Monitoring the Polymorphic Transformation of Imidacloprid Using in

Article pubs.acs.org/OPRD

Monitoring the Polymorphic Transformation of Imidacloprid Using in Situ FBRM and PVM Jing Zhao,† Mingliang Wang,*,† Baoli Dong,† Qi Feng,† and Chunxiang Xu‡ †

School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, People’s Republic of China State Key Laboratory of Bioelectronics, Southeast University, Nanjing 210096, People’s Republic of China

‡

ABSTRACT: The objective of this work was to study the polymorphic transformation of imidacloprid from form II to form I in ethanol by using in situ focused beam reflectance measurement (FBRM) and particle vision measurement (PVM). The solubility and metastable zone width of the two forms were measured, and the influences of temperature and amounts of added imidacloprid to the transformation were investigated. Higher temperature accelerates the transformation and improves the transformation efficiency. More substrates prolong the time of the transformation. The transformation was identified as a solution-mediated transformation. The single crystals of the two forms were obtained. The crystal structure of form I has not been reported before. Tautomerism exists between the two polymorphs of imidacloprid. Analysis of molecular structures and stacking modes shows that more hydrogen bonds exist in form I. It indicates that the change of the hydrogen bond interaction maybe the driving force of the transformation. In this study, the transformation process of imidacloprid from form II to form I in ethanol solvent was mainly discussed. The single crystals of the two forms were obtained, and their molecular structures and stacking modes were discussed. In order to obtain some critical information, in situ techniques of FBRM and PVM were used to determine the solubility of both the forms in ethanol and to monitor chord counts, chord length distribution, and morphology of the particles. The influences of temperature and amounts of added imidacloprid were studied systematically.

1. INTRODUCTION

diagram to increase product yield. It is potentially applicable to other enantiotropic systems.18 FBRM is used to monitor chord counts and chord length distribution (CLD) of particles in solution, and it provides a precise and sensitive measurement that allows the user to quantify in process. With FBRM Tom Leyssens19 demonstrated how CLD properties can be defined for needle-shaped particles and how their variation over time can be linked to different physical mechanisms of crystallization. It is also used for determination the solubility and metastable zone width of substances in solvents.20 Kee et al.21 suggested that the saturation temperature and the corresponding solute concentration were determined at the lowest temperature where the particle counts and solute concentration profiles approached a constant value, indicating complete dissolution. This approach requires fewer materials and less manual labor compared to other techniques such as the gravimetric method. A polymorphic transformation is often accompanied by a change in the crystal habit. PVM, as an in-line video camera, is a unique, patented, in-process imaging system capable of providing high-resolution images of particle size and morphology in suspension. Imidacloprid (1-[(6-chloro-3-pyridinyl)methyl]-N-nitro-2imidazolidinimine, Scheme 1) is a new generation of nicotine insecticide. It has the advantages of broad spectrum, high efficiency, low toxicity, and low residue.22 Imidacloprid has two polymorphic forms reported: form I and form II. The single crystal of form I was discussed by Chopr23 As a typical nicotine insecticide, the polymorphic transformation of imidacloprid has not been studied until now.

Polymorphism is known as a phenomenon wherein the same compounds in different conditions generate different structures, shapes, and physical properties of crystals.1 Although identical in chemical composition, polymorphs differ in bioavailability, solubility, dissolution rate, chemical stability, physical stability, melting point, filterability, and many other properties. The subject of polymorphism seizes the attention of a large number of chemists and crystal engineers associated with the pharmaceutical industry.2 The polymorphic transformation that crystals convert from one form to another is a phase transition process. There are two kinds of mechanisms reported at present,3 solid-state polymorphic transformation and solvent-mediated polymorphic transformation. The solid-state polymorphic transformation occurs due to different stability. The solvent-mediated polymorphic transformation is driven by the difference in solubility of the polymorphs in a solvent. In the process of the solvent-mediated polymorphic transformation, the metastable form dissolves in the solution first, and then a more stable form nucleates and grows steadily. Recently, the process analytical technology (PAT) is applied widely in the study of polymorphic transformation, such as Raman spectroscopy,4−6 focused beam reflectance measurement (FBRM),7,8 particle vision measurement (PVM),9,10 in situ attenuated total reflectance Fourier transform infrared (ATRFTIR) spectroscopy,11,12 and ATR-UV spectroscopy.13 The application of these in situ apparatuses can give instant details of the process.14−16 Kee et al.17 developed a process model for crystallization models with a large number of parameters such as pseudopolymorphic and polymorphic systems using in situ probes. Also, they presented a methodology for the selective growth of metastable crystals which extended the useful range of the phase © 2013 American Chemical Society

Received: November 7, 2012 Published: January 29, 2013 375

dx.doi.org/10.1021/op300320a | Org. Process Res. Dev. 2013, 17, 375−381

Organic Process Research & Development

Article

higher temperatures after addition of a specified amount of form I to make a slurry. The solubility of form II of imidaclopid was also determined as in above-mentioned method. 2.4. Transformation Experiments. The transformation experiments were performed by adding 0.1 g of form II of imidacloprid into the saturated ethanol solution of form I at a certain temperature in a 100 mL jacketed glass vessel under a constant stirring rate. The temperature was controlled using a thermostatted bath, and the stirring rate was controlled by the stirrer speed controller. According to the solubility measurement results before, this solution was saturated with respect to form II but supersaturated for form I. At the same time, the FBRM and PVM probes were simultaneously immersed into the system and began to track the process.

Scheme 1. Molecular structure of imidacloprid

In this study, the transformation process of imidacloprid from form II to form I in ethanol solvent was discussed. The single crystals of the two forms were obtained, and their molecular structures and stacking modes were discussed. In situ techniques of FBRM and PVM were used to determine the solubility of imidacloprid in ethanol, monitor chord counts, chord length distribution, and morphology of particles during the transformation. The influences of temperature and amounts of added imidacloprid were studied systematically. In addition, there were other off-line techniques used in the experiments to identify the two forms: powder X-ray diffraction (XRPD), differential scanning calorimeter (DSC), DXR laser micro-Raman spectrometer, and hot stage optical microscopy.

3. RESULTS AND DISCUSSION 3.1. Identification of Form I and Form II. Form I shows flakiness, and form II is thin needles under the optical microscopy (Figure 1). The Raman spectra of both forms, shown in Figure 2,

2. EXPERIMENTAL SECTION 2.1. Materials. Imidacloprid was purchased from Nanjing Red Sun Group Limited, China, 97% in purity. Methanol, dichloromethane, ethanol, and acetone used for experiments were analytical reagent grade. Form I was prepared by recrystallization from ethanol. Form II was crystallized by rapid cooling of a saturated acetone solution of imidacloprid below 0 °C in the refrigerator. The single crystal of form I grew in an ethanol/ acetone solution by slow evaporation at room temperature. Similarly, form II was obtained by the same method in a methanol/ dichloromethane solution at room temperature. 2.2. Instruments. The FBRM probe (Mettler-Toledo model S400A) has a measurement range of 1−1000 μm. The probe measurement duration was set at 15 s. The PVM probe (Mettler-Toledo model A700S) was operated with an image update rate of three images per second. The sample analyzed with the XRPD (D/MAX 2500 Japan) was scanned from 5° to 60° 2θ at a step size of 0.02° with a dwell time of 1 s. The DSC (Mettler-Toledo TGA/DSC) analysis was carried out with samples in an open aluminum pan from 40 to 200 °C at a rate of 5 °C/min. Raman spectra were recorded using a DXR Laser micro-Raman spectrometer (Thermo Fisher) with an approximately 250 mW, 532 nm laser excitation. The optical microscopy (Leica DM 750P) was connected with a hot stage device (Mettler-Toledo FP900). Single X-ray diffraction data for the two crystals were collected on a Rigaku SCXmini diffractometer with Mercury2 CCD area-detector by using graphite-monochromatized Cu Kα radiation (λ = 0.71073 Å). Direct methods were used to solve the crystal structure. The structure is solved with direct methods using the SHELXS-97 program and refined anisotropically with SHELXTL-97 using full-matrix least-squares procedure. All non-hydrogen atoms were refined with anisotropic displacement parameters, and they were placed in idealized positions and refined as rigid atoms with the relative isotropic displacement parameters. 2.3. The Solubility of the Two Forms. The solubility for both forms of imidaclopid was determined by using in situ FBRM. A fixed quantity of form I of imidaclopid was added to a 100 mL jacketed glass vessel with 40 mL ethanol, creating saturated slurry. The FBRM probe was inserted into the slurry to detect the clear point. The slurry was heated at the rate of 0.1 °C/min. The dissolving temperature was determined at the lowest temperature where the count of particles approached zero, indicating complete dissolution. The cycle was repeated at

Figure 1. Optical microscopy images of imidacloprid form I (a) and form II (b).

Figure 2. Raman spectra of form I and form II of imidacloprid.

exhibit several differences. Both crystalline forms were also subjected to off-line DSC and PXRD analysis (Figures 3 and 4) to verify the solid forms. Especially, the experimental PXRD patterns for form I and form II coincide with the simulated patterns which were obtained from the single crystal data. 3.2. Crystal Structures of Form I and Form II. The single crystals of the two forms were also obtained, and the crystal structure of form I has never been reported before. The 376



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Table 1. Crystal data of form I and form II formula formula weight (g/mol) temperature (K) wavelength (Å) crystal system space group a (Å) b (Å) c (Å) α (deg) β (deg) γ (deg) volume (Å3) Z density (g/mL) F(000) θ (min, max) h,k,l (min, max) no. of refln measured no. of unique reflns R_obs wR2_all GoF

Figure 3. DSC curves of form I and form II of imidacloprid.

structures of two single crystals are different in stacking models. There are two different conformational molecules in the crystal structure of form I, while the conformations of the molecules in the crystal structure of form II are the same. The crystal data of form I and form II are listed in Table1 and the selected bond lengths and bond angles were listed in Table 2. The bond lengths of N4−C9 and N4′−C9′ in form I are 1.339 Å and 1.333 Å, respectively. They are shorter than the bond length of N4−C9 (1.351 Å) in form II. The bond lengths of N4−N5 and N4′−N5′ in form I are 1.347 Å and 1.352 Å, respectively. They are longer than the bond length of N4−N5 (1.337 Å) in form II. The tautomerism should exist between the two polymorphs of imidacloprid. The torsion angles of C7−N2−C6−C4 and C7′−N2′−C6′−C4′ in form I are −87.88° and 83.62°, respectively, which are different from the C7−N2−C6−C4 (70.02°) in form II. The torsion angles of C5−C4−C6−N2 and C5′−C4′−C6′−N2′ in form I are −18.13° and −154.88°, respectively, which are also different from the torsion angle of C5−C4−C6−N2 (−117.84°) in form II. C (9), N (3), C (8), C (7), and N (2) atoms form a five-membered ring which is approximately planar. This ring makes dihedral angle with the pyridine ring and is 84.12° and 76.59° in form I and form II, respectively.

form I

form II

C9H10ClN5O2 255.67 293(2) 0.71073 monoclinic P21/n 12.600(3) 9.685(19) 18.881(4) 90.00 102.94(3) 90.00 2245.6(8) 8 1.5125 1056 (1.8, 25.4) (0,15)(0,11)(−22,22) 4317 4118 0.0591 0.1968 1.00

C9H10ClN5O2 255.67 293(2) 0.71073 monoclinic P21/c 19.462(4) 4.881(10) 11.881(2) 90.00 99.21(3) 90.00 1114.1(4) 4 1.524 528 (3.2, 27.5) (−25,24)(−6,6)(−15,15) 10879 2553 0.0582 0.1882 1.07

Table 2. Selected bond lengths (Å) and bond angles (deg) form I N2−C9 N2′−C9′ N3−C9 N3′−C9′ N2−C6−C4 N2′−C6′−C4′ C7−N2−C6−C4 C7′−N2′−C6′−C4′

1.342 1.344 1.311 1.312 114.40 113.82 −87.88 83.62

N4−C9 N4′-C9′ N4−N5 N4′−N5′ C5−C4−C6−N2 C5′−C4′−C6′−N2′

1.339 1.333 1.347 1.352 −18.31 −154.88

form II N2−C9 N3−C9 N2−C6−C4 C7−N2−C6−C4

1.341 1.324 112.62 70.02

N4−C9 N4−N5 C5−C4−C6−N2

1.351 1.337 −117.84

Figure 4. X-ray powder diffraction patterns of imidacloprid form I and form II. 377



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Figures 5 and 6 show the molecular structures, packing modes, and intermolecular interactions in two forms, respectively.

Figure 6. Crystal packing diagrams in unit cells of form I and form II.

Figure 5. Thermal ellipsoid plots of form I and form II.

Different molecular forces were presented as a result of different conformation in two forms. The intramolecular N−H···O hydrogen bond in the structure forms a pseudo six-membered ring which restricts the conformational freedom in both the crystal structures of form I and form II. In form I, an asymmetry unit contains two imidacloprid molecules. There are intermolecular N−H···O interactions, intermolecular N−H···N interactions, intermolecular C−H···O interactions, and intermolecular C−H···N interactions. In form II, there are only intermolecular N−H···O interactions and C−H···O interactions. 3.2. Solubilities of Form I and Form II of Imidacloprid. The measured solubility of form I and form II of imidacloprid in ethanol are shown in Figure 7. The two solubility curves intersect at 53 °C which indicates that imidacloprid is an enantiotropic compound over the studied temperature range. The temperature and concentration data were correlated mathematically with the Van’t Hoff equation (eqs 1 and 2). The R2 values for eqs 1 and 2 are 0.9981 and 0.9905, respectively. The cross temperatures were determined at 53.8 °C (Figure 8). It suggests that form II has higher solubility than form I above 53.8 °C where the transformation happens smoothly. ln x = −

3615.70 + 5.2154 T

(1)

ln x = −

5078.75 + 9.6829 T

(2)

Figure 7. Solubility curves of form I and form II.

where x is the mole fraction of imidacloprid in the solution, and T is the thermodynamic temperature. 3.3. Tracking a Polymorphic Transition using FBRM and PVM. Figure 9 shows particle counts of imidacloprid in different ranges measured by the FBRM during the transformation process at 65 °C. The number of particles has a steep increase at the beginning by the addition of an amount of form II, then decreases quickly as the result of the dissolution of form II due to its higher solubility compared to that of form I at this temperature. Since the dissolution of form II occurs, the solution supersaturation with respect to form I increases steadily, which results in the nucleation and growth of form I. Thus, the number of small 378



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Figure 8. Van’t Hoff curves of the solubilities of form I and form II. Figure 10. FBRM chord length distribution of the transformation at 65 °C.

To demonstrate and provide a better understanding of the phase transition process between form I and form II, the transformation process was monitored by in situ PVM. Figure 11 shows images at different times during transformation. There are only needlelike crystals suspended in solution at the beginning of the process when form II was added. After about 1 h, it is clearly observed that a small number of fine, flaky crystals are suspended in the solution, which means it is the nucleation and growth stage of form I. The picture at 4 h shows the obvious large crystal size of form I at the end of the transformation. Changes in the crystal habit of the two forms from the PVM images support the FBRM data discussed above intuitively. It proves that the transformation of imidacloprid is accompanied by the dissolution of the metastable form and subsequent nucleation and growth of the stable one. The transformation from form II to form I was observed with the PVM images by the change in the particle morphologies. To support this observation, we have compared the XRD patterns of imidaclopid before and after the transformation. The PXRD of the solids added in the solution matched that of form II completely, whereas that of the solid after the transformation was similar to that of form I (Figure 12). It indicates that form II of imidaclopid actually transforms to form I at 65 °C. 3.4. Influence of Temperature. Temperature typically has a positive influence on chemical processes. According to the classical theory, the molecular motion can be accelerated by higher temperature, and the interfacial energy between the solid and liquid phases can be lower when temperature increases. To illustrate the influence of temperature on the polymorphic transformation process, three experiments were performed at 55, 60, and 65 °C, respectively, with fixed stirring rate. The experiments were with different initial supersaturation. As discussed before the trend of the fine chords (0−50 μm) is more strongly emphasized than that of the coarse chords for the nucleation stage. The trends of fine particle counts were similar in Figures 13, 14, and 9. It shows that it nucleates first at 65 °C because the solution reaches supersaturation faster at higher temperature, followed by 60 and 55 °C. It can also be observed from the comparison that the temperature is higher and the time is shorter for transformation. With the increase of the temperature, the ending points of polymorphic transformation between

Figure 9. FBRM counts of polymorphic transformation process at 65 °C.

particles (0−50 μm) initially rises first and fast for the spontaneous nucleation of form I in the solution. When the crystallization of form I consumes the supersaturation, the dissolution can proceed continuously. When measuring needlelike crystals, FBRM chord length is a function of the width of these needles as well as their length. The dissolution of form II and nucleation of form I made the counts of small ones have a gradual rise later. An increase in the number of large chord lengths is attributed to crystal growth or agglomeration. The counts of the coarse chords (50−150 μm and 150−300 μm) have a gradual rise, which is most likely the sign of the growth of form I. In the process, nucleation greatly consumes supersaturation and then the growth of form I begins. After approximately 4 h, the particle counts reach a constant value which means the system is in equilibrium. Through comparing the increase rate of the particles, it can be concluded that the nucleation stage happens mainly in the first hour; the growth stage of crystals happens during the remaining time since the supersaturation is gradually reduced. Chord length distributions (CLD) from FBRM embody two parts: the unweighted CLD which is dominated by the small chord lengths, and the square-weighted CLD which is dominated by the larger chord lengths. In Figure 10, the counts of unweighted CLD increase fast in the first hour which corresponds to the nucleation stage of form II of imidacloprid, whereas the shift in the mode of the distribution is due to crystal growth. 379



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Figure 11. PVM images taken at different times during the polymorphic transformation process.

Figure 12. X-ray powder diffraction patterns of imidacloprid before and after the transformation.


decreased fine particles and increased coarse particles are consistent. It is speculated that high temperature can facilitate the polymorphic transformation from form II to form I, which directly leads to the drop of transformation time. Besides, the difference between the solubility of the two forms at 55 °C is relatively small, and the transition from form II to form I should be slow and difficult. 3.5. Influence of Amounts of Added Imidacloprid. The influence of amounts of added imidacloprid to the transformation process was also studied. Different amounts (0.15 g

and 0.2 g) of form II were added into the same 100 mL saturated ethanol solution under isothermal conditions of 65 °C. More substrates take more time to dissolve as shown in Figure 15 compared with Figure 9. While the supersaturation does not change in the same temperature and solvent in the solutionmediated polymorphic transformation, the rate of crystal growth should be constant. The effect of substrate on nucleation is also limited. More substrate means that a longer time was required to complete the transformation. 380



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ACKNOWLEDGMENTS This project was supported by the National Basic Research Program of China (2011CB302004).


Figure 15. FBRM counts of polymorphic transformation process with 0.2 g of imidacloprid at 65 °C.

4. CONCLUSIONS The transformation mechanism for imidacloprid from form II to form I in ethanol solvent can be identified as a solutionmediated transformation. Increasing temperature accelerates the transformation and improves the transformation efficiency. More substrates prolong the time of the transformation. There is tautomerism existing between the two polymorphs of imidacloprid. More hydrogen bonds exist in form I than that in form II. This transformation in ethanol can be driven by changes of intermolecular interaction. The combination of these in situ and off-line tools facilitates a significant increase in process understanding with respect to the mechanism of the polymorphic transformation process. The methods proposed in this paper will be used further to study other polymorphic systems in the pharmaceutical industry.

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REFERENCES

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The authors declare no competing financial interest. 381


Monitoring the Polymorphic Transformation of Imidacloprid Using in

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