Solution-Mediated Phase Transformation of Argatroban: Ternary

Article pubs.acs.org/IECR

Solution-Mediated Phase Transformation of Argatroban: Ternary Phase Diagram, Rate-Determining Step, and Transformation Kinetics Yaping Wang,†,‡ Panpan Sun,†,‡ Shijie Xu,†,‡ Shichao Du,†,‡ Teng Zhang,†,‡ Bo Yu,†,‡ Shixin Zhang,§ Yang Wang,§ Yuewei Wang,§ and Junbo Gong*,†,‡ †

School of Chemical Engineering, Tianjin University, Tianjin 300072, China Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300072, China § Tianjin Hengbida Chemical Synthesis Company Ltd., Tianjin 300072, China ‡

S Supporting Information *

ABSTRACT: In this work, an ethanol solvate of argatroban was first discovered and fully characterized. The ternary phase diagrams for ethanol− water−argatroban at 35.0, 40.0, and 45.0 °C were established to determine the thermodynamic stability. In situ Raman and IR spectroscopy were applied for the analysis of the solution-mediated phase transformation of argatroban from monohydrate to ethanol solvate in ethanol−water solvent. It is evident that the rate-controlling step is the growth of ethanol solvate at the initial stage and the dissolution of monohydrate at the later stage. To further understand and control the transformation process, the effects of solvent composition, temperature, and solid loading on the transformation behavior were investigated in detail. Furthermore, a kinetic model was established to get a more detailed insight into the temperature’s role in this transformation process. This work can provide important instruction for optimum process control during the industrial production of argatroban.

1. INTRODUCTION Many pharmaceuticals are found to have more than one crystalline form, which can exist in such diverse solid forms as polymorphs, solvates, salts, cocrystals, and amorphous solids.1 Solvates, also regarded as pseudopolymorphs, are crystalline solids having unit cells that differ from their original substance through the inclusion of one or more solvent molecules.2,3 Different crystalline forms can exhibit significant variations of physical and chemical properties, such as melting point, solubility, stability, and bioavailability. As for solvatomorphism, it can improve many pharmaceutical-related properties and be of great interest for its researching potentials. For example, in the purification process of paclitaxel, solvates containing organic solvents were found to be useful intermediates.4 Moreover, the dimethylformamide solvate of cefprozil was demonstrated to be effective for the preparation.5 Besides, solvates undergoing desolvation may contribute to the final products in the pharmaceutical industry. Argatroban is currently the only synthetic compound that gains the world’s approval for the treatment of acute ischemic stroke. The structure of argatroban is shown in Figure 1. It has better anticoagulant and antithrombotic effects than heparin, with small molecular weight and high affinity for thrombin. If taken within 48 h after the onset of disease, it demonstrates high treatment efficiency and low incidence of side effects6−8 However, the drug’s efficacy is closely related to the crystalline form.9 For different crystalline forms of a substance, there is © 2017 American Chemical Society

Figure 1. Chemical structure of argatroban.

generally one thermodynamically stable form under certain conditions, whereas other forms are metastable forms. Metastable solid forms have the tendency to transform into the stable form under some conditions,10,11 which will significantly affect the crystalline purity of the drug product. In the industrial production of argatroban, recrystallization in a mixture of ethanol and water is often used, which may cause the phase transformation of argatroban.12,13 Therefore, to obtain the desired crystalline form, it is essential to screen and characterize all available forms. Then, uncovering the mechanism of the phase transformation process of argatroban Received: Revised: Accepted: Published: 4539

December 9, 2016 February 20, 2017 March 28, 2017 March 28, 2017 DOI: 10.1021/acs.iecr.6b04760 Ind. Eng. Chem. Res. 2017, 56, 4539−4548

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Industrial & Engineering Chemistry Research

determine the solid forms during the phase transformation process. The samples were scanned over a range of 2−50° 2θ using a step size of 0.02° 2θ and a scan speed of 8° 2θ/min. The Raman spectra of the two forms were obtained by Raman spectroscopy (RXN2T, Kaiser Optical Systems, Inc., Ann Arbor, MI, USA), with an excitation wavelength of 785 nm, a scanning step of 4 cm−1, and an exposure time of 30 s. 2.4. Determination of the Ternary Phase Diagram. Prediction and precise control of a specific polymorph are critical for achieving desired solubility and stability requirements.20 The solubility of monohydrate and ethanol solvate in ethanol−water mixed solvent was evaluated by using a gravimetric method described in the literature.21 Excess solid of monohydrate was added to the mixed solvent (methanol/mwater = 1, 9:1, 8:2, 7:3, 6:4, 5:5, 4:6, 3:7, 2:8, 1:9, 0) to determine the solubility of monohydrate. To check if phase transformation occurs, suspension samples withdrawn from the crystallizer were analyzed by PXRD. In some mixed solvents (methanol/ mwater = 1, 9:1, 8:2, 7:3, 6:4), a phase transformation from monohydrate to ethanol solvate was detected by PXRD. Therefore, in these above solvents, an excess of ethanol solvate was added into the mixed solvent to measure the solubility of solvate. 2.5. Calculation of Activity. It is common that the stability of solvate in pure aqueous solution depends on the temperature. However, the phase transformation temperature for many cases is relatively high, which can reduce the efficacy of APIs. For such situations, a mixed solvent can be considered.22 A change of solvent may give rise to phase transformation at lower temperature. The formation of ethanol solvate crystals from monohydrate crystals may be represented by the equilibrium

allows a theoretical basis for controlling parameters and optimizing the crystallization process of argatroban. At present, the polymorphic phenomenon12−14 of argatroban has been studied, whereas the most widely used crystalline form of argatroban in prescription drugs is monohydrate. It is reported that argatroban is hardly soluble in water,15 which can seriously affect the efficacy of active pharmaceutical ingredients (APIs).16,17 Besides, the monohydrate has poor crystal habit and flow property. Ethanol is one of the solvents that can be used in medicine. In our work, a new crystal form considered to be an ethanol solvate of argatroban was found. The new ethanol solvate has higher solubility in water than the monohydrate, and it has good crystal habit as well as good flow property. In addition, the phase transformation from monohydrate to ethanol solvate of argatroban has not been reported in the literature. To determine the relative stability of the two forms and to ensure that the preferable pure forms are produced, it is necessary to study the phase transformation process of argatroban. In addition, attenuated total reflection Fourier transform infrared spectroscopy (ATR-FTIR) and Raman spectroscopy have been used to detect polymorphic transformations during crystallization processes.18,19 The aim of this study is, first, to determine the ternary phase diagram of argatroban in the binary solvent mixtures of ethanol and water at different temperatures, which can provide the theoretical basis and guidance for the industrial production of argatroban; second, to determine the rate-controlling step of the phase transformation of argatroban and investigate the effects of operating parameters on phase transformation of argatroban by using process analytical technologies (PAT); and, third, obtain the kinetics of phase transformation of argatroban at 35.0, 40.0, and 45.0 °C.

Kh

2. EXPERIMENTAL SECTION 2.1. Materials. Monohydrate of argatroban was supplied by Tianjin Hengbida Chemical Synthesis Co., Ltd., Tianjin, China, and was used without further purification, with a mass purity of 99.5%. Anhydrous ethanol was purchased from Tianjin Kewei Chemical Co. Ltd., China (99% pure). Deionized water was produced using a Millipore system. 2.2. Preparation of Ethanol Solvate. Approximately 4 g of monohydrate of argatroban was dissolved in 60 mL of ethanol−water solvent with a water mass fraction of 5−10%. Then the slurries were heated to 40−75 °C and agitated by magnetic stirrer with an agitation speed of 250 rpm to dissolve completely. Afterward, the solution was cooled to 5−15 °C at a cooling rate of 0.2 °C/min and kept at the temperature for 2−4 h. Then the ethanol solvate was obtained by filtration, washing, and drying. 2.3. Characterization of Different Crystal Forms of Argatroban. Differential scanning calorimetry (DSC, model DSC 1/500, Mettler-Toledo, Greifensee, Switzerland) was employed to observe the melting processes of the two forms under protection of nitrogen (dry nitrogen, 100 mL min−1). Approximately 5−10 mg samples were taken into the aluminum pans, and the measurement temperature range was from 25.0 to 220.0 °C with a heating rate of 10 K/min. Thermogravimetric analysis (TGA, Mettler-Toledo TGA/DSC 1/SF, Greifensee, Switzerland) was carried out under protection of nitrogen (dry nitrogen, 20 mL/min). The heating rate and the measurement temperature range were the same as for the DSC experiments. Powder X-ray diffraction (PXRD) (D/max-2500, Rigaku, Tokyo, Japan) was adopted to

A·H 2O(solid) + C2H5OH ⇔ A·C2H5OH(solid) + H 2O (1)

Kh =

a[A· C2H5OH(solid)]a[H 2O] a[A· H 2O(solid)]a[C2H5OH]

(2)

where Kh is the equilibrium constant for the process shown in eq 1 and a[C2H5OH], a[A·C2H5OH(solid)], a[A·H2O(solid)], and a[H2O] are the thermodynamic activities of ethanol, ethanol solvate, monohydrate, and water, respectively. When Kh > 1, the monohydrate will be more stable than the ethanol solvate. The ethanol solvate will be more stable than the monohydrate in the inverse situation. If the reference states of the solids are assumed to be their pure phases and therefore exhibit an activity of 1, eq 2 can be simplified to Kh =

a[H 2O] a[C2H5OH]

(3)

According to eq 3, the relative stability of monohydrate and ethanol solvate in the surrounding medium depends on the water activity and ethanol activity at a specific temperature. It is also known that the dissolved drug in the aqueous solvent mixtures influences ai to a much smaller extent when the concentration of the dissolved drug is not high.23,24 Therefore, values of ai in mixtures can be calculated by the equation

ai = γixi

(4)

where xi is the mole fraction of water or ethanol in the mixture and γi is the appropriate activity coefficient. 4540

DOI: 10.1021/acs.iecr.6b04760 Ind. Eng. Chem. Res. 2017, 56, 4539−4548

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Industrial & Engineering Chemistry Research 2.6. In Situ Monitoring of the Phase Transformation Progress of Argatroban. The solvent-mediated phase transformation of argatroban from monohydrate to ethanol solvate in mixed solvent (methanol/mwater = 20:1) was monitored by using ATR-FTIR spectroscopy (ReactIRTM45, MettlerToledo). A volume of 60 mL of mixed solvent was added in the crystallizer, and the temperature was controlled by a thermostatic bath. In addition, an agitation speed of 250 rpm was controlled by a magnetic stirrer. Next, the ATR-FTIR probe (Duradisc Dicomp probe) was immersed into the crystallizer below the solution surface, and the slurries were scanned with an interval of 1 min. A certain amount of argatroban was added to the crystallizer quickly, and the concentration was monitored using the ATR-FTR in real time. When the online signal showed the system was no longer changing, the experiment was stopped and the crystals were obtained by filtration. The crystal form was then immediately measured by powder X-ray diffraction. Moreover, the Raman RXN2 equipped with an MR probe was used to in situ monitor the solid contents of two crystal forms, and the Raman spectrum was collected with an interval of 1 min. 2.7. Kinetic Experiments of Phase Transformation of Argatroban. PXRD can be used to determine the relative weight percentages of the crystalline phases in the quantitative analysis of phase transformation.25 According to the change of the characteristic peak intensity, the relative mass fraction of two crystal forms in the suspended solutions was calculated by using eqs 5 and (6),26 and the calculated data were fitted by the Avrami−Erofeev model.27 The model parameter values can be obtained to predict the phase transformation rate: XA = Ii A /(Ii A + Ij B(I A° /IB°))

(5)

XB = Ij B/(Ij B + Ii A(IB°/I A°))

(6)

D = 1 − exp[−(k × t )1/ n ]

(7)

Figure 2. Microscope images of monohydrate (a) and ethanol solvate (b) of argatroban.

Figure 3. Powder X-ray diffraction patterns of argatroban.

monohydrate, whereas the peak at 7.60°m which cannot be seen in the monohydrate, is selected to monitor the ethanol solvate.28,29 The TGA and DSC thermograms of the monohydrate and ethanol solvate are shown in Figures 4 and 5, respectively. From Figure 4, it can be seen that there is a weight loss of 3.27% (3.41% in theory30) in total weight in the monohydrate TGA curve corresponding to one water molecule in one

In the above formula, X A is the mass fraction of monohydrate, whereas XB stands for the mass fraction of ethanol solvate. IiA and IjB stand for i and j characteristic peak intensity of monohydrate and ethanol solvate, respectively. In addition, I°A and I°B stand for characteristic peak intensity of pure monohydrate and pure ethanol solvate. Besides, D represents the conversion rate of argatroban, t is the transformation time, and k and n are model parameters (k stands for rate constant, and 1/n represents reaction order).

3. RESULTS AND DISCUSSION 3.1. Characterization of Different Argatroban Crystal Forms. The ethanol solvate is the novel crystal form we discovered. An optical microscope (Olympus BX51, Tokyo, Japan) was employed to observe the morphologies of the two forms. The crystal morphology of the monohydrate and ethanol solvate is shown in Figure 2. Monohydrate exhibits a needle morphology, whereas ethanol solvate has a rod-like shape. Therefore, it is relatively easy to identify the two forms by their shapes. The powder X-ray diffraction of the monohydrate and ethanol solvate exhibits some obvious differences that can distinguish the two forms, as shown in Figure 3. The monohydrate is identical to the crystalline form reported by Song et al.14 Peaks at 9.16° where the ethanol solvate has no peak are chosen as the main characteristic peaks of

Figure 4. TGA thermograms of argatroban: (a) monohydrate; (b) ethanol solvate. 4541


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monohydrate has characteristic peaks at 1653 and 1296 cm−1, whereas ethanol solvate here has characteristic peaks at 1224, 653, and 468 cm−1. Raman and IR spectra of water−ethanol solvent and two forms of argatroban in mixed solvent solution at experimental temperature are determined and are shown in Figure 6b. The solvent patterns are substracted to eliminate the solvent influence. In Figure 6b, the red line stands for the monohydrate of argatroban, which is monitored by Raman spectroscopy at the beginning of experiment. It is evident from Figure 6b that Raman peak at 1324 cm−1 (−CCH−) or peaks marked by green dotted line are the characteristic peaks of monohydrate of argatroban in solutions that can be applied to represent the content of monohydrate of argatroban in solutions. Nevertheless, it is obvious that peaks at 750 cm−1 (C−O, C−N) and 423 cm−1 (acid chloride) are the characteristic peaks of ethanol solvate of argatroban in solutions. Thus, 750 and 423 cm−1 were chosen for tracking the ethanol solvate content trends. It can also be observed that the ATR-FTIR peak at 1632 cm−1 (NH2, CN, and NH) is the characteristic peak of argatroban in solution, which can be used to represent the concentration of argatroban in solution. 3.2. Ternary Phase Diagram and Thermodynamic Analysis. 3.2.1. Determination of Ternary Phase Diagrams. By means of the solubility data, the ternary phase diagrams for ethanol−water−argatroban were obtained under different temperatures, as shown in Figure 7. The solubilities of the two crystal forms are shown in Table S1 in the Supporting Information. It can be seen from the ternary phase diagram that the solubilities of both kinds of crystal forms increase with rising temperature at constant solvent composition, which suggests that cooling crystallization by using the mixed solvent is an appropriate way to recrystallize argatroban. Meanwhile, it can be seen that the solubility of argatroban reaches a maximum point at a specific composition (xe = 0.6), which is also the transition point. Besides, it is clear that phase area A shows a downtrend with increasing temperature. As a consequence, we can conclude that the amounts of anhydrous ethanol and water must be controlled in a solvent dosage range corresponding to different phase areas to obtain different solvates. Moreover, a lower temperature is beneficial to the

Figure 5. DSC curves of argatroban: (a) monohydrate; (b) ethanol solvate.

argatroban monohydrate molecule. However, the ethanol solvate has a weight loss of 8.25% (8.30% in theory30), which is demonstrated not to be water by Karl Fischer titration and corresponds to an ethanol molecule in one ethanol solvate molecule. Identification of the form was further confirmed by 1 H NMR, and these data are presented in Figure S1 in the Supporting Information. The DSC curve of two kinds of argatroban is shown in Figure 5. For the monohydrate, the DSC heating curve showed a single endothermic peak with a value of 169.43 °C coupled with no mass loss in TGA, namely, the dehydration process accompanied by a melting process. It can be concluded that the water molecule in crystal lattice is hardly removed, whereas ethanol solvate presented double endothermic peaks. The first endothermic peak is at 79.82 °C, which correspond to deducting the ethanol endotherm. The second endothermic peak at 172.96 °C is a fusion endotherm for the desoluentized resultant argatroban phase. Raman spectroscopy is also successfully used to identify the crystalline forms, as shown in Figure 6a. The Raman spectra of the two forms display some distinct differences. In this study,

Figure 6. Raman and ATR-FTIR spectra: (a) Raman spectra of solids; (b) Raman and ATR-FTIR spectra of argatroban in solutions. 4542


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Industrial & Engineering Chemistry Research Table 1. Parameters of NRTL NRTL parameter (J mol−1)

35 °C

40 °C

45 °C

g12 − g22 g21 − g11 α12

−2514.0874 7060.2023 0.1448

−2493.3619 7102.4123

−2472.6364 7144.6223

using eq 4. The values of ai and xi are listed in Table S1 in the Supporting Information. 2 ⎡ ⎤ τ21G21 τ12G12 ⎥ ln γ2 = x 22⎢ + (x 2 + x1G12)2 ⎦ ⎣ (x1 + x 2G21)2

(8)

2 ⎡ ⎤ τ12G12 τ21G21 ⎥ ln γ2 = x12⎢ + 2 2 (x1 + x 2G21) ⎦ ⎣ (x 2 + x1G12)

(9)

In the above equations G12 = exp( −α12τ12)

(10)

G21 = exp( −α12τ21)

(11)

τ12 = (g12 − g22)/RT = Δg12 /RT

(12)

τ21 = (g21 − g11)/RT = Δg21/RT

(13)

It is evident that the stability of monohydrate and ethanol solvate changes with solvent composition. For example, in the case of higher anhydrous ethanol content, monohydrate will gradually transform to ethanol solvate at the same temperature. However, when the water content is higher, ethanol solvate is metastable and monohydrate is stable. Moreover, the activity is connected with solvent composition. As shown in Table S1, the values of aw at the transition point from 35 to 45 °C are 0.6872, 0.6864, and 0.6817, respectively. The water activities at transition point are almost the same but a little reduced with the increment of temperature. At the same time, monohydrate and ethanol solvate are in equilibrium at the transition point, so Kh can be calculated by using eq 3. The values of Kh are 1.0950, 1.0844, and 1.0678 at 35, 40, and 45 °C, which are similar and also drop a little with increasing time. Besides, the monohydrate is more stable than ethanol solvate when aw > 0.6864 (xw > 0.6253,Kh > 1.0950), whereas the stable form is ethanol solvate when aw< 0.6864 (xw < 0.6253, Kh < 1.0950) at 35 °C. In addition, the identification of the stable form and the metastable form at 40 and 45 °C is the same as that at 35 °C. As a consequence, by tuning the value of aw, one can obtain the desired solvation form of argatroban. 3.3. Solution-Mediated Phase Transformation from Monohydrate to Ethanol Solvate. 3.3.1. Rate-Controlling Step of Phase Transformation of Argatroban. To take a more detailed look into the phase transformation process of argatroban, ATR-FTIR spectroscopy and Raman spectroscopy were used to detect the phase transformation process. The operating conditions were selected from phase area C in the ternary phase diagram. Thus, the solvent-mediated phase transformation from monohydrate to ethanol solvate was carried out at 40 °C by adding an excess amount of 0.5 g of monohydrate into 60 mL of mixed solvent of water and ethanol. The results are shown in Figure 8. In this study, the definition of the metastable form is monohydrate, whereas ethanol solvate is defined as the stable form. Figure 8 shows the concentration−time profile and the characteristic peak changes of the two forms over time. If the

Figure 7. Ternary phase diagram of argatroban for transformation: (a) 35.0 °C; (b) 40.0 °C; (c) 45.0 °C. Phase regions A, B, C, and D stand for monohydrate and its saturated solution, monohydrate and ethanol solvate as well as their saturated solution, ethanol solvate and its saturated solution, and unsaturated solution, respectively.

production of monohydrate, whereas a higher temperature is in favor of the production of ethanol solvate. 3.2.2. Determination of the Stable Form. The values of γi in ethanol−water mixtures at different temperatures can be obtained by the non-random two-liquid (NRTL) equation, the parameters of which have been reported previously31 and are listed in Table 1. Therefore, γi can be calculated by using eq 8, and the activity of water and ethanol can be calculated by 4543


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Figure 8. Solvent-mediated phase transformation from monohydrate to ethanol solvate at 40 °C in situ monitored by Raman, ATR-FTIR: (a) Raman relative intensity of ethanol solvate; (b) concentration of solutions detected by IR; (c) Raman relative intensity of monohydrate.

Figure 9. Effect of temperature on the transformation from monohydrate to ethanol solvate at 30.0, 35.0, 40.0, and 45.0 °C.

from 1320 s at 30.0 °C to 180 s at 45.0 °C, whereas the total transformation time declines from 3060 s at 30.0 °C to 1080 s at 45.0 °C. As can be seen from the fitted curve in Figure S2, the transformation time drops more rapidly than the plateau time with increasing temperature. In addition, it is found that both the transformation time−temperature profile and the plateau time−temperature profile coincide with the exponential equation. Generally, the solid−liquid surface tension will decrease with increasing temperature and, thus, promote the nucleation process.34,35 Besides, the increasing temperature will enhance the thermodynamic driving force (defined as Gibbs free energy difference between the two forms) for the transformation progress. Thus, the increment of temperature has a driving effect on the phase transformation. 3.3.3. Influence of Solvent Composition on Phase Transformation of Argatroban. To reveal the influence of solvent composition on the phase transformation, a series of experiments was performed at 35 °C by adding an excess amount of 0.5 g of monohydrate into 60 mL of mixed solvent (methanol/mwater = 20:1), including binary solvent of ethanol and water (xe = 1, xe = 0.9725, xe = 0.95, xe = 0.9). The results are shown in Figure 10. It can be seen that the plateau time and the total transformation time increase dramatically with the reduction of xe. Figure S3 in the Supporting Information indicates the plateau time drops from 8220 s in mixed solvent (xe = 0.9) to 420 s in pure ethanol, whereas the complete transformation time decreases from 11520 s in mixed solvent (xe = 0.9) to 620 s in pure ethanol. In addition, the total transformation time declines dramatically, whereas the plateau time goes down slowly relative to the total transformation time. Moreover, the transformation time and the plateau time variation trend are fitted well with an exponential equation. The solubility of ethanol solvate is higher in the mixed solvent with more water; thus, this can be explained by the fact that the absolute supersaturation of ethanol solvate will decrease with the increment of water content. Besides, solute−solute or solute−solvent interactions may be taken into consideration for further explaining their possible influence on the nucleation kinetics.36 3.3.4. Influence of Solid Loading on Phase Transformation of Argatroban. To investigate the effect of the amount of solid loading on the transformation from monohydrate to ethanol solvate, phase transformation experiments with an added

dissolution of the metastable form is the rate-determining step, then the first plateau concentration lies close to the solubility of the stable form. If the first plateau concentration lies close to the solubility of the metastable form, the nucleation and growth of the stable form will be the rate-determining step.32,33 In this study, the dissolution of the metastable form seems to be fast during the plateau stage, and the plateau concentration lies close to the solubility of the metastable form, so the nucleation and growth of the stable form is the rate-determining step during this stage (I). On the other hand, at the initial stage of the transformation (I), the amount of stable form represented by Raman data is increasing and the amount of the metastable monohydrate is decreasing, whereas the solution concentration maintains the plateau, which is indicated by ATR-FTIR data. This result indicates that the overall dissolution rate of the metastable form is faster than the overall nucleation and growth rate of the stable form. Thus, the nucleation and growth of the stable form is the controlling step in this stage. However, at the later stage of the phase transformation progress (II), the concentration of the solution begins to decrease, which suggests that the overall dissolution rate of the metastable form becomes slower than the nucleation and growth of the stable form due to the decreasing solid loading of the metastable form. Therefore, the dissolution of the metastable form becomes the limiting factor in this stage. 3.3.2. Influence of Temperature on Phase Transformation of Argatroban. To evaluate the influence of temperature on the phase transformation from monohydrate to ethanol solvate, slurry experiments at 30.0, 35.0, 40.0, and 45.0 °C were carried out by adding an excess amount of 0.5 g of monohydrate into 60 mL of mixed solvent (methanol/mwater = 20:1). The results are shown in Figure 9. In this study, the plateau time is defined as the time from the beginning of the plateau stage to the sudden concentration decrease, whereas the transformation time is defined as the time from the addition of monohydrate to the point when the concentration of ethanol solvate decreases to a constant value. The effect of temperature on phase transformation is further revealed in Figure S2 in the Supporting Information. It is clear that, as the temperature increases, the plateau time and complete transformation time decrease significantly and the transformation rate drops notably. The plateau time decreases 4544


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increases concurrently with the larger growth surface area of stable form caused by the absolute amount of seeds. 3.4. Kinetics of Phase Transformation of Argatroban. According to the characteristics of the phase transformation, the kinetics of phase transformation of argatroban at 35.0, 40.0, and 45.0 °C was studied by adding an excess amount of 0.5 g of monohydrate into 60 mL of mixed solvent (methanol/mwater = 20:1). The samples collected at different times during the phase transformation process were determined by PXRD. The results are shown in Figure 12. It is obvious that the PXRD patterns at

Figure 10. Effect of solvent composition on the transformation from monohydrate to ethanol solvate at 35.0 °C: (a) 90% ethanol; (b) 95% ethanol; (c) 97.25% ethanol; (d) 100% ethanol.

amount of solid loading of 0.3, 0.5, 0.8, and 1.3 g of monohydrate into 60 mL of mixed solvent (methanol/mwater = 20:1) were carried out at 35 °C. The results are shown in Figure 11. It is evident that the transformation time is shorter

Figure 12. PXRD patterns of argatroban at different times: (a) 0 min; (b) 5 min; (c) 10 min; (d) 15 min; (e) 20 min; (f) 25 min.

the initial time fit perfectly with the PXRD patterns of monohydrate, which have the characteristic peak of 9.16° 2θ. At 10 min, PXRD patterns of ethanol solvate come to appear with a characteristic peak of 7.60° 2θ. The evolution of the relative intensity of the characteristic peak represents a process of transformation from monohydrate to ethanol solvate. Along with the decrease of the characteristic peak intensity of monohydrate, the intensity of the characteristic peak of ethanol solvate increases gradually, and the kinetics analysis of the phase transformation is carried out by measuring the rate of occurrence or disappearance of the characteristic peaks. The peaks at 9.16° 2θ and 7.60° 2θ are chosen as the characteristic peaks of monohydrate and ethanol solvate, respectively, to calculate the mass fraction of monohydrate and ethanol solvate at different times. The well-known Avrami−Erofeev model (eq 7) commonly used in crystallization kinetics is employed to correlate the experimental value, as shown in Figure 13. The parameters’ values of k and n at different times, the calculated complete transformation time (D = 99.9%), and standard deviations Sk and Sn are listed in Table 2. It can be seen that k and n go up with increasing temperature. It can also be seen from Figure 14 that the value of k increases linearly with temperature, whereas the value of n presents a nonlinear increase with the increment of temperature. Moreover, n increases more rapidly than k with increasing temperature. There is a positive correlation between the increase in phase transformation rate and both parameters k and n according to eq 7. Therefore, higher temperature can accelerate the phase transformation. Generally speaking, the transformation rate constant k reflects the transformation rate and 1/n reflects the mechanism of crystallization. For instance,

Figure 11. Effect of solid loading on the transformation from monohydrate to ethanol solvate at 35.0 °C.

with more solid loading. Furthermore, it can be seen from Figure S4 in the Supporting Information that the plateau time and the total transformation time decline significantly with increasing solid loading. The plateau time drops from 900 s at a solid loading of 0.3 g to 120 s at a solid loading of 1.3 g, whereas the complete transformation time decreases from 2400 s at a solid loading of 0.3 g to 900 s at a solid loading of 1.3 g. Furthermore, empirically, it is found that the transformation time variation tendency with solid loading can be fitted well with an exponential equation. Thus, the transformation rate is slightly faster in the experiments with the higher solid loading of monohydrate. In accordance with the work of Croker and Hodnett,37 it is considered that the nucleation of the stable form tends to occur on or at the surface of the metastable form. When the amount of solid loading is higher, the absolute amount of seeds is larger. Therefore, the transformation rate 4545


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Figure 13. Plots of transformation kinetics analysis at 35.0, 40.0, and 45.0 °C.

Table 2. Avrami−Erofeev Model Parameters and Complete Transformation Time for Phase Transformation from Monohydrate to Ethanol Solvate T/°C

k

n

R2

Sk

Sn

t

35 40 45

0.04484 0.07373 0.11146

0.19986 0.20764 0.30062

0.99996 0.99471 0.99749

0.00030 0.00047 0.00098

0.00672 0.00669 0.03595

30.2 17.0 10.7

Figure 15. Microphotograph during the phase transformation of argatroban at 40.0 °C: (a) 0 min; (b) 5 min; (c) 10 min; (d) 15 min.

with the advance of the phase transformation, the number and size of the needlelike crystals in solution decrease (Figure 15c,d), whereas the number and size of the rod-like crystals increase gradually.

4. CONCLUSIONS In this work, a new ethanol solvate of argatroban was obtained using the cooling crystallization method. The ternary phase diagram of argatroban was determined at 35.0, 40.0, and 45.0 °C. It was found that the transition point is xe = 0.6. Monohydrate gradually transforms to the ethanol solvate with lower water activity at constant temperature, whereas when the water activity is higher, ethanol solvate is metastable and monohydrate is stable. In a word, one can obtain the desired solvation form of argatroban by tuning the water activity. Furthermore, the solvent-mediated phase transformation monitored by PAT shows that the nucleation and growth of ethanol solvate is the controlling step at the initial stage of the transformation process. At the later stage of the transformation process, the dissolution of the monohydrate will become more and more important. Besides, with the ethanol content, solid loading, and temperature increase, the rate of phase transformation of argatroban increases. Furthermore, empirically, it is found that both tplat and ttran have an exponent relationship to T, xe, and m. In addition, the Avrami−Erofeev model is found to correlate well with phase transformation results at 35.0, 40.0, and 45.0 °C.

Figure 14. Avrami−Erofeev model parameters k and n change with temperature from monohydrate to ethanol solvate.

for 1/n = 2, 3, 4, the model is known as the random nucleation and growth mechanism.38,39 In the kinetic experiment, the value of 1/n is close to 3 or 4, so the phase transformation proceeds by a nucleation and growth mechanism. This is consistent with the conclusion that the transformation process is nucleation−growth rate limited. The phase transformation from monohydrate to ethanol solvate was also observed by microscope with interval sampling. The results are shown in Figure 15. It can be seen that monohydrate is needlelike, whereas the ethanol solvate is rodlike. At the initial time (Figure 15a), monohydrate in solution takes on a three-dimensional ball cactus shape, then the acicular monohydrate in ball cactus shape disperses to the bulk solution after being stirred with an agitator paddle (Figure 15b). Along

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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.iecr.6b04760. Solubilities and activities of the two forms (Table S1); 1 H NMR spectra (Figure S1); complete transformation time and induction time variation trend (Figures S2−S4) (PDF) 4546


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AUTHOR INFORMATION

Corresponding Author

*(J.G.) Tel.: 86-22-27405754. Fax: 86-22-27314971. E-mail: [email protected]. ORCID

Junbo Gong: 0000-0002-3376-3296 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We are grateful for the financial support of the National Natural Science Foundation of China (NNSFC 81361140344, NNSFC 21376164, and NNSFC 21676179), National 863 Program (2015AA021002), Major Project of Tianjin (15JCZDJC33200), and Major National Scientific Instrument Development Project (No. 21527812).

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SYMBOLS t, time (s) tplat, plateau time (s) ttran, transformation time (s) T, temperature (°C) xe, mass fraction of ethanol in mixed solvent m, amount of solid loading (g) XA, mass fraction of monohydrate XB, mass fraction of ethanol solvate IiA, characteristic peak intensity of monohydrate IiB, characteristic peak intensity of ethanol solvate IA°, characteristic peak intensity of monohydrate I°B, characteristic peak intensity of ethanol solvate D, conversion rate of argatroban (%) k, n, parameters of Avrami−Erofeev model; k is the rate constant, and 1/n is the reaction order Sk, Sn, standard deviation of k and n

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Solution-Mediated Phase Transformation of Argatroban: Ternary

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