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Nov 21, 2013 - Guan Wang , Youguang Ma , Yongli Wang , Hongxun Hao , and Yang Jiang ... Ting Zhang , Liping Wang , Ying Bao , Qi Yang , Lina Zhou ...
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Crystal Structures and Solvent-Mediated Transformation of the Enantiotropic Polymorphs of 2,3,5-Trimethyl-1,4-diacetoxybenzene Liqiang Yang, Hongxun Hao, Lina Zhou, Wei Chen, Baohong Hou, Chuang Xie, and Qiuxiang Yin* State Key Laboratory of Chemical Engineering, School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, People’s Republic of China S Supporting Information *

ABSTRACT: The crystal structures of form A and form B of 2,3,5-trimethyl-1,4-diacetoxybenzene (TMHQ-DA) were elucidated for the first time by using the single crystal X-ray diffraction method. It was found that form A and form B can be distinguished by different space group of P21/c and P21/n, respectively, although both of them belong to monoclinic crystal system. The methyl groups on the benzene ring of TMHQ-DA molecule in form B crystal lattice are disordered over four positions, with occupancies of 0.600(3) and 0.900(3) at C2 and C3 and the same at their symmetric location (C2a and C3a), while there is not any position disorder observed in the crystal structure of form A. Several offline analytical tools, such as scanning electron microscopy, powder X-ray diffraction, Fourier transform infrared spectroscopy, Raman spectroscopy, and solidstate 13C NMR spectroscopy, were used to further characterize the crystal structures of these two polymorphs. The solventmediated polymorphic transformation of the enantiotropic polymorphs of TMHQ-DA was investigated in detail. Raman, FTIR, and FBRM were used to in situ monitor the transformation processes. It was found that the polymorphic transformation processes between TMHQ-DA polymorphs can be controlled by different steps at different stage of the whole process. To further understand the mechanism of the transformation and to find out how to control it, the effects of solvent, temperature, seeding, and amount of solid loading on the transformation behavior were investigated in detail. The influence mechanism was also analyzed.

1. INTRODUCTION Polymorphism, the existence of multiple crystalline forms of organic compounds, is of utmost importance for the manufacture and performance of chemicals; however, the understanding and control of this phenomenon are still not very in-depth.1,2 Polymorphism may be conformational polymorphism or packing polymorphism in the light of the existence of crystal forms of the same molecule in different conformations or arrangements in the crystalline lattice.3,4 Different polymorphs may exhibit different mechanical and physicochemical properties, which have led to tight regulation of polymorphism in the chemical and pharmaceutical industries. For all the polymorphs of one compound, there is only one thermodynamically stable form, and the other forms are metastable or unstable polymorphs that could transform over time into the most stable form. Therefore, the stability of the desired polymorph and the mutual transformation of different polymorphs is just critical.5,6 The solvent-mediated polymorphic transformation can be affected by numerous factors, such as solvent,7,8 temperature,9 additive,10−12 seeding,13 amount of solid loading,14 particle size,15 specific surface area of the metastable polymorph,16−18 and scale of operation.13,17 The influence mechanism of these parameters are not very wellknown so far. With the advance of process analytical technology (PAT), in situ monitoring of solvent-mediated polymorphic transformation is now possible.15,19 Raman spectroscopy has been extensively used for in situ monitoring the solid state concentration of polymorphic systems.20 Attenuated total © 2013 American Chemical Society

reflectance Fourier transform infrared spectroscopy (ATRFTIR) has been adapted to in situ monitor the solution concentrations during polymorphic transformation.21,22 Focused beam reflectance measurement (FBRM) has been developed to monitor the particle size and particle amount in real time.23 As one important basic chemical, 2,3,5-trimethyl-1,4diacetoxybenzene (CAS Registry No. 7479-28-9, hereinafter referred to as TMHQ-DA) is typically used as an intermediate for production of vitamin E and used as an antioxidant. In our earlier reports,24,25 the polymorphism phenomenon of TMHQDA has been studied. Isolation methods for enantiotropic polymorph A and polymorph B of TMHQ-DA have been developed, and their solubility data and the transition point have been determined. However, the crystal structures of the two forms, which are very important to understand the molecular mechanism of the polymorph phenomenon, are still not solved. Furthermore, the mutual transformation between the two forms of TMHQ-DA, which could change the physiochemical and mechanical properties of the two forms, is also not investigated. In this work, the crystal structures of the two polymorphs of TMHQ-DA will be elucidated for the first time by single crystal X-ray diffraction and analyzed by comprehensive solid-state characterization. The transformation behavior between the two forms of TMHQ-DA will be Received: Revised: Accepted: Published: 17667

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two forms were recorded using a RAMAN RXN2 system (Kaiser Optical Systems, Inc., U.S.A.). The 13C NMR crosspolarization/magic angle spinning (CP/MAS) spectra of these two forms were collected on an Infinity Plus 300 MHz spectrometer (Varian, U.S.A.). The powder samples were packed into 7.5 mm rotor and spun with a rate of 4.0 kHz. 2.4. Establishment of Raman Spectra Calibration Curve of Form A and Form B of TMHQ-DA for Quantitative Analysis. The Raman spectra calibration curve of form A and form B of TMHQ-DA for quantitative analysis was constructed by using pure form A and form B. In order to obtain a reliable calibration model that is applicable to suspensions, binary mixtures of form A and form B with known form A fraction XA (=0, 0.1, 0.2, 0.3,..., 0.8, 0.9, 1.0, respectively) of TMHQ-DA were dispersed under stirring into saturated 2-propanol solution at 314.5 K. The Raman spectra of the slurries were collected. Then, the calibration line was constructed using Raman spectra from series of slurries. It has been proven in our previous work that polymorphic transformation will not happen at around 314.5 K since this temperature point is the transition point of the enantiotropic polymorphs.25 So the calibration curve at this temperature is reliable. 2.5. Solvent-Mediated Polymorphic Transformation. The solvent-mediated polymorphic transformation experiments between form A and form B of TMHQ-DA were performed in a 300 mL cylindrical double-jacketed glass crystallizer equipped with an impeller and a thermostatic bath. The mixing intensity was kept constant for all operations by keeping the agitation speed at 400 rpm. In order to avoid the effect of particle size and specific surface area of the metastable polymorph on transformation process, the products of form A and form B were ground and screened with 70−100 mesh sieve. Then, a certain amount of the pretreated crystals of form A or form B were adding into 200 mL saturation solution. The MR probe of Raman RXN2 (Kaiser Optical Systems, Inc. U.S.A.) was immersed into the suspensions to in situ monitor polymorphic form of TMHQ-DA, and the Raman spectrum data were collected using an exposure time of 5 s with 8 accumulations. An ATR-FTIR ReactIR 45m reaction analysis system equipped with Duradisc DiComp probe (Mettler Toledo, Switzerland) was used to monitor the solution concentration. The measurement duration was set at 15 s. A M400LF FBRM (Mettler Toledo, Switzerland) was employed to in situ monitor the change of particle size and particle amount with a 10 s duration. IC Raman, IC IR, and IC FBRM software were adopted to collect and analyze the data during and after the experiments.

investigated by using process analytical technologies such as Raman, ATR-FTIR, and FBRM. The rate limiting steps of the transformation and the effect of solvent, temperature, seeding, and amount of solid loading on the enantiotropic transformations will be analyzed. This is valuable to the process design in the chemical and pharmaceutical industries.

2. MATERIALS AND EXPERIMENTS 2.1. Material. Methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, and deionized water were purchased from Tianjin Ke Wei Chemical Co. Ltd. in China. All the organic solvents were analytical reagent grade, and their molar purities are higher than 99.5%, which were determined by High Performance Liquid Chromatography (HPLC, type Agilent 1100, Agilent Technologies, U.S.A.) form A and B of TMHQ-DA were obtained by using the cooling crystallization method described in the previous work.24 Their mass fraction purities are higher than 99.8%, which were determined by Gas Chromatography (GC, type GC-9790 II, Zhejiang Fu Li Analytical Instrument Co. Ltd., China), and their forms were identified and confirmed by powder X-ray diffraction patterns (PXRD, type D/max-2500, Rigaku, Japan). 2.2. Single Crystals Growth and Crystal Structures Determination of Form A and Form B. The single crystals of form A and form B of TMHQ-DA were grown by using the solvent evaporation method. A small amount of slightly unsaturated methanol solution of TMHQ-DA with temperature of 293.15 K was placed into a 10 mL beaker and sealed with plastic film. Then, the beaker with solution was placed into an oven and kept at 293.15 K. The solvent evaporated slowly and crystals of form A (plates) with appropriate size for single crystal X-ray diffraction were obtained after several days. A small amount of slightly unsaturated ethanol solution of TMHQ-DA with temperature of 318.15 K was placed into a 20 mL beaker and sealed with plastic film. Then, the beaker with solution was placed into an oven and kept at 318.15 K. The solvent evaporated slowly and crystals of form B (rods) with appropriate size for single crystal X-ray diffraction were obtained after several days. Single crystal X-ray diffraction data of these two forms were collected on a Rigaku-Rapid II diffractometer with Mercury2 CCD area-detector by using graphite-monochromatized Mo Kα radiation (λ = 0.71073 Å). The structures were solved with direct methods using the SHELXS-97 program and refined anisotropically with SHELXTL-97 using full-matrix least-squares procedure. 2.3. Characterization of Form A and Form B. Several analytical methods have been used to characterize polymorphic crystalline materials offline, including scanning electron microscopy (SEM), powder X-ray diffraction (PXRD), Fourier transform infrared spectroscopy (FTIR), Raman spectroscopy, and solid-state 13C NMR spectroscopy. The crystal habits of form A and form B were observed by using an X-650 Field Emission SEM (Hitachi, Japan) under a voltage of 20 kV. The powder X-ray diffraction data of these two forms were collected by a D/max-2500 diffractometer (Rigaku, Japan) at 40 kV and 100 mA with a Cu Kα radiation source (λ = 1.54056 Å) at 298 K. The samples were scanned from 5° to 30° (2θ) at a step size of 0.02° and at a scanning rate of 4°/min. The FTIR spectra of the two forms were collected from KBr disk with a Nicolet nexus spectrophotometer (Thermo, U.S.A.). The measured wavenumber range was from 3250 to 400 cm−1 with ground KBr powder as the background in the measurements. The Raman spectra of the

3. RESULTS AND DISCUSSION 3.1. Crystal Structures of Form A and Form B. The crystal structures of the two polymorphs of TMHQ-DA were elucidated for the first time by using single crystal X-ray diffraction data. A summary of the crystallographic data for the two crystal forms are presented in Table S1 in the Supporting Information. The thermal capped sticks plots and the crystal packing diagrams in unit cells of form A and form B are shown in Figures 1 and 2, respectively. It is worth noting that since the molecule by itself does not possess any symmetry, the number of molecules in asymmetric unit of form B (Z′ = 0.5) indicates positional disorder26−31 of methyl groups and hydrogen atom of benzene ring in crystal lattice on form B. The accurate characterization of the crystal structure of form B was obtained 17668

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Figure 1. Thermal capped sticks plots of form A and form B. Figure 2. Crystal packing diagrams in unit cells of form A and form B.

by careful refinements. The occupancies of the disordered hydrogen atom at the 2- and 3-position C atoms are 0.400(3) and 0.100(3), respectively, and are the same at their symmetric location (C2a and C3a). The methyl groups of the benzene ring are also disordered over four positions, with occupancies of 0.600(3) and 0.900(3) at C2 and C3 and the same at their symmetric location (C2a and C3a). However, no position disorder of methyl group and hydrogen atom of benzene ring was observed in the crystal structure of form A. There are two different conformational molecules in the crystal structure of form A while the conformations of the molecules in the crystal structure of form B are the same. The selected bond lengths and bond angles are listed in Table S2 in the Supporting Information. The bond lengths of carbon atoms between aromatic ring and methyl groups for the two polymorphs exhibit obvious difference which may be related to the positional disorder of methyl groups and hydrogen atom. Additionally, the bond lengths and bond angles of C−OC are very different for the two polymorphs. For example, the bond lengths of O(1)C(1) and O(1′)C(1′) in form A are 1.391 Å and 1.404 Å, respectively. They are shorter than the bond length of O(1)C(1) (1.411 Å) in form B. Furthermore, it was also found that the crystal structures of these two single crystals are also different in packing models, which can be clearly seen in the crystal packing diagrams in unit cells. Finally, by using the single crystal structure data and the molecular dynamic simulation software (Mercury software), the simulated results of the PXRD patterns of the two forms were obtained. The simulated results and the experimental results of PXRD patterns of form A and form B are shown and compared in

Figure 3. It can be seen that the experimental results are consistent with the simulated results. This can confirm that the accuracy of the crystallographic data elucidated from the single crystals is reliable. 3.2. Characterization of Form A and Form B. The crystal morphology of the two polymorphs of TMHQ-DA is shown in Figure 4. Form B exhibits a rod-like morphology while form A has a thin plate-like shape. So, it is relatively easy to identify the two polymorphs by their shapes. FTIR, Raman, and solid-state 13C NMR spectroscopy, which can offer not only form fingerprints but also insights into the crystalline arrangements of molecules, were also applied to further characterize the two polymorphs. In the mid-infrared spectra (Figure 5), the CH out-of-plane bending vibration of aromatic ring of form A occurs at 871 cm−1, which suggests that there is only one hydrogen atom at benzene ring, and the other five hydrogen atoms of aromatic ring are replaced by other groups. This conclusion is consistent with the molecular structure. However, the CH out-of-plane bending vibration of aromatic ring of form B gives rise to a band at 858 cm−1. This indicates that the only hydrogen atom of benzene ring occupies more than a single site. In other words, the only hydrogen atom is positional disorder. Besides, the symmetric and asymmetric CH stretching vibration of methyl occur at 2870−2958 cm−1 for form A while occur at 2874−2992 cm−1 for form B. This might be also attributed to the positional disorder of the hydrogen atom and methyl groups. In the Raman spectra (Figure 6), the characterization peak at 872 cm−1 for form A and at 859 cm−1 for form B could be observed. These bands 17669

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Figure 4. SEM photographs of form A and form B of TMHQ-DA. Figure 3. X-ray powder diffraction patterns of form A and form B of TMHQ-DA.

can be assigned mainly to the COC stretching symmetric vibrations. The difference of the Raman spectra reflects the difference of the crystal structures of these two forms. Finally, the solid-state 13C NMR spectra (Figure 7) of the two polymorphs exhibit relatively large changes in the chemical shift, including the numbers of bands and the relative peak area, which may be caused by the positional disorder of form B and then the intramolecular symmetry. 3.3. Solvent-Mediated Polymorphic Transformation from Form A to Form B. 3.3.1. Identification of Rate Limiting Steps of the Transformation. The solvent-mediated polymorphic transformation from form A to form B, which was monitored in situ using Raman, ATR-FTIR, and FBRM, was carried out at 320.65 K by adding 10.0 g form A into 200 mL saturated 2-propanol solution. The results are shown in Figure 8. It can be observed from Figure 8 that form B was not detected and the solution concentration maintained at the solubility of the metastable form A before 7000 s, which indicates that the nucleation of the stable polymorph was the controlling step in the transformation process. At the initial stage of the transformation, the amount of the stable polymorph B (represented by Raman data) was increasing and the amount of the metastable polymorph A was decreasing while the solution concentration still kept the plateau

Figure 5. FTIR spectra of form A and form B of TMHQ-DA.

(indicated by ATR-FTIR data). This result revealed that the overall dissolution rate of the metastable polymorph was faster than the overall nucleation and growth rate of the stable polymorph. Therefore, the nucleation and growth of the stable polymorph was the limiting factor. However, at the later stage of the transformation, the concentration of the solution began to decrease, which infers that the overall dissolution rate of the 17670

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the later stage of the transformation process. The slow decline of total counts of solid phase monitored by FBRM may be caused by the Ostwald ripening or aggregation while the steep decreasing of the total counts at the later stage of the transformation was caused by the size and morphology differences of these two forms. The total numbers of particles decreased a lot when small plate-shape particles of form A transformed into big rod-shape particles of form B. The combination of Raman, ATR-FTIR, and FBRM data can provide a clear picture of the transformation process from form A to form B. 3.3.2. Calibration Curve between Solid State Concentration and Raman Data. In order to quantitatively analyze the polymorphic concentration in the solid phase during the solvent-mediated transformation process, the calibration curve between form A and form B concentration and Raman data was constructed. The peak heights of characteristic Raman peak of form A at 872 cm−1 (HA) and form B at 859 cm−1 (HB) were selected to represent the concentration of form A and form B, respectively. The calibration model was built up by correlating the relative peak height HA/(HA + HB) with the actual mole fraction of form A in the slurry nearly the transition temperature. And the calibration curve is shown in the Figure 9.

Figure 6. Raman spectra of form A and form B of TMHQ-DA.

Figure 7. 13C NMR spectra of form A and form B of TMHQ-DA.

Figure 9. Calibration curve constructed by using the relative Raman peak height of form A and form B, HA/(HA + HB).

3.3.3. Influence of Solvent. In order to reveal the influence of solvent on the polymorphic transformation, a series of experiments was performed at 320.65 K by adding 10.0 g form A into 200 mL different saturated solution, including methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, and binary solvents (2-propanol + water). The results are shown in Figure 10. It can be seen from Figure 10a that the induction time of the nucleation of form B was quite short in methanol while it was relatively long in 1-butanol, which can be explained by the driving force and the nucleation rate constant of the stable polymorph. Correspondingly, the transformation time is 1butanol > propanol > ethanol > methanol. In binary solvents, the induction time and transformation time increased with the increasing of the content of water, which can be seen in Figure 10b. This can be explained by the fact that the absolute supersaturation of stable polymorph will decrease with the increasing of water content.

Figure 8. Solvent-mediated polymorphic transformation from form A to form B at 320.65 K in situ monitored by Raman, ATR-FTIR, and FBRM.

metastable polymorph A became slower than the nucleation and growth of stable polymorph B due to the decreasing amount of solid loading of polymorph A. Thus, the dissolution of the metastable polymorph A became the controlling step at 17671

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Figure 11. Effect of temperature on the polymorphic transformation from form A to form B.

to form B, the polymorphic transformation experiments were carried out by first adding 10.0 g form A into 200 mL 2propanol saturated solution at 320.65 K, and then adding 1%, 3% and 5% (w/w) seeds (form B) into the slurry, respectively. The results are shown in Figure 12. It can be seen that the

Figure 10. Effect of solvent on the polymorphic transformation from form A to form B: (a) different pure solvent, (b) 2-propanol + water binary solvent. xp is the mole fraction of 2-propanol.

3.3.4. Influence of Temperature. According to the classical theory, the molecular motion can be accelerated by increasing temperature while the interfacial energy between the solid and liquid phases can be reduced by increasing temperature. Thus, temperature typically has a positive effect on crystal nucleation rate constant and growth rate constant. To illustrate the influence of temperature on the polymorphic transformation, a series of experiments was carried out by adding 10.0 g form A into 200 mL 2-propanol saturated solution at 318.15, 320.65, and 323.15 K, respectively. The results are shown in Figure 11. It can be clearly seen that the induction time and transformation time dropped apparently with the increasing of temperature. This can be explained by the larger nucleation rate constant and larger growth rate constant at higher temperature. Besides, when the temperature was above the transition temperature, the difference between the solubility of the two polymorphs was larger at higher temperature, which could be found from the solubility data of the two polymorphs published in our earlier paper.25 Therefore, there will be a larger driving force for the polymorphic transformation. 3.3.5. Influence of Seeding. In order to investigate the effect of seeding on the transformation of TMHQ-DA from form A

Figure 12. Effect of seeding on the polymorphic transformation from form A to form B.

polymorphic transformation from form A to form B began straightaway once the seeds were added into the slurry, and the transformation time shortened with the increase of the amount of seeds. The results obtained from the seeded experiments further confirmed the conclusion that the nucleation of the stable polymorph was the controlling step in the polymorphic transformation of TMHQ-DA from form A to form B. 3.3.6. Influence of Amount of Solid Loading. To investigate the effect of amount of solid loading on the transformation of TMHQ-DA from form A to form B, the polymorphic transformation experiments with adding 5.0 g, 10.0 g, and 15.0 g of form A into 200 mL saturated 2-propanol solution were carried out at 320.65 K. And in all experiments, 5% (w/w) form B seeds were added into the slurry to eliminate the effect of induction time of the spontaneous nucleation on the transformation processes. The results are shown in Figure 13. As can be seen, the transformation rate was slightly faster in the experiments with the higher loading of form A. The reason 17672

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the metastable polymorph was the controlling step in the polymorphic transformation. The total counts measured by FBRM began to increase once the occurrence of the transformation. This can be explained by the fact that big rod-like particles of form B transformed into small plate-like particles of form A. 3.4.2. Influence of Solvent. To investigate the influence of solvent on the polymorphic transformation from form B to form A, a series of experiments was performed at 293.15 K by adding 10.0 g form B into 200 mL different saturated solution, including methanol, ethanol, 1-propanol, 2-propanol, and 1butanol. The results are shown in Figure 15. Similar results with the transformation from form A to form B were observed.

Figure 13. Effect of amount of solid loading on the polymorphic transformation from form A to form B.

behind this might be that the transformation process was governed by the growth of the stable form in the seeded transformation process. When the amount of solid loading was higher, the absolute amount of seeds was larger although the percentage of the seeds is the same. Therefore, the transformation rate increased concurrently with the growth surface area of stable polymorph caused by the absolute amount of seeds. 3.4. Solvent-Mediated Polymorphic Transformation from Form B to Form A. 3.4.1. Identification of Rate Limiting Steps of the Transformation. Similar to the transformation from form A to form B, the solvent-mediated polymorphic transformation from form B to form A was carried out at 293.15 K by adding 10.0 g form B into 200 mL saturated 2-propanol solution, which was monitored in situ using Raman, ATR-FTIR, and FBRM. The results are shown in Figure 14. It

Figure 15. Effect of solvent on the polymorphic transformation from form B to form A.

3.4.3. Influence of Temperature. To evaluate the influence of temperature on the polymorphic transformation from form B to form A, polymorphic transformation experiments at 278.15, 283.15, 293.15, and 303.15 K were carried out by adding 10.0 g form B into 200 mL saturated 2-propanol solution. The results are shown in Figure 16. Contrary to the transformation from form A to form B, the induction time and transformation time from form B to form A dropped obviously

Figure 14. Solvent-mediated polymorphic transformation from form B to form A at 293.15 K in situ monitored by Raman, ATR-FTIR, and FBRM.

can be observed that the nucleation of the stable polymorph was the governing factor in the transformation process as a result of the induction time of the stable polymorph. At the initial stage of the transformation, the solution concentration still kept the plateau for quite some time, indicating that the nucleation and growth of the stable polymorph was the limiting factor. However, at the later stage of the transformation, the concentration began to decrease, suggesting the dissolution of

Figure 16. Effect of temperature on the polymorphic transformation from form B to form A. 17673

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with the decrease of the temperature. The reason might be that the transformation from form B to form A occurred below the transition temperature, and the difference between the solubility of the two polymorphs would be larger at lower temperature, which could be found from the solubility data of the two polymorphs published in our earlier paper.25 In other words, the driving force of the polymorphic transformation from form B to form A would be higher when the temperature was lower. 3.4.4. Influence of Seeding. To investigate the effect of seeding on the transformation from form B to form A, the polymorphic transformation experiments were performed by first adding 10.0 g form B into 200 mL 2-propanol saturated solution at 293.15 K, and then adding 1%, 3%, and 5% (w/w) seeds (form A) into the slurry, respectively. The results are demonstrated in Figure 17. Similar results with the transFigure 18. Effect of amount of solid loading on the polymorphic transformation from form B to form A.

4. CONCLUSIONS In this work, the crystal structures of form A and form B of TMHQ-DA were solved for the first time by using single crystal X-ray diffraction data. It was found that form A and form B can be distinguished by different space group of P21/c and P21/n, respectively, although both of them belong to monoclinic crystal system. Especially, the position disorder of the methyl groups of the benzene ring of form B was analyzed thoroughly. The information on the crystal structure of TMHQ-DA polymorphs was further confirmed by the FTIR, Raman, and solid-state 13C NMR data. By polymorphic transformation experiments between form A and form B of TMHQ-DA, it was found that the nucleation of the stable polymorph is the controlling step at the initial stage of the transformation processes under the situation of no seeding was introduced. At the later stage of the transformation processes, the crystal growth and the dissolution of the metastable form will become more and more important. The operating parameters, such as solvent, temperature, seeding, and solid loading, can influence the transformation processes significantly.

Figure 17. Effect of seeding on the polymorphic transformation from form B to form A.

formation from form A to form B were observed. The seeding had successfully eliminated the induction time of nucleation of the stable polymorph and the transformation rate increased with the increase of the amount of seeds. One thing to be noted was that the transformation rate in the experiment without seed was higher than experiments with seeding once nucleation has happened. This can be explained by the fact that spontaneous nucleation will generally produce enormous amount of nuclei that will result in large surface area for subsequent crystal growth. 3.4.5. Influence of Amount of Solid Loading. To investigate the effect of amount of solid loading on the transformation from form B to form A, polymorphic transformation experiments with adding 5.0 g, 10.0 g, and 15.0 g form B into 200 mL saturated 2-propanol solution were carried out at 293.15 K. All experiments were performed with adding 1% (w/w) form A seeds into the slurry to eliminate the effect of induction time of the nucleation of the stable polymorph on the transformation processes. The results are shown in Figure 18. As can be seen, the transformation rate was slightly faster in the experiments with the higher solid loading of form B, which was similar to the transformation from form A to form B. The reason behind this phenomenon can also be explained by the larger crystal surface for the growth of stable form in the higher solid loading situation.

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ASSOCIATED CONTENT

S Supporting Information *

Tables S1 and S2 as described in the text. This material is available free of charge via the Internet at http://pubs.acs.org/.

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AUTHOR INFORMATION

Corresponding Author

*Phone: 86-22-27405754. Fax: 86-22-27314971. E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work is supported by National Natural Science Foundation of China (No. 21176173) and Tianjin Municipal Natural Science Foundation (No. 11JCZDJC20700). The Raman systems used in this study is supported by Kaiser Optical Systems.

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REFERENCES

(1) Grant, D. J. W. Polymorphism in Pharmaceutical Solids; Brittain, H. G., Ed.; Marcel Dekker: New York, 1999; pp 1−34. 17674

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dx.doi.org/10.1021/ie4028389 | Ind. Eng. Chem. Res. 2013, 52, 17667−17675