Article pubs.acs.org/IECR
Thermodynamic Properties of Form A and Form B of Florfenicol Zhihong Sun,† Hongxun Hao,*,†,‡ Chuang Xie,†,‡ Zhao Xu,†,‡ Qiuxiang Yin,†,‡ Ying Bao,†,‡ Baohong Hou,†,‡ and Yongli Wang†,‡ †
State Key Laboratory of Chemical Engineering, School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, China ‡ Collaborative Innovation Center of Chemical Science and Chemical Engineering (Tianjin), Tianjin 300072, China S Supporting Information *
ABSTRACT: In this research, a new polymorph of florfenicol (form B) was discovered and successfully prepared. The new polymorph was characterized and identified by powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC) techniques. It was found that form A has lower melting temperature while higher fusion enthalpy. The solubility of both florfenicol polymorphs in methanol, 2-propanol, acetone, acetonitrile, ethanol, and ethyl acetate were experimentally determined from 278.15 to 318.15 K with a dynamic method. For all tested solvents, the solubility data of florfenicol form B are higher than those of form A. The modified Apelblat model, the NRTL model, and the λh model were adopted to calculate the solubility of florfenicol two forms with satisfactory correlation results. In addition, the dissolution thermodynamic properties of florfenicol form A and form B, including dissolution enthalpy, dissolution entropy, and Gibb’s dissolution energy in all tested solvents, were obtained. Combining the results of DCS determination, the solubility, and all the dissolution thermodynamic data, it was confirmed that florfenicol polymorph A and polymorph B belong to the enantiotropic polymorph system.
1. INTRODUCTION Florfenicol (C12H14Cl2FNO4S, CAS No. 73231-34-2), as shown in Figure 1, is a broad-spectrum antibiotic and has
different physicochemical properties, such as solubility, stability, dissolution properties, and density. In addition, these physicochemical properties will also determine the pharmaceutical bioavailability and crystallization operating conditions. In the literature review, no report about the polymorph phenomenon of florfenicol was found, although the solubility of florfenicol in several kinds of single solvent and 1,2-propanediol/water mixtures has been reported.3,4 In this research, a new polymorph (named form B in this work) that is different from the common used florfenicol (named form A in this work) was found. It is important to understand the thermodynamics of both florfenicol form A and form B, which is helpful to obtain the target form of florfenicol and optimize the crystallization process.5 The thermodynamic properties of the new polymorph B and the common form A were investigated and compared with each other. The solubility of both forms of florfenicol in six kinds of pure solvent was measured from 278.15 to 318.15 K with a synthetic method at atmospheric pressure. The modified Apelblat model, NRTL model, and λh model were adopted to calculate the solubility. The dissolution properties of florfenicol were also determined and discussed to compare the dissolution behavior of the two forms.
Figure 1. Chemical structure of florfenicol.
been widely used to treat animal bacterial diseases and infections. Compared to chloramphenicol, florfenicol demonstrates high efficacy against many micro-organisms.1 In industry, crystallization is a very important unit process. It is also a key step used to purify florfenicol, and crystallization will have significant impact on the quality of florfenicol. It is generally known that pharmaceuticals may exist in different polymorphs if different crystallization conditions are applied. Polymorphism refers to a substance that has the ability to crystallize into different structures but with identical chemical composition. The Gibbs free energy is also different in different polymorphs, including conformational polymorphs and configuration polymorphs.2 Polymorphism is very important to pharmaceutical industry as different crystal structures may have © 2014 American Chemical Society
2. EXPERIMENTAL SECTION 2.1. Materials. Florfenicol form A and form B were prepared by crystallization of commercial products from Ringpu Bio-Pharmacy Co. Ltd., China. Florfenicol form A Received: Revised: Accepted: Published: 13506
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was obtained by slow cooling crystallization (0.1 °C/min) in acetone solution. Florfenicol form B was obtained by rapid cooling crystallization (1 °C/min) in isobutanol solution. The mass fraction purities of both forms, confirmed by highperformance liquid chromatography (Agilent 1200, Agilent Technologies, U.S.A.), are above 99.5%. Powder X-ray diffraction (PXRD) (D/max, 2500, Rigaku, Japan) was adopted to identify both forms of florfenicol. The mass fraction purities of all tested solvents, including acetonitrile, methanol, acetone, ethanol, ethyl acetate. and 2-propanol, are higher than 99.5%. All the solvents were provided by Tianjin Kewei Chemical Co., China, and used without further purification. 2.2. Thermal Analysis. The melting analyses of both florfenicol forms were carried out on a Mettler-Toledo DSC 1/ 500 calorimeter under protection of nitrogen. Approximately 4−8 mg sample was put in an aluminum pan, and then, the sample was heated by 2 K/min from 298.15 to 473.15 K. Thermogravimetric experiments were carried out on a MettlerToledo TGA 1/SF thermo-balance. Approximately 5−10 mg sample was heated from 298.15 to 473.15 K by 5 K/min. These instruments were calibrated before thermal analysis. The uncertainties of melting point and melting enthalpy were estimated to be 0.5 K and 5%, respectively. 2.3. Solubility Experiments. The solubility of both florfenicol forms in tested solvents were determined by a dynamic method.6 The experimental devices are the same as those described in the previous study.7 The solubility determination was performed on an 80 mL jacketed vessel with magnetic agitation. The experiments were maintained at a constant temperature by a thermostat (Julabo CF41, Germany). The equilibrium temperature was measured by inserting a thermometer into solution with temperature accuracy of ±0.05 K. The dissolution of florfenicol in pure solvent was determined by a laser monitoring system, which consists of a laser generator and a light-intensity display with an accuracy of ±3%. At first, the known weight of florfenicol and solvent were put into a container, which was maintained at certain temperature. When all the solute dissolves completely, the penetrated laser intensity will reach the maximum. Then, more florfenicol (a known amount) was added to the vessel until the penetrated laser intensity was just 90 percent of the maximum value. To measure the mass of florfenicol and solvent added into the vessel, an analytical balance (Mettler Toledo AB204-N, Switzerland) with uncertainty of 0.0001 mg was used. The mole fraction solubility of florfenicol was calculated as eq 1. x=
m/M (m / M ) + (m s / M s )
Figure 2. Comparison of the experimental solubility data of florfenicol form A with the data from literature in methanol (● experimental; ○ literature) and acetone (■ experimental; □ literature).
3. THERMODYNAMIC MODELS 3.1. Modified Apelblat Model. The solubility data of solid−liquid equilibrium are widely correlated by the modified Apelblat model,8 which can be calculated by ln x = A +
B + C ln T T
(2)
where A, B, and C represent empirical parameters. Parameter A and parameter B denote the impact of nonideality of solution while parameter C indicates the effect of T on ΔfusH. 3.2. λh Model. The λh model, which also could be used to calculate the solubility, is described as follows:9 ⎛1 ⎛ 1 − x ⎞⎟ 1 ⎞ ln⎜1 + λ = λh⎜ − ⎟ ⎝ x ⎠ Tm ⎠ ⎝T
(3)
where λ and h represent regulable parameters, which indicate solution mixing properties. Tm represents the melting point of florfenicol. 3.3. NRTL Model. The local composition models are widely applied to calculate the fugacity coefficients of solute in the solid−liquid equilibrium. A general simplified equation, which can be deduced from literature,10 is described in eq 4.
(1)
ln x =
where m and ms are the mass of the florfenicol and solvent and M and Ms represent the molar mass of florfenicol and solvent. Every point of the solubility was carried out three times, and x was the mean value of the three experiments. It was estimated that the relative uncertainty of the solubility measurement was about 5%. To verify the reliability of solubility measurements, the solubility data of florfenicol form A in methanol and acetone measured in this paper were compared with those from literature.3 From Figure 2, it can be seen that the solubility fractional deviations between this measurement and those of the literature were below 5%, which confirms the reliability and accuracy of the method used in this paper.
ΔfusH ⎛ 1 1⎞ − ⎟ − ln γ1 ⎜ R ⎝ Tm T⎠
(4)
where ΔfusH and γ1 stand for fusion enthalpy and activity coefficient of flofenicol in the solvent, respectively. The NRTL equation is a well-established local composition equation for calculating the activity coefficient of solute.11 The activity coefficient of solute calculated by NRTL model in the pure solvent can be obtained from the following equation: 2 ⎤ ⎡ τ21G21 τ12G12 ⎥ ln γ1 = x 22⎢ + 2 2 (x 2 + G12x1) ⎦ ⎣ (x1 + G21x 2)
(5)
in which 13507
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G12 = exp( −α12τ12) G21 = exp( −α12τ21) τ12 = (g12 − g22)/RT τ21 = (g21 − g11)/RT
(6)
where Δg12 = (g12 − g22) and Δg21 = (g21 − g11) are parameters representing cross interaction energy. Additionally, α 12 represents an adjustable parameter that generally varies from 0.2 to 0.47. In this paper, α12 = 0.3 was used for the correlation of solubility data.
Figure 4. Microscope pictures of florfenicol of (a) form A and (b) form B.
4. RESULTS AND DISCUSSION 4.1. Polymorph Identification and Characterization. The PXRD data of form A has been reported before.12 The PXRD of form A obtained in this paper is shown in Figure 3.
Figure 5. Thermal analysis (DSC) for form A and form B of florfenicol. Figure 3. Powder X-ray diffraction patterns for form A and form B of florfenicol.
thought to be the melting point of polymorph A. The DSC curve also shows another endothermic peak of florfenicol polymorph A, which is in good agreement with the melting peak of flofenicol polymorph B, and the consistency of these two endothermic peak can be explained by the transition of florfenicol polymorph A to florfenicol polymorph B during the melting process of florfenicol polymorph A. Generally, the polymorph with the higher fusion point is the more stable polymorph at melting point.13 Compared with florfenicol polymorph A, florfenicol polymorph B has higher fusion temperature and thus should be the stable form at melting temperature. However, from the fusion enthalpy of these two forms, the fusion enthalpy of flofenicol form A is much larger than the fusion enthalpy of florfenicol polymorph B, which indicates that these two forms are probably enantiotropic related polymorphs with form B stable at melting temperature. This can also be confirmed by the fact that the transition process of florfenicol polymorph A to florfenicol polymorph B is endothermic. To further investigate the heat phenomena, thermogravimetric analyses of both forms were also performed. The results show that no mass loss is observed in the experimental temperature range, confirming that both forms of florfenicol are not solvated and hydrated forms. 4.2. Solubility Data. To compare the dissolving properties of these two forms, the solubility of florfenicol polymorph A and polymorph B were measured from 278.15 to 318.15 K in
The PXRD of form A obtained in this paper is consistent with the reported data, which confirms the identification of form A. In addition to form A, a new polymorph, which is named as form B and has not been published anywhere, was successfully obtained in this paper. The PXRD of form B is also given in Figure 3. From Figure 3, there are many differences between the PXRD of the two forms. Compared to florfenicol form A, florfenicol form B exhibits new peaks at 4.04°, 12.22°, and 27.36°. This confirms the existence of new florfenicol form B and provides necessary method for identifying these two different forms. In addition, the morphology of these two forms of florfenicol in Figure 4 shows that crystals of polymorph A are plate-like, while crystals of polymorph B are needle-like. To further prove the difference of these two forms, the DSC data of the two forms are determined and plotted in Figure 5. Seen from Figure 5, the melting point and fusion enthalpy of florfenicol form B are 427.25 K and 17.82 kJ·mol−1, respectively. Form A exhibits two endothermic peaks with onset temperature at 425.45 and 427 K, respectively. The fusion enthalpy of form A was calculated to be 32.42 kJ·mol−1. The DSC data of form A obtained in this paper also agree with that of literature.3,12 The DSC curve in Figure 5 shows that when florfenicol polymorph A was heated to 425.45 K, the sample began to absorb heat and the temperature of 425.45 K is 13508
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Figure 6. Mole fraction solubility of florfenicol form A and form B in six solvents. Experimental solubility: (a) acetone, (b) 2-propanol, (c) methanol, (d) acetonitrile, (e) ethanol, (f) ethyl acetate; solid lines, calculated data by the Modified Apelblat Model.
six organic solvents. The results are visually plotted in Figure 6 and listed in Supporting Information Table S1. As shown in Figure 6, the solubility of florfenicol’s two forms both increase nonlinearly with the increasing of temperature in all tested solvents. This indicates that the dissolving processes of both forms of florfenicol are endothermic in the experimental temperature range. At a specific temperature, the solubility order is 2-propanol < ethanol < ethyl acetate < methanol < acetonitrile < acetone. Florfenicol has different solubility in different solvents and this difference is probably caused by the different interaction energy between solute and solvents. Furthermore, Figure 6 also shows that for every solvent studied, the solubility data of florfenicol form B are higher than the solubility data of florfenicol form A. According to the method described by Haleblian and McCrone, the more stable
polymorph should have lower solubility at given temperature and pressure.14 So florfenicol form A, which is the less soluble one, should be the more stable form at given condition. Combing the melting information mentioned above, florfenicol form A should be the less stable polymorph at melting temperature but the more stable polymorph at room temperature. This confirms again that florfenicol polymorph A and florfenicol polymorph B should be enantiotropically related, which can also be verified by the well-known Burger− Ramberger Rules about enantiotropic systems. The Burger− Ramberger Rules describe that if polymorph I compared with polymorph II has higher solubility below transition temperature while has lower fusion enthalpy, or when the transition of polymorph II to polymorph I is endothermic, then polymorph I and II belong to enantiotropic system.15 For florfenicol, form B 13509
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Figure 7. Plots of ln x versus 104(1/T − 1/Thm) for form A (a) and form B (b):▲, acetone, ▼, acetonitrile; ■, methanol; ▶, ethyl acetate; ●, ethanol; ⧫,
2-propanol.
solubility of nonideal solution. And the general van’t Hoff equation is described by eq 9.7
compared with form A has higher solubility while has lower fusion enthalpy. Also, the transition of florfenicol polymorph A to florfenicol polymorph B is endothermic. So the Burger− Ramberger Rules are applicable to the two forms of florfenicol and these two forms should be said to be interconvertible polymorphs. The solubility of florfenicol form A and florfenicol form B were calculated by the modified Apelblat model, NRTL model, and λh model. The purpose of using the three thermodynamic models is to alleviate the application of experimental solubility and to extent the application of temperature range of solubility. The correlated results and the obtained model parameters are shown in Supporting Information Tables S1 and S2, respectively. To evaluate the accuracy and applicability of the equations, RMSD (root-mean-square deviation) and ARD (average relative deviation) are introduced and are expressed as follows:5 ⎡ n (x − x cal)2 ⎤1/2 i ⎥ RMSD = ⎢∑ i ⎢⎣ i = 1 N − 1 ⎥⎦
ARD =
1 N
N
∑ i=1
xi − xical xi
ln x = −
ΔHd ΔSd + RT R
(9)
where ΔHd and ΔSd are dissolution enthalpy and dissolution entropy, respectively. T represents experimental temperature. R represents the gas constant, which equals 8.314 J·mol−1·K−1. Under the experimental conditions, the thermodynamic magnitudes of solution can be considered constant. Then, the dissolution enthalpy of solution can be derived from the modified van’t Hoff equation16 and can be expressed as follows: ⎤ ⎡ ⎡ ∂ln x ⎤ ∂ln x ΔHd = −R ⎢ ⎥ ⎥ = −R ⎢ ⎣ ∂(1/T ) ⎦ ⎣ ∂(1/T ) − (1/Thm) ⎦
(10)
where
Thm = (7)
n n 1 T
∑1
where Thm represents the mean harmonic temperature,17 and n represents the number of temperature points of each solvent. Figure 7 graphically shows the plot of ln x versus 104(1/T − 1 /Thm) for florfenicol form A and form B. It is clear to see from
(8)
Figure 7 that the plot of ln x versus 104(1/T − 1/Thm) for florfenicol form A and form B is linear. The ΔHd can be calculated from the slope of these plots. And Supporting Information Table S3 lists the values of slope from plots of lnx versus 104(1/T − 1/Thm). As described in literature,18 the Gibb’s energy of dissolution ΔGd in six pure solvents can be obtained by
where xical and xi are the correlated and experimental solubility data, and N represents the number of data points. Supporting Information Table S2 gives the values of ARD and RMSD. As shown in Supporting Information Table S2, the correlated values of solubility by the NRTL model, λh model and modified Apelblat model have good consistency with the experimental solubility of both florfenicol forms with ARD% less than 5.5%. Based the values of ARD and RMSD, the modified Apelblat model compared with the other two models could provide better relevant calculated results. The calculated data by Apelblat equation are also plotted in Figure 6 and the figure shows clearly that the correlated values by modified Apelblat equation are pretty consistent with experimental data. 4.3. Dissolution Properties. The van’t Hoff model could be adopted to calculate dissolution properties and predict
ΔGd = −RThm × Intercept
(11)
where Intercept is the intercept of plots of ln x vs 10 ( /T − 1 /Thm), which equals the value of ln x. Supporting Information Table S3 gives all the values of Intercept. The dissolution entropy can be calculated by the following equation. 4 1
ΔSd = (ΔHd − ΔGd)/Thm 13510
(12)
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Table 1. Dissolution Properties of Florfenicol Polymorphs in Six Solventsa solvent
a
Thm (K)
ΔHd (kJ·mol−1)
methanol ethanol acetone acetonitrile 2-propanol ethyl acetate
297.59 297.59 297.62 297.59 297.59 297.59
29.22 31.14 16.44 27.36 39.95 22.67
methanol ethanol acetone acetonitrile 2-propanol ethyl acetate
297.59 297.59 297.59 297.71 297.59 297.59
28.90 29.79 16.18 26.62 38.50 21.53
ΔSd (J·mol−1K−1) Form A 58.84 56.16 28.56 58.26 78.65 31.95 Form B 58.05 52.33 27.90 56.28 74.85 29.07
ΔGd (kJ·mol−1)
ζH
ζTS
11.71 14.43 7.940 10.02 16.54 13.16
0.6253 0.6507 0.6592 0.6121 0.6306 0.7045
0.3747 0.3493 0.3408 0.3879 0.3694 0.2955
11.62 14.22 7.877 9.865 16.22 12.88
0.6259 0.6607 0.6609 0.6137 0.6335 0.7134
0.3741 0.3453 0.3391 0.3863 0.3665 0.2866
The combined expanded uncertainties U are Uc(ΔHd) = 0.050ΔHd, Uc(ΔSd) = 0.050ΔSd, Uc(ΔGd) = 0.065ΔGd (0.95 level of confidence).
florfenicol form A is thermodynamically more stable at room temperature. The dissolution enthalpy, dissolution entropy and Gibb’s dissolution energy of both forms were also determined. From all thermodynamic data of these two forms, it was found that florfenicol form A and florfenicol form B are interconvertible polymorphs. The dissolution processes of both forms are entropy-driven and not spontaneous. The thermodynamics of florfenicol two forms is helpful for developing and optimizing the crystallization processes for producing different forms of florfenicol.
The calculated results of ΔHd, ΔSd and ΔGd are given in Table 1. Gibb’s dissolution energy change could be contributed by the dissolution enthalpy and dissolution entropy. And to contrast the relative contribution of these two dissolution properties to ΔGd, ζH and ζTS, which indicate contribution of dissolution enthalpy and dissolution entropy, are introduced and expressed as ζH = |ΔHd| /(|ΔHd| + |T ΔSd|) ζTS = |T ΔSd| /(|ΔHd| + |T ΔSd|)
■
(13)
The calculated results of eqs 10−13 are given in Table 1. It can be found from all the data in Table 1 that for all solvents tested the values of ΔSd, ΔHd, and ΔGd are all positive, indicating that the dissolution process not only is entropydriven and endothermic but also could not spontaneously dissolve. The order of ΔGd values in various solvents is exactly contrary to the order of solubility, which conforms to basic thermodynamics theory. Table 1 also shows that dissolution enthalpy accounts for a bigger contributor of the Gibb’s dissolution energy of florfenicol. Owing to the fact that florfenicol molecules contain groups such as −N−, −F, and −OH, florfenicol may get involved into different forces such as electrostatic force, hydrogen bond, and hydrophobic interaction in the dissolution process. More importantly, the values of dissolution enthalpy and Gibb’s dissolution energy of form A are higher than those of form B in all tested solvents. These results are consistent with the solubility data and further confirm that at room temperature florfenicol polymorph A is the more stable form. And the differences in dissolution properties between these two forms might arise from the different molecular arrangements of florfenicol molecules.
ASSOCIATED CONTENT
S Supporting Information *
Experimental and calculated solubility of both florfenicol forms, parameters of three empirical equations, values of ARD and RMSD, values of slope and intercept. This material is available free of charge via the Internet at http://pubs.acs.org/.
■
AUTHOR INFORMATION
Corresponding Author
*Tel: +86-22-27405754. Fax: +86-22-27314971. Email:
[email protected]. Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS This research is financially supported by National Natural Science Foundation of China (No. 21376165) and Key Project of Tianjin Science and Technology Supporting Program (No. 13ZCZDNC08900).
■
5. CONCLUSIONS A new polymorph of florfenicol, named form B, was discovered and characterized. The DSC data show that polymorph B is the more stable form in the high temperature range because florfenicol form B has higher melting point compared with form A, however florfenicol form A has higher fusion enthalpy. The equilibrium solubility of two forms of florfenicol in six pure solvents were measured with a dynamic method in the temperature ranging from 278.15 to 318.15 K and the solubility data of both forms increase nonlinearly with the increasing of temperature. Comparison of solubility of two forms shows that
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