Journal of Molecular Liquids 249 (2018) 53–60
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Solubility of a poorly soluble immunosuppressant in different pure solvents: Measurement, correlation, thermodynamics and molecular interactions Mohd Abul Kalam a, Abdul Arif Khan a, Aws Alshamsan a, Anzarul Haque b, Faiyaz Shakeel c,⁎ a b c
Nanomedicine Research Unit, Department of Pharmaceutics, College of Pharmacy, King Saud University, P.O. Box: 2457, Riyadh 11451, Saudi Arabia Department of Pharmacognosy, College of Pharmacy, Prince Sattam bin Abdulaziz University, Al-Kharj, Saudi Arabia Department of Pharmaceutics, College of Pharmacy, King Saud University, P.O. Box: 2457, Riyadh 11451, Saudi Arabia
a r t i c l e
i n f o
Article history: Received 10 October 2017 Received in revised form 2 November 2017 Accepted 3 November 2017 Available online 05 November 2017 Keywords: Activity coefficient Dissolution thermodynamics Immunosuppressant Molecular interaction Pure solvent Solubility
a b s t r a c t The objective of this research work was to measure the solubility of mycophenolate mofetil (MPM) in ten different pure solvents at temperatures T = 298.2 K to 318.2 K and pressure p = 0.1 MPa. The solubilities of MPM in mole fraction were obtained maximum in ethyl acetate (9.28 × 10−2) and minimum in water (4.16 × 10−6) at “T = 318.2 K” and similar trends were also observed at each temperature investigated. Higher solute-solvents molecular interactions were observed in MPM-ethyl acetate and MPM-Transcutol. Apparent thermodynamic analysis indicated an endothermic and entropy-driven dissolution of MPM in each solvent investigated. © 2017 Elsevier B.V. All rights reserved.
1. Introduction Mycophenolate mofetil (MPM) (Fig. 1; IUPAC name: 2-(morpholin4-yl)ethyl (4E)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3dihydro-2-benzofuran-5-yl)-4-methylhex-4-enoate; molecular formula: C23H31NO7; molar mass: 433.49 g mol−1 and CAS registry number: 128794-94-5) occurs as a white to beige colored powder [1–3]. It is 2morpholinoethyl ester of mycophenolic acid (MPA), a transplant, antirheumatic, a major immunosuppressive agent and inosine monophosphate dehydrogenase inhibitor [1]. MPM undergoes rapid hydrolysis to give MPA which actually exerts its effects in vivo [4]. It is an antimetabolite and potent immunosuppressive agent used as adjunctive therapy in prevention of allograft rejection and in the treatment of serious autoimmune disorders [2,4]. It has been recommended for the treatment of an autoimmune disease (lupus) which is characterized by systemic inflammation and organ damage, where the efficacy of MPM was accomplished partly by attenuating the inflammatory and stimulatory capacity of dendritic cells [5,6]. According to USFDA database, MPM has been reported as practically insoluble in water [7]. The pKa values for MPM have been reported as 5.6 for the morpholino group and 8.5 for the phenolic group [1,7]. However, ⁎ Corresponding author at: Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia. E-mail address:
[email protected] (F. Shakeel).
https://doi.org/10.1016/j.molliq.2017.11.028 0167-7322/© 2017 Elsevier B.V. All rights reserved.
the apparent partition coefficient of MPM in 1-octanol/water system has been reported as 238 [7]. It is an innovator product of Roche Diagnostics GmbH which is marketed under the trade name of CellCept® for the treatment of autoimmune disorders [7]. It is commercially available in the form of tablets, capsules and oral suspensions. However, its hydrochloride salt is commercially available as intravenous injection. Due to its poor aqueous solubility, the development of liquid dosage forms of MPM is very difficult. The solubility data of poorly soluble drugs in neat/pure “aqueous and organic solvents” are important in various industrial process such as “purification, recrystallization, preformulation studies and formulation development” of such drugs [8–13]. Hence, the solubility of MPM must be determined properly in these solvents. Apelblat and van't Hoff models are commonly used computational models for the correlation/curve fitting of experimental solubility data of solutes in pure solvents with calculated solubility data [13–16]. Therefore, these models were applied for the correlation of experimental solubility data of MPM with calculated ones. Some formulations approaches such as tablets, enteric coated tablets, capsules, suspensions, nanoparticles, nanosuspensions and nanogels have been investigated for the evaluation of drug delivery potential, dissolution and bioavailability of MPM [5,6,17–25]. The solubility (as mole fraction) of MPM in water at ambient temperature (T = 298.2 K) has been reported as 1.79 × 10−6 [7]. However, the solubility data of MPM in any organic solvent have not been reported so far in literature. Therefore, the objective of this research work was to measure the solubility of
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M.A. Kalam et al. / Journal of Molecular Liquids 249 (2018) 53–60
Fig. 1. Molecular structure of MPM (molar mass: 433.49 g mol−1).
MPM in ten different pure solvents including water, ethanol, Transcutol, polyethylene glycol-400 (PEG-400), propylene glycol (PG), ethylene glycol (EG), isopropanol (IPA), n-butanol, ethyl acetate (EA) and dimethyl sulfoxide (DMSO) were measured at temperatures T = 298.2 K to 318.2 K and pressure p = 0.1 MPa. These solvents have been categorized as the eco-friendly solvents which are being utilized for various industrial applications such as purification, pre-formulation studies and dosage form design of pharmaceuticals/drugs in pharmaceutical industries [26,27]. Therefore, the investigated solvents were selected in this work. Apparent thermodynamic analysis on measured solubility data of MPM was also performed for the evaluation of dissolution behavior of MPM. The activity coefficients were calculated in order to evaluate the molecular interactions between solute and solvent molecules. The solubility data of MPM generated in this work would be useful in various industrial processes such as “purification, recrystallization, drug discovery and formulation development” of MPM. 2. Experimental 2.1. Materials (RS)-MPM, Transcutol® [IUPAC name: 2-(2-ethoxyethoxy) ethanol] and ethyl alcohol (IUPAC name: ethanol) were obtained from “Roche Diagnostics GmbH (Mannheim, Germany)”, “Gattefosse (Lyon, France)” and “Scharlab SL (Barcelona, Spain)”, respectively. IPA (IUPAC name: isopropanol) and n-butyl alcohol (IUPAC name: n-butanol) were obtained from “Sigma Aldrich (St. Louis, MO)”. EG (IUPAC name: 1,2-ethanediol), PG (IUPAC name: 1,2-propanediol), PEG-400 (IUPAC name: polyethylene glycol-400), EA (IUPAC name: ethyl ethanoate) and DMSO (IUPAC name: dimethyl sulfoxide) were obtained from “EMerck (Darmstadt, Germany)”. Water (specific conductivity was b1.0 μS cm−1) was collected from “Milli-Q water purification unit”. The information about these materials is presented in Supplementary Table 1 (Table S1). 2.2. Analysis of MPM “Waters Acquity H-class Ultra-Performance Liquid Chromatography (UPLC)” system coupled with a Waters diode-array-ultra-violet detector (DAD-UV) by Acquity “UPLC (Waters, MA)” was used for the analysis of MPM in solubility samples. The chromatographic system includes quaternary solvent manager, sample manager (Acquity, UPLC Waters) with injection capacity of 10 μL and a column heater. The elution of MPM was performed on “Acquity UPLC BEH™ C18 column (2.1 × 50 mm, 1.7 μm, Waters, USA)” maintained at T = 323.2 K. The reported liquid chromatographic method was used for the analysis of MPM contents with slight modifications [21]. In reported method, HPLC-UV technique was used but in the present work, UPLC-UV method has been used. The mobile phase was consisted of 82% methanol and 18% 0.02 M phosphate buffer (containing 0.1% triethylamine and pH of the buffer was adjusted to 4.0 by using 85% orthophosphoric acid) which was pumped at an isocratic flow rate of 0.17 mL min−1. The injection volume was 5 μL and column oven temperature was maintained at T = 323.2 ± 2 K. MPM was detected by UV-detector at 214 nm. The
retention time of MPM was 0.922 min. The “EMPOWER software” was used to control the UPLC-UV system as well as for data acquisition and processing. The standard solution of MPM was prepared in the concentration of 500 μg g−1. From this standard solution, the serial dilutions were made on mass/mass basis in order to obtain the concentration in the range of (0.5 to 400) μg g−1. The calibration curve was plotted between the concentration of MPM (μg g−1) and peak area obtained from UPLC analysis. The calibration curve of MPM was observed linear in the concentration range of (0.5 to 400) μg g−1 with coefficient of determination (R2) of 0.9965. The regressed equation for calibration data was obtained as peak UPLC area = 158,746 ∗ concentration + 964,750. The proposed UPLC method for the analysis of MPM was validated well in terms of “linearity, precision, accuracy, sensitivity, selectivity and robustness”. 2.3. Solid state characterization of MPM The solid state characterization of MPM was performed using “Differential Scanning Calorimetry (DSC)”. DSC analysis was performed for the investigation of different thermal parameters and the possibility of polymorphic transformations of MPM. This analysis was performed both on pure MPM (initial material) and equilibrated MPM. The equilibrated MPM was recovered from equilibrium sample (water) by slow evaporation of water [28]. DSC analysis on pure and equilibrated MPM was performed using “DSC-8000 Instrument (Perkin Elmer, USA)”. DSC instrument was equipped with chiller (T = 253.2 K) and autosampler. The calibration of instrument was carried out using pure indium at T = 283.2 K to 773.2 K. For DSC analysis, a mass of accurately weighed 5.0 mg of pure and equilibrated MPM was taken to an aluminium pan and sealed hermetically. DSC thermogram of pure and equilibrated MPM was recorded under a nitrogen purge of 20 mL min−1 at a heating rate of 10.0 K min− 1 with the temperature range from 303.2 K to 423.2 K. 2.4. Measurement of MPM solubility The solubility of pure MPM in ten different pure solvents including water, ethanol, IPA, EG, PG, n-butanol, EA, DMSO, PEG-400 and Transcutol was measured using an isothermal method at "T = 298.2 K to 318.2 K″ and p = 0.1 MPa [29]. The excess quantity of pure MPM was added in known quantities of each pure solvent in triplicates manner. Each solute-solvent mixture was vortexed and transferred to the “Biological Shaker (Julabo, PA)” at 100 rpm for 72 h. After 72 h, each solute-solvent mixture was taken out from the shaker and allowed to settle MPM solid particles for 24 h [13]. After 24 h settling of MPM particles, the supernatants were carefully taken, diluted suitably with mobile phase and subjected for the analysis of MPM content by the proposed UPLC method at 214 nm. The concentration of MPM (μg g−1) in solubility samples was determined from calibration curve of MPM. Then, the experimental mole fraction solubilities of MPM (xe) were calculated using Eq. (1) [12,28]: xe ¼
m1 =M1 m1 =M 1 þ m2 =M 2
ð1Þ
Here, the symbols m1 and m2 are the masses of pure MPM and respective pure solvent (g), respectively. The symbols M1 and M2 are the molar masses of MPM and respective pure solvent (g mol− 1), respectively. 3. Results and discussion 3.1. Solid state characterization of MPM DSC analysis on pure and equilibrated MPM was performed in order to evaluate different thermal parameters and the possibility of
M.A. Kalam et al. / Journal of Molecular Liquids 249 (2018) 53–60
polymorphic transformation of MPM. The representative DSC spectra of pure MPM are shown in Fig. 2. The DSC thermogram of pure MPM presented a sharp endothermic peak at the fusion/melting temperature (Tfus) of 370.40 K with fusion enthalpy (ΔHfus) and molar heat capacity (ΔCp) of 46.73 kJ mol−1 and 126.10 J mol−1 K−1, respectively. However, the DSC thermogram (Figure not shown because it was similar to Fig. 2) of equilibrated MPM showed a sharp endothermic peak at Tfus value of 369.90 K with ΔHfus and ΔCp values of 46.64 kJ mol− 1 and 125.91 J mol− 1 K− 1, respectively. Thermal parameters of pure and equilibrated MPM were very close to each other which indicated that MPM was not transformed to different polymorphic states during equilibrium. Therefore, MPM was found to show no polymorphic behavior in this work. These results were in good agreement with those reported in literature [3]. In literature, an endothermic peak of pure MPM was obtained at Tfus value of 370.20 K [3]. In our study, an endothermic peak of pure MPM was obtained at Tfus value of 370.40 K which was very close to its reported value.
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Table 1 Experimental solubilities (xe) of MPM in mole fraction in different pure solvents (S) at T = 298.2 K to 318.2 K and p = 0.1 MPaa. S
xe
Water Ethanol IPA EG PG PEG-400 Transcutol n-Butanol EA DMSO xidl a
T = 298.2 K
T = 303.2 K
T = 308.2 K
T = 313.2 K
T = 318.2 K
−6
−6
−6
−6
4.16 × 10−6 9.06 × 10−3 1.21 × 10−2 1.40 × 10−3 1.93 × 10−3 4.49 × 10−2 5.22 × 10−2 1.59 × 10−2 9.28 × 10−2 4.39 × 10−2 9.97 × 10−2
1.75 × 10 6.13 × 10−3 8.52 × 10−3 7.15 × 10−4 1.05 × 10−3 2.71 × 10−2 3.93 × 10−2 1.08 × 10−2 6.89 × 10−2 2.30 × 10−2 3.72 × 10−2
2.29 × 10 6.76 × 10−3 9.34 × 10−3 8.58 × 10−4 1.26 × 10−3 3.12 × 10−2 4.21 × 10−2 1.19 × 10−2 7.44 × 10−2 2.72 × 10−2 4.79 × 10−2
2.87 × 10 7.49 × 10−3 1.02 × 10−2 1.03 × 10−3 1.47 × 10−3 3.55 × 10−2 4.52 × 10−2 1.32 × 10−2 8.02 × 10−2 3.28 × 10−2 6.14 × 10−2
3.49 × 10 8.33 × 10−3 1.11 × 10−2 1.20 × 10−3 1.68 × 10−3 3.99 × 10−2 4.86 × 10−2 1.44 × 10−2 8.56 × 10−2 3.88 × 10−2 7.84 × 10−2
The standard uncertainties u are u(T) = 0.16 K, u(p) = 0.003 MPa and ur(xe) = 1.55%.
3.2. Experimental solubility data of MPM The xe values of pure MPM in ten different pure solvents at T = 298.2 K to 318.2 K and p = 0.1 MPa are furnished in Table 1. The saturated solubility of MPM in water at ambient temperature (T = 298.2 K) has been reported as 43.0 μg mL−1 which was converted into mole fraction solubility as 1.79 × 10−6 [7]. The solubility of MPM as mole fraction in water at T = 298.2 K was recorded as 1.75 × 10−6 in this work. The mole fraction solubility of MPM in water recorded in this work was very close with its reported value [7]. These results indicated that experimental solubility values of MPM obtained in this work were in good agreement with literature. In general, the xe values of MPM were observed as increasing with the rise in temperature in all pure solvent investigated (Table 1). There was significant enhancement in the mole fraction solubility of MPM with the rise in temperature. The xe values of MPM were recorded highest in EA (9.28 × 10−2), followed by Transcutol (5.22 × 10−2), PEG400 (4.49 × 10−2), DMSO (4.39 × 10−2), n-butanol (1.59 × 10−2), IPA (1.21 × 10− 2), ethanol (9.06 × 10−3), PG (1.93 × 10−3), EG (1.40 × 10−3) and water (4.16 × 10−6) at “T = 318.2 K” and similar trends
were also observed at each temperature investigated. The xe values of MPM in EA and Transcutol were exceptionally higher as compared to its xe values in other pure solvents investigated which could be due to the fact that polarity/dielectric constants of MPM might be similar with that of EA and Transcutol. The dielectric constants of various pure solvents have been reported in literature [30]. Reported values of dielectric constants for different pure solvents are presented in Table 2. Between ethanol and IPA, the xe values of MPM were slightly higher in IPA because of lower dielectric constant/polarity of IPA as compared to ethanol [13]. Between EG and PG, the xe values of MPM were slightly higher in PG because of lower polarity of PG as compared to EG [11]. Between IPA and n-butanol, the xe values of MPM in nbutanol were slightly higher in n-butanol because of slightly lower polarity of n-butanol as compared to IPA [28]. Based on these results, MPM has been proposed as freely soluble in EA, Transcutol and DMSO, soluble in PEG0-400, n-butanol, IPA and ethanol, sparingly soluble in EG and PG and practically insoluble in water [13,28]. Hence, EA, Transcutol and DMSO were chosen as the best solvents and water was chosen as the anti-solvent for MPM.
Fig. 2. DSC thermogram of pure MPM.
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Table 2 The values of dielectric constants of different pure solvents at T = 298.2.
Table 4 The δ value of MPM and different pure solvents at T = 298.2 K.
Components
Dielectric constant
Reference
Components
δ/MPa1/2
Reference
Water Ethanol PG PEG-400 Transcutol EG IPA n-Butanol EA DMSO
79.00 25.00 32.00 14.10 12.60 37.00 17.90 17.80 6.00 47.00
[30] [30] [30] [30] [30] [30] [30] [30] [30] [30]
MPM Water Ethanol PG PEG-400 Transcutol EG IPA n-Butanol EA DMSO
23.80 47.80 26.50 30.20 23.11 22.30 32.90 23.50 23.10 18.10 26.70
Calculated [31] [31] [31] [31] [35] [31] [31] [31] [31] [31]
3.3. Hildebrand solubility parameter for MPM and different pure solvents In this research work, Hildebrand solubility parameter (δ) for solute MPM and different pure solvents was calculated using “Fedors group substitution method” as described in literature using Eq. (2) [31]:
δ¼
hX
X i U0 V 1=2
ð2Þ
Here, the symbols U0 and V are the vaporization energy and molar volume, respectively. Using the values of U0 and V, the δ values for different pure solvents including those used in this work have been calculated and reported well in literature [32–35]. However, the δ value for MPM has not been calculated and reported in literature. Hence, this value was calculated in this study. The details about calculation of δ value for MPM using “Fedors group substitution method” are presented in Table 3. The calculated δ value for MPM and reported δ values for different pure solvents are furnished in Table 4. The δ value for MPM was calculated as 23.80 MPa1/2. The calculated δ value of MPM showed that it had lower polarity. The investigated solvents were selected based on their pharmaceutical applications. The range of solvents used was not much enlarged because many solvents such as chloroform, acetonitrile and acetone are much toxic and not suitable in dosage form design of drugs [26,27]. Broad range of solvents was used which ranges from lower polarity to higher polarity based on their pharmaceutical applications. For example ethyl acetate (δ = 18.10) to water (δ = 47.80). These solvents have different chemical groups and polarity. Therefore, these solvents were chosen in this study. The xe values of MPM were recorded higher in pure solvents with lower or medium δ values including EA, Transcutol, PEG-400, DMSO IPA, n-butanol and ethanol because MPM had lower polarity. However, the xe value of MPM was obtained lowest in water which was possible due to the highest δ value of water.
3.4. Ideal solubilities, activity coefficients and solute-solvent molecular interactions The ideal solubility of MPM (xidl) was calculated using Eq. (3) [36]: idl
ln x
−ΔH fus T fus −T ΔC p T fus −T T þ ln þ ¼ RT fus T T T fus R
ð3Þ
Here, R is the universal gas constant (R = 8.314 J mol−1 K−1) and ΔCp is the molar heat capacity [36,37]. It has been reported in literature that the value of ΔCp may be set approximately as the entropy of fusion (ΔSfus) [38,39]. The reasons for this hypothesis have already described by Neau and Flynn [40]. The ΔSfus value for MPM was calculated using Eq. (4) [36]: ΔSfus ¼
ΔH fus T fus
ð4Þ
From DSC results of pure MPM described in above section, the Tfus value for MPM was obtained as 370.40 K and ΔHfus value for MPM was obtained as 46.73 kJ mol− 1. Using Eq. (4), the value of ΔSfus or ΔCp was obtained as 126.10 J mol−1 K−1. The xidl values of MPM were calculated using Eq. (3) resulting values are listed in Table 1. The activity coefficients (γ) of MPM in each pure solvent were calculated using Eq. (5) [36,38]: γ¼
xidl xe
ð5Þ
The γ values for MPM in each pure solvent at T = 298.2 K to 318.2 K are presented in Table 5. Based on the γ values for MPM in different pure solvents, the solutesolvent molecular interactions have been discussed. The γ values for MPM were obtained significantly larger in water at each temperature in comparison with other pure solvents evaluated. However, this
Table 3 Details calculation of internal energy (ΔU0), molar volume (V) and Hildebrand solubility parameters (δ) of MPM at T = 298.2 K using Fedors method [31]. Atom or group
Group number
ΔU0/cal mol−1
V/cm3 mol−1
\ \CH3 \ \CH2\ \ NC_ \ \CH_ Hexasubstituted Phenyl ring \ \COO\ \ \ \OH \ \O\ \ NN\ \ Ring closure, 5 or more atoms Total
3 10 1 1 1 2 1 2 1 2
3 × 1125 = 3375 10 × 1180 = 11,800 1 × 1030 = 1030 1 × 1030 = 1030 1 × 7630 = 7630 2 × 4300 = 8600 1 × 7120 = 7120 2 × 800 = 1600 1 × 1000 = 1000 2 × 250 = 500 ∑ΔU0 = 182,778 δ = (182,778/322.5)1/2 = 23.80 MPa1/2
3 × 33.50 = 100.5 10 × 16.1 = 161 −5.5 × 1.0 = −5.5 13.5 × 1.0 = 13.5 1 × −23.6 = −23.6 1 × 18 = 36 1 × 10 = 10 2 × 3.8 = 7.6 1 × −9 = −9 2 × 16.0 = 32.0 ∑V = 322.5
M.A. Kalam et al. / Journal of Molecular Liquids 249 (2018) 53–60 Table 5 Activity coefficients (γ) of MPM in different pure solvents (S) at T = 298.2 K to 318.2 K. S
xe T = 298.2 K
Water Ethanol IPA EG PG PEG-400 Transcutol n-Butanol EA DMSO
21,300.00 6.08 4.37 52.10 35.40 1.37 0.94 3.44 0.54 1.62
T = 303.2 K 21,000.00 7.10 5.13 55.80 38.00 1.53 1.14 3.99 0.64 1.76
T = 308.2 K 21,400.00 8.20 6.05 59.70 41.70 1.72 1.36 4.21 0.76 1.87
T = 313.2 K 22,500.00 9.42 7.06 65.30 46.60 1.96 1.61 5.41 0.91 2.02
T = 318.2 K 24,000.00 11.00 8.28 71.20 51.80 2.21 1.91 6.24 1.08 2.27
value was much smaller in EA at each temperature studied. The γ values for MPM were slightly higher in Transcutol, DMSO and PEG-400 in comparison with EA. In general, the results of γ value were in good agreement with its solubility data in various pure solvents. Because, the γ values for MPM in EA and Transcutol were significantly smaller than other pure solvents studied, the maximum solute-solvent molecular interactions were recorded in MPM-EA and MPM-Transcutol in comparison with other combination of solute and solvent. However, the lowest solute-solvent molecular interactions were obtained in water due to higher γ values. It was also noted that the γ values for MPM were N1.0 in most of the solvents including water, ethanol, IPA, n-butanol, EG, PG, PEG-400 and DMSO which indicated repulsive solute-solvent interactions in these solvents [28]. However, the γ values for MPM were b1.0 in EA and Transcutol which indicated attractive solute-solvent interactions in EA and Transcutol [28].
57
Table 6 The parameters of Apelblat model (A, B and C) along with R2 and % RMSD values for MPM in different pure solvents (S). S
A
B
C
R2
RMSD (%)
Water Ethanol PG PEG-400 Transcutol EG IPA n-Butanol EA DMSO
574.53 26.54 250.04 114.97 −71.15 168.25 −25.59 8.65 −60.13 297.71
−30,314.60 −3034.55 −14,138.50 −7431.08 1957.63 −10,713.00 −437.72 −2155.48 1444.68 −16,425.40
−85.31 −3.76 −36.76 −16.43 10.76 −24.49 3.91 −1.04 9.23 −43.24
0.9993 0.9993 0.9990 0.9996 0.9999 0.9998 0.9998 0.9995 0.9991 0.9991
4.49 3.85 2.91 4.11 2.86 3.86 1.68 2.12 2.13 3.69
[13–15]. The Apelblat model solubilities (xApl) of MPM were calculated using Eq. (6) [14,15]: ln xApl ¼ A þ
B þ C ln ðT Þ T
ð6Þ
Here, the symbols A, B and C are the parameters/coefficients of Eq. (6). The values of Apelblat parameters were determined by applying nonlinear multivariate regression analysis of xe values of MPM presented in Table 1 [11]. The xe values of MPM were fitted with xApl values of MPM using root mean square deviations (RMSD) and R2 values. The RMSD values for MPM were calculated using Eq. (7): " RMSD ¼
2 #12 1 N xApl −xe ∑ N i¼1 xe
ð7Þ
3.5. Correlation/curve fitting of experimental solubilities of MPM The xe values of MPM were correlated/fitted using two different computational models including Apelblat and van't Hoff models
Here, the symbol N represents the number of experimental temperature points. The graphical correlation/fitting between logarithm solubilities (ln xe) and ln xApl values of MPM in each pure solvent against
Fig. 3. Correlation/curve fitting of ln xe values of MPM with Apelblat model in ten different pure solvents as a function of 1/T (symbols represent the experimental solubilities of MPM and solid lines represent the solubilities of MPM calculated by Apelblat model).
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Table 7 The parameters of van't Hoff model (a and b) along with R2 and % RMSD values for MPM in different pure solvents (S). S
a
b
R2
RMSD (%)
Water Ethanol PG PEG-400 Transcutol EG IPA n-Butanol EA DMSO
0.52 1.20 2.69 4.39 1.30 3.46 0.74 1.64 2.00 6.76
−4102.00 −1880.80 −2845.30 −2384.10 −1354.80 −3191.40 −1644.40 −1838.70 −1396.50 −3140.20
0.9954 0.9992 0.9976 0.9992 0.9994 0.9993 0.9998 0.9995 0.9989 0.9973
2.09 1.10 1.23 0.60 0.38 0.80 1.04 0.31 0.79 1.24
3.6. MPM dissolution thermodynamics studies
1/T is presented in Fig. 3 which presented good correlation/curve fitting between ln xe and ln xApl values of MPM in each neat solvent studied. The resulting data of Apelblat correlation are presented in Table 6. The RMSD values in different pure solvents were obtained in the range of (1.68 to 4.49) %. The RMSD value for MPM was recorded highest in water (4.49%) and lowest in IPA (1.68%). The R2 values for MPM in different pure solvents were obtained in the range of 0.9990 to 0.9999. These results showed good correlation of xe values of MPM with Apelblat model. The van't Hoff model solubilities (xvan't) of MPM were calculated using Eq. (8) [13]: ln xVan0t ¼ a þ
b T
Hoff correlation are presented in Table 7. The RMSD values for MPM in different pure solvents were obtained in the range of (0.31 to 2.09) %. The RMSD value for MPM was obtained highest in water (2.08%) and lowest in n-butanol (0.31%). The R2 values for MPM in different pure solvents were obtained in the range of 0.9954 to 0.9998. These results again indicated good correlation/fitting of xe values of MPM with van't Hoff model.
ð8Þ
Here, the symbols a and b are parameters of Eq. (8) which were determined by plotting ln xe values of MPM against 1/T. The xe values of MPM were correlated/fitted with xvan't values of MPM using RMSD and R2 values. The graphical correlation/curve fitting between ln xe and ln xvan't values of MPM in each pure solvent against 1/T is presented in Fig. S1 which indicated good correlation/curve fitting. The results of van't
The dissolution thermodynamics of MPM in different pure solvents was evaluated using apparent thermodynamic analysis on experimental solubilities of MPM. Different apparent standard thermodynamic parameters including apparent standard dissolution enthalpy (ΔsolH0), apparent standard Gibbs free energy (ΔsolG0) and apparent standard dissolution entropy (ΔsolS0) for MPM dissolution were calculated by applying van't Hoff and Krug et al. analysis. The ΔsolH0 values for MPM dissolution in different neat solvents were calculated at the mean harmonic temperature (Thm) of 308 K using van't Hoff analysis with the help of Eq. (9) [36,41]: 0
1 ∂ ln xe
Δ H @ A ¼ − sol R ∂ 1 =T −1 =T hm
0
ð9Þ
P
According to Eq. (9), the ΔsolH0 values for MPM dissolution were calculated by van't Hoff plots constructed between ln xe values of MPM
against 1 T −1 T . The results of van't Hoff plots for MPM dissolution hm
are shown in Fig. 4. These van't Hoff plots were found to be linear with R2 values in the range of 0.9953 to 0.9998 (Fig. 4). The ΔsolG0 values for MPM dissolution were also calculated at Thm value of 308 K using Krug et al. analysis approach with the help of Eq. (10) [42]: Δsol G0 ¼ −RT hm intercept
Fig. 4. van't Hoff plots for the determination of apparent thermodynamic parameters of MPM constructed between ln xe and 1/T − 1/Thm in ten different pure solvents.
ð10Þ
M.A. Kalam et al. / Journal of Molecular Liquids 249 (2018) 53–60 Table 8 Apparent thermodynamic quantities (ΔsolH0, ΔsolG0 and ΔsolS0) along with R2 values for MPM in different pure solvents (S)a. S
ΔsolH0/kJ mol−1
ΔsolG0/kJ mol−1
ΔsolS0/J mol−1 K−1
R2
Water Ethanol PG PEG-400 Transcutol EG IPA n-Butanol EA DMSO
34.14 15.65 23.68 19.84 11.12 26.56 13.68 15.30 11.62 26.14
32.76 12.53 16.74 8.56 7.92 17.65 11.75 11.08 6.46 8.79
4.50 10.13 22.54 36.62 10.88 28.93 6.28 13.71 16.73 56.32
0.9953 0.9992 0.9965 0.9992 0.9994 0.9962 0.9998 0.9995 0.9989 0.9972
a The relative uncertainties are u(ΔsolH0) = 0.38 kJ mol−1, u(ΔsolG0) = 0.57 kJ mol−1 and u(ΔsolS0) = 0.77 J mol−1 K−1.
Here, the values of intercept for MPM in each pure solvent were calculated from van't Hoff plot presented in Fig. 4. Finally, the ΔsolS0 values for MPM dissolution were calculated using the combined approaches of van't Hoff and Krug et al. analysis using Eq. (11) [36,41,42]: Δsol S0 ¼
0
0
Δsol H −Δsol G T hm
ð11Þ
Different thermodynamic quantities measured by apparent thermodynamic analysis for MPM dissolution in various pure solvents are presented in Table 8. It was observed that the ΔsolH0 values for MPM dissolution in different pure solvents were obtained as positive values in the range of (11.12 to 34.14) kJ mol−1. The ΔsolH0 value for MPM dissolution was obtained highest in water (34.14 kJ mol− 1) and lowest in Transcutol (11.12 kJ mol−1). The mean ΔsolH0 value for MPM dissolution was recorded as 19.79 kJ mol−1 with relative standard deviation (RSD) value of 0.38. The ΔsolG0 values for MPM dissolution in different pure solvents were also obtained as positive values in the range of (6.46 to 32.76) kJ mol−1. The ΔsolG0 value for MPM dissolution was recorded highest in water (32.76 kJ mol− 1) and lowest in EA (6.46 kJ mol− 1). The mean ΔsolG0 value for MPM dissolution was recorded as 13.42 kJ mol− 1 with RSD value of 0.57. The lowest ΔsolG0 value for MPM dissolution was recorded in EA that could be possible due to the highest solubility and lower polarity/dielectric constant of MPM in EA. The results of ΔsolG0 for MPM dissolution were in good agreement with experimental solubility data of MPM. Relatively, lower values of ΔsolH0 and ΔsolG0 were obtained in EA, DMSO, Transcutol and PEG-400 which indicated that lower energies are required for the solubilization of MPM in these solvents. The positive values of ΔsolH0 and ΔsolG0 for MPM in all pure solvents indicated an endothermic dissolution of MPM in all these pure solvents [11,13,28]. The ΔsolS0 values for MPM dissolution in different pure solvents were also obtained as positive values in the range of (4.50 to 56.32) J mol−1 K−1. The mean ΔsolS0 value for MPM dissolution was obtained as 20.66 J mol−1 K−1 with RSD value of 0.77. The positive ΔsolS0 values for MPM showed an entropy-driven dissolution of MPM in each pure solvent studied [11]. Overall, the dissolution of MPM was obtained as an endothermic and entropy-driven in all pure solvents studied [13,28]. 4. Conclusion The solubility of a poorly soluble immunosuppressant MPM was measured in ten different neat solvents at T = 298.2 K to 318.2 K and p = 0.1 MPa. The experimental solubilities of MPM were correlated/ fitted well with van't Hoff and Apelblat models. The solubility of MPM was recorded as increasing with the rise in temperature in each pure solvent studied. The results of activity coefficients showed higher solute-solvent molecular interaction in MPM-EA and MPM-Transcutol
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in comparison with other combinations of solute and solvent. The mole fraction solubility of MPM was obtained highest in EA, followed by Transcutol, PEG-400, DMSO, n-butanol, IPA, ethanol, PG, EG and water at T = 318.2 K and similar trends were also observed at each temperature investigated. Apparent thermodynamic analysis showed an endothermic and entropy-driven dissolution of MPM in each pure solvent studied. Based on solubility data of this work, MPM has been considered as freely soluble in EA, Transcutol and DMSO, soluble in PEG0400, n-butanol, IPA and ethanol, sparingly soluble in EG and PG and practically insoluble in water. Hence, EA, Transcutol and DMSO were selected as the best solvents and water was selected as the anti-solvent for MPM. Conflict of interest “The authors report no conflict of interest associated with this manuscript”. Acknowledgement “The authors would like to extend their sincere appreciation to the Deanship of Scientific Research and Research Center, College of Pharmacy, King Saud University.” Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi. org/10.1016/j.molliq.2017.11.028. References [1] E. Nieto, E. Escudero, E. Navarro, M. Yanez-Mo, A. Martin, G.P. de Lema, F. SanchezMadrid, F. Mampaso, J. Amer. Soc. Nephrol. 13 (2002) 937–945. [2] C. Patrutescu, G. Vlase, V. Turcus, D. Ardelean, T. Vlase, P. Albu, J. Therm. Anal. Calorim. 121 (2015) 983–988. [3] G. Vlase, M. Budiul, C. Patrutescu, P. Albu, T. Vlase, J. Therm. Anal. Calorim. (2017)https://doi.org/10.1007/s10973-017-6192-9. [4] S.P.M. Janssen, M. Phernambucq, P. Martinez-Martinez, M.H. De Baets, M. Losen, J. Neuroimmunol. 201–202 (2008) 111–120. [5] M. Look, E. Stern, Q.A. Wang, L.D. DiPlacido, M. Kashgarin, J. Craft, T.M. Fahmy, J. Clin. Invest. 123 (2013) 1741–1749. [6] M. Look, W.M. Saltzman, J. Craft, T.M. Fahmy, Biomaterials 35 (2014) 1089–1095. [7] FDA, US Department of Health and Human Services, Food and Drug Administration Centre for Drug Evaluation and Research (CDER), Guidance for Industry, Clinical Pharmacology and Biopharmaceutics Review, 1995. [8] F. Shakeel, N. Haq, F.K. Alanazi, I.A. Alsarra, J. Mol. Liq. 209 (2015) 280–283. [9] F. Shakeel, N. Haq, G.A. Shazly, F.K. Alanazi, I.A. Alsarra, J. Chem. Eng. Data 60 (2015) 2510–2514. [10] D.H. Alshora, N. Haq, F.K. Alanazi, M.A. Ibrahim, F. Shakeel, J. Chem. Thermodyn. 94 (2016) 230–233. [11] F. Shakeel, N. Haq, M. Raish, M.K. Anwer, R. Al-Shdefat, J. Mol. Liq. 222 (2016) 167–171. [12] F. Almarri, N. Haq, F.K. Alanazi, K. Mohsin, I.A. Alsarra, F.S. Aleanizy, F. Shakeel, J. Mol. Liq. 229 (2017) 477–481. [13] F. Shakeel, N. Haq, F.K. Alanazi, I.A. Alsarra, Int. J. Pharm. 523 (2017) 410–417. [14] A. Apelblat, E. Manzurola, J. Chem. Thermodyn. 31 (1999) 85–91. [15] E. Manzurola, A. Apelblat, J. Chem. Thermodyn. 34 (2002) 1127–1136. [16] F. Shakeel, M. Imran, N. Haq, Abida, F.K. Alanazi, I.A. Alsarra, J. Mol. Liq. 230 (2017) 511–517. [17] M. Salvadori, H. Holzer, A. de Mattos, S. Sollinger, W. Arns, F. Oppenheimer, J. Maca, M. Hall, Am. J. Transplant. 4 (2003) 231–236. [18] K. Budde, S. Bauer, P. Hambach, U. Hahn, H. Roblitz, I. Mai, F. Diekmann, H.H. Neumayer, P. Glander, Am. J. Transplant. 7 (2007) 888–898. [19] F.E. Estevez-Carrizo, S. Parillo, M. Cedres, F.T. Estevez-Parillo, P. Rodriguez, Int. J. Clin. Pharmacol. Ther. 48 (2010) 621–627. [20] T. Akelesh, R. Ramaya, P. Venkatesh, D. Jacob, R. Venkatnarayanan, Res. J. Pharm. Dos. Form Technol. 3 (2011) 148–151. [21] X.G. Wu, M. Xin, L.N. Yang, W.Y. Shi, J. Pharm. Sci. 100 (2011) 1350–1361. [22] F. Fahimi, S. Baniasadi, S.A. Mortazavi, H. Dehghan, A. Zarghi, Iranian J. Pharm. Res. 11 (2012) 171–175. [23] E. Scheubel, L. Adamy, J.M. Cardot, Dissolut. Technol. 19 (2012) 52–55. [24] A.L.D.O. Costa, P.C.R. Eneas, T.A. Miranda, S.A. Mingoti, C.D.V. Soares, G.A. Pianetti, Braz. J. Pharm. Sci. 49 (2013) 311–319. [25] N.N. Akel, I.A. Popescu, D. Lopuleasa, D.M. Miron, F.S. Radulescu, Stud. Uni. Vas. Gol. Ser. Stin. Viet. 24 (2014) 323–327. [26] F. Shakeel, N. Haq, N.A. Siddiqui, Food Chem. 180 (2015) 244–248.
60
M.A. Kalam et al. / Journal of Molecular Liquids 249 (2018) 53–60
[27] P.T. Anastas, J.C. Warner, Green Chemistry: Theory and Practice, Oxford University Press, New York, 1998. [28] F. Shakeel, M.M. Salem-Bekhit, N. Haq, N.A. Siddiqui, J. Mol. Liq. 236 (2017) 144–150. [29] T. Higuchi, K.A. Connors, Adv. Anal. Chem. Instrum. 4 (1965) 117–122. [30] C. Wohlfarth, Static Dielectric Constants of Pure Liquids and Binary Liquid Mixtures, Supplement to IV/6, vol. 17, Springer, New York, 2008. [31] R.F. Fedors, Polym. Eng. Sci. 14 (1974) 147–154. [32] A.F.M. Barton, CRC Handbook of Solubility Parameters and Other Cohesion Parameters, 2nd ed. CRC Press, New York, 1983 57–185. [33] J.L. Gomez, G.A. Rodríguez, D.M. Cristancho, D.R. Delgado, C.P. Mora, A. Yurquina, F. Martínez, Rev. Colomb. Cienc. Quim. Farm. 42 (2013) 103–121. [34] F. Martínez, A. Jouyban, W.E. Acree Jr., J. Mol. Liq. 218 (2016) 35–38.
[35] M. Imran, N. Haq, Abida, F.K. Alanazi, I.A. Alsarra, F. Shakeel, J. Mol. Liq. 238 (2017) 455–461. [36] M.A. Ruidiaz, D.R. Delgado, F. Martínez, Y. Marcus, Fluid Phase Equilib. 299 (2010) 259–265. [37] J.H. Hildebrand, J.M. Prausnitz, R.L. Scott, Regular and Related Solutions, Van Nostrand Reinhold, New York, 1970. [38] Y.J. Manrique, D.P. Pacheco, F. Martínez, J. Solut. Chem. 37 (2008) 165–181. [39] D.M. Aragón, A. Sosnik, F. Martínez, J. Solut. Chem. 38 (2009) 1493–1503. [40] S.H. Neau, G.L. Flynn, Pharm. Res. 7 (1990) 1157–1162. [41] A.R. Holguín, G.A. Rodríguez, D.M. Cristancho, D.R. Delgado, F. Martínez, Fluid Phase Equilib. 314 (2012) 134–139. [42] R.R. Krug, W.G. Hunter, R.A. Grieger, J. Phys. Chem. 80 (1976) 2341–2351.