Investigation into the Cooling Crystallization and ... - NSFC

Article pubs.acs.org/OPRD

Investigation into the Cooling Crystallization and Transformations of Carbamazepine Using in Situ FBRM and PVM Wenju Liu,†,‡ Hongyuan Wei,*,†,‡ Junting Zhao,† Simon Black,§ and Chen Sun† †

College of Chemistry and Chemical Engineering, Henan University of Technology, Zhengzhou, China School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, China § Pharmaceutical Development, AstraZeneca, Macclesfield SK10 2NA, U.K. ‡

ABSTRACT: The cooling crystallization of carbamazepine (CBZ) from 1-propyl alcohol has been investigated experimentally using in situ FBRM and PVM to study crystal growth and transformations. The effects of seeding strategies and cooling profiles on nucleation, growth, and polymorphism were investigated. The trigonal form II of CBZ, which has a needle-like morphology, was obtained in 72% yield from an unseeded crystallization process. Block-shaped crystals of CBZ form III were obtained in 86% yield from a crystallization process that was seeded with form III. Both product CSD and crystal form were influenced significantly by cooling profiles. As the cooling rate in the seeded process increased, the levels of form II in the product decreased. The transformation from form II to form III during crystallization was studied using online tools and offline measurements by optical microscopy, X-ray powder diffraction (XRPD), and differential scanning calorimetry (DSC).

1. INTRODUCTION Polymorphism, in which multiple crystal forms exist for the same chemical compound, is of significant interest to the pharmaceutical industry. Various crystal forms (polymorphs and/or solvates) may appear during crystallization, depending on factors such as solvent, temperature, additives, and cooling rate.1−7 These forms may exhibit significantly different physicochemical properties, such as crystal shape, solubility, hardness, color, melting point, and chemical reactivity. Because of differences in stability and solubility, transformation from one form into another can occur either in the solid state or more readily via solvent-mediated transformation. However, the crystallization behavior of such systems and the transformation processes are usually complex and not yet well understood. Various offline analytical techniques, including X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC),8 and thermal gravimetric analysis (TGA), have been used to characterize the forms obtained during crystallization. Recently there has been increased interest in using in-line technology9−11 to study crystallization processes. Focused beam reflectance measurement (FBRM) and particle vision measurement (PVM) instruments are powerful in-line tools for monitoring changes in particle size and morphology. Applying these tools in the crystallization process of polymorphs has been of great benefit in understanding the process dynamics and phase conversion,12−15 as well as other associated processes such as agglomeration and breakage. Carbamazepine (CBZ, Scheme 1), a first generation anticonvulsant used in the treatment of epilepsy and trigeminal neuralgia, is an interesting system not only from a pharmacological view but also as a model compound for the study of polymorphs,16−18 solvates,19 and cocrystals,20 as well as computational studies of the real and hypothetical (computer-generated) polymorphs.21−23 There has been much confusion about the naming of CBZ polymorphs.18,24−26 For the purpose of this paper and for clarity, the nomenclature © 2013 American Chemical Society

Scheme 1. Structure of CBZ

of Grzesiak et al.18 is adopted here. CBZ has at least four anhydrous polymorphs and a dihydrate, as well as a lengthy list of solvates. The stability of the four anhydrous forms of CBZ at ambient temperatures is form III > form I > form IV > form II (trigonal). Form III is the most stable polymorph at room temperature and always is used as commercial material. Transformations involving forms I and III, and forms III and dihydrate, have been investigated previously.27−29 The focus of this study is on transformations from form II to form III and the implications for attempts to crystallize form III. Form III crystallizes as blocks, whereas form II gives thin needles. Preliminary experiments confirmed that the transformation from thin needles of CBZ form II to blocks of CBZ form III was accompanied by a large decrease in Lasentec FBRM total counts. In this study, the effects of seeding strategies and cooling profiles on nucleation, growth, and polymorphs of CBZ are investigated using in situ FBRM and PVM. Also, the influence of temperature on the transformation of form II to form III was studied using X-ray powder diffraction (XRPD). Received: March 15, 2013 Published: October 9, 2013 1406

dx.doi.org/10.1021/op400066u | Org. Process Res. Dev. 2013, 17, 1406−1412

Organic Process Research & Development

Article

2. EXPERIMENTAL SECTION 2.1. Materials. Carbamazepine (CBZ; 5H-dibenz[b,f ]azepine-5-carboxamide) as obtained from Suzhou Hengyi Pharmaceutical Co. Ltd., China is 99% pure and is form III, verified by XRPD. 1-Propyl alcohol, purchased from Tianjin Kewei Chemical Reagent Co., China, was of analytical reagent grade, purity >99%, and was used as supplied. Figures 1 and 2

images updated every 10 s. The FBRM and PVM probes were inserted into the middle of the crystallizer under the surface of the solution 15 mm in depth. The cooling profiles in seven experiments are given in Table 1. Experiments 1−4 were Table 1. CBZ crystallization experiments expt

seed

cooling profile

1 2 3

none 1% 1%

4 5 6 7

1% none none none

0.5 K/min to 47 °C, hold 30 min; 0.5 K/min to 5 °C 0.1 K/min to 40 °C; 0.2 K/min to 20 °C; 0.5 K/min to 5 °C 0.5 K/min to 58 °C, hold 1 h; 0.5 K/min to 47 °C, hold 30 min; 0.5 K/min to 5 °C 0.5 K/min to 47 °C, hold 30 min; 0.2 K/min to 5 °C 3 K/min to 50 °C, hold 10 h 3 K/min to 40 °C, hold 10 h 3 K/min to 30 °C, hold 10 h

designed to investigate the effect of cooling profile and seeding on the crystallization of CBZ. Experiment 1 was unseeded, whereas in experiments 2−4, 1% form III seed was added at 58 °C. Experiments 5−7 were cooled rapidly and held at different temperatures for 10−12 h. During this time, the solventmediated transformation from form II to form III was expected to occur, and samples were taken intermittently and filtered immediately using a micromembrane filter. After being dried at 40 °C for 12 h, powder diffraction data were collected using Xray powder diffraction. 2.3. Sample Analysis. The samples were measured with the X-ray diffractometer (D/MAX 2500) at 40 kV, 200 mA, and a scanning rate of 0.02°/min over the range 2θ = 3−50°, using Cu Kα radiation of wavelength 1.5406 Å. Crystal morphologies were examined with a scanning electron microscope (Philips 30 XL Holland) operating at 20 kV, 100 mA. The samples were mounted on a glass stub with double adhesive tape and coated under vacuum with gold in an argon atmosphere prior to observation. The CSDs (crystal size distributions) were measured by Malvern Mastersizer. The form(s) present in solid samples crystalline can be monitored by XRPD,30 differential scanning calorimetry (DSC), solid-state NMR, infrared spectroscopy (IR), or Raman spectroscopy.31 In this study, we chose to use XRPD on the basis of the following advantages. Quantitative X-ray diffraction analysis has been applied in many areas, such as the

Figure 1. XRPD spectra of CBZ forms II (top) and III (bottom).

show the characteristic XRPD patterns and scanning electron micrographs for both forms, illustrating that crystals of form III are prismatic, whereas those of form II are needle-like. 2.2. Crystallization Experiments. A 500-mL glass cylindrical crystallizer with a jacket to circulate the thermostatted water was used. All crystallizations were carried out by dissolving 18.6 g of carbamazepine in 250 mL of 1-propyl alcohol at 70 °C (10 °C above saturation) with an impeller (with two lune blades of diameter 65 mm) at 160 rpm. The system was held at a steady state at 70 °C for 30 min and then cooled at various rates. The final crystals were filtered and then dried. Two probes were used to visualize the crystallization processes in real time. A Lasentec FBRM (model M400LF) probe, with a chord length measurement range of 0.25−1000 μm, was used with the sampling interval set at 5 s. A PVM probe (model 800L) was also used to provide microscale online

Figure 2. SEM photographs of CBZ forms II and III. 1407



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Figure 3. Variation of FBRM particle counts over time in experiment 1.

Figure 4. Variation of FBRM particle counts over time in experiment 3.

Figure 5. Comparison of FBRM total count profiles (left) and PVM images (right) for experiments 1 and 3.

and IoB represent the intensities of the strongest diffraction peaks for pure forms A and B respectively.

analysis of mine dust, quartz, heavy metal carbides, inorganic compounds, organic compounds, and pharmaceutical systems. By measuring the rate of disappearance or appearance of a unique peak, the kinetics of the transformation between two crystal forms can be monitored. However, preferred orientation may limit the accuracy of this method. In this study, ratios of peak intensities were calculated used to track the progress of the transformation from form II to form III, as suggested by Zhu.32 The parameter XA, as defined in eq 1, was used to monitor the transformation: XA = Ii A /(Ii A + Ij B(I o A /I o B))

3. RESULTS AND DISCUSSIONS 3.1. Comparative Study of Unseeded and Seeded Crystallization. Figure 3 shows the development of various FBRM chord length parameters over time, during experiment 1. At t1 there is a sharp increase in the particle counts measured by the FBRM, which may be attributed to the spontaneous nucleation of CBZ form II. The signal is almost constant for 30 min during the temperature hold, increasing again during cooling, with a relatively small increase towards the end. The counts in smaller size channels of 0−10, 10−20, and 20−50 μm show similar trends. The curves for the larger three channels of 50−100, 100−200, and 200−1000 μm show a sharp increase in

(1)

where IiA and IjB are the intensity of diffraction peak of the ith and jth diffraction line of form A and form B, respectively. IoA 1408



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Figure 6. Optical micrographs (left, the upper picture is of solvent-wet crystals, and the lower picture is after drying at 50 °C) and TG−DTA (centre) and DSC (right) of CBZ form II, as prepared in experiment 1.

Figure 7. Effect of different cooling rates in experiments 2, 3, and 4.

the form II CBZ crystals grown from 1-propyl alcohol revealed a clear 3.4% loss of weight between 143 and 205 °C. This weight loss is consistent with the very small endothermic event in the DSC trace. These crystals also became dark, when viewed in an optical microscope, after drying at 50 °C under vacuum. These observations can be explained by the release of 1-propyl alcohol from the crystal structure. This structure (CCDC reference CBMZPN03) is characterized by the presence of large structural voids and shows a channel-like structure. Previous studies34 have shown that these channels in the lattice can fill with various small solvent molecules. These can be nearly removed under vacuum, but when the last molecules acting as ‘pit-props’ are removed, then the lattice collapses and turns into form III. This model has been confirmed by single-crystal X-ray diffraction, 1H NMR, and hot stage microscopy, which were used to identify the solvents that can be accommodated in the form II structure and how they were released.35,36 3.2. Effect of the Cooling Rate on Crystal Polymorph. The cooling profiles, FBRM curves, and CSD for the seeded experiments 2, 3, and 4 are shown in Figure 7. Faster cooling rates (a) give lower the particle counts (b). The PVM images (Figure 5) show that the product from experiments 3 and 4 is mainly form III, while a mixture of form II and form III was observed in experiment 2. This phenomenon was consistent with the FBRM measurements: experiment 2 has the highest counts and the most needle crystals of form II. Typical results of offline crystal size distribution (CSD) measurements are presented in Figure 7c. The slowest cooling rate (experiment 2) gave the most form II and the smallest crystals. It is difficult to avoid mixtures of forms under these cooling conditions. 3.3. Transformation. The effect of holding temperature on the transformation behavior was investigated. Temperature profiles and FBRM results for experiments 5, 6, and 7 are shown in Figure 8a and b, respectively. The particle number,

the FBRM counts before the hold and then level off. These data are consistent with nucleation and growth of form II, as expected for a metastable form in a rapid crystallization.33 This is confirmed by the PVM images (Figure 5, top right), which also show no obvious crystal breakage. The FBRM signal shows very little change after 80 min, indicating that breakage is insignificant during this crystallization process. Figure 4 displays the profiles of particle counts from different size channels of FBRM measurement in experiment 3, which was seeded with form III. In Figure 4a, the counts in the three channels covering 0−100 μm exhibit the same trend. However, the counts for the largest channel, 200−1000 μm, are nearly constant as shown in Figure 4b. The distinct increase in the counts measured by the FBRM before t1 corresponds to the addition of the seed. The profiles are flat during the 1-h hold at 58 °C. After t2,, the crystallizer is cooled down from 58 to 47 °C, and the profile increases significantly, possible due to secondary nucleation. In this experiment the final crystals were mainly form III (block-shaped) with only a small fraction of needle-like form II crystals. The significant differences between the profiles for seeded (experiment 3) and unseeded (experiment 1) crystallizations are shown in Figure 5. The higher counts in the unseeded crystallization compared to seeded crystallization are consistent with the PVM images. Experiment 1 gave needles of form II, whereas experiment 3 gave agglomerated blocks. A line drawn across both images will traverse many more needles of form II than agglomerated blocks of form III. This illustrates how the FBRM measurement detects many more particles of form II. The yields of crystallization for experiment 1 and experiment 3 are 72% and 86%, respectively. The difference of the yield may be caused by solubility differences between trigonal polymorph and III of CBZ. Figure 6 shows analysis of the product from experiment 1 by optical microscopy, TG-DTA, and DSC. TG-DTA analysis of 1409



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Figure 8. Cooling profiles (left) and FBRM profiles (right) in experiments 5, 6 and 7.

Figure 10 shows the temporal evolution of the chord length distribution during experiment 6. Nucleation and growth of

which reflects the crystal form, varies with holding temperature. There is a steep increase for particle counts when the system is cooled from 70 °C. Thereafter the increase in particle counts is very slow in the systems operated at holding temperatures of 30 and 50 °C. However, in the system held at 40 °C, the particle counts increased rapidly to reach a peak, then decreased, and leveled off. These observations suggest that form II crystallizes rapidly during cooling and then transforms slowly during the hold to form III. This was confirmed by PVM observations and XRD measurements. The results suggest the conditions in experiment 6 were particularly favorable for the initial crystallization of form II. The progress of the transformation was monitored by offline XRPD. Figure 9 shows XRPD measurements of CBZ crystals

Figure 9. XRPD spectrum of CBZ sampled at different times in experiment 5.

Figure 10. FBRM chord length distributions at various times during experiment 6.

sampled at different times in experiment 5. The temporal evolution of XRPD patterns of the crystal samples clearly indicate the transformation occurring in the solution. t = 0 min in Figure 9 is the time when the temperature reaches 50 °C, which is different with the time scale used for FBRM profiles (Figures 7 and 8). The amount of form II (characteristic peak at 13.6°) decreased from 0 to 30 min. After 30 min, the intensity of the peak changed very little. The PVM observations also confirm that form III crystals start to appear at 3 min. No significant change was observed after 30 min, even when left for a long period of 10 h. The final crystal product is a mixture of trigonal polymorph (needle-like) and form III (block-like). Hence the transformation at 50 °C is slow and incomplete.

form II are observed by a steady rise in counts in the first 15 min. From 15 to 21 min the FBRM chord length distribution is almost constant. Figure 10b shows that after 21 min there is a decrease of peak in chord length distribution, and the amount of smaller crystals decreased. The change is due to the dissolution of form II. After 37 min, the amount of the bigger crystals increases, consistent with growth of form III. No differences in chord length distribution are observed after 60 min (not shown), which indicates the transformation had almost finished or became very slow. PVM images of a typical polymorphic transformation of CBZ at 40 °C are shown in Figure 11; 0 min is the time when the 1410



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Figure 11. PVM images during experiment 6.

system temperature reaches at 40 °C. The images confirm that the transformation from form II to form III is solutionmediated. Form III crystals start to appear at 30 min, and the transformation is almost complete after 70 min. Furthermore, it was found that the CBZ crystals in form III grow from the surface of form II. The surfaces of new crystals of CBZ form III are normally uneven, and the crystals have some extent of agglomeration. Figure 12 shows XRPD data of the samples from experiment 6 (at 40 °C) in a three-dimensional format. The intensities of

taken at times between 0 and 30 min, then a diminution of the peak at 2θ ≈ 8°, accompanied by a shift of many of the other peaks to slightly higher 2θ values, would be expected. This would be caused by disordering and escape of the solvent and shrinkage of the lattice, prior to the transformation to form III. Figure 13 shows the monitoring the transformation by the ratio of XRPD peak heights using eq 1 and peaks at 4.9° (form

Figure 12. XRPD of CBZ sampled at different times during experiment 6. Figure 13. Variation of XRPD peak height ratios (X) for samples taken during experiment 6.

form II peaks (4.7°, 8.6°, 13.6° and 24.5°) decrease with the time, while those of form III (15.7° and 25°) increase. There was no significant change for either form after 70 min. This is consistent with the PVM data in Figure 11. This confirms that form II is metastable with respect to form III at 40 °C, consistent with the literature.18 In Figures 9 and 12, the peak at 2θ ≈ 8° may be due to the presence of ordered 1-propyl alcohol molecules in the crystal structure. If diffractograms were

II) and 15.7° (form III). The results are qualitatively consistent with data from the PVM (Figure 11) and FBRM (Figure 10) from the same experiment. From the PVM images of experiment 7 (not shown), it can be seen that needles of form II appeared during the cooling process. However, once the system temperature is below 40 °C, 1411



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rapid nucleation of form III occurs, and form II starts to disappear. By the time the temperature reaches 30 °C, most crystals are form III, with little change during the hold of 7 h. XRPD data (not shown) from the same experiment show little change in samples taken at the beginning and the end of the hold. These experimental data indicate that the temperature is a key parameter for CBZ crystallization and transformation.

4. CONCLUSIONS Unseeded and seeded experiments for CBZ cooling crystallization in a solvent of 1-propyl alcohol were studied using in situ FBRM, PVM, and offline CSD. An unseeded crystallization produced form II with a yield of 72%, whereas crystallizations seeded with form III gave predominantly form III with a yield of 86%. Needle-like crystals of form II nucleated readily in the unseeded crystallization and to a small but significant extent in the presence of form III seed. The progress of the transformation from form II to form III was sensitive to temperature. These results demonstrate how difficult it is to avoid obtaining mixtures of form II and form III when crystallizing CBZ from 1-propyl alcohol. This study also illustrates the challenges that channel solvates pose for characterization and process development.

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AUTHOR INFORMATION

Corresponding Author

*Tel/Fax: +86 22 27400287. E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors would like to thank AstraZeneca UK Limited, National Nature and Science Foundation of China (NSFC, No. 21206032), the Science Foundation of Henan Province (No. 13A530196), and Science Foundation Henan University of technology (No. 2012CXRC08) for their financial assistance in this project.

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REFERENCES

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Investigation into the Cooling Crystallization and ... - NSFC

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