in the presence of ChCl malonic acid and lowest in neat water The solubility of the drug in the presence of co-solvent containing ChCl malonic acid has increased 62700-fold than its solubility in pure water In general the solubility of CLX in different co-solvents decreases according to the order ChCl malonic acid gt ChCl ethylene glycol gt ChCl urea gt ChCl glycerol The solubility is determined by the competition of the interaction between the solute-solvent and solvent-solvent Figure 1 shows that the CLX molecule contains both hydrogen donor and hydrogen acceptor groups then hydrogen bonds can be formed between the solute and solvents molecules35 Thus in these systems both van der Waals interactions (represented by polarity) and hydrogen bonding (represented by hydrogen bond donoracceptor propensity) solvation were favorable driving forces for solutendashsolvent interactions In addition According to Jouyban et al 4 the solubility of CLX in water at 29815 K is 802 times 10minus8 this value is in good agreement with the obtained value in this work (801times 10minus8) Also it is well adapted for other investigated temperatures

Figure 2 The relationship between mole fraction solubility of CLX (x1) in the aqueous DESs mixtures versus temperature (T) and weight fractions (wDES)



Table 3 The experimental CLX solubilities in aqueous mixtures of DESs ( exp1x )a and calculated values ( calx1 ) from Apelblat and Yalkowsky

models at T = (29815ndash31315)b K and P = 863 hPa

T K Apelblat equation Yalkowsky model

CLX + water + ChCl Uw3=0020029815 00239 00245 -279 00249 -41930315 00702 00645 811 00670 44930815 00913 00995 -902 00909 04431315 00960 00932 290 00937 238

w3=00500

29815 00299 00302 -111 00298 02930315 00885 00856 333 00967 -91930815 01384 01433 -352 01472 -63831315 01483 01465 117 01542 -396

w3=0070029815 00344 00346 -053 00336 24230315 01227 01207 162 01234 -05530815 02144 02180 -168 02031 52531315 02136 02124 057 02148 -054

w3=0100029815 00428 00436 -172 00403 60330315 01899 01802 510 01780 62930815 03382 03568 -549 03292 26831315 03606 03541 180 03533 202

w3=0150029815 00518 00525 -136 00544 -49430315 03220 03090 406 03277 -17730815 07193 07504 -433 07359 -23031315 08076 07960 143 08096 -025

CLX + water + ChCl MAw3=0020029815 00252 00256 -148 00239 53630315 00980 00937 441 00962 18830815 01673 01752 -472 01726 -31431315 01772 01744 156 01772 -070

w3=0050029815 00369 00373 -121 00364 11330315 01514 01459 363 01525 -07330815 02700 02804 -385 02852 -56331315 02804 02768 128 02994 -678

w3=0070029815 00458 00460 -046 00483 -55930315 02100 02071 139 02074 12430815 04295 04357 -144 03987 71731315 04511 04489 049 04248 584

w3=0100029815 00682 00678 057 00738 -82730315 03118 03173 -176 03289 -550

Shekaari et al


Table 3 Continued30815 07082 06957 177 06590 69431315 07447 07492 -061 07177 362

w3=0150029815 01598 01620 -137 01495 64830315 07312 07014 408 07094 29730815 14342 14965 -434 15228 -61831315 16693 16453 144 17203 -306

CLX + water + ChCl EGw3=0020029815 00293 00296 -111 00304 -37730315 00818 00791 334 00865 -57230815 01323 01370 -353 01374 -38831315 01599 01581 117 01576 144

w3=0050029815 00388 00392 -107 00382 14830315 01323 01280 321 01264 44530815 02199 02274 -34 02121 35431315 02310 02284 113 02359 -210

w3=0070029815 00445 00452 -142 00445 00530315 01680 01609 423 01627 31630815 02854 02983 -451 02833 07331315 03044 02999 149 03086 -137

w3=0100029815 00596 00601 -086 00559 61730315 02387 02325 260 02376 04430815 04431 04552 -273 04374 13031315 04754 04711 091 04617 288

w3=0150029815 00783 00793 -127 00818 -44430315 04359 04193 381 04469 -25230815 08841 09199 -405 09017 -19931315 08977 08856 134 09038 -068 CLX + water + ChCl Gw3=0020029815 00135 00138 -179 00137 -08830315 00447 00423 530 00438 20330815 00724 00766 -572 00689 48331315 00862 00846 188 00878 -193

w3=0050029815 00189 00191 -105 00184 25230315 00551 00533 316 00582 -57530815 00972 01005 -334 01004 -32831315 01324 01309 111 01327 -024

w3=0070029815 00225 00229 -202 00224 02030315 00711 00668 594 00704 08830815 01233 01313 -646 01290 -46331315 01821 01783 211 01746 412

w3=0100029815 00292 00295 -083 00302 -343



Table 3 Continued30315 00982 00957 250 00937 45530815 01902 01952 -262 01879 11931315 02596 02573 088 02637 -161

w3=0150029815 00503 00495 162 00496 13330315 01480 01556 -514 01508 -18730815 03583 03404 499 03516 18531315 05208 05300 -176 05243 -067

a Standard uncertainty u(x1exp) = 1 b Standard uncertainty u(T)= 01 K c Standard uncertainty u(w3)=00005

Table 4 The calculated solubilities values of CLX ( calx1 ) from Jouyban-Acree model at T = (29815ndash31315) K and P = 863 hPa

Jouban-Acree model

w3 T = 29815 K T = 30315 K T = 30815 K T = 31315 KCLX + water + ChCl EG

00000 00080 00094 00139 0015700200 00123 00175 00355 0037900500 00215 00447 01134 0115700700 00293 00705 02184 0214701000 00439 01389 04813 0469501500 00713 07684 10216 1120002000 00997 08154 15238 1895704000 02326 41091 13438 2878006000 11816 67170 28655 3293708000 27249 293848 86869 114073809000 146909 2878234 4778924 5296825

CLX + water + ChCl G00000 00080 00094 00138 0015600200 00110 00180 00286 0032500500 00167 00408 00712 0082600700 00211 00641 01170 0139001000 00284 01131 02130 0265301500 00424 02049 04207 0581002000 00557 03020 05954 0921404000 01336 03622 06425 1157006000 04842 07718 14762 1531308000 52674 94479 252816 35290509000 111981 538913 1360013 1721680

CLX + water + ChCl MA00000 00080 00094 00139 0015700200 00127 00254 00378 0043400500 00228 00888 01353 0157900700 00321 01763 02752 0323601000 00476 04050 06811 0784801500 00785 10561 18637 2277102000 01112 17571 37023 4297304000 02784 19671 66644 7643406000 21683 41275 165374 21161308000 582723 737275 2002261 272457709000 2799740 3950926 8036523 12085182

CLX + water + ChCl U00000 00080 00094 00138 0015500200 00121 00213 00417 0096000500 00206 00598 00972 0103300700 00277 01048 01705 0184701000 00406 02063 03556 0375101500 00641 04446 08081 0859302000 00873 06564 11891 13610

Shekaari et al


Table 4 Continued04000 01705 05798 11936 1861406000 05758 10922 26389 4793408000 55472 193841 526669 81627109000 204181 1322978 2934671 3539852

Modeling resultsIn the next step the generated solubility data points were correlated with the Apelblat Yalkowsky equations and Jouyban-Acree model The modeling results are summarized in Tables 3 and 4 The calculated parameters of Jouyban-Acree model are given in Table S1 (Supplementary Data) respectively The calculated ARD values are given in Table 5 for the used models in this work As shown in these tables the overall ARD results for these three models are Apelblat (263) Yalkowsky (264) and Jouyban-Acree (108) As one can see the Jouyban-Acree model presents better results in respect to the other models even this model is more accurate than the modified Apelblat and Yalkowsky correlations Thus the performance of

these models in correlation of the experimental solubility data can be ordered as Jouyban-Acree gt modified Apelblat gt Yalkowsky

Apparent thermodynamic quantities of dissolutionThermodynamic properties of a solute dissolved in a particular solvent may provide essential information about the dissolution procedure Table 6 reports the apparent standard molar thermodynamic functions for dissolution of CLX (1) in all the water (2) + DES (3) solvent mixtures As expected the standard Gibbs energies of dissolution of this drug are positive in every case as also are the standard enthalpies and entropies of dissolution (except ΔSo

soln in

neat water)

Table 5 The calculated average relative deviation percent (ARD) for the solubility of the CLX in the aqueous DES solutions at several temperatures from different models

ApelblatCLX + water + DES

w3 ChCl U ChCl MA ChCl EG ChCl G00200 571 304 229 36700500 228 249 220 21700700 110 094 291 41301000 353 118 178 17101500 279 281 262 340Average 308 209 236 302

YalkowskyCLX + water +DES

T K ChCl U ChCl MA ChCl EG ChCl G29815 298 447 265 13930315 372 205 271 25130815 284 484 191 26331315 153 322 141 143Average 277 364 217 199

Table 6 Thermodynamic functions of dissolution of CLX for different weight fractions of DESs (w3) at mean harmonic temperature (Thm) and P = 863 hPa

w3 ΔHosoln kJ∙mol-1 TMΔSo

soln kJ∙mol-1 ΔGosoln kJ∙mol-1 ζH ζTS

CLX + water + ChCl MA00000 3387 -684 4072 8319 168100200 10427 6894 3533 6020 398000500 11348 7922 3426 5889 357800700 12508 9185 3323 5766 423401000 13764 10548 3217 5662 433801500 15899 12851 3048 5530 447002000 16769 13770 2999 5491 450904000 17706 15013 2694 5412 458806000 13338 10991 2347 5482 451808000 8866 7138 1728 5540 446009000 7025 5675 1350 5532 4468



Thus the dissolution processes are endothermic The relative contributions by enthalpy (ζH) and entropy (ζTS) toward all the dissolution processes are given In addition it can be found that the values of apparent molar enthalpy of dissolution are all positive which illustrates that the dissolution process of CLX in (DESs + water) systems is always endothermic and the entropy is the driving force for the dissolution process

ConclusionThe solubility of the celecoxib in four aqueous DESs solutions namely ChCl urea ChCl ethylene glycol ChCl glycerol and ChCl malonic acid were determined experimentally by spectrophotometric absorbance measurements at different temperatures The celecoxib solubility has increased 35000-fold in the presence of co-solvent containing ChCl malonic acid regarding its solubility in pure water Some correlations have been made using the modified Apelblat Yalkowsky and Jouyban-Acree models It turned out that the Jouyban-Acree model gave a satisfactory correlation results compared with those

obtained by using the Apelblat and Yalkowsky models Moreover according to the thermodynamic properties of the drug dissolution the apparent dissolution enthalpies were positive and the celecoxib has an endothermic dissolution process in every case and the driving force of this process is entropy On the basis of the experimental solubility values and the thermodynamic results of this drug in the presence of deep eutectic solvents it is remarkable that this information can be useful in the aspects of the co-crystals preparation and the synthesis and improvement of celecoxib derivatives

AcknowledgmentsThe authors wish to acknowledge the financial support received from the graduate council of the University of Tabriz

Conflict of InterestThe authors declare they have no conflict of interest

Table 6 ContinuedCLX + water + ChCl U

00000 3387 -684 4072 8319 168100200 6944 3313 3631 6770 323000500 8207 4659 3548 6379 257500700 9431 5963 3468 6126 387401000 10888 7525 3364 5913 408701500 14121 10902 3219 5643 435702000 14109 10954 3155 5629 437104000 10840 7827 3012 5807 419306000 13951 11199 2752 5547 445308000 9980 7884 2096 5587 441309000 17979 16244 1736 5254 4746

CLX + water + ChCl EG00000 3387 -684 4072 8319 168100200 10504 6932 3572 6024 397600500 10473 7015 3458 5989 396400700 11022 7629 3393 5909 409101000 11710 8420 3290 5817 418301500 12880 9745 3134 5693 430702000 12403 9296 3107 5716 428404000 7197 4232 2965 6297 370306000 1034 7757 2583 5714 428608000 6990 5018 1972 5821 417909000 5581 4156 1425 5732 4268

CLX + water + ChCl G00000 3387 -684 4072 8319 168100200 10157 6435 3723 6122 387800500 10759 7124 3635 6016 359800700 11091 7519 3572 5960 404001000 11341 7852 3489 5909 409101500 12523 9170 3352 5773 422702000 12872 9596 3276 5729 427104000 9798 6673 3125 5949 405106000 8632 5722 2910 6014 398608000 7592 5324 2268 5878 412209000 15306 1342 1886 5328 4672

Shekaari et al


Supplementary DataSupplementary file contains Table S1 which is available on the journalrsquos web site along with the published article

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acetaminophen in some aqueous solutions of choline based deep eutectic solvents at T=(28815 to 31815) K Eur J Pharm Sci 2017109121-30 doi101016jejps201707021

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19 Apelblat A Manzurola E Solubility of oxalic malonic succinic adipic maleic malic citric and tartaric acids in water from 27815 to 33815 K J Chem Thermodyn 198719(3)317-20 doi1010160021-9614(87)90139-X

20 Yalkowsky SH Roseman TJ Techniques of solubilization of drugs M Dekker 1981

21 Ruidiaz M Miller A Rodriacuteguez D Sylvia J Neita R Paula C et al Performance of the Jouyban-Acree model for correlating the solubility of indomethacin and ethylhexyl triazone in ethyl acetate+ ethanol mixtures Vitae 201017(3)309-16

22 Jouyban A Acree Jr WE Mathematical derivation of the Jouyban-Acree model to represent solute solubility data in mixed solvents at various temperatures J Mol Liq 2018256541-7 doi101016jmolliq201801171

23 Grant DJW Mehdizadeh M Chow AHL Fairbrother JE Non-linear vanrsquot Hoff solubility-temperature plots



and their pharmaceutical interpretation Int J Pharm 198418(1-2)25-38 doi1010160378-5173(84)90104-2

24 Jouyban V Khoubnasabjafari M Martinez F Pentildea A Jouyban A Solubility of drugs in ethyl acetate-ethanol mixtures at various temperatures J Drug Del Sci Tec 201222(6)545-7 doi101016S1773-2247(12)50094-8

25 Xie Y Dong H Zhang S Lu X Ji X Effect of Water on the Density Viscosity and CO2 Solubility in Choline ChlorideUrea J Chem Eng Data 201459(11)3344-52 doi101021je500320c

26 Forte A Melo CI Bogel-Łukasik R Bogel-Łukasik E A favourable solubility of isoniazid an antitubercular antibiotic drug in alternative solvents Fluid Phase Equilibria 201231889-95 doi101016jfluid201201022

27 Zhang X Song L Zhao D Wu D Zhu C Yang C Measurement and correlation of solubility of carbendazim in lower alcohols Thermochim Acta 2018659172-5 doi101016jtca201712007

28 Li S Liu Y Yin F Ye X Solubility measurement and thermodynamic properties of levetiracetam in pure and mixed solvents J Chem Eng Data 201863(12)4669-81 doi101021acsjced8b00720

29 Apelblat A Manzurola E Solubilities ofo-acetylsalicylic 4-aminosalicylic 3 5-dinitrosalicylic andp-toluic acid and magnesium-DL-aspartate in water fromT=(278 to 348) K J Chem Thermodyn 199931(1)85-91 doi101006jcht19980424

30 Li W Zhang N Farajtabar A Feng X Chen G Li X et al Experimental solubility evaluation and thermodynamic analysis of quinocetone in aqueous co-solvent solutions of ethanol isopropanol dimethyl sulfoxide and N N-dimethylformamide J Chem Thermodyn 2019131449-59 doi101016jjct201811021

31 Jouyban A Review of the cosolvency models for predicting solubility of drugs in water-cosolvent mixtures J Pharm Pharm Sci 200811(1)32-58 doi1018433j3pp4k

32 Shayanfar A Acree Jr WE Jouyban A Solubility of lamotrigine diazepam clonazepam and phenobarbital in propylene glycol+ water mixtures at 29815 K J Chem Eng Data 200954(3)1153-7 doi101021je800931z

33 Housaindokht MR Haghighi B Bozorgmehr MR A comparison among three equations of state in predicting the solubility of some solids in supercritical carbon dioxide Korean J Chem Eng 200724(1)102-5 doi101007s11814-007-5017-0

34 Wang G Wang Y Ma Y Hao H Luan Q Wang H Determination and correlation of cefuroxime acid solubility in (acetonitrile+ water) mixtures J Chem Thermodyn 201477144-50 doi101016jjct201405018

35 Gu CH Grant DJ Estimating the relative stability of polymorphs and hydrates from heats of solution and solubility data J Pharm Sci 200190(9)1277-87 doi101002jps1080

Shekaari et al


are prepared by simply mixing the components without waste and no purification step of the solvent is required Preparation of ILs is difficult and costly Finally ILs are organic salts that are wholly composed of ions DES are the result of complexation between a hydrogen bond acceptor (HBA) and a hydrogen bond donor (HBD) whose interactions involve mostly hydrogen bonds1011 The current work represents a continuation of our systematic study on drugs solubility and related properties12-18 and to develop the application of DESs as novel co-solvents in pharmaceutical science the CLX was used for investigation of its solubility in four DESs (ChClurea malonic acid ethylene glycol and glycerol) using UV spectrophotometry and shake flask method for drug quantification at T = (29815 to 31315) K For correlation of the experimental solubility data of CLX in these solvents the Apelblat19 Yalkowsky20 and JouybanndashAcree2122 models were used Comparison and discussion of the solubility and used equations were carried out Additionally we evaluated the apparent thermodynamic properties of the systems by using the experimental solubility data and Vanrsquot Hoff equation23

Materials and MethodsMaterialsCelecoxib (099 mass fraction purity) was obtained from Zahravi pharmaceutical company (Tabriz Iran) Urea malonic acid ethylene glycol glycerol and choline chloride extra pure and absolute ethanol (was used for dilution of the samples prior to spectrophotometric analysis) were purchased from Merck (Germany) All chemicals were used as received without further purification The description of the materials has been comprehensively collected in Table 1

Preparation of DESsThe DESs were prepared by weighing choline chloride (ChCl) as hydrogen bonding acceptor (HBA) with urea malonic acid ethylene glycol and glycerol as hydrogen bonding donors with mole ratios of 12 11 12 and 12 respectively10 using an electronic balance with a

precision of plusmn10-4 g (AW 220 GR220 Shimadzu Japan) After continuous stirring for about 1 h at 35315 K a homogeneous colorless liquid was obtained Finally the mixture was allowed to cool down to room temperature naturally Water content was analyzed by applying the KarlndashFisher titration technique (method TitroLine KF) for the prepared DESs and it has been used for calculation of concentrations Some of the thermophysical properties of these solvents as measured in this study and these findings are similar to those reported by other researchers they are listed in Table 2

Apparatus and procedureDensity measurement Density and speed of sound measurements of neat DESs were made with an accuracy of plusmn 4times10-3 kg∙m-3 and plusmn1 m∙s-1 using a vibrating-tube densimeter (Anton Paar DSA 5000 densimeter and speed of sound analyzer Austria) The densimeter is calibrated with dry air and water as reference fluid Furthermore the speed of sound of samples is measured using a propagation time method

Solubility determinationThere are various methodological approaches for solubilization studies reported in the literature24 In this study for solubility measurement the shake flask method was chosen In order to measure the solubility of drug in the aqueous solutions of DESs an excess amount of drug with 5 g of solvent was poured to a glass tube The electrical heating plates with magnetic stirring and thermostat control (ED Julabo Co Germany temperature variation plusmn 01 K) were used to heat the mixtures (solid + liquid) Then the samples were placed in water bath thermostat until equilibrium is reached (for 3 days) Samples were centrifuged for 15 min to remove the solid phase (D-7200 Tuttlingen Hettich Co USA) in addition the undissolved crystals was removed by filtration at isothermal condition through a membrane filters (Duraporereg membrane filters type HV 045 microm Millipore MA USA) A certain

Table 1 The sources and some properties of the materials

Chemical name Provenance Molar mass (gmol-1) CAS No Mass fraction (purity)Celecoxib Zahravi Pharmaceutical Co (Tabriz Iran) 38137 - gt099Choline Chloride Merck 13962 67-48-1 gt099Urea Merck 6006 57-13-6 gt099Malonic Acid Merck 10406 141-82-2 gt099Ethylene glycol Merck 6209 107-21-1 gt099Glycerol Merck 9209 56-81-5 gt099

Table 2 Some properties of DESs used in the article at 29815 K 863 hPa

DES designation Molar ratio Water content ρ g∙cm-3(exp) ρ g∙cm-3(Lit) u m∙s-1(exp)ChCl U 100200 lt003 1193926 1197925 206227ChCl MA 100100 lt001 1251470 1250010 196269ChCl EG 100200 lt001 1115551 111607210 190920ChCl G 100200 lt006 1186358 117696310 201242

Standard uncertainties (u) for each variables are u (ρ) = 0004 gcm-3 u (u) = 1 m∙s-1 u (T) = 10-2 K u (p) = 10 hPaStandard uncertainty (u) for DESs composition was estimated to be less than 005 molar ratio












Eq (1)

Eq (2)

Eq (3)

Eq (4)

Eq (5)

where expix cal




Eq (6)


Shekaari et al


ΔHosoln



soln-ΔGosoln



Eq (7)

Eq (8)









CLX + water + ChCl Uw3=0020029815 00239 00245 -279 00249 -41930315 00702 00645 811 00670 44930815 00913 00995 -902 00909 04431315 00960 00932 290 00937 238

w3=00500

29815 00299 00302 -111 00298 02930315 00885 00856 333 00967 -91930815 01384 01433 -352 01472 -63831315 01483 01465 117 01542 -396

w3=0070029815 00344 00346 -053 00336 24230315 01227 01207 162 01234 -05530815 02144 02180 -168 02031 52531315 02136 02124 057 02148 -054

w3=0100029815 00428 00436 -172 00403 60330315 01899 01802 510 01780 62930815 03382 03568 -549 03292 26831315 03606 03541 180 03533 202

w3=0150029815 00518 00525 -136 00544 -49430315 03220 03090 406 03277 -17730815 07193 07504 -433 07359 -23031315 08076 07960 143 08096 -025


w3=0050029815 00369 00373 -121 00364 11330315 01514 01459 363 01525 -07330815 02700 02804 -385 02852 -56331315 02804 02768 128 02994 -678

w3=0070029815 00458 00460 -046 00483 -55930315 02100 02071 139 02074 12430815 04295 04357 -144 03987 71731315 04511 04489 049 04248 584

w3=0100029815 00682 00678 057 00738 -82730315 03118 03173 -176 03289 -550

Shekaari et al


Table 3 Continued30815 07082 06957 177 06590 69431315 07447 07492 -061 07177 362

w3=0150029815 01598 01620 -137 01495 64830315 07312 07014 408 07094 29730815 14342 14965 -434 15228 -61831315 16693 16453 144 17203 -306


w3=0050029815 00388 00392 -107 00382 14830315 01323 01280 321 01264 44530815 02199 02274 -34 02121 35431315 02310 02284 113 02359 -210

w3=0070029815 00445 00452 -142 00445 00530315 01680 01609 423 01627 31630815 02854 02983 -451 02833 07331315 03044 02999 149 03086 -137

w3=0100029815 00596 00601 -086 00559 61730315 02387 02325 260 02376 04430815 04431 04552 -273 04374 13031315 04754 04711 091 04617 288


w3=0050029815 00189 00191 -105 00184 25230315 00551 00533 316 00582 -57530815 00972 01005 -334 01004 -32831315 01324 01309 111 01327 -024

w3=0070029815 00225 00229 -202 00224 02030315 00711 00668 594 00704 08830815 01233 01313 -646 01290 -46331315 01821 01783 211 01746 412

w3=0100029815 00292 00295 -083 00302 -343



Table 3 Continued30315 00982 00957 250 00937 45530815 01902 01952 -262 01879 11931315 02596 02573 088 02637 -161

w3=0150029815 00503 00495 162 00496 13330315 01480 01556 -514 01508 -18730815 03583 03404 499 03516 18531315 05208 05300 -176 05243 -067



Jouban-Acree model


00000 00080 00094 00139 0015700200 00123 00175 00355 0037900500 00215 00447 01134 0115700700 00293 00705 02184 0214701000 00439 01389 04813 0469501500 00713 07684 10216 1120002000 00997 08154 15238 1895704000 02326 41091 13438 2878006000 11816 67170 28655 3293708000 27249 293848 86869 114073809000 146909 2878234 4778924 5296825

CLX + water + ChCl G00000 00080 00094 00138 0015600200 00110 00180 00286 0032500500 00167 00408 00712 0082600700 00211 00641 01170 0139001000 00284 01131 02130 0265301500 00424 02049 04207 0581002000 00557 03020 05954 0921404000 01336 03622 06425 1157006000 04842 07718 14762 1531308000 52674 94479 252816 35290509000 111981 538913 1360013 1721680

CLX + water + ChCl MA00000 00080 00094 00139 0015700200 00127 00254 00378 0043400500 00228 00888 01353 0157900700 00321 01763 02752 0323601000 00476 04050 06811 0784801500 00785 10561 18637 2277102000 01112 17571 37023 4297304000 02784 19671 66644 7643406000 21683 41275 165374 21161308000 582723 737275 2002261 272457709000 2799740 3950926 8036523 12085182

CLX + water + ChCl U00000 00080 00094 00138 0015500200 00121 00213 00417 0096000500 00206 00598 00972 0103300700 00277 01048 01705 0184701000 00406 02063 03556 0375101500 00641 04446 08081 0859302000 00873 06564 11891 13610

Shekaari et al


Table 4 Continued04000 01705 05798 11936 1861406000 05758 10922 26389 4793408000 55472 193841 526669 81627109000 204181 1322978 2934671 3539852




soln in

neat water)









CLX + water + ChCl MA00000 3387 -684 4072 8319 168100200 10427 6894 3533 6020 398000500 11348 7922 3426 5889 357800700 12508 9185 3323 5766 423401000 13764 10548 3217 5662 433801500 15899 12851 3048 5530 447002000 16769 13770 2999 5491 450904000 17706 15013 2694 5412 458806000 13338 10991 2347 5482 451808000 8866 7138 1728 5540 446009000 7025 5675 1350 5532 4468









00000 3387 -684 4072 8319 168100200 6944 3313 3631 6770 323000500 8207 4659 3548 6379 257500700 9431 5963 3468 6126 387401000 10888 7525 3364 5913 408701500 14121 10902 3219 5643 435702000 14109 10954 3155 5629 437104000 10840 7827 3012 5807 419306000 13951 11199 2752 5547 445308000 9980 7884 2096 5587 441309000 17979 16244 1736 5254 4746

CLX + water + ChCl EG00000 3387 -684 4072 8319 168100200 10504 6932 3572 6024 397600500 10473 7015 3458 5989 396400700 11022 7629 3393 5909 409101000 11710 8420 3290 5817 418301500 12880 9745 3134 5693 430702000 12403 9296 3107 5716 428404000 7197 4232 2965 6297 370306000 1034 7757 2583 5714 428608000 6990 5018 1972 5821 417909000 5581 4156 1425 5732 4268

CLX + water + ChCl G00000 3387 -684 4072 8319 168100200 10157 6435 3723 6122 387800500 10759 7124 3635 6016 359800700 11091 7519 3572 5960 404001000 11341 7852 3489 5909 409101500 12523 9170 3352 5773 422702000 12872 9596 3276 5729 427104000 9798 6673 3125 5949 405106000 8632 5722 2910 6014 398608000 7592 5324 2268 5878 412209000 15306 1342 1886 5328 4672

Shekaari et al






















































Eq (1)

Eq (2)

Eq (3)

Eq (4)

Eq (5)

where expix cal




Eq (6)


Shekaari et al


ΔHosoln



soln-ΔGosoln



Eq (7)

Eq (8)









CLX + water + ChCl Uw3=0020029815 00239 00245 -279 00249 -41930315 00702 00645 811 00670 44930815 00913 00995 -902 00909 04431315 00960 00932 290 00937 238

w3=00500

29815 00299 00302 -111 00298 02930315 00885 00856 333 00967 -91930815 01384 01433 -352 01472 -63831315 01483 01465 117 01542 -396

w3=0070029815 00344 00346 -053 00336 24230315 01227 01207 162 01234 -05530815 02144 02180 -168 02031 52531315 02136 02124 057 02148 -054

w3=0100029815 00428 00436 -172 00403 60330315 01899 01802 510 01780 62930815 03382 03568 -549 03292 26831315 03606 03541 180 03533 202

w3=0150029815 00518 00525 -136 00544 -49430315 03220 03090 406 03277 -17730815 07193 07504 -433 07359 -23031315 08076 07960 143 08096 -025


w3=0050029815 00369 00373 -121 00364 11330315 01514 01459 363 01525 -07330815 02700 02804 -385 02852 -56331315 02804 02768 128 02994 -678

w3=0070029815 00458 00460 -046 00483 -55930315 02100 02071 139 02074 12430815 04295 04357 -144 03987 71731315 04511 04489 049 04248 584

w3=0100029815 00682 00678 057 00738 -82730315 03118 03173 -176 03289 -550

Shekaari et al


Table 3 Continued30815 07082 06957 177 06590 69431315 07447 07492 -061 07177 362

w3=0150029815 01598 01620 -137 01495 64830315 07312 07014 408 07094 29730815 14342 14965 -434 15228 -61831315 16693 16453 144 17203 -306


w3=0050029815 00388 00392 -107 00382 14830315 01323 01280 321 01264 44530815 02199 02274 -34 02121 35431315 02310 02284 113 02359 -210

w3=0070029815 00445 00452 -142 00445 00530315 01680 01609 423 01627 31630815 02854 02983 -451 02833 07331315 03044 02999 149 03086 -137

w3=0100029815 00596 00601 -086 00559 61730315 02387 02325 260 02376 04430815 04431 04552 -273 04374 13031315 04754 04711 091 04617 288


w3=0050029815 00189 00191 -105 00184 25230315 00551 00533 316 00582 -57530815 00972 01005 -334 01004 -32831315 01324 01309 111 01327 -024

w3=0070029815 00225 00229 -202 00224 02030315 00711 00668 594 00704 08830815 01233 01313 -646 01290 -46331315 01821 01783 211 01746 412

w3=0100029815 00292 00295 -083 00302 -343



Table 3 Continued30315 00982 00957 250 00937 45530815 01902 01952 -262 01879 11931315 02596 02573 088 02637 -161

w3=0150029815 00503 00495 162 00496 13330315 01480 01556 -514 01508 -18730815 03583 03404 499 03516 18531315 05208 05300 -176 05243 -067



Jouban-Acree model


00000 00080 00094 00139 0015700200 00123 00175 00355 0037900500 00215 00447 01134 0115700700 00293 00705 02184 0214701000 00439 01389 04813 0469501500 00713 07684 10216 1120002000 00997 08154 15238 1895704000 02326 41091 13438 2878006000 11816 67170 28655 3293708000 27249 293848 86869 114073809000 146909 2878234 4778924 5296825

CLX + water + ChCl G00000 00080 00094 00138 0015600200 00110 00180 00286 0032500500 00167 00408 00712 0082600700 00211 00641 01170 0139001000 00284 01131 02130 0265301500 00424 02049 04207 0581002000 00557 03020 05954 0921404000 01336 03622 06425 1157006000 04842 07718 14762 1531308000 52674 94479 252816 35290509000 111981 538913 1360013 1721680

CLX + water + ChCl MA00000 00080 00094 00139 0015700200 00127 00254 00378 0043400500 00228 00888 01353 0157900700 00321 01763 02752 0323601000 00476 04050 06811 0784801500 00785 10561 18637 2277102000 01112 17571 37023 4297304000 02784 19671 66644 7643406000 21683 41275 165374 21161308000 582723 737275 2002261 272457709000 2799740 3950926 8036523 12085182

CLX + water + ChCl U00000 00080 00094 00138 0015500200 00121 00213 00417 0096000500 00206 00598 00972 0103300700 00277 01048 01705 0184701000 00406 02063 03556 0375101500 00641 04446 08081 0859302000 00873 06564 11891 13610

Shekaari et al


Table 4 Continued04000 01705 05798 11936 1861406000 05758 10922 26389 4793408000 55472 193841 526669 81627109000 204181 1322978 2934671 3539852




soln in

neat water)









CLX + water + ChCl MA00000 3387 -684 4072 8319 168100200 10427 6894 3533 6020 398000500 11348 7922 3426 5889 357800700 12508 9185 3323 5766 423401000 13764 10548 3217 5662 433801500 15899 12851 3048 5530 447002000 16769 13770 2999 5491 450904000 17706 15013 2694 5412 458806000 13338 10991 2347 5482 451808000 8866 7138 1728 5540 446009000 7025 5675 1350 5532 4468









00000 3387 -684 4072 8319 168100200 6944 3313 3631 6770 323000500 8207 4659 3548 6379 257500700 9431 5963 3468 6126 387401000 10888 7525 3364 5913 408701500 14121 10902 3219 5643 435702000 14109 10954 3155 5629 437104000 10840 7827 3012 5807 419306000 13951 11199 2752 5547 445308000 9980 7884 2096 5587 441309000 17979 16244 1736 5254 4746

CLX + water + ChCl EG00000 3387 -684 4072 8319 168100200 10504 6932 3572 6024 397600500 10473 7015 3458 5989 396400700 11022 7629 3393 5909 409101000 11710 8420 3290 5817 418301500 12880 9745 3134 5693 430702000 12403 9296 3107 5716 428404000 7197 4232 2965 6297 370306000 1034 7757 2583 5714 428608000 6990 5018 1972 5821 417909000 5581 4156 1425 5732 4268

CLX + water + ChCl G00000 3387 -684 4072 8319 168100200 10157 6435 3723 6122 387800500 10759 7124 3635 6016 359800700 11091 7519 3572 5960 404001000 11341 7852 3489 5909 409101500 12523 9170 3352 5773 422702000 12872 9596 3276 5729 427104000 9798 6673 3125 5949 405106000 8632 5722 2910 6014 398608000 7592 5324 2268 5878 412209000 15306 1342 1886 5328 4672

Shekaari et al











































Shekaari et al


ΔHosoln



soln-ΔGosoln



Eq (7)

Eq (8)









CLX + water + ChCl Uw3=0020029815 00239 00245 -279 00249 -41930315 00702 00645 811 00670 44930815 00913 00995 -902 00909 04431315 00960 00932 290 00937 238

w3=00500

29815 00299 00302 -111 00298 02930315 00885 00856 333 00967 -91930815 01384 01433 -352 01472 -63831315 01483 01465 117 01542 -396

w3=0070029815 00344 00346 -053 00336 24230315 01227 01207 162 01234 -05530815 02144 02180 -168 02031 52531315 02136 02124 057 02148 -054

w3=0100029815 00428 00436 -172 00403 60330315 01899 01802 510 01780 62930815 03382 03568 -549 03292 26831315 03606 03541 180 03533 202

w3=0150029815 00518 00525 -136 00544 -49430315 03220 03090 406 03277 -17730815 07193 07504 -433 07359 -23031315 08076 07960 143 08096 -025


w3=0050029815 00369 00373 -121 00364 11330315 01514 01459 363 01525 -07330815 02700 02804 -385 02852 -56331315 02804 02768 128 02994 -678

w3=0070029815 00458 00460 -046 00483 -55930315 02100 02071 139 02074 12430815 04295 04357 -144 03987 71731315 04511 04489 049 04248 584

w3=0100029815 00682 00678 057 00738 -82730315 03118 03173 -176 03289 -550

Shekaari et al


Table 3 Continued30815 07082 06957 177 06590 69431315 07447 07492 -061 07177 362

w3=0150029815 01598 01620 -137 01495 64830315 07312 07014 408 07094 29730815 14342 14965 -434 15228 -61831315 16693 16453 144 17203 -306


w3=0050029815 00388 00392 -107 00382 14830315 01323 01280 321 01264 44530815 02199 02274 -34 02121 35431315 02310 02284 113 02359 -210

w3=0070029815 00445 00452 -142 00445 00530315 01680 01609 423 01627 31630815 02854 02983 -451 02833 07331315 03044 02999 149 03086 -137

w3=0100029815 00596 00601 -086 00559 61730315 02387 02325 260 02376 04430815 04431 04552 -273 04374 13031315 04754 04711 091 04617 288


w3=0050029815 00189 00191 -105 00184 25230315 00551 00533 316 00582 -57530815 00972 01005 -334 01004 -32831315 01324 01309 111 01327 -024

w3=0070029815 00225 00229 -202 00224 02030315 00711 00668 594 00704 08830815 01233 01313 -646 01290 -46331315 01821 01783 211 01746 412

w3=0100029815 00292 00295 -083 00302 -343



Table 3 Continued30315 00982 00957 250 00937 45530815 01902 01952 -262 01879 11931315 02596 02573 088 02637 -161

w3=0150029815 00503 00495 162 00496 13330315 01480 01556 -514 01508 -18730815 03583 03404 499 03516 18531315 05208 05300 -176 05243 -067



Jouban-Acree model


00000 00080 00094 00139 0015700200 00123 00175 00355 0037900500 00215 00447 01134 0115700700 00293 00705 02184 0214701000 00439 01389 04813 0469501500 00713 07684 10216 1120002000 00997 08154 15238 1895704000 02326 41091 13438 2878006000 11816 67170 28655 3293708000 27249 293848 86869 114073809000 146909 2878234 4778924 5296825

CLX + water + ChCl G00000 00080 00094 00138 0015600200 00110 00180 00286 0032500500 00167 00408 00712 0082600700 00211 00641 01170 0139001000 00284 01131 02130 0265301500 00424 02049 04207 0581002000 00557 03020 05954 0921404000 01336 03622 06425 1157006000 04842 07718 14762 1531308000 52674 94479 252816 35290509000 111981 538913 1360013 1721680

CLX + water + ChCl MA00000 00080 00094 00139 0015700200 00127 00254 00378 0043400500 00228 00888 01353 0157900700 00321 01763 02752 0323601000 00476 04050 06811 0784801500 00785 10561 18637 2277102000 01112 17571 37023 4297304000 02784 19671 66644 7643406000 21683 41275 165374 21161308000 582723 737275 2002261 272457709000 2799740 3950926 8036523 12085182

CLX + water + ChCl U00000 00080 00094 00138 0015500200 00121 00213 00417 0096000500 00206 00598 00972 0103300700 00277 01048 01705 0184701000 00406 02063 03556 0375101500 00641 04446 08081 0859302000 00873 06564 11891 13610

Shekaari et al


Table 4 Continued04000 01705 05798 11936 1861406000 05758 10922 26389 4793408000 55472 193841 526669 81627109000 204181 1322978 2934671 3539852




soln in

neat water)









CLX + water + ChCl MA00000 3387 -684 4072 8319 168100200 10427 6894 3533 6020 398000500 11348 7922 3426 5889 357800700 12508 9185 3323 5766 423401000 13764 10548 3217 5662 433801500 15899 12851 3048 5530 447002000 16769 13770 2999 5491 450904000 17706 15013 2694 5412 458806000 13338 10991 2347 5482 451808000 8866 7138 1728 5540 446009000 7025 5675 1350 5532 4468









00000 3387 -684 4072 8319 168100200 6944 3313 3631 6770 323000500 8207 4659 3548 6379 257500700 9431 5963 3468 6126 387401000 10888 7525 3364 5913 408701500 14121 10902 3219 5643 435702000 14109 10954 3155 5629 437104000 10840 7827 3012 5807 419306000 13951 11199 2752 5547 445308000 9980 7884 2096 5587 441309000 17979 16244 1736 5254 4746

CLX + water + ChCl EG00000 3387 -684 4072 8319 168100200 10504 6932 3572 6024 397600500 10473 7015 3458 5989 396400700 11022 7629 3393 5909 409101000 11710 8420 3290 5817 418301500 12880 9745 3134 5693 430702000 12403 9296 3107 5716 428404000 7197 4232 2965 6297 370306000 1034 7757 2583 5714 428608000 6990 5018 1972 5821 417909000 5581 4156 1425 5732 4268

CLX + water + ChCl G00000 3387 -684 4072 8319 168100200 10157 6435 3723 6122 387800500 10759 7124 3635 6016 359800700 11091 7519 3572 5960 404001000 11341 7852 3489 5909 409101500 12523 9170 3352 5773 422702000 12872 9596 3276 5729 427104000 9798 6673 3125 5949 405106000 8632 5722 2910 6014 398608000 7592 5324 2268 5878 412209000 15306 1342 1886 5328 4672

Shekaari et al
















































CLX + water + ChCl Uw3=0020029815 00239 00245 -279 00249 -41930315 00702 00645 811 00670 44930815 00913 00995 -902 00909 04431315 00960 00932 290 00937 238

w3=00500

29815 00299 00302 -111 00298 02930315 00885 00856 333 00967 -91930815 01384 01433 -352 01472 -63831315 01483 01465 117 01542 -396

w3=0070029815 00344 00346 -053 00336 24230315 01227 01207 162 01234 -05530815 02144 02180 -168 02031 52531315 02136 02124 057 02148 -054

w3=0100029815 00428 00436 -172 00403 60330315 01899 01802 510 01780 62930815 03382 03568 -549 03292 26831315 03606 03541 180 03533 202

w3=0150029815 00518 00525 -136 00544 -49430315 03220 03090 406 03277 -17730815 07193 07504 -433 07359 -23031315 08076 07960 143 08096 -025


w3=0050029815 00369 00373 -121 00364 11330315 01514 01459 363 01525 -07330815 02700 02804 -385 02852 -56331315 02804 02768 128 02994 -678

w3=0070029815 00458 00460 -046 00483 -55930315 02100 02071 139 02074 12430815 04295 04357 -144 03987 71731315 04511 04489 049 04248 584

w3=0100029815 00682 00678 057 00738 -82730315 03118 03173 -176 03289 -550

Shekaari et al


Table 3 Continued30815 07082 06957 177 06590 69431315 07447 07492 -061 07177 362

w3=0150029815 01598 01620 -137 01495 64830315 07312 07014 408 07094 29730815 14342 14965 -434 15228 -61831315 16693 16453 144 17203 -306


w3=0050029815 00388 00392 -107 00382 14830315 01323 01280 321 01264 44530815 02199 02274 -34 02121 35431315 02310 02284 113 02359 -210

w3=0070029815 00445 00452 -142 00445 00530315 01680 01609 423 01627 31630815 02854 02983 -451 02833 07331315 03044 02999 149 03086 -137

w3=0100029815 00596 00601 -086 00559 61730315 02387 02325 260 02376 04430815 04431 04552 -273 04374 13031315 04754 04711 091 04617 288


w3=0050029815 00189 00191 -105 00184 25230315 00551 00533 316 00582 -57530815 00972 01005 -334 01004 -32831315 01324 01309 111 01327 -024

w3=0070029815 00225 00229 -202 00224 02030315 00711 00668 594 00704 08830815 01233 01313 -646 01290 -46331315 01821 01783 211 01746 412

w3=0100029815 00292 00295 -083 00302 -343



Table 3 Continued30315 00982 00957 250 00937 45530815 01902 01952 -262 01879 11931315 02596 02573 088 02637 -161

w3=0150029815 00503 00495 162 00496 13330315 01480 01556 -514 01508 -18730815 03583 03404 499 03516 18531315 05208 05300 -176 05243 -067



Jouban-Acree model


00000 00080 00094 00139 0015700200 00123 00175 00355 0037900500 00215 00447 01134 0115700700 00293 00705 02184 0214701000 00439 01389 04813 0469501500 00713 07684 10216 1120002000 00997 08154 15238 1895704000 02326 41091 13438 2878006000 11816 67170 28655 3293708000 27249 293848 86869 114073809000 146909 2878234 4778924 5296825

CLX + water + ChCl G00000 00080 00094 00138 0015600200 00110 00180 00286 0032500500 00167 00408 00712 0082600700 00211 00641 01170 0139001000 00284 01131 02130 0265301500 00424 02049 04207 0581002000 00557 03020 05954 0921404000 01336 03622 06425 1157006000 04842 07718 14762 1531308000 52674 94479 252816 35290509000 111981 538913 1360013 1721680

CLX + water + ChCl MA00000 00080 00094 00139 0015700200 00127 00254 00378 0043400500 00228 00888 01353 0157900700 00321 01763 02752 0323601000 00476 04050 06811 0784801500 00785 10561 18637 2277102000 01112 17571 37023 4297304000 02784 19671 66644 7643406000 21683 41275 165374 21161308000 582723 737275 2002261 272457709000 2799740 3950926 8036523 12085182

CLX + water + ChCl U00000 00080 00094 00138 0015500200 00121 00213 00417 0096000500 00206 00598 00972 0103300700 00277 01048 01705 0184701000 00406 02063 03556 0375101500 00641 04446 08081 0859302000 00873 06564 11891 13610

Shekaari et al


Table 4 Continued04000 01705 05798 11936 1861406000 05758 10922 26389 4793408000 55472 193841 526669 81627109000 204181 1322978 2934671 3539852




soln in

neat water)









CLX + water + ChCl MA00000 3387 -684 4072 8319 168100200 10427 6894 3533 6020 398000500 11348 7922 3426 5889 357800700 12508 9185 3323 5766 423401000 13764 10548 3217 5662 433801500 15899 12851 3048 5530 447002000 16769 13770 2999 5491 450904000 17706 15013 2694 5412 458806000 13338 10991 2347 5482 451808000 8866 7138 1728 5540 446009000 7025 5675 1350 5532 4468









00000 3387 -684 4072 8319 168100200 6944 3313 3631 6770 323000500 8207 4659 3548 6379 257500700 9431 5963 3468 6126 387401000 10888 7525 3364 5913 408701500 14121 10902 3219 5643 435702000 14109 10954 3155 5629 437104000 10840 7827 3012 5807 419306000 13951 11199 2752 5547 445308000 9980 7884 2096 5587 441309000 17979 16244 1736 5254 4746

CLX + water + ChCl EG00000 3387 -684 4072 8319 168100200 10504 6932 3572 6024 397600500 10473 7015 3458 5989 396400700 11022 7629 3393 5909 409101000 11710 8420 3290 5817 418301500 12880 9745 3134 5693 430702000 12403 9296 3107 5716 428404000 7197 4232 2965 6297 370306000 1034 7757 2583 5714 428608000 6990 5018 1972 5821 417909000 5581 4156 1425 5732 4268

CLX + water + ChCl G00000 3387 -684 4072 8319 168100200 10157 6435 3723 6122 387800500 10759 7124 3635 6016 359800700 11091 7519 3572 5960 404001000 11341 7852 3489 5909 409101500 12523 9170 3352 5773 422702000 12872 9596 3276 5729 427104000 9798 6673 3125 5949 405106000 8632 5722 2910 6014 398608000 7592 5324 2268 5878 412209000 15306 1342 1886 5328 4672

Shekaari et al











































Shekaari et al


Table 3 Continued30815 07082 06957 177 06590 69431315 07447 07492 -061 07177 362

w3=0150029815 01598 01620 -137 01495 64830315 07312 07014 408 07094 29730815 14342 14965 -434 15228 -61831315 16693 16453 144 17203 -306


w3=0050029815 00388 00392 -107 00382 14830315 01323 01280 321 01264 44530815 02199 02274 -34 02121 35431315 02310 02284 113 02359 -210

w3=0070029815 00445 00452 -142 00445 00530315 01680 01609 423 01627 31630815 02854 02983 -451 02833 07331315 03044 02999 149 03086 -137

w3=0100029815 00596 00601 -086 00559 61730315 02387 02325 260 02376 04430815 04431 04552 -273 04374 13031315 04754 04711 091 04617 288


w3=0050029815 00189 00191 -105 00184 25230315 00551 00533 316 00582 -57530815 00972 01005 -334 01004 -32831315 01324 01309 111 01327 -024

w3=0070029815 00225 00229 -202 00224 02030315 00711 00668 594 00704 08830815 01233 01313 -646 01290 -46331315 01821 01783 211 01746 412

w3=0100029815 00292 00295 -083 00302 -343



Table 3 Continued30315 00982 00957 250 00937 45530815 01902 01952 -262 01879 11931315 02596 02573 088 02637 -161

w3=0150029815 00503 00495 162 00496 13330315 01480 01556 -514 01508 -18730815 03583 03404 499 03516 18531315 05208 05300 -176 05243 -067



Jouban-Acree model


00000 00080 00094 00139 0015700200 00123 00175 00355 0037900500 00215 00447 01134 0115700700 00293 00705 02184 0214701000 00439 01389 04813 0469501500 00713 07684 10216 1120002000 00997 08154 15238 1895704000 02326 41091 13438 2878006000 11816 67170 28655 3293708000 27249 293848 86869 114073809000 146909 2878234 4778924 5296825

CLX + water + ChCl G00000 00080 00094 00138 0015600200 00110 00180 00286 0032500500 00167 00408 00712 0082600700 00211 00641 01170 0139001000 00284 01131 02130 0265301500 00424 02049 04207 0581002000 00557 03020 05954 0921404000 01336 03622 06425 1157006000 04842 07718 14762 1531308000 52674 94479 252816 35290509000 111981 538913 1360013 1721680

CLX + water + ChCl MA00000 00080 00094 00139 0015700200 00127 00254 00378 0043400500 00228 00888 01353 0157900700 00321 01763 02752 0323601000 00476 04050 06811 0784801500 00785 10561 18637 2277102000 01112 17571 37023 4297304000 02784 19671 66644 7643406000 21683 41275 165374 21161308000 582723 737275 2002261 272457709000 2799740 3950926 8036523 12085182

CLX + water + ChCl U00000 00080 00094 00138 0015500200 00121 00213 00417 0096000500 00206 00598 00972 0103300700 00277 01048 01705 0184701000 00406 02063 03556 0375101500 00641 04446 08081 0859302000 00873 06564 11891 13610

Shekaari et al


Table 4 Continued04000 01705 05798 11936 1861406000 05758 10922 26389 4793408000 55472 193841 526669 81627109000 204181 1322978 2934671 3539852




soln in

neat water)









CLX + water + ChCl MA00000 3387 -684 4072 8319 168100200 10427 6894 3533 6020 398000500 11348 7922 3426 5889 357800700 12508 9185 3323 5766 423401000 13764 10548 3217 5662 433801500 15899 12851 3048 5530 447002000 16769 13770 2999 5491 450904000 17706 15013 2694 5412 458806000 13338 10991 2347 5482 451808000 8866 7138 1728 5540 446009000 7025 5675 1350 5532 4468









00000 3387 -684 4072 8319 168100200 6944 3313 3631 6770 323000500 8207 4659 3548 6379 257500700 9431 5963 3468 6126 387401000 10888 7525 3364 5913 408701500 14121 10902 3219 5643 435702000 14109 10954 3155 5629 437104000 10840 7827 3012 5807 419306000 13951 11199 2752 5547 445308000 9980 7884 2096 5587 441309000 17979 16244 1736 5254 4746

CLX + water + ChCl EG00000 3387 -684 4072 8319 168100200 10504 6932 3572 6024 397600500 10473 7015 3458 5989 396400700 11022 7629 3393 5909 409101000 11710 8420 3290 5817 418301500 12880 9745 3134 5693 430702000 12403 9296 3107 5716 428404000 7197 4232 2965 6297 370306000 1034 7757 2583 5714 428608000 6990 5018 1972 5821 417909000 5581 4156 1425 5732 4268

CLX + water + ChCl G00000 3387 -684 4072 8319 168100200 10157 6435 3723 6122 387800500 10759 7124 3635 6016 359800700 11091 7519 3572 5960 404001000 11341 7852 3489 5909 409101500 12523 9170 3352 5773 422702000 12872 9596 3276 5729 427104000 9798 6673 3125 5949 405106000 8632 5722 2910 6014 398608000 7592 5324 2268 5878 412209000 15306 1342 1886 5328 4672

Shekaari et al













































Table 3 Continued30315 00982 00957 250 00937 45530815 01902 01952 -262 01879 11931315 02596 02573 088 02637 -161

w3=0150029815 00503 00495 162 00496 13330315 01480 01556 -514 01508 -18730815 03583 03404 499 03516 18531315 05208 05300 -176 05243 -067



Jouban-Acree model


00000 00080 00094 00139 0015700200 00123 00175 00355 0037900500 00215 00447 01134 0115700700 00293 00705 02184 0214701000 00439 01389 04813 0469501500 00713 07684 10216 1120002000 00997 08154 15238 1895704000 02326 41091 13438 2878006000 11816 67170 28655 3293708000 27249 293848 86869 114073809000 146909 2878234 4778924 5296825

CLX + water + ChCl G00000 00080 00094 00138 0015600200 00110 00180 00286 0032500500 00167 00408 00712 0082600700 00211 00641 01170 0139001000 00284 01131 02130 0265301500 00424 02049 04207 0581002000 00557 03020 05954 0921404000 01336 03622 06425 1157006000 04842 07718 14762 1531308000 52674 94479 252816 35290509000 111981 538913 1360013 1721680

CLX + water + ChCl MA00000 00080 00094 00139 0015700200 00127 00254 00378 0043400500 00228 00888 01353 0157900700 00321 01763 02752 0323601000 00476 04050 06811 0784801500 00785 10561 18637 2277102000 01112 17571 37023 4297304000 02784 19671 66644 7643406000 21683 41275 165374 21161308000 582723 737275 2002261 272457709000 2799740 3950926 8036523 12085182

CLX + water + ChCl U00000 00080 00094 00138 0015500200 00121 00213 00417 0096000500 00206 00598 00972 0103300700 00277 01048 01705 0184701000 00406 02063 03556 0375101500 00641 04446 08081 0859302000 00873 06564 11891 13610

Shekaari et al


Table 4 Continued04000 01705 05798 11936 1861406000 05758 10922 26389 4793408000 55472 193841 526669 81627109000 204181 1322978 2934671 3539852




soln in

neat water)









CLX + water + ChCl MA00000 3387 -684 4072 8319 168100200 10427 6894 3533 6020 398000500 11348 7922 3426 5889 357800700 12508 9185 3323 5766 423401000 13764 10548 3217 5662 433801500 15899 12851 3048 5530 447002000 16769 13770 2999 5491 450904000 17706 15013 2694 5412 458806000 13338 10991 2347 5482 451808000 8866 7138 1728 5540 446009000 7025 5675 1350 5532 4468









00000 3387 -684 4072 8319 168100200 6944 3313 3631 6770 323000500 8207 4659 3548 6379 257500700 9431 5963 3468 6126 387401000 10888 7525 3364 5913 408701500 14121 10902 3219 5643 435702000 14109 10954 3155 5629 437104000 10840 7827 3012 5807 419306000 13951 11199 2752 5547 445308000 9980 7884 2096 5587 441309000 17979 16244 1736 5254 4746

CLX + water + ChCl EG00000 3387 -684 4072 8319 168100200 10504 6932 3572 6024 397600500 10473 7015 3458 5989 396400700 11022 7629 3393 5909 409101000 11710 8420 3290 5817 418301500 12880 9745 3134 5693 430702000 12403 9296 3107 5716 428404000 7197 4232 2965 6297 370306000 1034 7757 2583 5714 428608000 6990 5018 1972 5821 417909000 5581 4156 1425 5732 4268

CLX + water + ChCl G00000 3387 -684 4072 8319 168100200 10157 6435 3723 6122 387800500 10759 7124 3635 6016 359800700 11091 7519 3572 5960 404001000 11341 7852 3489 5909 409101500 12523 9170 3352 5773 422702000 12872 9596 3276 5729 427104000 9798 6673 3125 5949 405106000 8632 5722 2910 6014 398608000 7592 5324 2268 5878 412209000 15306 1342 1886 5328 4672

Shekaari et al











































Shekaari et al


Table 4 Continued04000 01705 05798 11936 1861406000 05758 10922 26389 4793408000 55472 193841 526669 81627109000 204181 1322978 2934671 3539852




soln in

neat water)









CLX + water + ChCl MA00000 3387 -684 4072 8319 168100200 10427 6894 3533 6020 398000500 11348 7922 3426 5889 357800700 12508 9185 3323 5766 423401000 13764 10548 3217 5662 433801500 15899 12851 3048 5530 447002000 16769 13770 2999 5491 450904000 17706 15013 2694 5412 458806000 13338 10991 2347 5482 451808000 8866 7138 1728 5540 446009000 7025 5675 1350 5532 4468









00000 3387 -684 4072 8319 168100200 6944 3313 3631 6770 323000500 8207 4659 3548 6379 257500700 9431 5963 3468 6126 387401000 10888 7525 3364 5913 408701500 14121 10902 3219 5643 435702000 14109 10954 3155 5629 437104000 10840 7827 3012 5807 419306000 13951 11199 2752 5547 445308000 9980 7884 2096 5587 441309000 17979 16244 1736 5254 4746

CLX + water + ChCl EG00000 3387 -684 4072 8319 168100200 10504 6932 3572 6024 397600500 10473 7015 3458 5989 396400700 11022 7629 3393 5909 409101000 11710 8420 3290 5817 418301500 12880 9745 3134 5693 430702000 12403 9296 3107 5716 428404000 7197 4232 2965 6297 370306000 1034 7757 2583 5714 428608000 6990 5018 1972 5821 417909000 5581 4156 1425 5732 4268

CLX + water + ChCl G00000 3387 -684 4072 8319 168100200 10157 6435 3723 6122 387800500 10759 7124 3635 6016 359800700 11091 7519 3572 5960 404001000 11341 7852 3489 5909 409101500 12523 9170 3352 5773 422702000 12872 9596 3276 5729 427104000 9798 6673 3125 5949 405106000 8632 5722 2910 6014 398608000 7592 5324 2268 5878 412209000 15306 1342 1886 5328 4672

Shekaari et al



















































00000 3387 -684 4072 8319 168100200 6944 3313 3631 6770 323000500 8207 4659 3548 6379 257500700 9431 5963 3468 6126 387401000 10888 7525 3364 5913 408701500 14121 10902 3219 5643 435702000 14109 10954 3155 5629 437104000 10840 7827 3012 5807 419306000 13951 11199 2752 5547 445308000 9980 7884 2096 5587 441309000 17979 16244 1736 5254 4746

CLX + water + ChCl EG00000 3387 -684 4072 8319 168100200 10504 6932 3572 6024 397600500 10473 7015 3458 5989 396400700 11022 7629 3393 5909 409101000 11710 8420 3290 5817 418301500 12880 9745 3134 5693 430702000 12403 9296 3107 5716 428404000 7197 4232 2965 6297 370306000 1034 7757 2583 5714 428608000 6990 5018 1972 5821 417909000 5581 4156 1425 5732 4268

CLX + water + ChCl G00000 3387 -684 4072 8319 168100200 10157 6435 3723 6122 387800500 10759 7124 3635 6016 359800700 11091 7519 3572 5960 404001000 11341 7852 3489 5909 409101500 12523 9170 3352 5773 422702000 12872 9596 3276 5729 427104000 9798 6673 3125 5949 405106000 8632 5722 2910 6014 398608000 7592 5324 2268 5878 412209000 15306 1342 1886 5328 4672

Shekaari et al











































Shekaari et al











































Significant Increase in the Solubility of Celecoxib in Presence of … · solubility data of CLX in...

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Transcript of Significant Increase in the Solubility of Celecoxib in Presence of … · solubility data of CLX in...