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Polymorph Control by Investigating the Effects of Solvent and Supersaturation on Clopidogrel Hydrogen Sulfate in Reactive Crystallization Teng Zhang, Yumin Liu, Shichao Du, Songgu Wu, Dandan Han, Shiyuan Liu, and Junbo Gong Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.7b01311 • Publication Date (Web): 11 Oct 2017 Downloaded from http://pubs.acs.org on October 13, 2017

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Crystal Growth & Design

Polymorph Control by Investigating the Effects of Solvent and Supersaturation on Clopidogrel Hydrogen Sulfate in Reactive Crystallization Teng Zhang1,2, Yumin Liu1,2, Shichao Du1,2,Songgu Wu1,2, Dandan Han1,2, Shiyuan Liu1,2, Junbo Gong1,2* 1

School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072,

China; 2

The Co-Innovation Center of Chemistry and Chemical Engineering of Tianjin, Tianjin

University, Tianjin 300072, China.

ABSTRACT Reactive crystallization and polymorphic transformation of Clopidogrel Hydrogen Sulfate (CHS) in nine pure solvents were studied at 313.15 K. It is found that thermodynamically stable polymorphic form tends to be obtained in solvents with higher solubility of CHS and the conversion rates from Form I to Form II are also mainly increased with increasing solubility. The solvent hydrogen bond donor ability is essential for determining the solvent effects on solubility and polymorphic formation of CHS. Besides, the reactive crystallization of CHS at different supersaturations in 2-propanol and 2-butanol was online monitored by using ATR-FTIR and FBRM with a calibration-based approach. The results indicate the nucleation induction period is the kinetic–determining stage and supersaturation is a direct factor to determine the polymorphic formation of CHS: Form II was obtained with s under 18 while Form I was produced when s increases above 21. Keywords: Polymorph, Supersaturation, Reactive Crystallization, Clopidogrel, Hydrogen Bonding

1. Introduction Compounds display different solid-state forms (crystalline or amorphous) that offers distinctive challenges in product development and manufacture. Polymorphism is essential in 1

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pharmaceutical research and development due to different polymorphs exhibiting significantly different pharmaceutical relevant properties, including stability, solubility, and different bioavailability. Polymorphic instability is often found during solution crystallization and pharmaceutical formulation. Especially for the metastable polymorph drugs, which usually have improved bioavailability and higher solubility, polymorph changes would influence their stability and curative effect. Hence, it’s quite challenging to produce metastable forms because of conversion into a more thermodynamically stable one often occurs during crystallization, dissolution or storage.1-3 Solvent-mediated polymorphic transformation during solution crystallization generally happens in accordance with Ostwald’s Law. The thermodynamically less stable polymorph often be generated first, and then in the metastable form-suspended solution, the more stable polymorph will nucleate and grow accompanied by the dissolution of metastable one.4-5 However, it is quite tough to control the transition process to produce pure solid form, especially the metastable form, because of various influencing factors (temperature, solvent, supersaturation etc.). For a specific solution crystallization process, the solvent effects on the polymorphs during solution crystallization are especially obvious. The effects of solvent on polymorphic nucleation and transformation have been studied by many researchers.6-8 Prof. Davey did researches concerning the influence of solvent on polymorphic formation of 2, 6-Resorcylic acid by effecting the molecular self-assembly during nucleation from solution. Their results showed that polymorph I preferred to be obtained in toluene while polymorph II preferred to be generated from chloroform.

9

Du et al.10 studied reactive crystallization of

prasugrel hydrochloride in different pure solvents and found that polymorph formation directly depends on the solvents used in the experiments: Form I obtained in solvents with low values of hydrogen bond donor ability (HBD) while form II could be crystallized in solvents with high values of HBD. In addition, supersaturation is one of the most important factors in polymorphic nucleation and conversion and has been a hot topic studied by many researchers until now. However, there are many uncertainties in the mechanisms of the formation and transformation of the polymorph depending on the solvent and supersaturation. Clopidogrel Hydrogen Sulfate (CHS), one of the most important antithrombotic drug over the world, was developed by Sanofi. Figure 1 shows the molecular structure of CHS. There 2


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are only two polymorphs of CHS for medicine use. Form I, the less stable thermodynamically polymorph with higher solubility, is hard to prepare by solution crystallization and Form II is the stable one under ambient conditions. Prof. Kim reported some valuable researches about the drowning-out crystallization of CHS in several solvents. Their study focused on the impact of supersaturation on polymorphs during drowning out crystallization and provided guidelines for polymorph screening of CHS.11-13 However, it is hard to examine the influence of pure

solvent on polymorphs formation and transition during the drowning-out

crystallization. Moreover, reactive crystallization has been widely used in CHS industry production which can rapidly create high supersaturation and is appropriate to the study of CHS-mono-solvent system. In this work, we mainly investigate the formation of the two forms of CHS depending on different mono-solvents and supersaturation in reactive crystallization and discuss transformation mechanism in different mono-solvents. Nine different pure solvents (propanol, butanol, pentanol, 2-propanol, 2-butanol, butanone, Methyl isobutyl ketone (MIBK), methyl acetate, ethyl acetate) were selected in reactive crystallization and suspension polymorphic transformation experiments to elucidate the link between solvent−solute interactions and the obtained polymorphs. Besides, in order to look into the interactional mechanism of solvent and supersaturation effects, IR spectroscopy and FBRM techniques were applied in online measurement of reactive crystallization process in different solvents with different supersaturations.

2. EXPERIMENTS 2.1. Materials and Process Analysis Tools. CHS (supplied by Shenzhen Salubris Pharmaceuticals China Ltd) was used after recrystallization. The product’s purity was examined by High Performance Liquid Chromatography (HPLC, Agilent Technologies 1200 Series, Tokyo) and the mass fraction was ensured to be larger than 98%. The solvents (analytical reagent grade, molar purities are higher than 99.5%) used in the experiments are shown in Table 1, which were supplied by Tianjin Yuanli Chemical China Ltd. In this work, the pure clopidogrel (or clopidogrel free base) was released from the clopidogrel hydrogen sulfate by reaction with sodium 3



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bicarbonate in an aqueous solvent followed by extractive work-up. The clopidogrel was then converted into its hydrogen sulfate salt by dissolving in different solvent, reacting with sulfuric acid to precipitation.14 Powder X-ray Diffraction (PXRD, D/max-2500/PC, Rigaku Corporation, Japan) was applied to identify the solid form. The ATR-FTIR spectroscopy (ReactIR 45m, Duradisc DiComp probe, Mettler Toledo) was used for in-situ measurement of real time concentration during crystallization. A lab level FBRM instrument was used to measure the total counts of particles and determine the nucleation point during crystallization (Model M400LF, Mettler Toledo). 2.2. Solubility Measurement. The solubility of CHS polymorphs in different solvents were measured by two methods in this work. Because Form II is more stable thermodynamically in the tested temperature than Form I,11 the solubility of Form II in propanol, butanol, pentanol, 2-propanol, 2-butanol, butanone, Methyl isobutyl ketone (MIBK), methyl acetate, ethyl acetate were measured at different temperature from 293.15 to 313.15 K with a static equilibrium method. Excessive solid of Form II were added in each solvent (20 mL) to prepare suspension solution. After pre-experiments we found that 3 hours for shaking the suspension was sufficient to reach thermodynamic equilibrium and no polymorphic transition happened. With fully stirring for 3 h and standing for 1 h at every experimental temperature, the saturated solution was sampled and filtered by membrane filter. Then filtered samples were dried entirely at 333.15 K. Gravimetric analysis were performed in the sampling process, and the solubility was measured from the weight of the residual dried solid and the total weight of the sampled solution. The solubility of Form I in the above solvents were measured by a dynamic method by using FBRM and EasyMax (METTLER TOLEDO, Switzerland) at 293.15K, 303.15K and 313.15 K.15 The experiments were performed in a tightly sealed container (100 mL) of EasyMax with a stirring device. In experiments, predetermined amounts of CHS were dissolved in the solvent (40 mL) in the container. The particle numbers monitored by FBRM decreased with the dissolving process to minimum when completely dissolved. Then a finite amount (2.00-5.00 mg) of CHS were added repeatedly into the clear solution until dissolved again. When the particle counts remain unchanged nearby a constant value for about 15 min, 4


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which means that the solid would not continue to dissolve, the dissolution equilibrium was reached. The undissolved solid were analyzed by PPXRD and weighted after drying. The results showed that there were no polymorphic transformation during the experiment and the solubility is just the dissolved mass in the saturated solution. Three times parallel experiments were carried out to give the average result. The solubility is defined as mole fraction (x) in the selected solvents, which was determined by using Eq. (1): x =

m1 ⁄M1 m1 ⁄M1 + m2 ⁄M2

(1)

Where m1 and m2 represent the weight of dissolved CHS and that of experimental solvent (propanol, butanol, pentanol, 2-propanol, 2-butanol, butanone, Methyl isobutyl ketone (MIBK), methyl acetate, ethyl acetate), respectively. M1 and M2 are their molecular masses. 2.3 Polymorphic Formation Experiments of CHS by Reactive Crystallization. The formation of CHS by reactive crystallization was investigated in nine different pure solvents (propanol, butanol, pentanol, 2-propanol, 2-butanol, butanone, Methyl isobutyl ketone (MIBK), methyl acetate, ethyl acetate) at 313.15 K. Clopidogrel (6.00 g) was dissolved in 30.0 mL of the experimental pure solvent and 1.80 g concentrated sulfuric acid was added into 20.0 mL of the same solvent. Then the two solution were mixed at once. A thermostat (Model CF41 , JULABO GmbH, Germany) was used to control the experimental temperature. The solid was isolated from the suspension quickly after nucleation to avoid potential polymorphic transition, which were then identified by PXRD. 2.4. Suspension Polymorphic Transformation Experiments of CHS. The experiments of solution-mediated polymorphic transformation of CHS were performed in the selected solvents at 313.15 K. For each solvent system, the experiments were performed by suspending the CHS solids in its presaturated solution at 313.15 K. In this work we carried out two sets of experiments: (Form II) unseeded and seeded suspension experiments. With the aim of determining the nucleation induction time of Form II in different solvents, we set the experiment without Form II seeds: only Form I in the suspension at 313.15 K (2.0 g/50 mL). A thermostatic bath shaker was used to promote 5



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mixing of the slurries and maintain the temperature. Through sampling interval every 0.5h and PXRD analysis, we tracked the polymorphic changes during the suspending process. The suspension experiments was performed in 240 h and repeated once to get the accurate results. Besides, we set the Form II seeded experiment to measure the conversion time of Form I to Form II in presence of seeds (Form II): Form I (90%) and Form II (10%) were mixed in proportion, 2.0 g totally, and were also suspended in 50 mL presaturated solutions at 313.15 K. In this part, with the seeds of Form II, the primary nucleation stage of Form II was cut down, and the polymorphs transition process mainly include the second nucleation and the crystals growth. The same method was used to measure the conversion time for the Form I (90%) changing to Form II completely. 2.5. In Situ Measurement for Formation of CHS in Reactive Crystallization. The formation of CHS in reactive crystallization with different supersateration was investigated in 2-propanol and 2-butanol at 313.15 K. Different concentration reaction solution in 2-propanol were prepared by adding (3.50−14.50) g clopidogrel into 70 mL 2-propanol at 313.15 K. After fully mixing, a mixture of (1.10−4.30) g concentrated sulfuric acid and 30 mL 2-propanol by the reaction stoichiometric ratio were added into the solution. The method in 2-propanol was same to that in 2-butanol. ATR-FTIR spectroscopy and FBRM were employed in online measurement of the reactive crystallization of CHS. In this work, we applied the calibration-based method to control supersaturation by using ATR-FTIR spectroscopy. A 200 mL crystallizer was used in the experiments to collect the solution spectra under measurement of IR system at 313.15 K. The concentration data (C0-C19), given in Table S4. The typical IR spectra from CHS (Form II) solution with different concentration at 313.15 K are shown in Figure S3. And the calibration results and the validation results (Figure S4, Figure S5) are available in Supporting Information. We also give the model error analysis summarized in Table S5. Kinetics of the reactive crystallization of CHS were also analyzed by the process analysis tools. PXRD was applied to identify the suspended solid forms by quickly isolating from the suspension after nucleation to avoid potential polymorphic conversion.

3. RESULTS AND DISCUSSION 6


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3.1. Characterization of CHS Polymorphs. CHS generally has two polymorphic forms and Form II is more stable thermodynamically than Form I in ambient conditions. This work PXRD to analyze the solid state samples during experiments. The PXRD spectra of the polymorphs are presented in Figure 2. According to the results, we can determine the polymorphic formation of CHS in reactive crystallization and the kinetics of solution-mediated polymorphic transformation. From the experiments, we found that amorphous maybe obtained during the crystallization at high supersaturation or in some solvents. As shown in Figure 2, different polymorphic forms obviously have different PXRD characteristic peaks.16-17 3.2. The Solubility of CHS Polymorphs in Different Solvents The solubility of different solid forms are essential thermodynamic data for polymorphic screening and transformation controlling. The solubility of CHS polymorphs and amorphous have been measured in some pure solvents and solvent mixtures.18-24 In this study, we want to comprehensively determine the solvent influence on CHS polymorphic formation and transformation, so we selected nine organic agents (propanol, butanol, pentanol, 2-propanol, 2-butanol, butanone, Methyl isobutyl ketone (MIBK), methyl acetate and ethyl acetate) to build the solvent environment / solution system, some of which lack the thermodynamic data. Most of these solvents have been used in the preparation of CHS, which give moderate or low solubility of CHS polymorphs. Hence, we measured the solubility of CHS Form II with a gravimetric method and Form I by using FBRM from 293.15 K to 313.15 K, which is different from the method in the references. We also compared our measured solubility with the literature data by Song,18-19 and the results show little error: the deviations of Form I solubility are less than 4.0 % and that of Form II solubility are less than 7.0 %. The results are presented in Table S1 and Table S2, and graphically shown in Figure 3-6. It illustrates that the solubility in different solvents decreases with the order: propanol < butanol < pentanol < 2-propanol < 2-butanol < butanone < methyl acetate < Methyl isobutyl ketone (MIBK) < ethyl acetate. And also, the solubility of CHS certainly increases with the increasing temperature. From the reference literatures and our experiments, the CHS polymorphic investigation results show that the solubility of Form I is always larger than that of Form II of CHS in the investigated conditions, which means that Form I is less stable 7



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thermodynamically than Form II in the experimental temperature and solvent. In this work, van’t hoff equation was applied to fit the association between temperature and solubility of CHS in the nine solvents. It could be described as following 25: ln = -

∆Hd ∆Sd + RT R

(2)

Where represents mole fraction of solute in solution; R represents the gas constant; T

represents the absolute temperatureof the system; ∆ and ∆ are the dissolution entropy and enthalpy, respectively.

Furthermore, the root-mean-square deviations (RMSD), the average relative deviation (ARD %) and the relative deviations (RD) of the equation were calculated using the following equations 26: ∑

=

−

(3)

− 100 % = " # #

(4)

RD=

(5)

xexp -xcal xexp

Where N represents the data number,

and are the measured and the calculated

solubility value, respectively. The experimental value, calculated value of CHS and the value of RD were shown in Table S1 and Table S2. The value of ARD %, RMSD, Supporting Information gives the value of ∆Hd and ∆Sd in Table S3. According to van’t hoff model, we drew the correlation plots of the value of ln(x) against that of 1/T in different solvents, which were graphically shown in Figure S1 and S2. The results show that van’t hoff model could fit well with the experimental data. 3.3. Effects of Solvent on Polymorphic Formation in Reactive crystallization. Reactive crystallization of CHS was performed in nine different pure solvents at 40 °C. The same amount of clopidogrel, sulfuric acid and solvent were mixed when changing the solvent. Clopidogrel and sulfuric acid could reacted fast to generate high supersaturation in a short time, then crystallization happened after the induction time of nucleation. The procedure can be described as follow:10, 14 8


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Clopidogrel (aq) + H2SO4 (aq) = clopidogrel hydrogen sulfate (aq) = clopidogrel hydrogen sulfate (solid) ↓ The crystallized products were quickly collected from the solution after nucleation. Then the solid samples were analyzed by PXRD to determine the polymorphic forms. According to the PXRD characteristics of different forms (Figure 2), we give the results of polymorphic formation in Table 1. It is shown that the Form II was preferred in propanol, butanol, pentanol and 2-propanol, while Form I was favored in 2-butanol. In addition, amorphous were obtained in butanone, MIBK, methyl acetate and ethyl acetate. The results show that the polymorphic formation is significantly associated with the solvents used during the reactive crystallization. In the reactive crystallization process of CHS, supersaturation is generated by the reaction between clopidogrel and sulfuric acid. Both reaction kinetics and crystallization kinetics will be affected by solvent. Because the reaction is an acid-base reaction, the reactive rate is generally fast. Therefore, the solvent effects on the formation of different polymorphs in the process of reactive crystallization is mainly manifested in its influence on crystallization thermodynamics and kinetics, and the crystallization kinetics can be represented by its effect on nucleation and growth. Generally, the solvent may affect the crystal nucleation and growth rate, which could be evaluated by interaction of solute and solvent molecules. Hydrogen bonding and Van der Waals force generally determine the solvent−solute interaction.27 Here we use the hydrogen bond donor ability, α, or the hydrogen bond acceptor ability, β, evaluate the force of hydrogen bond, while the dipolar polarizability, π*, evaluate the Van der Waals force. The parameters of α, β and π* of different solvents are listed in Table 1. 28 According to the results, it seems that the hydrogen bond donor ability is the main factor that affects the polymorph formation of CHS. In solvents which produced Form II, the α values are larger than 70, while form I tends to be crystallized when α-value decreases under 70. When α value is close to 0, amorphous would be generated. This can be explained by the molecular structure of CHS, which has a high propensity to accept protons to form a hydrogen bond with solvent. From Figure 1, it can be seen that the two carbonyl groups, the sulfur and the nitrogen can serve as hydrogen bond acceptor sites. So, in one word, relative stable polymorph tends to be obtained in solvents which have high ability of hydrogen bond donor. 9



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It seems that the influences of the solvents properties of the dipolar polarizability and hydrogen bond acceptor tendency on CHS polymorphic formation are less important. Therefore, we can speculated the effects of solvent on polymorph formation of CHS is mainly reflected through the hydrogen bonding interactions of the molecules of solute and solvent, and increasing the solvents’ ability of hydrogen bond donor could prefer to generate Form II. We list the solubility of Form II CHS at 313.15 K in Table 1. Thus, combined with the results of polymorphic formation of CHS, it can be seen from Table 1 that the more thermodynamically stable polymorphic form (Form II) was obtained in solvents with higher solubility of CHS, while Form I was produced in 2-butanol and amorphous would be generated in solvents with lower solubility. The effects of solvent on the solubility can also be evaluated by the solute − solvent interaction strength. The linear free energy model was used here to correlate the solubility in perspective of solute-solvent interaction. 28

ln x = $ + %& + '( + )* + +, ∗

(6)

where x represents mole fraction; a, b, c, d, and e could be obtained by regression fitting, which are constans determined by the investigational API; δ represents solubility parameter of solvents standing for cohesive energy density; and α, β, and π* are defined as above. In eq. 6, δ = 0.5 for polychlorinated aliphatic solvents, 1.0 for aromatic solvents, and 0 for all other aliphatic solvents. Thus, bδ2 should be equal to 0 in this study, and eq. 6 can be rewritten as:10, 27

ln x = $ + '( + )* + +, ∗

(7)

By fitting the solubility data obtained in this study to eq. 7, we can express the solubility of

form II by the following relationships: ln x = -14.4293+ 0.0992α + 0.0449 β + 0.0761π*

(8)

From eq. 4, the fitting result eq. (7) show that the coefficient for hydrogen bond donor tendency (α) is larger than either of the coefficients for hydrogen bond acceptor ability (β) and for polarity/polarizability (π*). That is c value is higher than that of d or e, which results in that the change of α value affects solubility more greatly. Certainly the dipolar polarizability (π*) and hydrogen bond acceptor (β) ability also play important roles in 10


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determining the solubility of CHS in different solvents because of the similar values of the three coefficient (c, d and e). From Table 1 it can be seen that the order of the solubility is basically consistent with the ability of hydrogen bond donor. As a result, from thermodynamic perspective, the polymorphic formation of CHS is mainly affected by the ability of hydrogen bond donor (α value): solvent with higher α value lead to higher solubility of CHS, which generates more thermodynamically stable form in polymorphic formation. That is to say solvent’s hydrogen bond donor tendency is crucial for determining the solvent effects on solubility and polymorphic formation of CHS during reactive crystallization in different solvents.

3.4. Effects of Solvent on Polymorphic Nucleation and Transformation Processes. Suspension polymorphic transformation experiments were performed to investigate the solvent effects on the polymorphic nucleation and transition kinetics of CHS in the nine solvents. In our work, we described the period from suspension of Form I to the point when Form II was first detectable as the nucleation induction. From Table 2, the induction times of Form II at 313.15 K differed dramatically from the selected solvents, which indicates that the nucleation rate in different solvents varied significantly. Generally the nucleation rate increases with the increasing solubility, like in low alcohols. Besides, when the mole solubility was under 0.00035, the II form of CHS could not be found from the suspension for 10 days. We applied the classical nucleation rate theory to describe the thermodynamic effects on nucleation of CHS. The definition is given by: 16, 30

∆5 ∗ 6 (9) 9 78 where . represents nuclei number in unit volume and time; 6 represents the factor of . = / 0 exp 4−

heterogeneous nucleation; 0 represents molecule transportation frequency at interface of

liquid-nucleus; N0 represents solute molecules number in unit volume; ∆G* , Nucleation critical free energy barrier, is expressed as follows:

∆5 ∗ =

16,< = > (ln ) 3(78)

(10)

k represents Boltzmann constant; S represents supersaturation degree, equating to the ratio of 11



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the 2 different forms activities; < represents solute molecular volume. = , interfacial energy

in unit area, is described as:

= = 0.41478('F G )⁄> (ln 'F − ln 'H )

(11)

Where 'H represents solubility at equilibrium; G represents Avogadro’s number, 'F equate to specific value of solute density and molecular weight. The discrepancy of free energy of different polymorphs determine the value of S, which is

the same at the same temperature even in different solvents. = increases with the decreasing

solubility along with equation 11. Because agitation degree is the major factor to influence 0, it is taken as a constant. The value of / equate to solute molecule concentration and

increases with the increasing solubility. Relating to the interrelation of the suspended I form

solid and the II form pre-nuclei, 6 changes in the range of 0 -1 and is considered as the same in this work. 27,30 As a result, when the solubility in solvent increases, from equation 9,

the value of / will be higher; form equation 11, = will decrease, and other influences stay unchanged, . in equation 9 will increase, leading to faster nucleation and transformation. We

can see from Table 2 that, basically, with the increasing solubility the nucleation induction time decreased. Generally, the kinetics of nucleation and crystal growth is driven mainly by the solubility and molecular conformation. Kitamura and Horimoto

31

investigated the solvent effect on by

analyzing the stable polymorph relative growth rate in different solvents. They also demonstrates that the interaction between solvent and solute molecules would positively influence the stable polymorph nucleation. Besides, the nucleation and crystal growth kinetics are the controlling factor to determine the solvent effects on polymorphs in different solvents, which are similar to our results. Nevertheless, the determining influence would be different among systems. Maher et al.

32

just demonstrates a counterexample differ from the

general trend. A stronger solute–solvent interaction is observed in the case of 2-propanol than for the other solvents, thereby decreasing the transformation rate in this solvent by retarding the nucleation and growth of FIII. The results show that the solute-solvent interaction maybe dominates the solvent effect on the polymorphic transformation process. All told, the influence of solvent on polymorphic nucleation behavior should be the results of the 12


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combined action of solvent−solute interaction and solubility, which could be also feed-back controlled by the crystallization kinetics. As is known that the solvent properties affect the dissolution thermodynamics, and then determine different supersaturation in different solvents. We have discussed the relationship between solubility and solute-solvent interaction to explain the polymorphic formation and transformation of CHS. It is found that solvent with higher hydrogen bond donor ability lead to higher solubility of CHS, which results in generating more thermodynamically stable form in polymorphic formation and faster transformation rate from polymorph I to polymorph II in the solvent. For better screening and controlling CHS polymorphs to get the desired product, it is necessary to directly investigate the effects of supersaturation on polymorphs of CHS during reactive crystallization in different solvents. 3.5. Effects of Supersaturation on Polymorphs of CHS in Reactive Crystallization In this work we would like to determine the real time concentration of CHS during the reactive crystallization to study the influence of supersaturation on the polymorphs in different solvents. We chose 2-propanol and 2-butanol as the solvents for CHS reactive crystallization systems. Absorbance spectra were collected with one minute interval for the reaction solution in the reaction process of clopidogrel and sulfuric acid at 313.15 K. The results in 2-propanol are shown in Figure 7 and Figure 8, which are the solution spectra and solvent-background-subtracted spectra, respectively. From the figures, it is clear that the absorbance at some wavenumbers are strengthened obviously with the increasing CHS concentration in the reaction process. The peaks at the wavenumber 1050 cm-1 were most sensitive to the concentration change, which was selected as the characteristic wavenumber for CHS.33-35 In section 3.2, we discussed the effects of solvent on polymorphic formation in reactive crystallization of CHS at 313.15 K. The experiments were performed in nine solvents by mixing same amount of clopidogrel, sulfuric acid and solvent when changing the solvent, but the supersaturation in each reaction solution are not the same because of different solubility in different solvents. Thus we would like to directly study the relationship between supersaturation and polymorphic formation of CHS in reactive crystallization in 2-propanol and 2-butanol, which produced Form II and Form I in polymorphic formation experiment, 13



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respectively. In this section, we applied ATR-FTIR and FBRM in online measurement of CHS reactive crystallization, including monitoring the kinetics and real time concentration.34, 35

Figure 9 presents the spectra of the reaction solution at different times and Figure 10 illustrates the changes of the characteristic peak (1050 cm-1) height with time, which was used in this work to describe the changing trend of CHS concentration in solution. We could see the CHS concentration rose steeply after mixing of clopidogrel and sulfuric acid. It demonstrates that the reaction into CHS of sulfuric acid and clopidogrel react is quite fast. And the peak height of CHS remained constant for about 30 min. Then CHS nucleation occurred and the liquid concentration should have started to decrease. However, according to the results, the changing trend begun to rise instead after nucleation because the IR probe was fouled after nucleation. The phenomenon of probe encrustation is common in crystallization and it relates to the molecular structure of the products.33 Different experimental parameters were examined for preventing the probe fouling, but the results were not as expected. Actually the encrustation wouldn’t affect this study purpose and we could still obtain the reaction time, induction time and polymorphs of products from Figure 10. Thus, different supersaturation levels were obtained by changing the amount of clopidogrel and sulfuric acid and accurate in situ real time concentration were measured by applying the ATR-FTIR calibration approach. In this work, relative supersaturation ratio (s, the ratio of real–time concentration to solubility at the constant temperature) was used to reflect the supersaturation level in the experiments. Figure 11 and Figure 12 show the online measurement results in 2-propanol (s=13.24) and 2-butanol (s=13.48), respectively. From the figures, we can see that the changing trends of concentration, supersaturation and characteristic peak height are basically consistent with each other. After the onset of spontaneous crystallization we quickly isolated the products from the suspension and analyzed the form of the solid by using PXRD. The experimental results are listed in Table 3, which shows that: the reaction of clopidogrel and sulfuric acid quickly finished within 2 min which would not be the rate controlling stage; nucleation induction should be the kinetic– determining stage during reactive crystallization and the time of nucleation induction period increases by the decreasing supersaturation; besides, we could find that the induction period 14


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in 2-propanol were shorter than that in 2-butanol,which can be explained that solvent with higher solubility leads to faster crystallization nucleation rates. In addition, in both of 2-propanol and 2-butanol, the observed polymorph was Form II with s under 18 while that was Form I when s increases to more than 21. When supersaturation was set at an intermediate level (18 < s < 21), we found that the obtained products were Form I or Form II. Both forms in this zone were possible, but we didn’t find concomitant polymorphism of CHS in Reactive Crystallization. We can conclude that the supersaturation is the direct factor to determine the polymorphic formation of CHS reactive crystallization in the experimental solvents. In the tested temperature and solvents, the thermodynamically stable polymorph would be obtained at s21). The results obtained in this work would give some guidelines for the preparation of different pure polymorphs of CHS by selecting suitable solvent and controlling supersaturation in reactive crystallization. For preparation of Form II of CHS, we can choose the solvent with high hydrogen bond donor ability (α) and control the supersaturation to inhibit the formation of thermodynamically metastable form, Form I. When Form I is desired in manufacture, high supersaturation should be prepared in the solvent system with a relative low α value, which are favorable to the formation of metastable form and also can slow down the transformation to Form II. Extensive studies need to be investigated at various supersaturation rank in more solvents and the results could give a detailed direction for polymorphic screening of CHS in reactive crystallization.

4. CONCLUSIONS The influences of solvent on polymorphic formation and transformation of CHS reactive crystallization process were studied in nine different pure solvents (propanol, butanol, pentanol, 2-propanol, 2-butanol, butanone, Methyl isobutyl ketone (MIBK), methyl acetate, ethyl acetate). This work investigated the relationship between solubility and solute-solvent interaction to explain the polymorphic formation and transformation of CHS. It was found that the formation of different polymorphs directly depends on solvent types: solvent with higher hydrogen bond donor ability lead to higher solubility of CHS, which generates more 15



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thermodynamically stable form in polymorphic formation. That is to say the solvent property of hydrogen bond donor tendency is essential for determining solvent effects on solubility and polymorphic formation of CHS during reactive crystallization in different solvents. In addition, the polymorphic transformation experiments was carried out in Form II seeded and unseeded suspension to study solvent influence on the transformation process. The consequences indicates that the rates of nucleation and crystal growth differ dramatically in different solvents and mainly increase with increasing solubility. Besides, the reactive crystallization of CHS at different supersaturations in 2-propanol and 2-butanol was online monitored by using ATR-FTIR and FBRM with a calibration-based approach. The in situ measurements show that the nucleation induction period is the kinetic–determining stage of CHS reactive crystallization and supersaturation is a direct factor to determine the polymorphic formation of CHS: Form II was obtained with s under 18 while that was Form I when s increases to more than 21. The results obtained in this work have some guidance function on the production and control of different pure polymorphic form using supersaturation control in different solvents. AUTHOR INFORMATION Corresponding Author *E-mail: [email protected] Tel.: 86-22-27405754. Fax: 86-22-27314971. Notes No rival ﬁnancial interest

ACKNOWLEDGMENTS We are appreciate with the funding assistance of National Natural Science Foundation of China (NNSFC 21676179), National Natural Science Funds for Innovation Research Groups 21621004. Major Science and Technology Program for Water Pollution Control and Treatment (NO.2015ZX07202-013)

and

Tianjin

Science

(15JCZDJC33200). 16


and

Technology

Project

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ASSOCIATED CONTENT Supporting Information Solubility of Form II and Form II of CHS (Table S1, Table S2) and the correlation results by van’t hoff model (Table S3, Figure S1 and Figure S2), the description of the ATR-FTIR Univariate Calibration approach: FTIR Calibration Data Collection (Table S4), ATR-FTIR Univariate Model Error Analysis (Table S5), IR spectra of CHS-2-propanol (Figure S3), the calibration results and the validation results (Figure S4, Figure S5) are available in Supporting Information.

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REFERENCES (1) Hilfiker, R. Polymorphism in the Pharmaceutical Industry; WileyVCH: Weinheim, Germany, 2006; pp 1−3 (2) Grant, D. J. W. Theory and origin of polymorphism; Marcel Dekker: New York, 1999; pp 1-33. (3) Rodrıguez-Hornedo, N.; Murphy, D. Significance of controlling crystallization mechanisms and kinetics in pharmaceutical systems. J Pharm Sci. 1999, 88, 651–660. (4) Davey, R. J.; Garside, J. From Molecules to Crystallizers- An Introduction to Crystallization. Oxford: Oxford University Press, 2000. (5) Ostwald, W. Studien Über Die Bildung und Umwandlung Fester Körper. Z. Physik. Chem. 1897, 22, 289–330. (6) Guillory J. Generation of polymorphs, hydrates, solvates, and amorphous solids; Marcel Dekker, New York, 1999; pp 183-226. (7) Musumeci, D.; Hunter, C. A.; McCabe, J. F. Solvent Effects on Acridine Polymorphism. Cryst. Growth Des. 2010, 10, 1661−1664. (8) Threlfall, T. Crystallisation of Polymorphs: Thermodynamic Insight into the Role of Solvent. Org. Process Res. Dev. 2000, 4, 384-390. (9) Davey, R. J.; Blagden, N.; Righini, S.; Alison, H.; Quayle, M. J.; Fuller, S. Crystal Polymorphism as a Probe for Molecular Self-Assembly during Nucleation from Solutions: The Case of 2,6-Dihydroxybenzoic Acid. Cryst. Growth Des. 2003, 1 (1), 59−65. (10) Du, W.; Yin, Q.; Gong, J. Effects of Solvent on Polymorph Formation and Nucleation of Prasugrel Hydrochloride. Cryst. Growth Des. 2014, 14, 4519-4525. (11) Kim, H. J.; Kim, K. J. In situ monitoring of polymorph transformation of clopidogrel hydrogen sulfate using measurement of ultrasonic velocity. J. Pharm. Sci. 2008, 97, 4473-4484. (12) Jim, M.; Kim, K. Effect of Supersaturation on Polymorphs of Clopidogrel Hydrogen Sulfate in Drowning‐out Crystallization. Cryst. Res. Technol. 2012, 35, 995-1002. (13) Kim, K.; Doherty, M. F. Crystallization of selective polymorph using relationship between supersaturation and solubility. AIChE J. 2015, 61(4):1372-1379. (14) Kumar, A.; Bhayani, P. J.; Doshi, V. C.; Saxena, A.; Pathak, G. P.; Abhyankar, R. Process 18


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for preparation of crystalline clopidogrel hydrogen sulphate form I. E.P. Patent 2, 114, 957, Nov. 11, 2009. (15) Hao, H.; Barrett, M.; Hu, Y. The Use of in Situ Tools to Monitor the Enantiotropic Transformation of p-Aminobenzoic Acid Polymorphs. Org. Process Res. Dev. 2012, 16, 35-41. (16) Bousquet, A.; Castro, B.; Saint-Germain, J. Polymorphic clopidogrel hydrogenesulphate form. U.S. Patent 6, 429, 210, Aug. 2, 2002. (17) Lu, J, Wang, J, Rohani, S. Preparation and characterization of amorphous, I and II forms of clopidogrel hydrogen sulfate. Cryst. Res. Technol. 2012, 47(5):505-510. (18) Song, L.; Yuan, G.; Gong, J. Measurement and Correlation of Solubility of Clopidogrel Hydrogen Sulfate (Metastable Form) in Lower Alcohols. J. Chem. Eng. Data 2011, 56, 2553-2556. (19) Song, L.; Li, M.; Gong, J. Solubility of Clopidogrel Hydrogen Sulfate (Form II) in Different Solvents. J. Chem. Eng. Data 2010, 55, 4016-4018. (20) Fang, Z.; Zhang, L.; Mao, S. Solubility measurement and prediction of clopidogrel hydrogen sulfate polymorphs in isopropanol and ethyl acetate. J. Chem. Thermodynamics 2015, 90, 71-78. (21) Liu, Y.; Zhao, Z. P.; Cui J. Solubility of Amorphous Clopidogrel Hydrogen Sulfate in Different Pure Solvents. J. Chem. Eng. Data 2015, 60, 2442–2446 (22) Guo, H.; Song, L.; Yang, C. Solubility of Clopidogrel Hydrogen Sulfate (Form II) in Ethanol + Cyclohexane Mixtures at (283.35 to 333.75) K. J. Chem. Eng. Data 2015, 60, 545-550. (23) Jim, M.; Kim, K. J. Solubility of Forms I and II of Clopidogrel Hydrogen Sulfate in Formic Acid, N-Methylpyrrolidone, and N, N-Dimethylformamide. J. Chem. Eng. Data 2012, 57, 598–602. (24) Choi, W. S.; Kim, K. J. Solubility of Forms I and II of Clopidogrel Hydrogen Sulfate in Methanol and 2-Propanol Mixture. J. Chem. Eng. Data 2010, 56, 43-47. (25) Li, Z.; Zhang, T.; Huang C. et al. Measurement and Correlation of the Solubility of Maltitol in Different Pure Solvents, Methanol–Water Mixtures, and Ethanol–Water Mixtures. J. Chem. Eng. Data 2016, 61, 1065-1070. 19



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(26) Zhang, T.; Li, Z.; Wang Y, et al. Determination and correlation of solubility and thermodynamic properties of l -methionine in binary solvents of water + (methanol, ethanol, acetone). J. Chem. Thermodynamics, 2016, 96, 82–92. (27) Gu, C. H.; Jr, Y. V.; Grant D. J. Polymorph screening: influence of solvents on the rate of solvent-mediated polymorphic transformation. J. Pharm. Sci. 2001, 90, 1878-1890. (28) Marcus, Y. The properties of organic liquids that are relevant to their use as solvating solvents. Chem. Soc. Rev. 1993, 22, 409-416. (29) Codan L.; Bäbler M. U.; Mazzotti M. Phase Diagram of a Chiral Substance Exhibiting Oiling Out in Cyclohexane. Cryst. Growth Des. 2010, 10(9):4005-4013. (30) Du, W.; Yin, Q.; Hao, H. et al. Solution-Mediated Polymorphic Transformation of Prasugrel Hydrochloride from Form II to Form I. Ind. Eng. Chem. Res. 2014, 53, 5652–5659. (31) Kitamura M.; Horimoto K. Role of kinetic process in the solvent effect on crystallization of BPT propyl ester polymorph. J. Cryst. Growth, 2013, 373,151-155. (32) Maher A.; Croker D. M.; Seaton C. C. et al. Solution-Mediated Polymorphic Transformation: Form II to Form III Piracetam in Organic Solvents. Cryst. Growth Des. 2014, 14, 3967-3974. (33) Borissova, A.; Khan, S.; Mahmud, T. et al. In Situ Measurement of Solution Concentration during the Batch Cooling Crystallization of l-Glutamic Acid using ATR-FTIR Spectroscopy Coupled with Chemometrics. Cryst. Growth Des. 2008, 9, 692-706. (34) Grön, H.; Borissova, A.; Roberts, K. J. In-Process ATR-FTIR Spectroscopy for Closed-Loop Supersaturation Control of a Batch Crystallizer Producing Monosodium Glutamate Crystals of Defined Size. Ind. Eng. Chem. Res. 2015, 42, 198-206. (35) Gomez, L. E.; Bommarius, A. S.; Rousseau, R. W. Crystallization kinetics of ampicillin using online monitoring tools and robust parameter estimation. Ind. Eng. Chem. Res. 2016, 55, 2153–2162.

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TABLE CAPTIONS: TABLE 1. Properties of the Solvent and the Polymorphic Formation of CHS from Reactive Crystallization. TABLE 2. Polymorphic Transformation Rate in suspension experiments and solubility of CHS in Various Solvents at 313.15 K. TABLE 3. Polymorphic Formation of CHS from Reactive Crystallization at various supersaturation.

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FIGURE CAPTIONS: FIGURE 1. Molecular structure of Clopidogrel Hydrogen Sulfate. FIGURE 2. Powder X-ray diffraction (PXRD) results of different forms of CHS. FIGURE 3. Solubility (x) of CHS (Form I) versus temperature T in different solvents. FIGURE 4. Solubility (x) of CHS (Form II) versus temperature T in different solvents. FIGURE 5. Solubility (x) of two forms of CHS versus temperature T in 2-propanol. FIGURE 6. Solubility (x) of two forms of CHS versus temperature T in 2-butanol. FIGURE 7. The IR spectra of CHS-2-propanol solution during reaction process FIGURE 8. The solvent-background-subtracted spectra of CHS-2-propanol solution during reaction process. FIGURE 9. The solvent-background-subtracted spectra of CHS-2-propanol solution in reaction and crystallization. FIGURE 10. Change of characteristic peak height of CHS during reactive crystallization. FIGURE 11. In situ measurement results of reactive crystallization of CHS in 2-propanol at 313.15 K FIGURE 12. In situ measurement results of reactive crystallization of CHS in 2- butanol at 313.15 K.

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TABLES Table 1. Properties of the Solvent and the Polymorphic Formation of CHS from Reactive Crystallization at 313.15 K. solvent

Solubility 103x(Form II)

α

β

propanol butanol pentanol 2-propanol 2-butanol butanone methyl acetate MIK ethyl acetate

6.7672 3.5611 2.1834 1.4002 1.0948 0.3424 0.2289 0.0241 0.0170

84 84 84 76 69 06 00 02 00

90 84 86 84 80 48 42 48 45

23


π* 52 47 40 48 40 42 60 68 55

observed polymorph II II II II I amorphous amorphous amorphous amorphous


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Table 2. Polymorphic Transformation Rate in suspension experiments and solubility of CHS in Various Solvents at 313.15 K. solvent

Induction time（h）

Conversion Time (h) for Form II (10% to 100%)

Form II Solubility 103x

α

β

π*

propanol butanol pentanol 2-propanol 2-butanol butanone methyl acetate MIK ethyl acetate

79 140.5 152 186 205 >240 >240 >240 >240

39.5 110 151 152 225 >240 >240 >240 >240

6.7672 3.5611 2.1834 1.4002 1.0948 0.3424 0.2289 0.0241 0.0170

84 84 84 76 69 06 00 02 00

90 84 86 84 80 48 42 48 45

52 47 40 48 40 42 60 68 55

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Table 3. Polymorphic Formation of CHS from Reactive Crystallization at various supersaturation Solvent

Supersaturation

Reactive Time (min)

Introduction Time (min)

observed polymorph

2-propanol

6.24 13.24 18.08 21.20 6.02

≤2 ≤2 ≤2 ≤2 ≤2

44 34 22 13 64

II II II I II

13.48 17.95 21.07

≤2 ≤2 ≤2

40 33 21

II II I

2-butanol

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FIGURES

Figure 1. Molecular structure of clopidogrel hydrogen sulfate.

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Figure 2. Powder X-ray diffraction results of different solid phases of CHS

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Figure 3. Solubility (x) of CHS (Form I) versus temperature T in different solvents: ■, propanol; ●, butanol; ▼, pentanol; ▲, 2-propanol; ◄, 2-butanol; ►, butanone; , methyl acetate; ○ MIBK; +, ethyl acetat.

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Figure 4. Solubility (x) of CHS (Form II) versus temperature T in different solvents: ■, propanol; ●, butanol; ▼, pentanol; ▲, 2-propanol; ◄, 2-butanol; ►, butanone; , methyl acetate; ○ MIBK; +, ethyl acetat.

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Figure 5. Solubility (x) of the two polymorphs versus temperature T in 2-propanol: ■, Form I; ●, Form II.

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Figure 6. Solubility (x) of the two polymorphs of CHS versus temperature T in 2-butanol: ■, Form I; ●, Form II.

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Figure 7. The IR spectra of CHS-2-propanol solution during reaction process.

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Figure 8. The solvent-background-subtracted spectra of CHS-2-propanol solution during reaction process.

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Figure 9. The solvent-background-subtracted spectra of CHS-2-propanol solution in reaction and crystallization.

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Figure 10. Change of characteristic peak height of CHS during reactive crystallization.

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Figure 11. In situ measurement results of reactive crystallization of CHS in 2-propanol at 313.15 K.

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Figure 12. In situ measurement results of reactive crystallization of CHS in 2- butanol at 313.15 K.

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For Table of Contents Use Only Polymorph Control by Investigating the Effects of Solvent and Supersaturation on Clopidogrel Hydrogen Sulfate in Reactive Crystallization Teng Zhang1,2, Yumin Liu1,2, Shichao Du1,2,Songgu Wu1,2, Dandan Han1,2, Shiyuan Liu1,2, Junbo Gong1,2* 1

School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072,

China; 2

The Co-Innovation Center of Chemistry and Chemical Engineering of Tianjin, Tianjin University, Tianjin 300072, China.

Reactive crystallization of CHS in different solvents and supersaturation were in-situ monitored by using ATR-FTIR. HBD ability (α) plays a key role in determining solvent effects on polymorphic formation: Form II was generated in solvents with α>70, while Form I was gained when α≤70. Both in 2-propanol and 2-butanol, relative supersaturation (s) 21 obtained Form I.

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