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Real-time formation monitoring of cocrystals with a different stoichiometry using probe-type low-frequency Raman spectroscopy Motoki Inoue, Hiroshi Hisada, Tatsuo Koide, James Carriere, Randy Heyler, and Toshiro Fukami Ind. Eng. Chem. Res., Just Accepted Manuscript • DOI: 10.1021/acs.iecr.7b03141 • Publication Date (Web): 24 Oct 2017 Downloaded from http://pubs.acs.org on October 28, 2017

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Industrial & Engineering Chemistry Research

Real-time formation monitoring of cocrystals with a different stoichiometry using probe-type low-frequency Raman spectroscopy Motoki Inoue1*, Hiroshi Hisada1, Tatsuo Koide2, James Carriere3, Randy Heyler3, and Toshiro Fukami1

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Department of Molecular Pharmaceutics, Meiji Pharmaceutical University, Kiyose,

Tokyo 204-8588, Japan, 2Division of Drugs, National Institute of Health Sciences, Setagaya, Tokyo 158-8501, Japan, 3 Ondax Inc., Duarte Rd., Monrovia, CA 91016, USA

*Corresponding author: Motoki INOUE

Department of Molecular Pharmaceutics, Meiji Pharmaceutical University

2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan

TEL. & FAX: +81-42-495-8915

E-mail: [email protected]

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KEYWORDS: low-frequency Raman spectroscopy; cocrystallization; process analytical technology (PAT); reaction crystallization method (RCM); carbamazepine; 4-aminobenzoic acid

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Abstract In the cocrystallization process, real-time monitoring is effective for obtaining cocrystal products with a consistent quality. Low-frequency Raman spectra reflect the lattice vibration derived from crystalline differences; therefore, Raman spectroscopy is expected to be useful for monitoring pharmaceutical cocrystals, which are difficult to distinguish by Raman spectroscopy in the fingerprint region. We attempted to monitor the formation of cocrystals with 1:1 and 2:1 cocrystals consisting of carbamazepine and 4-aminobenzoic acid using probe-type low-frequency Raman spectroscopy. Real-time measurements were performed while stirring a composition known to form 1:1 and 2:1 cocrystals via reaction crystallization methods, and the spectra derived from the cocrystals were confirmed after 5 min. To monitor the transition of cocrystals toward a stoichiometry of 2:1 from 1:1 and toward 1:1 from 2:1, specified amounts of raw materials were added to the cocrystals suspended in ethanol. The cocrystals with a different stoichiometry were transformed after 3 hours.

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1. Introduction A cocrystal is a molecular crystal formed by hydrogen bonding or intermolecular interactions between active pharmaceutical ingredients (APIs) and coformers. The cocrystallization of APIs can improve their physicochemical properties, such as solubility and melting point, as well as their mechanical properties.1-6 As a result of recent research, pharmaceutical dosage forms containing cocrystals with improved physicochemical properties of the API have been marketed in Japan.7 Cocrystals show different crystalline structures compared with those of the original APIs and coformers, enabling their analysis by powder X-ray diffraction (PXRD), solid state NMR, thermal analysis, and vibrational spectroscopic methods.8 Raman spectroscopy is widely used in the pharmaceutical industry because it is not affected by the adsorption of water molecules, in contrast to near-infrared (NIR) and IR spectroscopy.9-11 Some studies have performed in situ monitoring of cocrystallization using probe-type Raman spectroscopy. Rodriguez et al. monitored cocrystal formation during the reaction crystallization method (RCM) using Raman spectra in real time.12 13 Soares et al. performed data collection in-line and on-line by Raman spectroscopy coupled to multivariate curve resolution (MCR) analysis to understand crystal transformation.14 These studies have reported only the fingerprint region of Raman

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spectra; however, it is difficult to analyze similar spectra in the fingerprint region of crystalline polymorphs and cocrystals such as caffeine and new promising API candidates.15 The signal intensity of low-frequency Raman spectra is higher than that in the Raman spectra of the fingerprint region, and low-frequency Raman spectra reflect lattice vibrations derived from the crystalline form.16,17 In a previous study, we revealed that low-frequency Raman spectroscopy could be used for chemical imaging of cocrystals in a physical mixture consisting of caffeine and 4-hydroxybenzoic acid.18 In addition, it is expected that low-frequency Raman spectroscopy can monitor the formation of cocrystals during the manufacturing process. The manufacturing of cocrystals involves crystallization from solution, spray- and freeze-drying, grinding and hot-melt extrusion.19,20 We have reported the properties of probe-type low-frequency Raman spectroscopy for real-time monitoring of crystalline API transformation.

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The

low-frequency Raman spectra analyzed using a chemometrics tool are expected to be useful for cocrystal formation monitoring as a process analytical technology (PAT). Since functional groups between cocrystals with different stoichiometry are not different, it is difficult to distinguish using Raman spectra from the fingerprint region. We

therefore

choose

cocrystals

with

different

stoichiometry

consisting

of

carbamazepine and 4-aminobenzoic acid as model. This is the first report in which the

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monitoring of cocrystal formation uses probe-type low frequency Raman spectroscopy analyzed by MCR. We conclude that probe-type low-frequency Raman spectroscopy can be applied for the cocrystal formation process as a PAT tool.

2. Experimental 2.1. Materials Carbamazepine (CBZ) and 4-aminobenzoic acid (PABA) were purchased from Tokyo Chemical Industry (Tokyo, Japan). Ethanol was purchased from Wako Pure Chemical Industries, Ltd. (Osaka, Japan). 2.2. Preparation of cocrystals with a different stoichiometry For the preparation of 1:1 and 2:1 cocrystals,12 a mixture of CBZ:PABA:ethanol of 5:15:80 and 9.3:5.7:85 (w/w)% was placed into 50 mL tubes and stirred with a magnetic stirrer (1000 rpm). After monitoring the formation process in a suspension, the precipitates were collected by filtration, and the amounts of the precipitates of 1:1 and 2:1 cocrystals in the suspension were 0.86 g and 1.51 g, respectively. The crystalline form of the obtained precipitates was identified using powder X-ray diffraction (PXRD, Rigaku Miniflex, Rigaku Corp., Tokyo, Japan). PXRD was performed at a voltage of 30 kV and a current of 15 mA, with scanning angles in the range of 5-35°, a scan speed of

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4° min-1, and a Cu Ka radiation source. The PXRD patterns of the prepared cocrystals were in agreement with those from a previous report. The obtained cocrystals were confirmed by PXRD (Supporting Information, Figure S1). 2.3. Monitoring of the early reaction stage during the RCM To investigate the ability to discriminate raw materials and the quantitatively measure the mixing ratio using MCR, CBZ (1.7 g) and PABA (1.7 g) were stirred and monitored, and then, after 2 min, 16.6 g of ethanol was added. 2.4. Monitoring of the transition to cocrystals with a different stoichiometry To monitor the transition to 2:1 cocrystals (CBZ:PABA:ethanol= 4.55 g:2.79 g:39.15 g= 9.3:5.7:85 (w/w%)) from 1:1 cocrystals, 3.62 g of CBZ and 24.15 g of ethanol were added to the suspension of 1:1 cocrystals (CBZ:PABA:ethanol of 0.93 g:2.79 g:15 g= 5:15:80 (w/w)%). In addition, for the transition to 1:1 cocrystals (CBZ:PABA:ethanol of 1.65 g:4.95 g:25.4 g= 5:15:80 (w/w)%) from 2:1cocrystals, 3.95 g of PABA and 10.4 g of ethanol were added to the suspension of 2:1 cocrystals (CBZ:PABA:ethanol= 1.65 g:1.0 g:15 g = 9.3:5.7:85 (w/w)%). 2.5. Spectroscopic data A THz-Raman® Probe system (TR-PROBE, excitation laser wavelength: 853 nm, notch filter, Ondax Inc., Monrovia, CA, USA) with a BallProbe (1/2 inch diameter, 10

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inch length by MarqMetrix, Seattle, WA, USA) was attached to an RXN2 Raman spectrometer (Kaiser Optical Systems Inc., Ann Arbor, MI, USA). The tip of the probe was immersed into the tubes. A dedicated computer system was used to collect the spectra using Holograms software version 4.2 (Kaiser Optical Systems Inc.). The measurement region was -900 to +900 cm-1 at an excitation wavelength of 853 nm and with a spectral resolution of 4 cm-1. The obtained spectra were pre-treated by normalization and then analyzed using HoloReact software (Kaiser Optical Systems, Inc.). The analysis region was 10–200 cm-1. Real-time measurements were obtained using the Hologram software (Kaiser Optical Systems, Inc.). The crystallization analysis was performed using MCR, which was part of the HoloReact software.22,23

3. Results and discussion 3.1. Low-frequency Raman spectra of cocrystals with a different stoichiometry In the batch manufacturing of cocrystals, it is important to monitor the quality of the resulting cocrystals. Raman spectroscopy is a useful PAT technique because it can be simply and quickly analyzed without pretreatment. Rodrigez et al. reported Raman spectra for a fingerprint region of cocrystals with a different stoichiometry. However, only small peak shifts were observed in the range of 250–270 cm-1. In our study,

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monitoring of cocrystals with a different stoichiometry was performed using low-frequency Raman spectroscopy, which can detect skeletal vibrations derived from the differences in the crystalline forms. Figure 1 shows the low-frequency Raman spectra of ethanol, CBZ, PABA, and 2:1 and 1:1 cocrystals. Clear differences were observed between the compounds, and the same was expected when monitoring the formation of cocrystals using MCR analysis. 3.2. Formation monitoring of 1:1 cocrystals Figure 2 (a) shows the formation of 1:1 cocrystals with external view changes during the RCM, and Figure 2 (b) shows the waterfall plot of the spectra, which subtract the ethanol spectrum from each spectrum. In this study, the focal length of the BallProbe is enough short, so signal from the empty tube was not detected. So, only ethanol was subtracted from each spectrum. 0 min indicates just before the ethanol was added. As can be seen in Figure 2(a), the solution turned white and turbid. After 3 min, the turbidity was low enough to visualize the probe and stirrer; this finding indicated that CBZ and PABA had dissolved into the ethanol. After 5 min, as the suspension became darker, and spectra with peaks at 44, 75, 121, 174, and 180 cm-1 derived from the 1:1 cocrystals were confirmed. Therefore, it was considered that the resultant suspension was derived from 1:1 cocrystals; however, spectra were not detected for the raw

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materials CBZ and PABA because they immediately dissolved in the ethanol. 3.3. Detection of the API and coformer at an early reaction stage As noted in the previous section, the raw materials could not be detected because they rapidly dissolved in ethanol. Therefore, attempts were made to monitor the process at an early reaction stage during the RCM when the raw materials CBZ and PABA were dissolving in ethanol. The usual assumption in MCR is that the obtained spectral data are mixtures of a plurality of the pure components (principal components: PCs). This means it can be divided into pure components (S) with associated concentration (C) from the obtained spectrum (X) according to the equation.24 X=CST＋E Where E is residuals not explained by the chemical species. In this study, PC-1 and PC-2 corresponded to pure components (S), relative intensity corresponded to C, respectively. Figure 3 shows the spectra changes obtained by MCR analysis, resulting in 3 components: Principal component-1 (PC-1), PC-2, and PC-3, which correspond to the spectra of ethanol, PABA, and CBZ, respectively. Before ethanol was added, the relative intensity of CBZ to PABA was 0.31 to 0.69 from MCR analysis. This intensity agreed with the molar charge ratio (CBZ:PABA = 0.37:0.63). After ethanol was added, the signals of CBZ and PABA immediately decreased, and then, both signals were

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undetectable after 1 min. Therefore, a concentrated suspension of crystalline compounds can be monitored using probe-type low-frequency Raman spectrometry. 3.4. Determination of the formation time of 2:1 cocrystals To determine the formation time of 2:1 cocrystals, similar experiments were performed. Figure 4 shows an overview of the changes in the RCM and the waterfall plot of the spectra, which subtract the ethanol spectrum from each spectrum. Turbidity appeared after 5 min, with indicative peaks at 40, 57, 82, 101, and 171 cm-1 of the 2:1 cocrystals, indicating that the precipitates corresponded to 2:1 cocrystals. The spectra were resolved by MCR analysis, resulting in two components, PC-1 and PC-2 (Figure 5(a)). PC-1 and PC-2 correspond to ethanol and 2:1 cocrystals, respectively. Figure 5(b) shows the signal intensity of the 2:1 cocrystals (PC-2), and the intensity after 10 min was set as 1. After 3 min, the intensity increased rapidly, and then, after 5 min, the intensity was constant. Therefore, the reaction was nearly complete after 5 min. 3.5. Transition monitoring of cocrystals between different stoichiometries We investigated the distinguishability of cocrystals as they transitioned between different stoichiometries. Figure 6(a) shows PC-1, -2, and -3 extracted from the spectral data by MCR analysis. The obtained PC-1, -2, and -3 correspond to 1:1 cocrystals, 2:1 cocrystals, and ethanol, respectively. The intensities of 1:1 and 2:1 cocrystals are plotted

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in Figure 6 (b). The plots intersected after 1 h, which indicated that approximately half the amount of 1:1 cocrystals transformed into 2:1 cocrystals. After 3 h, the intensities of PC-1 and PC-2 showed constant values, and the reaction was complete. We also investigated the transition to 1:1 cocrystals from 2:1 cocrystals. Figure 7 shows the monitoring of this transition according to the MCR analysis, along with the relative concentration changes in PC-1 and PC-2. Similar results were obtained with changes to 2:1 cocrystals from 1:1 cocrystals. In both experiments (Figures 6 and 7), the extracted loading plots are PC-1, -2 and -3. The noise in the spectrum obtained in Figure 6 is smaller than that in Figure 7, because the final sample concentration used in Figure 6 is higher than that in Figure 7. Therefore, the profiles of PC-1 and PC-2 (Figures 6(a) and 7(a)) are different, but there are no differences in major peak positions between PC-1 and PC-2 in Figure 6 and 7, so we can extract the same components.25 The differences in sample concentration result in a negative relative intensity change for both PC-1 and PC-2 in Figure 7(b). At the end of the reaction, the average of the PC-1 and PC-2 shows approximately 1 and 0, respectively. The time of the change between the cocrystals with different stoichiometries was longer than the formation time of cocrystals from the raw materials because the 1:1 and 2:1 cocrystals were considered to coexist in equilibrium states in solution.12 The above results reveal that probe-type low-frequency Raman

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spectroscopy can be used for in situ formation monitoring of cocrystals with a different stoichiometry.

4. Conclusion In this study, we clarified that probe-type low-frequency Raman spectroscopy can be used for in situ monitoring of the formation of cocrystals. Furthermore, this technique can be used to monitor the transformation between cocrystals with a different stoichiometry and determine the reaction rate and time. Therefore, probe-type low-frequency Raman spectroscopy is a useful PAT for cocrystallization processes.

Acknowledgements The authors thank Kaiser Optical Systems Inc. for their instrumental support. This work was supported by JSPS KAKENHI Grant Numbers 16K18867.

Supporting Information Figure S1 showing PXRD patterns of CBZ, PABA, 1:1 and 2:1 cocrystals.

References

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Figure 1 Low-frequency Raman spectra of ethanol, CBZ form III, PABA, and 1:1 and 2:1 cocrystals of CBZ and PABA, from top to bottom. 190x190mm (96 x 96 DPI)


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Figure 2 Changes of CBZ:PABA:ethanol = 5:15:80 (w/w%) during the RCM: (a) an overview and (b) lowfrequency Raman spectra. 199x144mm (96 x 96 DPI)



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Figure 3 Monitoring of the initial state of RCM (a) principal components (PCs) from MCR analysis and (b) relative intensity changes of PC-2 and PC-3. 228x128mm (96 x 96 DPI)


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Figure 4 Changes of CBZ:PABA:ethanol = 9.3:5.7:85 (w/w%) during the RCM: (a) an overview and (b) lowfrequency Raman spectra. 188x129mm (96 x 96 DPI)



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Figure 5 Formation monitoring of 2:1 cocrystals (a) principal components (PCs) from MCR analysis and (b) relative intensity changes of PC-2 (2:1 cocrystals). 249x126mm (96 x 96 DPI)


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Figure 6 Monitoring the change to 2:1 cocrystals from 1:1 cocrystals (a) principal components (PCs) from MCR analysis and (b) relative intensity changes of PC-1 and PC-2. 244x151mm (96 x 96 DPI)



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Figure 7 Monitoring the change to 1:1 cocrystals from 2:1 cocrystals (a) principal components (PCs) from MCR analysis and (b) relative intensity changes of PC-1 and PC-2. 245x150mm (96 x 96 DPI)


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