SolidâLiquid Equilibrium Measurements for Posaconazole and

Article Cite This: J. Chem. Eng. Data XXXX, XXX, XXX−XXX

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Solid−Liquid Equilibrium Measurements for Posaconazole and Voriconazole in Several Solvents between T = 278.2 and 323.2 K Using Differential Thermal Analysis/Thermal Gravimetric Analysis Kuveneshan Moodley,* Thavashni Chetty, and Deresh Ramjugernath Thermodynamics Research Unit, School of Engineering, University of KwaZulu-Natal, Howard College Campus, King George V Avenue, Durban 4041, South Africa Downloaded via IDAHO STATE UNIV on July 19, 2019 at 00:58:15 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.

S Supporting Information *

ABSTRACT: Solid−liquid equilibrium measurements for systems of posaconazole (4-[4-[4-[4-[[(3R,5R)-5-(2,4-difluorophenyl)-5-(1,2,4-triazol-1-ylmethyl)oxolan-3yl]methoxy]phenyl]piperazin-1-yl]phenyl]-2-[(2S,3S)-2-hydroxypentan-3-yl]-1,2,4triazol-3-one) and voriconazole ((2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1,2,4-triazol-1-yl)butan-2-ol) in 10 pure solvents was determined by equilibration and subsequent analysis by differential thermal analysis with thermal gravimetric analysis (DTA/TGA) within the temperature limits T = 278.2−323.2 K at a pressure of 0.101 MPa. The temperatures and heats of fusion of the solutes were also measured by DTA/TGA. The maximum solubility for posaconazole and voriconazole was in dimethyl sulfoxide at T = 323.2 K. The minimum solubilities were in water at T = 278.2 K. In all the measured systems, the solubility increases nonlinearly with temperature. The solubility data was successfully correlated using the nonrandom two-liquid model and the modified Apelblat equation.

1. INTRODUCTION Crystallization is the formation of solid crystals from a liquid solution or precipitation directly from gas and a mature technology among separation and purification unit operations. The procedure is used extensively in the production of high-value niche products with specific properties and in designing efficient production processes.1 With crystallization, high-purity separation of complex organic components with different fusion points can be achieved, and it is therefore readily utilized in the pharmaceutical industry for the synthesis of active pharmaceutical ingredients (APIs). Recently, fungi have posed a significant threat to hospitalized patients who are severely immunocompromised2 mainly due to the increase in the incidence of immunodeficiency viruses. Due to the rise in the incidence of fungal infections caused by Candida and Aspergillus and the rapid development of new resistant and opportunistic fungi, the advancement of new antifungal agents is actively pursued. Azoles, specifically triazoles, comprise the major category of antifungal agents used medically for the treatment of invasive fungal infections. Posaconazole is a triazole that is used for the treatment and prevention of invasive fungal infections in immunocompromised patients,3 specifically neutropenic patients under treatment for acute myelogenous leukemia or myelodysplasia. Voriconazole ((2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1,2,4-triazol-1-yl)butan-2-ol) is a triazole antifungal API used to treat aggressive fungal infections. It is generally prescribed to treat invasive fungal infections, which include invasive candidiasis and invasive aspergillosis, but is also employed in the treatment of emerging fungal infections.4 © XXXX American Chemical Society

Solid−liquid equilibrium data of these API solutes with different solvents is essential for crystallization process design but is not readily available in the literature. With the aid of solubility data, separation methods currently being used for the production of these pharmaceutical solutes can potentially be improved, which may reduce the cost and time for API production. In this work, the solubility of posaconazole and voriconazole were determined in 10 solvents (ethanol, propan-1-ol, propan-2ol, butan-1-ol, 2-methyl-propan-1-ol, butan-2-one, pentan-2one, dimethyl sulfoxide, N,N-dimethylformamide, and water) at 0.101 MPa in the temperature range T = 278.2−323.2 K. To accomplish this, the thermoanalytic techniques of differential thermal analysis with thermal gravimetric analysis (DTA/TGA) were employed to measure solubility mole fractions at solid− liquid equilibrium (SLE). The solubility results were correlated using the nonrandom two-liquid model5 and the modified Apelblat model.6 This mixture data provides insight into the intermolecular behavior of the binary systems studied as the solvents are categorized as protic and aprotic, which also aid in suitable solvent selection during manufacturing.

2. THEORY 2.1. Thermodynamic Relationship for Solid−Liquid Equilibrium. According to Hildebrand and Scott,7 for solid−liquid Received: February 22, 2019 Accepted: July 3, 2019

A

DOI: 10.1021/acs.jced.9b00179 J. Chem. Eng. Data XXXX, XXX, XXX−XXX

Journal of Chemical & Engineering Data

Article

Table 1. Material Purities and Suppliers refractive index (RI)a

component

CAS no.

solvents ethanolc propan-1-olc propan-2-olc butan-1-olc 2-methyl-propan-1-olc butan-2-onec pentan-2-onec dimethyl sulfoxide N,N-dimethylformamide waterd solutes benzoic acid posaconazole (4-[4-[4-[4-[[(3R,5R)-5-(2,4-difluorophenyl)-5-(1,2,4-triazol-1ylmethyl)oxolan-3-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-2-[(2S,3S)-2hydroxypentan-3-yl]-1,2,4-triazol-3-one) voriconazole ((2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1(1,2,4-triazol-1-yl)butan- 2-ol)

b

supplier

exptl.

lit.

64-17-5 71-23-8 67-63-0 71-36-3 78-83-1 78-93-3 107-87-9 67-68-5 68-12-2 7732-18-5

Sigma-Aldrich Sigma-Aldrich Sigma-Aldrich Sigma-Aldrich Sigma-Aldrich Sigma-Aldrich Sigma-Aldrich Sigma-Aldrich Sigma-Aldrich

1.3613 1.3852 1.3774 1.3986 1.3957 1.3790 1.3892 1.4791 1.4303 1.3331

1.3611 1.3850 1.3776 1.3988 1.3955 1.3788 1.3895 1.4793 1.4305 1.3330

65-85-0 171228-49-2 137234-62-9

min. stated GC peak relative mass fraction area (mass purity fraction purity) ≥0.990 ≥0.995 ≥0.990 ≥0.990 ≥0.990 ≥0.990 ≥0.990 ≥0.990 ≥0.999

0.9999 0.9940 0.9999 0.9999 0.9999 0.9999 0.9999 0.9999 0.9999

Sigma-Aldrich Sigma-Aldrich

≥0.99.5 ≥0.99

≥0.99.5e ≥0.99e

Sigma-Aldrich

≥0.99

≥0.99e

a

Measured at 293.15 K and 0.101 MPa. Standard uncertainties (u) are u(RI) = 0.0001, u(T) = 0.01 K, and u(P) = 0.002 MPa. bHaynes19 at 293.15 K. cStored under molecular sieve. dConductivity of water = 19.6 μS m−1. eGC−MS fraction relative abundance.

equilibrium, the following relation characterizes a eutectic system Δ S( T ) Δ H( T ) ln(xiγi) = fus i fus i − fus i fus i R RT Δfus Cp ÄÅÅÅ i T y T i Å j fus i z zz − fus i + ÅÅlnjj − Å R ÇÅ k T { T

Gij = exp( −αijτij)

and ÉÑ ÑÑ 1ÑÑÑ ÑÑ Ö

τij =

yields ln(xiγi) = −

fusTi (Δ fus Si( fus T i) =

ΔfusHi( fus T i) ij fus T i yz zz lnjj R fus T i k T {

ΔfusHi( fus T i) ), fus T i

Aij RT

(5)

where R is the universal gas constant and T is the temperature in kelvin. The interaction parameters for the binary pair i and j (Aij) are calculated by fitting the experimental solubility data. αij is the nonrandomness parameter and can also be determined by regression. 2.2. The Modified Apelblat Equation. The dependence of the logarithm of solubility (ln xi) at equilibrium on temperature was described by the modified Apelblat equation6 shown below

(1)

where xi is the mole fraction composition of the solute in the solvent when the solution is saturated, γi is the activity coefficient of the solute in the solvent phase, ΔfusSi(fusTi) is the entropy of fusion, ΔfusHi(fusTi) is the fusion enthalpy estimated at the fusion temperature fusTi, ΔfusCp̅i is the difference in heat capacity between the solid and the theoretical subcooled liquid, R is the universal gas constant, and T is the experimental temperature at equilibrium. Hildebrand and Scott7 estimate ΔfusCpi ̅ with the entropy of fusion ΔfusSi(fusTi) at

(4)

ln xi = A + B /T + C ln T

(6)

where A, B, and C are empirical parameters and T is in kelvin. The empirical constants are obtained by data fitting. The modified Apelblat equation is often preferred for the direct empirical correlation of T−x solid−liquid equilibrium data in place of eq 2, which employs correlation via activity coefficients. This is because it has provided excellent fitting results for numerous solution systems in low solubility ranges as shown in recent studies.8−10 It is useful for the correlation of SLE data as precise interpolation to different solubility temperatures can be easily achieved within the experimental range.

which

(2)

Equation 2 assumes that a single solid phase exists. The activity coefficient can be determined by correlation using a Gibbs excess energy model. In this work, the nonrandom two-liquid (NRTL) model5 was used as it provided a better fit to the solubility data in comparison to the other local composition models that were considered. The NRTL model activity coefficient is given by ÅÄÅ ÑÉ ÅÅ ij Gji yz2 ij yzÑÑÑÑ τ G ij ij j z 2Å zz + j zzÑÑ ln γi = xj ÅÅÅτjijjjj jj ÅÅ j xi + xjGji zzz j (xj + xiGij)2 zzÑÑÑÑ ÅÅ k { k {ÑÖ (3) Ç

3. EXPERIMENTAL METHODS 3.1. Materials. Table 1 shows the purities and chemical suppliers of the solvents and solutes used. The stated purity of the solutes was >0.99 mass fraction. The solids were dried in a desiccator before use, and the purities of the solutes were validated by gas chromatography−mass spectrometry with a pyrolyzer. A GC 2010 Plus with a GCMS-QP2010 Ultra and EGA/PY-330D Multi-Shot Pyrolizer supplied by Shimadzu was employed. A capillary column (30 m × 0.25 mm × 0.25 μm film

where B



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thickness, Zebron 7HG-G010-11) was used. The carrier gas used was helium with a flow of 0.90 mL min−1, and a temperature ramping function was used at a rate of 5 K min−1. All organic solvents had a >0.99 mass fraction validated by refractometry with an ATAGO RX-7000α refractometer (sodium D line, λ = 589 nm) and gas chromatography using a Shimadzu GC 2014. Measurements of the refractive index for the liquids were determined at T = 293.15 K, and the uncertainty was determined to be 0.0001. Ultrapure water (conductivity = 19.6 μS m−1) was used. Molecular sieve was used to dehydrate the alcohols and ketones before use. 3.2. Equipment and Procedure. Double-walled gas tight glass vessels, as shown in Figure 1, were used in the experimental

Figure 1. Double-walled glass cell. (A) Water inlet. (B) Sample point. (C) 14 mm stirrer bead. (D) Temperature port. (E) Jacket. (F) Water outlet.

Figure 2. (a) T versus ln(x1) and (b) T versus x1 for the benzoic acid (1) + water (2) system. solid circle, this work; open triangle, Strong et al.;24 open square, Ren et al.;25 open diamond, Apelblat et al.;26 plus sign, Sunsandee et al.;20 open circle, Cuevas-Valenzuela et al.;27 multiplication sign, Wang et al.28

work. The temperature of the cell was controlled by flow of a thermostated fluid through the jacket from a water−ethylene glycol bath with a Grant GD120 temperature controller and a Polyscience KR80A chiller for sub-ambient temperatures. A magnetic stirrer bar was placed inside the equilibrium cell, and the cell was placed on a stirrer plate. Stirring was set at an intermediate rate to ensure thorough mixing but prevent milling of the solute. A Pt-100 type-A probe was utilized to measure the SLE temperature and calibrated against a WIKA CTB 9100 temperature standard. Synthetic mixtures of different initial compositions were prepared such that undersaturated and supersaturated mixtures were obtained, so equilibrium could be reached from both directions. The equilibration and analysis procedures are the same for both cases. The jacketed double-walled glass vessel was held at a constant temperature by the water−ethylene glycol bath with a precision of 0.1 K. The solute/solvent solution was stirred for 8 h and left for 24 h to equilibrate. It was assumed that 24 h is adequate for solid−liquid equilibrium to be achieved, as it was found that further changes in the clear saturated liquid phase composition at equilibrium did not occur. Trial systems for each different solute−solvent combination were allowed to equilibrate over a 72 h period, and it was confirmed that no changes in the equilibrium composition occurred after repeated sampling over this period. A gas tight syringe with a membrane filter was used to carefully extract the saturated solution without disrupting the underlying solute layer. Combined differential thermal/thermal gravimetric analysis was then employed to measure the composition of the saturated solution at solid−liquid equilibrium. A Shimadzu DTG-60AH (mass readability = 0.001 mg, temperature readability = 0.1 K) was utilized. The sample of ∼80 to 900 mg was injected into a sample pan, covered, inserted into the apparatus, and quickly weighed. Thereafter, the mixture sample was heated in the

Table 2. Experimental Enthalpy of Fusion and Melting Point Data of Posaconazole and Voriconazole at 0.101 MPa by DTA/TGAa experimental

literature

compound

ΔfusH (J mol−1)

fusT (K)

ΔfusH (J mol−1)

benzoic acid

17521.33a

396.80a

posaconazole

47675.82a

444.60a

17988.3020 18020.0021 17316.0019 48363.6314

voriconazole

26912.01a

403.40a

27100.0015

fusT

(K)

396.1520 395.5021 395.6019 449.4914 444.1522 442.1523 403.1415

a

Standard uncertainties (u) are u(T) = 0.5 K and u(P) = 0.002 MPa, and the standard relative uncertainties are ur(ΔHfus) = 0.05. Melting temperatures are reported at peak maxima.

DTA/TGA apparatus at 10 K/min and initially within 10 K lower than the bubble point of the solvent or 10 K below the solute melting temperature, depending on which is lower, under a nitrogen flow rate of 1.2 cm3 s−1. This allowed the solvent to evaporate at a constant rate without entrainment of solute particles out of the sample pan. The mass of the pure solute that remained in the sample pan after evaporation of the solvent was then found. To establish the suitability of the temperature rate and hold values, trial samples were processed at different conditions and left to evaporate for longer periods to ensure that no further change in the mass of the pan occurred, which confirmed that all the solvent had evaporated. The equilibrium C



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Table 3. Experimental SLE Data of Posaconazole (1) + Solvent (2) Mixtures at Several Temperatures (in kelvin, K) and Pressure at 0.101 MPaa x1exp solvent

278.2 ± 0.1 K

283.2 ± 0.1 K

288.2 ± 0.1 K

293.2 ± 0.1 K

298.2 ± 0.1 K

ethanol propan-1-ol propan-2-ol butan-1-ol 2-methyl-propan-1-ol butan-2-one pentan-2-one water dimethyl sulfoxide N,N-dimethylformamide solvent

0.000123 0.000115 0.000125 0.000096 0.000105 0.000240 0.000188 0.000021 0.000440 0.000399 303.2 ± 0.1 K

0.000160 0.000143 0.000157 0.000125 0.000134 0.000305 0.000241 0.000030 0.000524 0.000471 308.2 ± 0.1 K

0.000205 0.000180 0.000195 0.000155 0.000169 0.000388 0.000299 0.000041 0.000619 0.000583 313.2 ± 0.1 K

0.000283 0.000246 0.000259 0.000213 0.000227 0.000526 0.000408 0.000056 0.000815 0.000781 318.2 ± 0.1 K

0.000375 0.000314 0.000334 0.000270 0.000288 0.000690 0.000535 0.000080 0.001054 0.000990 323.2 ± 0.1 K

ethanol propan-1-ol propan-2-ol butan-1-ol 2-methyl-propan-1-ol butan-2-one pentan-2-one water dimethyl sulfoxide N,N-dimethylformamide

0.000486 0.000400 0.000427 0.000356 0.000371 0.000892 0.000684 0.000108 0.001355 0.001275

0.000658 0.000519 0.000547 0.000445 0.000461 0.001193 0.000919 0.000149 0.001805 0.001705

0.000910 0.000659 0.000695 0.000565 0.000590 0.001619 0.001253 0.000206 0.002453 0.002228

0.001193 0.000835 0.000898 0.000715 0.000741 0.002096 0.001642 0.000284 0.003206 0.002895

0.001656 0.001053 0.001164 0.000898 0.000975 0.002827 0.002260 0.000392 0.004465 0.003917

a

Standard uncertainties (u) are u(T) = 0.1 K, u(P) = 0.002 MPa, and u(xi) = 0.00002.

Table 4. Experimental SLE Data of Voriconazole (1) + Solvent (2) Mixtures at Several Temperatures (in kelvin, K) and Pressure at 0.101 MPaa x1exp solvent

278.2 ± 0.1 K

283.2 ± 0.1 K

288.2 ± 0.1 K

293.2 ± 0.1 K

298.2 ± 0.1 K

ethanol propan-1-ol propan-2-ol butan-1-ol 2-methyl-propan-1-ol butan-2-one pentan-2-one water dimethyl sulfoxide N,N-dimethylformamide solvent

0.000422 0.000370 0.000391 0.000320 0.000356 0.000451 0.000419 0.000019 0.000343 0.000213 303.2 ± 0.1 K

0.000558 0.000485 0.000509 0.000418 0.000467 0.000590 0.000549 0.000027 0.000445 0.000315 308.2 ± 0.1 K

0.000718 0.000623 0.000651 0.000534 0.000590 0.000740 0.000700 0.000037 0.000601 0.000435 313.2 ± 0.1 K

0.000997 0.000860 0.000900 0.000734 0.000815 0.001015 0.000960 0.000053 0.000836 0.000602 318.2 ± 0.1 K

0.001281 0.001103 0.001140 0.000939 0.001032 0.001275 0.001220 0.000076 0.001165 0.000823 323.2 ± 0.1 K


0.001707 0.001468 0.001505 0.001248 0.001325 0.001669 0.001607 0.000104 0.001498 0.001198

0.002135 0.001834 0.001869 0.001556 0.001620 0.002060 0.001995 0.000145 0.002002 0.001570

0.002731 0.002343 0.002376 0.001987 0.002042 0.002574 0.002540 0.000203 0.002735 0.002021

0.003468 0.002974 0.003007 0.002518 0.002542 0.003205 0.003204 0.000281 0.003657 0.002630

0.004376 0.003751 0.003734 0.003175 0.003177 0.004020 0.004012 0.000389 0.005054 0.003556

a

Standard uncertainties (u) are u(T) = 0.1 K, u(P) = 0.002 MPa, and u(xi) = 0.000019.

composition was found by the difference of the initial sample mass and the mass of the final pure solute. All experiments were conducted four times. This included duplicated runs of increasing and decreasing the bath temperature to beyond the temperature range reported and varying the overall composition of the synthetic solution. This was done in order to approach the equilibrium from supersaturation and

undersaturation. The average of the four values was used to determine the solubility (xi) of posaconazole and voriconazole in the 10 selected solvents at the equilibrium temperature. Pure component melting point and enthalpy of fusion data of unused solute were measured in a similar manner using the DTA/TGA (in quadruplet) apparatus. Additionally, the solute differential scanning calorimetry (DSC) curves were also determined using D



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Figure 3. T versus x1 for the posaconazole (1) + solvent (2) systems. (exp, NRTL model): black solid square/long dash, ethanol; black solid diamond/middle dot, propan-1-ol; black solid triangle/hyphen, propan-2-ol; multiplication sign/minus sign, butan-1-ol; asterisk/ hyphen-dotted line, 2-methyl-propan-1-ol; solid circle/em dash, butan-2-one; plus sign/long dash-dotted line, pentan-2-one; red solid square/long dash, water; red solid diamond/middle dot, dimethyl sulfoxide; red solid triangle/hyphen, N,N-dimethylformamide.

Figure 4. T versus x1 for the voriconazole (1) + solvent (2) systems. (exp, NRTL model): black solid square/long dash, ethanol; black solid diamond/middle dot, propan-1-ol; black solid triangle/hyphen, propan-2-ol; multiplication sign/minus sign, butan-1-ol; asterisk/ hyphen-dotted line, 2-methyl-propan-1-ol; black solid circle/em dash, butan-2-one; plus sign/long dash-dotted line, pentan-2-one; red solid square/long dash, water; red solid diamond/middle dot, dimethyl sulfoxide; red solid triangle/hyphen, N,N-dimethylformamide.

an SDT Q600 DSC by TA Instruments (0.1 μg mass precision, 0.1 K temperature, and 0.02 relative uncertainty for heat of fusion). A heating rate of 10 K/min was used with a nitrogen purge of 1 cm3 s−1. DSC was also used to analyze the solute phase after the mixture equilibrium measurements, which was compared to the DSC results of the unused solute. No significant differences between the signals were detected, which confirms that solid−solid transitions did not occur during the equilibrium measurement procedure. Example DSC curves for each solute are provided in Supporting Information, Figures S1−S3. The equilibration measurement procedure has been applied before in the literature8−10 and has been verified in previous works.11−13 To confirm the procedures used for the binary solubility data, a test measurement for the benzoic acid (1) + water (2) system was conducted and compared to literature data. This is shown in Figure 2. A good correlation between the data from this work and the literature was found, which validates the experimental procedure used.

Table 5. Dipole Moments and Dielectric Constants of the Studied Solvents at 293.15 K19 solvent

dipole moment (D)

dielectric constant


1.69 1.68 1.58 1.66 1.64 2.78 2.70 1.85 3.96 3.82

24.3 20.8 20.2 17.8 17.9 18.6 15.5 80 47.2 38.3

associated uncertainties, which were calculated by the procedures of JCGM.16 The data correlates reasonably well with literature, and any discrepancies are attributed to the apparatus and method used for the measurement (DTA/TGA vs differential scanning calorimetry and their associated uncertainties). The mole fraction solubilities (xi) of posaconazole and voriconazole in the 10 selected solvents are shown in Tables 3 and 4, respectively. The solvents selected were ethanol, propan1-ol, propan-2-ol, butan-1-ol, 2-methyl-propan-1-ol, butan-2one, pentan-2-one, dimethyl sulfoxide, N,N-dimethylformamide, and water. The solubility measurements were conducted in the range T = 278.15−323.15 K. Experimental uncertainties

4. DISCUSSION Comprehensive characterization of posaconazole and voriconazole was conducted in the literature.14,15 To confirm the purities of the solutes used here, the melting point temperature and enthalpy of fusion data of posaconazole and voriconazole were determined experimentally using DTA/TGA and compared to the data from the literature, shown in Table 2 along with their E



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Table 6. NRTL Model Parametersa solute (1)

solvent (2)

A12

A21

α12

RMSDa

posaconazole

ethanol propan-1-ol propan-2-ol butan-1-ol 2-methyl-propan-1-ol butan-2-one pentan-2-one water dimethyl sulfoxide N,N-Dimethylformamide ethanol propan-1-ol propan-2-ol butan-1-ol 2-methyl-propan-1-ol butan-2-one pentan-2-one water dimethyl sulfoxide N,N-dimethylformamide

4442.460 3356.337 1744.109 3525.524 3671.635 1457.204 4153.225 1481.820 1451.834 2101.715 1635.641 1678.933 1689.527 1715.448 1735.865 1684.893 1670.519 4851.425 1400.836 1591.944

−4296.841 422.067 1945.035 284.363 83.734 −397.966 −3347.200 1634.209 4253.514 4461.595 1934.543 1969.281 1980.393 1999.100 2020.191 1975.750 1951.272 −128.602 1710.418 1860.574

−0.509 −0.543 −1.547 −0.535 −0.491 −2.455 −0.472 −3.042 2.387 1.941 −2.529 −2.477 −2.432 −2.450 −2.373 −2.409 −2.480 −0.639 −3.360 −2.822

3.67 × 10−02 4.61 × 10−02 4.43 × 10−02 5.21 × 10−02 5.36 × 10−02 7.25 × 10−02 2.79 × 10−02 6.62 × 10−02 2.56 × 10−02 4.06 × 10−02 4.41 × 10−02 5.04 × 10−02 5.34 × 10−02 5.80 × 10−02 6.46 × 10−02 5.66 × 10−02 5.49 × 10−02 8.87 × 10−02 4.32 × 10−02 2.73 × 10−02

voriconazole

ÄÅ ÅÅ RMSD = ÅÅÅÅ ÅÅ ÅÇ

a

∑iN= 1(ln xiexp − ln xicalc)2 N

ÑÉÑ ÑÑ ÑÑ ÑÑ ÑÑÖ

are listed in these tables and were calculated according to the procedures of JCGM.16 These uncertainties include the uncertainty in temperature after calibration, the uncertainty in the mass measurements during phase analysis, and the uncertainty from the repeatability of the measurements. The T−x diagrams for posaconazole and voriconazole in the 10 different solvents are presented in Figures 3 and 4, respectively, to show the variation of the solubility data with temperature. From Figures 3 and 4, it is observed that the mole fractions of both solutes in solution increase nonlinearly with temperature. Protic solvents have hydrogen atoms bound directly to electronegative atoms, such as oxygen or nitrogen. They are characterized by their ability to form strong hydrogen bonds with suitable acceptors, particularly simple anions.17 They include alcohols, formamide, and other primary and secondary amides, formic acid and water. In the protic solvents, the solubility of posaconazole and voriconazole is maximum in ethanol and minimum in water with the order of solubility being ethanol > propan-1-ol > 1-butan-1-ol > water. For the aprotic solvents, the solubility is greater in dimethyl sulfoxide than in butan-2-one, pentan-2-one, and N,N-dimethylformamide. The solutes considered here have a large hydrogen bond acceptor site count. This suggests that the solubilities in the protic solvents are expected to be higher due to hydrogen bonding occurring between the solute and hydrogen bond donor solvents. This was not observed experimentally. In fact, solubilities were generally found to be higher in the aprotic solvents than the protic solvents. This suggests that van der Waals forces possibly affect the solubility to a large extent. The dipole moments and dielectric constants of the solvents are presented in Table 5, and these were compared to the solubility results at 323.15 K. This is shown in Figures S4 and S5, Supporting Information. The solubility for both posaconazole and voriconazole in the protic solvents was minimum in water

and maximum in ethanol with a proportional trend in the dielectric constants when considering the alcohols only. The values for the dipole moments of the alcohols are very close together. For the aprotic solvents, the solubility in the ketones is lower than in dimethyl sulfoxide with the dipole moment of dimethyl sulfoxide being greater than butan-2-one and pentan-2one. If N,N-dimethylformamide is excluded, then the solubility seems to increase with increasing dipole moment of the solvent in the remaining aprotic solvents. The results of the NRTL model regression for the activity coefficient in accordance to eq 2 are presented in Figures 3 and 4, with the regressed model parameters presented in Table 6. The data were fit by optimization to determine the minimum root-mean-square deviation (RMSD) between the experimental and calculated logarithm of the composition. This RMSD was selected based on the recommendation of Acree and Horton,18 who reported that a superior representation of the composition is yielded using this RMSD in comparison to other versions considered in that study. The RMSDs are also shown in Table 6. It is evident that the correlation is adequate but not excellent. This is attributed to the difficulties the model experiences with regards to attempting to simultaneously fit the low solubility binary data (in the solvent-rich region) and the pure component solute melting point. In Figures S6−S9, Supporting information, the ratios of the calculated activity coefficients for different solvents are compared against the ratios of the experimental composition data, which further confirm that a reasonable fit was obtained by the NRTL model within experimental uncertainty. The semiempirical modified Apelblat equation was used to correlate the experimental data for more practical applications such as pharmaceutical crystallization prediction for the binary measurement range only (solvent-rich region). Fitting parameters A, B, and C were found using the root-mean-square deviation (RMSD) between the logarithm of the calculated and F



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Table 7. Modified Apelblat Model Parametersa solute

solvent

A

B

C

RMSDb

posaconazole

ethanol propan-1-ol propan-2-ol butan-1-ol 2-methyl-propan-1-ol butan-2-one pentan-2-one water dimethyl sulfoxide N,N-dimethylformamide ethanol propan-2-ol propan-1-ol butan-1-ol 2-methyl-propan-1-ol butan-2-one pentan-2-one water dimethyl sulfoxide N,N-dimethylformamide

−101.96340 −88.93106 −88.84171 −89.88836 −89.90133 −97.70692 −97.88406 −115.56143 −110.23017 −114.68016 −91.36917 −90.75341 −88.85682 −90.87370 −87.51291 −85.88514 −88.84071 −119.82034 −105.85924 −108.68419

−211.69995 −208.51528 −196.47956 −176.17096 −113.71613 −179.64181 −187.44090 −205.27969 633.77343 789.13604 −209.46439 −209.15780 −196.62777 −176.32829 −113.62991 −183.23592 −185.76962 −206.26483 −150.32031 −201.08059

16.64040 14.31567 14.30550 14.43832 14.41481 15.98175 15.97356 18.74734 17.78235 18.45698 14.98881 14.85484 14.52014 14.82874 14.21454 14.01015 14.52294 19.48548 17.47880 17.94632

1.25 × 10−02 6.27 × 10−03 7.59 × 10−03 5.48 × 10−03 5.36 × 10−03 1.14 × 10−02 1.47 × 10−02 5.73 × 10−03 2.34 × 10−02 1.71 × 10−02 6.35 × 10−03 5.86 × 10−03 6.42 × 10−03 5.51 × 10−03 7.80 × 10−03 6.60 × 10−03 5.67 × 10−03 4.82 × 10−03 8.51 × 10−03 1.09 × 10−02

voriconazole

ÄÅ ÅÅ Standard error of each coefficient is 0.00001. The significant figures are necessary to preserve model integrity. bRMSD = ÅÅÅÅ ÅÅ ÅÇ

a

∑iN= 1(ln xiexp − ln xicalc)2 N

ÑÉÑ ÑÑ ÑÑ ÑÑ ÑÑÖ

Figure 5. (a) T versus ln(x1) and (b) T versus x1 plot for the systems of posaconazole in different solvents. Experimental mole fraction solubility: multiplication sign, ethanol; plus sign, propan-1-ol; solid circle, propan-2-ol; open triangle, butan-1-ol; solid diamond, 2-methylpropan-1-ol; solid triangle, butan-2-one; solid square, pentan-2-one; open square, water; open circle, dimethyl sulfoxide; open diamond, N,N-dimethylformamide. Dashed lines represent the calculated mole fraction solubility by the Apelblat equation.

Figure 6. (a) T versus ln(x1) and (b) T vs x1 plot for the systems of voriconazole in different solvents. Experimental mole fraction solubility: (on the lower horizontal axis) multiplication sign, ethanol; plus sign, propan-1-ol; solid circle, propan-2-ol; open triangle, butan-1ol; solid diamond, 2-methyl-propan-1-ol; solid triangle, butan-2-one; solid square, pentan-2-one; open circle, dimethyl sulfoxide; open diamond, N,N-dimethylformamide; (on the upper horizontal axis) open square, water. Dashed lines represent the calculated mole fraction solubility by the Apelblat equation.

the experimental compositions. The optimized parameters are presented in Table 7. Values for the calculated mole fraction

solubility using the modified Apelblat equation was plotted against the experimental mole fraction solubility as shown in G



Article

(9) Wang, H.; Cao, Y.; Feng, S.; Chen, G.; Farajtabar, A.; Zhao, H.; Li, X. Solubility and Molecular Interactions of Trimetazidine Hydrochloride in 12 Monosolvents and Solvent Mixtures of Methanol + (Ethanol, N , N -Dimethylformamide or Ethyl Acetate). J. Chem. Eng. Data 2018, 63, 3704−3714. (10) Dong, R.; Du, C.; Qiao, B.; Zhang, Y.; Ye, T.; Jin, Z.; Wang, M. Research on Dissolution Capability of Several Antofloxacin Salts. J. Chem. Eng. Data 2018, 63, 3018−3026. (11) Moodley, K.; Rarey, J.; Ramjugernath, D. Experimental Solubility Data for Prednisolone and Hydrocortisone in Various Solvents between (293.2 and 328.2) K by Employing Combined DTA/TGA. J. Mol. Liq. 2017, 240, 303−312. (12) Moodley, K.; Rarey, J.; Ramjugernath, D. Experimental Solubility for Betulin and Estrone in Various Solvents within the Temperature Range T = (293.2 to 328.2) K. J. Chem. Thermodyn. 2016, 98, 42−50. (13) Moodley, K.; Rarey, J.; Ramjugernath, D. Experimental Solubility of Diosgenin and Estriol in Various Solvents between T = (293.2− 328.2) K. J. Chem. Thermodyn. 2017, 106, 199−207. (14) Fule, R.; Amin, P. Hot Melt Extruded Amorphous Solid Dispersion of Posaconazole with Improved Bioavailability: Investigating Drug-Polymer Miscibility with Advanced Characterisation. Biomed Res. Int. 2014, 2014, 146781. (15) Ramos, J. J. M.; Diogo, H. P. The Slow Relaxation Dynamics in Active Pharmaceutical Ingredients Studied by DSC and TSDC: Voriconazole, Miconazole and Itraconazole. Int. J. Pharm. 2016, 501, 39−48. (16) ISO. JCGM 100:2008; International Organization for Standardization (ISO): Geneva, 2008, 50, 134. (17) Cox, B. G. Acids and Bases: Solvation and Acid−Base Strength; Oxford University Press: 2013; pp 21−38. (18) Acree, W. E., Jr.; Horton, M. Y. The Objective Minimization Function for the Mathematical Representation of Solubility Data for Solutes Dissolved in Binary Solvent Mixtures. J. Chem. Thermodyn. 2017, 104, 61−66. (19) Haynes, W. M. CRC Handbook of Chemistry and Physics; 95th Ed.; CRC Press: Hoboken 2014. (20) Sunsandee, N.; Suren, S.; Leepipatpiboon, N.; Hronec, M.; Pancharoen, U. Determination and Modeling of Aqueous Solubility of 4-Position Substituted Benzoic Acid Compounds in a High-Temperature Solution. Fluid Phase Equilib. 2013, 338, 217−223. (21) Qing-Zhu, J.; Pei-Sheng, M.; Huan, Z.; Shu-Qian, X.; Qiang, W.; Yan, Q. The Effect of Temperature on the Solubility of Benzoic Acid Derivatives in Water. Fluid Phase Equilib. 2006, 250, 165−172. (22) Tang, P.; Wang, L.; Ma, X.; Xu, K.; Xiong, X.; Liao, X.; Li, H. Characterization and In Vitro Evaluation of the Complexes of Posaconazole with β- and 2,6-Di-O-Methyl-β-Cyclodextrin. AAPS PharmSciTech 2017, 18, 104−114. (23) Figueirêdo, C. B. M.; Nadvorny, D.; de Medeiros Vieira, A. C. Q.; Sobrinho, J. L. S.; Neto, P. J. R.; Lee, P. I.; de La Roca Soares, M. F. Enhancement of Dissolution Rate through Eutectic Mixture and Solid Solution of Posaconazole and Benznidazole. Int. J. Pharm. 2017, 525, 32−42. (24) Strong, L. E.; Neff, R. M.; Whitesel, I. Thermodynamics of Dissolving and Solvation Processes for Benzoic Acid and the Toluic Acids in Aqueous Solution. J. Solution Chem. 1989, 18, 101−114. (25) Ren, G.; Wang, J.; Li, G. Solubility of Paroxetine Hydrochloride Hemi-Hydrate in (Water +acetone). J. Chem. Thermodyn. 2005, 37, 860−865. (26) Apelblat, A.; Manzurola, E.; Balal, N. A. The Solubilities of Benzene Polycarboxylic Acids in Water. J. Chem. Thermodyn. 2006, 38, 565−571. (27) Cuevas-Valenzuela, J.; González-Rojas, Á .; Wisniak, J.; Apelblat, A.; Pérez-Correa, J. R. Solubility of (+)-Catechin in Water and WaterEthanol Mixtures within the Temperature Range 277.6−331.2K: Fundamental Data to Design Polyphenol Extraction Processes. Fluid Phase Equilib. 2014, 382, 279−285. (28) Wang, H.; Wang, Q.; Xiong, Z.; Chen, C.; Shen, B. Solubilities of Benzoic Acid in Binary (Benzyl Alcohol+benzaldehyde) Solvent Mixtures. J. Chem. Thermodyn. 2015, 83, 61−66.

Figures 5 and 6. A good correlation for all the systems studied for both posaconazole and voriconazole can be observed.

5. CONCLUSIONS The SLE composition of posaconazole and voriconazole in several solvents was determined by combined DTA/TGA. The pure API temperatures and enthalpies of fusion were also determined. The solubility of both solutes increases nonlinearly with increasing temperature. The solubility data were correlated adequately with the NRTL model. The modified Apelblat equation was used to correlate the solubility data for all systems measured. The experimental SLE data correlated well with the model-calculated values for all systems. In the protic solvents, the solubility of posaconazole and voriconazole was maximum in ethanol and minimum in water. For the aprotic solvents, the solubilities were greater in dimethyl sulfoxide than in the ketones and in N,N-dimethylformamide.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jced.9b00179. Relationships between solubility and dielectric constants/ dipole moments and between relative activity coefficients and relative solubilities (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Tel.: +27 31 2601519. ORCID

Kuveneshan Moodley: 0000-0003-1544-3624 Deresh Ramjugernath: 0000-0003-3447-7846 Funding

This work is based on the research supported by the National Research Foundation of South Africa (grant number 64817). Notes

The authors declare no competing financial interest.

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REFERENCES

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