monitoring the polymorphic transformation of imidacloprid using in situ fbrm and pvm

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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, Peoples Republic of China State Key Laboratory of Bioelectronics, Southeast University, Nanjing 210096, Peoples 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 reectance measurement (FBRM) and particle vision measurement (PVM). The solubility and metastable zone width of the two forms were measured, and the inuences of temperature and amounts of added imidacloprid to the transformation were investigated. Higher temperature accelerates the transformation and improves the transformation eciency. More substrates prolong the time of the transformation. The transformation was identied 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 inuences of temperature and amounts of added imidacloprid were studied systematically. 1. INTRODUCTION Polymorphism is known as a phenomenon wherein the same compounds in dierent conditions generate dierent structures, shapes, and physical properties of crystals. 1 Although identical in chemical composition, polymorphs dier in bioavailability, solubility, dissolution rate, chemical stability, physical stability, melting point, lterability, 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 di erent stability. The solvent-mediated polymorphic transformation is driven by the dierence in solubility of the polymorphs in a solvent. In the process of the solvent-mediated polymorphic transformation, the metastable form dissolves in the solution rst, 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 reectance measure- ment (FBRM), 7,8 particle vision measurement (PVM), 9,10 in situ attenuated total reectance Fourier transform infrared (ATR- FTIR) 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 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 Leyssens 19 demonstrated how CLD properties can be dened for needle-shaped particles and how their variation over time can be linked to dierent physical mechanisms of crystallization. It is also used for determi- nation 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 proles approached a constant value, indicating complete dissolution. This approach requires fewer materials and less manual labor compared to other techniques such as the gravi- metric method. A polymorphic transformation is often accom- panied 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 morphol- ogy in suspension. Imidacloprid (1-[(6-chloro-3-pyridinyl)methyl]-N-nitro-2- imidazolidinimine, Scheme 1) is a new generation of nicotine insecticide. It has the advantages of broad spectrum, high eciency, 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 Chopr 23 As a typical nicotine insecticide, the polymorphic transformation of imidacloprid has not been studied until now. Received: November 7, 2012 Published: January 29, 2013 Article pubs.acs.org/OPRD © 2013 American Chemical Society 375 dx.doi.org/10.1021/op300320a | Org. Process Res. Dev. 2013, 17, 375-381

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Page 1: Monitoring the Polymorphic Transformation of Imidacloprid Using in Situ FBRM and PVM

Monitoring the Polymorphic Transformation of Imidacloprid Usingin Situ FBRM and PVMJing 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 inethanol by using in situ focused beam reflectance measurement (FBRM) and particle vision measurement (PVM). The solubilityand metastable zone width of the two forms were measured, and the influences of temperature and amounts of addedimidacloprid to the transformation were investigated. Higher temperature accelerates the transformation and improves thetransformation efficiency. More substrates prolong the time of the transformation. The transformation was identified as asolution-mediated transformation. The single crystals of the two forms were obtained. The crystal structure of form I has notbeen reported before. Tautomerism exists between the two polymorphs of imidacloprid. Analysis of molecular structures andstacking modes shows that more hydrogen bonds exist in form I. It indicates that the change of the hydrogen bond interactionmaybe the driving force of the transformation. In this study, the transformation process of imidacloprid from form II to form I inethanol solvent was mainly discussed. The single crystals of the two forms were obtained, and their molecular structures andstacking modes were discussed. In order to obtain some critical information, in situ techniques of FBRM and PVM were used todetermine the solubility of both the forms in ethanol and to monitor chord counts, chord length distribution, and morphology ofthe particles. The influences of temperature and amounts of added imidacloprid were studied systematically.

1. INTRODUCTION

Polymorphism is known as a phenomenon wherein the samecompounds in different conditions generate different structures,shapes, and physical properties of crystals.1 Although identicalin chemical composition, polymorphs differ in bioavailability,solubility, dissolution rate, chemical stability, physical stability,melting point, filterability, and many other properties. The subjectof polymorphism seizes the attention of a large number of chemistsand crystal engineers associated with the pharmaceutical industry.2

The polymorphic transformation that crystals convert from oneform to another is a phase transition process. There are two kindsof mechanisms reported at present,3 solid-state polymorphictransformation and solvent-mediated polymorphic transformation.The solid-state polymorphic transformation occurs due to differentstability. The solvent-mediated polymorphic transformation isdriven by the difference in solubility of the polymorphs in asolvent. In the process of the solvent-mediated polymorphictransformation, 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 asRaman spectroscopy,4−6 focused beam reflectance measure-ment (FBRM),7,8 particle vision measurement (PVM),9,10 insitu attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectroscopy,11,12 and ATR-UV spectroscopy.13 Theapplication of these in situ apparatuses can give instant details ofthe process.14−16 Kee et al.17 developed a process model forcrystallization models with a large number of parameters such aspseudopolymorphic and polymorphic systems using in situ probes.Also, they presented a methodology for the selective growth ofmetastable crystals which extended the useful range of the phase

diagram to increase product yield. It is potentially applicable toother enantiotropic systems.18

FBRM is used to monitor chord counts and chord lengthdistribution (CLD) of particles in solution, and it provides aprecise and sensitive measurement that allows the user toquantify in process. With FBRM Tom Leyssens19 demonstratedhow CLD properties can be defined for needle-shaped particlesand how their variation over time can be linked to differentphysical mechanisms of crystallization. It is also used for determi-nation the solubility and metastable zone width of substances insolvents.20 Kee et al.21 suggested that the saturation temperatureand the corresponding solute concentration were determined atthe lowest temperature where the particle counts and soluteconcentration profiles approached a constant value, indicatingcomplete dissolution. This approach requires fewer materials andless manual labor compared to other techniques such as the gravi-metric method. A polymorphic transformation is often accom-panied by a change in the crystal habit. PVM, as an in-line videocamera, is a unique, patented, in-process imaging system capableof providing high-resolution images of particle size and morphol-ogy in suspension.Imidacloprid (1-[(6-chloro-3-pyridinyl)methyl]-N-nitro-2-

imidazolidinimine, Scheme 1) is a new generation of nicotineinsecticide. It has the advantages of broad spectrum, highefficiency, low toxicity, and low residue.22 Imidacloprid has twopolymorphic forms reported: form I and form II. The singlecrystal of form I was discussed by Chopr23 As a typical nicotineinsecticide, the polymorphic transformation of imidacloprid hasnot been studied until now.

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

Article

pubs.acs.org/OPRD

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

Page 2: Monitoring the Polymorphic Transformation of Imidacloprid Using in Situ FBRM and PVM

In this study, the transformation process of imidacloprid fromform II to form I in ethanol solvent was discussed. The single crystalsof the two forms were obtained, and their molecular structures andstacking modes were discussed. In situ techniques of FBRM andPVM were used to determine the solubility of imidacloprid inethanol, monitor chord counts, chord length distribution, andmorphology of particles during the transformation. The influences oftemperature and amounts of added imidacloprid were studiedsystematically. In addition, there were other off-line techniques usedin the experiments to identify the two forms: powder X-raydiffraction (XRPD), differential scanning calorimeter (DSC), DXRlaser micro-Raman spectrometer, and hot stage optical microscopy.

2. EXPERIMENTAL SECTION2.1. Materials. Imidacloprid was purchased from Nanjing

Red Sun Group Limited, China, 97% in purity. Methanol,dichloromethane, ethanol, and acetone used for experimentswere analytical reagent grade. Form I was prepared by recrystal-lization from ethanol. Form II was crystallized by rapid coolingof a saturated acetone solution of imidacloprid below 0 °C inthe 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. Theprobe measurement duration was set at 15 s. The PVM probe(Mettler-Toledo model A700S) was operated with an imageupdate rate of three images per second. The sample analyzedwith the XRPD (D/MAX 2500 Japan) was scanned from 5° to60° 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 withsamples in an open aluminum pan from 40 to 200 °C at a rateof 5 °C/min. Raman spectra were recorded using a DXR Lasermicro-Raman spectrometer (Thermo Fisher) with an approx-imately 250 mW, 532 nm laser excitation. The opticalmicroscopy (Leica DM 750P) was connected with a hotstage device (Mettler-Toledo FP900). Single X-ray diffractiondata for the two crystals were collected on a Rigaku SCXminidiffractometer with Mercury2 CCD area-detector by usinggraphite-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-97program and refined anisotropically with SHELXTL-97 usingfull-matrix least-squares procedure. All non-hydrogen atomswere refined with anisotropic displacement parameters, andthey were placed in idealized positions and refined as rigidatoms 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 situFBRM. A fixed quantity of form I of imidaclopid was added to a100 mL jacketed glass vessel with 40 mL ethanol, creatingsaturated slurry. The FBRM probe was inserted into the slurryto detect the clear point. The slurry was heated at the rate of0.1 °C/min. The dissolving temperature was determined at thelowest temperature where the count of particles approachedzero, indicating complete dissolution. The cycle was repeated at

higher temperatures after addition of a specified amount ofform I to make a slurry. The solubility of form II of imidaclopidwas also determined as in above-mentioned method.

2.4. Transformation Experiments. The transformationexperiments were performed by adding 0.1 g of form II ofimidacloprid into the saturated ethanol solution of form I at acertain temperature in a 100 mL jacketed glass vessel under aconstant stirring rate. The temperature was controlled using athermostatted bath, and the stirring rate was controlled by thestirrer speed controller. According to the solubility measure-ment results before, this solution was saturated with respect toform II but supersaturated for form I. At the same time, theFBRM and PVM probes were simultaneously immersed intothe system and began to track the process.

3. RESULTS AND DISCUSSION

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

exhibit several differences. Both crystalline forms were also subjectedto off-line DSC and PXRD analysis (Figures 3 and 4) to verify thesolid forms. Especially, the experimental PXRD patterns for form Iand form II coincide with the simulated patterns which wereobtained from the single crystal data.

3.2. Crystal Structures of Form I and Form II. The singlecrystals of the two forms were also obtained, and the crystalstructure of form I has never been reported before. The

Scheme 1. Molecular structure of imidacloprid

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

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

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structures of two single crystals are different in stacking models.There are two different conformational molecules in the crystalstructure of form I, while the conformations of the molecules inthe crystal structure of form II are the same. The crystal data ofform I and form II are listed in Table1 and the selected bondlengths and bond angles were listed in Table 2. The bondlengths of N4−C9 and N4′−C9′ in form I are 1.339 Å and1.333 Å, respectively. They are shorter than the bond length ofN4−C9 (1.351 Å) in form II. The bond lengths of N4−N5 andN4′−N5′ in form I are 1.347 Å and 1.352 Å, respectively. Theyare longer than the bond length of N4−N5 (1.337 Å) in formII. The tautomerism should exist between the two polymorphsof imidacloprid. The torsion angles of C7−N2−C6−C4 andC7′−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−N2and C5′−C4′−C6′−N2′ in form I are −18.13° and −154.88°,respectively, which are also different from the torsion angle ofC5−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 isapproximately planar. This ring makes dihedral angle with thepyridine ring and is 84.12° and 76.59° in form I and form II,respectively.

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

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

Table 1. Crystal data of form I and form II

form I form II

formula C9H10ClN5O2 C9H10ClN5O2

formula weight (g/mol) 255.67 255.67temperature (K) 293(2) 293(2)wavelength (Å) 0.71073 0.71073crystal system monoclinic monoclinicspace group P21/n P21/ca (Å) 12.600(3) 19.462(4)b (Å) 9.685(19) 4.881(10)c (Å) 18.881(4) 11.881(2)α (deg) 90.00 90.00β (deg) 102.94(3) 99.21(3)γ (deg) 90.00 90.00volume (Å3) 2245.6(8) 1114.1(4)Z 8 4density (g/mL) 1.5125 1.524F(000) 1056 528θ (min, max) (1.8, 25.4) (3.2, 27.5)h,k,l (min, max) (0,15)(0,11)(−22,22) (−25,24)(−6,6)(−15,15)no. of refln measured 4317 10879no. of unique reflns 4118 2553R_obs 0.0591 0.0582wR2_all 0.1968 0.1882GoF 1.00 1.07

Table 2. Selected bond lengths (Å) and bond angles (deg)

form I

N2−C9 1.342 N4−C9 1.339N2′−C9′ 1.344 N4′-C9′ 1.333N3−C9 1.311 N4−N5 1.347N3′−C9′ 1.312 N4′−N5′ 1.352N2−C6−C4 114.40 C5−C4−C6−N2 −18.31N2′−C6′−C4′ 113.82 C5′−C4′−C6′−N2′ −154.88C7−N2−C6−C4 −87.88C7′−N2′−C6′−C4′ 83.62

form II

N2−C9 1.341 N4−C9 1.351N3−C9 1.324 N4−N5 1.337N2−C6−C4 112.62 C5−C4−C6−N2 −117.84C7−N2−C6−C4 70.02

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

Different molecular forces were presented as a result of differentconformation in two forms. The intramolecular N−H···Ohydrogen bond in the structure forms a pseudo six-memberedring which restricts the conformational freedom in both the crystalstructures of form I and form II. In form I, an asymmetry unitcontains two imidacloprid molecules. There are intermolecularN−H···O interactions, intermolecular N−H···N interactions,intermolecular C−H···O interactions, and intermolecularC−H···N interactions. In form II, there are only intermolecularN−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 inethanol are shown in Figure 7. The two solubility curves intersectat 53 °C which indicates that imidacloprid is an enantiotropiccompound over the studied temperature range. The temperatureand concentration data were correlated mathematically with theVan’t Hoff equation (eqs 1 and 2). The R2 values for eqs 1 and 2are 0.9981 and 0.9905, respectively. The cross temperatures weredetermined at 53.8 °C (Figure 8). It suggests that form II hashigher solubility than form I above 53.8 °C where thetransformation happens smoothly.

= − +xT

ln3615.70

5.2154(1)

= − +xT

ln5078.75

9.6829(2)

where x is the mole fraction of imidacloprid in the solution, and Tis the thermodynamic temperature.

3.3. Tracking a Polymorphic Transition using FBRMand PVM. Figure 9 shows particle counts of imidacloprid indifferent ranges measured by the FBRM during the transformationprocess at 65 °C. The number of particles has a steep increase atthe beginning by the addition of an amount of form II, thendecreases quickly as the result of the dissolution of form II due toits higher solubility compared to that of form I at this temperature.Since the dissolution of form II occurs, the solution super-saturation with respect to form I increases steadily, which results inthe nucleation and growth of form I. Thus, the number of small

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

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

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

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particles (0−50 μm) initially rises first and fast for the spontaneousnucleation of form I in the solution. When the crystallization ofform I consumes the supersaturation, the dissolution can proceedcontinuously. When measuring needlelike crystals, FBRM chordlength is a function of the width of these needles as well as theirlength. The dissolution of form II and nucleation of form I madethe counts of small ones have a gradual rise later. An increase inthe number of large chord lengths is attributed to crystal growth oragglomeration. The counts of the coarse chords (50−150 μm and150−300 μm) have a gradual rise, which is most likely the sign ofthe growth of form I. In the process, nucleation greatly consumessupersaturation and then the growth of form I begins. Afterapproximately 4 h, the particle counts reach a constant value whichmeans the system is in equilibrium. Through comparing theincrease rate of the particles, it can be concluded that thenucleation stage happens mainly in the first hour; the growth stageof crystals happens during the remaining time since thesupersaturation is gradually reduced.Chord length distributions (CLD) from FBRM embody two

parts: the unweighted CLD which is dominated by the smallchord lengths, and the square-weighted CLD which is dominatedby the larger chord lengths. In Figure 10, the counts of unweightedCLD increase fast in the first hour which corresponds to thenucleation stage of form II of imidacloprid, whereas the shift in themode of the distribution is due to crystal growth.

To demonstrate and provide a better understanding of thephase transition process between form I and form II, thetransformation process was monitored by in situ PVM. Figure 11shows images at different times during transformation. There areonly needlelike crystals suspended in solution at the beginning ofthe process when form II was added. After about 1 h, it is clearlyobserved that a small number of fine, flaky crystals are suspendedin the solution, which means it is the nucleation and growth stageof form I. The picture at 4 h shows the obvious large crystal size ofform I at the end of the transformation. Changes in the crystalhabit of the two forms from the PVM images support the FBRMdata discussed above intuitively. It proves that the transformationof imidacloprid is accompanied by the dissolution of themetastable form and subsequent nucleation and growth of thestable one.The transformation from form II to form I was observed with

the PVM images by the change in the particle morphologies. Tosupport this observation, we have compared the XRD patterns ofimidaclopid before and after the transformation. The PXRD of thesolids added in the solution matched that of form II completely,whereas that of the solid after the transformation was similar tothat of form I (Figure 12). It indicates that form II of imidaclopidactually transforms to form I at 65 °C.

3.4. Influence of Temperature. Temperature typically hasa positive influence on chemical processes. According to theclassical theory, the molecular motion can be accelerated byhigher temperature, and the interfacial energy between thesolid and liquid phases can be lower when temperatureincreases. To illustrate the influence of temperature on thepolymorphic transformation process, three experiments wereperformed at 55, 60, and 65 °C, respectively, with fixedstirring rate. The experiments were with different initialsupersaturation. As discussed before the trend of the finechords (0−50 μm) is more strongly emphasized than that ofthe coarse chords for the nucleation stage. The trends of fineparticle counts were similar in Figures 13, 14, and 9. It showsthat it nucleates first at 65 °C because the solution reachessupersaturation faster at higher temperature, followed by 60and 55 °C. It can also be observed from the comparison thatthe temperature is higher and the time is shorter fortransformation. With the increase of the temperature, theending points of polymorphic transformation between

Figure 8. Van’t Hoff curves of the solubilities of form I and form II.

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

Figure 10. FBRM chord length distribution of the transformation at65 °C.

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decreased fine particles and increased coarse particles areconsistent. It is speculated that high temperature can facilitatethe polymorphic transformation from form II to form I, whichdirectly leads to the drop of transformation time. Besides, thedifference between the solubility of the two forms at 55 °C isrelatively small, and the transition from form II to form Ishould be slow and difficult.3.5. Influence of Amounts of Added Imidacloprid. The

influence of amounts of added imidacloprid to the trans-formation process was also studied. Different amounts (0.15 g

and 0.2 g) of form II were added into the same 100 mLsaturated ethanol solution under isothermal conditions of 65 °C.More substrates take more time to dissolve as shown in Figure 15compared with Figure 9. While the supersaturation does notchange in the same temperature and solvent in the solution-mediated polymorphic transformation, the rate of crystal growthshould be constant. The effect of substrate on nucleation is alsolimited. More substrate means that a longer time was required tocomplete the transformation.

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

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

Figure 13. FBRM counts of polymorphic transformation process at55 °C.

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4. CONCLUSIONSThe transformation mechanism for imidacloprid from form IIto form I in ethanol solvent can be identified as a solution-mediated transformation. Increasing temperature acceleratesthe transformation and improves the transformation efficiency.More substrates prolong the time of the transformation. Thereis tautomerism existing between the two polymorphs ofimidacloprid. More hydrogen bonds exist in form I than thatin form II. This transformation in ethanol can be driven bychanges of intermolecular interaction.The combination of these in situ and off-line tools facilitates

a significant increase in process understanding with respect tothe mechanism of the polymorphic transformation process. Themethods proposed in this paper will be used further to studyother polymorphic systems in the pharmaceutical industry.

■ AUTHOR INFORMATIONCorresponding Author*Telephone: +86 2585092237. E-mail: [email protected] authors declare no competing financial interest.

■ ACKNOWLEDGMENTSThis project was supported by the National Basic ResearchProgram of China (2011CB302004).

■ REFERENCES(1) Bernstein, J. Polymorphism in Molecular Crystals; OxfordUniversity Press: New York, 2002.(2) Gautam, R. D. Cryst. Growth Des. 2008, 8, 1−3.(3) Mullin, J. W. Crystallization, 4th ed.; Butterworth-Heinemann:London, 2001.(4) Ryo, K.; Yasuto, F.; Tatsuzo, U.; Yukio, H. Org. Process Res. Dev.2006, 10, 1219−1226.(5) Su, W. Y.; Hao, H. X.; Barrett, M.; Glennon, B. Org. Process Res.Dev. 2010, 14, 1432−1437.(6) Zhao, Y. Y.; Bao, Y.; Wang, J. K.; Rohani, S. Pharmaceutics 2012,4, 164−178.(7) Czaplaa, F.; Kailb, N.; Onculc, A.; Lorenza, H.; Briesend, H.;Seidel-Morgensterna, A. Chem. Eng. Res. Des. 2010, 88, 1494−1504.(8) Dhananjay, S.; Kamlesh, S.; Harish, M.; Tushar, N.; Manoj, D.Org. Process Res. Dev. 2010, 14, 1373−1378.(9) Liu, W. J.; Wei, H. Y.; Black, S. Org. Process Res. Dev. 2009, 13,494−500.(10) Jia, C. Y.; Yin, Q. X.; Zhang, M. J.; Wang, J. K.; Shen, Z. H. Org.Process Res. Dev. 2008, 12, 1223−1228.(11) Scholl, J.; Bonalumi, D.; Vicum, L.; Mazzotti, M. Cryst. GrowthDes. 2006, 6, 4.(12) Groen, H.; Roberts, K. J. J. Phys. Chem. 2001, 105, 10723−10730.(13) Nagy, Z. K.; Gillon, A. L.; Steele, G.; Makwana, N.; Rielly, C. D.8th International IFAC Symposium on Dynamics and Control of ProcessSystems 2007, 3, 6−8.(14) Wang, Z. Z.; Wang, J. K.; Dang, L. P. Org. Process Res. Dev. 2006,10, 450−456.(15) Liu, X. S.; Sun, D.; Wang, F.; Wu, Y. J.; Chen, Y.; Wang, L. G. J.Pharm. Sci. 2011, 100, 6.(16) O’Sullivan, B.; Barrett, P.; Hsiao, G.; Carr, A.; Glennon, B. Org.Process Res. Dev. 2003, 7, 977−982.(17) Kee, N. C. S.; Arendt, P. D.; Goh, L. M.; Tan, R. B. H.; Braatz,R. D. CrystEngComm 2011, 13, 1197−1209.(18) Kee, N. C. S.; Arendt, P. D.; Tan, R. B. H.; Braatz, R. D. Cryst.Growth Des. 2009, 9, 3052−3061.(19) Leyssens, T.; Baudry, C.; Hernandez, M. L. E. Org. Process Res.Dev. 2011, 15, 413−426.(20) Barrett, P.; Glennon, B. Trans. IChem. E. 2002, No. Part A, 180.(21) Kee, N. C. S.; Tan, R. B. H.; Braatz., R. D. Ind. Eng. Chem. Res.2011, 50, 1488−1495.(22) Kong, M. Z.; Shi, X. H.; Cao, Y. C.; Zhou, C. R. J. Chem. Eng.Data 2008, 53, 615−618.(23) Chopra, D.; Mohan, T. P.; Rao, K. S.; Guru Row, T. N. ActaCrystallogr., Sect. E 2004, 60, 2415−2417.

Figure 14. FBRM counts of polymorphic transformation process at 60 °C.

Figure 15. FBRM counts of polymorphic transformation process with0.2 g of imidacloprid at 65 °C.

Organic Process Research & Development Article

dx.doi.org/10.1021/op300320a | Org. Process Res. Dev. 2013, 17, 375−381381