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MCR-ALS analysis of IR spectroscopy and XRD for the investigation of ibuprofen - nicotinamide cocrystal formation
Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 221 (2019) 117142
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MCR-ALS analysis of IR spectroscopy and XRD for the investigation of ibuprofen - nicotinamide cocrystal formation Sae Ishihara a, Yusuke Hattori a,b, Makoto Otsuka a,b,⁎ a b
Faculty of Pharmacy, Musashino University, 1-1-20 Shin-machi, Nishi-Tokyo city, Tokyo 202-8585, Japan Research Institute of Pharmaceutical Sciences, Musashino University, 1-1-20 Shin-machi, Nishi-Tokyo City, Tokyo 202-8585, Japan
a r t i c l e
i n f o
Article history: Received 28 March 2019 Received in revised form 7 May 2019 Accepted 17 May 2019 Available online 18 May 2019 Keywords: MCR-ALS Cocrystal Ibuprofen Nicotinamide IR spectroscopy XRD
a b s t r a c t To improve aqueous solubility, a poorly water-soluble active ingredient is classically combined with a conformer to form cocrystals. Hot melt extrusion is one preparation method for the formation of cocrystal solids. The aim of our study was to determine the optimal temperature conditions for the formation of ibuprofen and nicotinamide cocrystals using real-time infrared (IR) and X-ray diffraction (XRD) measurements. IR spectra and XRD patterns were subjected to multivariate curve resolution alternating least squares (MCR-ALS) analysis and decomposed into several components. Each component was descriptive of a specific step in the formation of the cocrystal. Cocrystal formation was followed by a separation phase between amorphous ibuprofen and crystalline nicotinamide. Our results suggest that, when using the hot melt exclusion method, careful consideration should be made towards optimizing processing temperatures in order to prevent amorphization and promote control over the process of cocrystal formation. © 2019 Published by Elsevier B.V.
1. Introduction More than 70% of candidates currently in development exhibit poor water solubility [1]. The insolubility has hampered the pharmaceutical development of compounds with superior pharmacological properties. The Biopharmaceutical Classification System (BCS) categorizes active pharmaceutical ingredients (API) on the basis of water solubility and membrane permeability [2]. More than 30% of currently marketed drugs are classified as class II [3]. APIs classified as BCS class II are membrane permeable but present poor water solubility. A number of methods have been investigated to increase water solubility hence bioavailability of class II API. Several methods have been reported, and the following have been proposed: micronization [4], nanoisation [5], amorphization [6], solid dispersion [7,8], self-emulsifying drug delivery system [9], inclusion with other substances [10], salt formation [11], and cocrystalization [12]. Since 2000, the process of cocrystal solid formation has been actively studied, especially from the perspective of its crystalline structure, using primarily X-ray diffraction measurements [12]. Similarly to salts, a cocrystal exhibits different physical characteristics that are different from a pure crystal [13–15]. Because salts are formed on the basis of acid-base interactions and ionic bonds, salt formation can only be
⁎ Corresponding author at: Faculty of Pharmacy, Musashino University, 1-1-20 Shinmachi, Nishi-Tokyo City, Tokyo 202-8585, Japan. E-mail address: [email protected] (M. Otsuka).
https://doi.org/10.1016/j.saa.2019.117142 1386-1425/© 2019 Published by Elsevier B.V.
applied to APIs presenting dissociable ionic groups. On the other hand, cocrystals formed by an API and a conformer is reliant on weaker interactions such as hydrogen bond or van der Waals forces; hence, cocrystal formation is preferred when considering the use of APIs containing neutral functional groups. Cocrystals may be prepared using procedures such as co-grinding [16,17], solvent evaporation [18,19], slurry method [20,21], hot melt extrusion [22–24], or the antisolvent method [25]. More recently, supercritical fluid, solvent-mediated phase transition, and ultrasonic methods have also been described [26–28]. In a previous report, we reported that the purity of carbamazepine – nicotinamide cocrystal was dependent on the preparation methods [29]. For example, a solvent evaporation method provides cocrystal solids with a more highly ordered structure than a co-grinding method. As a result the disordered cocrystal obtained from the co-grinding method dissolved faster than the ordered cocrystal [29]. As such, the crystallinity of a cocrystal contributes significantly to the dissolution of API. Therefore, understanding of the mechanisms and kinetics of cocrystal formation allows for closer control and monitoring. There has been few reports on the kinetics of cocrystal formation. R, S-ibuprofen (IBF) [2- (4-isobutylphenyl) propanoic acid] is a nonsteroidal anti-inflammatory drug (NSAIDs) and is widely used for the treatment of arthritis and fever on the basis of its antipyretic and analgesic effects. NSAIDs, including IBF, are known to delay cognitive decline, reduce the incidence of Alzheimer's dementia and provide neuroprotection [30–32]. Nicotinamide (NA) is an amide derivative of niacin, it belongs to the vitamin B group, and was documented to restore cognitive function [33].
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IBF and NA are capable of forming cocrystals [34–41] and as such, may offer more benefits for the treatment of dementia disorders e.g., Alzheimer's disease [34]. The preparation of IBF-NA cocrystal solids was previously reported via solvent evaporation [35,37–39,41], slurry [35], and hot-melt [34,36,40] methods. Kelly et al. previously reported the use of hot-melt extrusion method for the synthesis of cocrystal and described the monitoring of cocrystal formation using in-line near-infrared spectroscopy and partial least squares regression method [36]. Processing temperature is a critical parameter to consider for the optimization of formation ratio and prevention of molecule decomposition. Soares et al. investigated cocrystal formation by evaporation and slurry methods using in-line Raman spectroscopic data and multivariate curve resolution alternating least squares (MCR-ALS) analysis [35]. MCR-ALS is one of the most chemometric methods, used globally for the analysis of spectral data such as IR [42] and Raman [43] spectra. MCR-ALS relies on the decomposition analysis of the corrected spectra of a mixture into the spectra of each individual component. In this study, we aimed to investigate the formation process of IBFNA cocrystal obtained by the hot-melt method with a focus on the processing temperature, using real-time IR and X-ray diffraction measurements. To decompose spectral patterns into single components, IR spectra and XRD patterns were subjected to MCR-ALS analysis. 2. Material and methods 2.1. Materials IBF was kindly provided by BASF Japan (Tokyo, Japan) while NA (3pyridinecarboxamide) was purchased from Wako Pure Chemical Industries (Osaka, Japan). The purity of both compounds was higher than 98.0%. An equimolecular mixture was prepared by mixing IBF (3.14 g, 15.2 mmol) and NA (1.86 g, 15.2 mmol) using a mortar and pestle. All subsequent measurements (detailed below) were made on this mixture. 2.2. Methods 2.2.1. Simultaneous measurements of X-ray diffraction and differential scanning calorimetry (XRD-DSC) XRD-DSC measurements were preformed using a DSC unit (DSC8230, Rigaku, Tokyo) equipped with an X-ray diffractometer (RINT-Ultima III, Rigaku). The XRD patterns were corrected with a Cu Kα radiation (1.54056 Å) with anode at a voltage of 40 kV and current of 40 mA. The XRD patterns and DSC curve of the physical mixture were measured using approximately 15 mg of specimen in a 7 mm- aluminum square pan with a 0.5 mm depth. Aluminum oxide (Al2O3) was used as the reference material. The measurements were performed within the temperature range of 25–100 °C at 1 °C/min heating rate under a nitrogen atmosphere. The diffraction angles were scanned from 5° to 35° in 2θ with 15°/min of scan speed, and thirty-eight patterns were collected. 2.2.2. ATR Fourier-transform infrared (FT-IR) spectroscopy IR spectra were recorded using a Fourier transform infrared spectrophotometer (FT/IR-4100, JASCO, Tokyo) with a temperature controlled attenuated total reflectance (ATR) attachment (Golden gate, Specac, Kent, UK). Approximately 20 mg of the physical mixture was placed on ATR prism of diamond and pressed down to the prism. The mixture was heated from 65 °C to 100 °C, and the spectra were continuously collected with an interval of 50 s upon heating the sample at 1 °C/min. Forty-three spectra were obtained within the spectral range of 600–3500 cm−1. 2.2.3. Non-isothermal kinetic analysis The collected XRD patterns and IR spectra were processed using MCR-ALS analysis to determine the conversion ratio when transitioning
from a state of physical mixture to a cocrystal. The MCR-ALS was carried out using Unscrambler X (CAMO Analytics, Oslo, Norway). Prior to the MCR-ALS calculation, both XRD patterns and IR spectra were processed by smoothing using the Savitzky-Golay method and were normalized to the peak area. Forty-three IR spectra within the spectral range of 600–2070 cm−1 and 2480–3450 cm−1 were used to remove the IR bands due to CO2 gas. For the calculation of XRD patterns, thirty-eight patterns were used within the 2θ range of 5–35°. 3. Results Simultaneously measured XRD-DSC profiles are shown in Fig. 1. The DSC curve showed two endothermic peaks i.e. at 67.9 and 88.6 °C. The DSC curves obtained for IBF and NA as pure materials denoted a single endothermic peak reflective of their melting behavior (data not shown). Since the melting temperatures of IBF and NA are 78.7 °C and 131.7 °C, respectively, the endothermic event observed at 67.9 °C corresponds to the depressed melting point of IBF due to the mixing with NA. The second peak is likely due to the melting of the other solid state. In the XRD patterns, the characteristic peak at 6.0° in 2θ of IBF disappeared with increasing temperature higher than 65 °C, and the peaks at 13.3°, 14.8° due to NA remained at higher temperatures than 65 °C. The changes observed in the XRD patterns also suggest that the former endothermic peak is due to the melting of crystalline IBF while NA is still in a crystalline state. The latter endothermic peak is representative of cocrystal melting, which is line with previous report by Müllers [44]. The diffraction peaks observed at 16.1° and 17.6° correspond to the peak characteristic of the cocrystal state between IBF and NA. These peaks disappeared at a temperature above the melting temperature of 88.6 °C. On the other hand, crystalline NA remained present at higher temperature due to its high melting temperature compared to the second endothermic event. In the mixture IR spectra, several peaks can be observed but they vary as the temperature increases (data not shown). In the higher wavenumber range, the peak observed at 3367 cm−1 decreased upon heating, which may be attributed to the antisymmetric stretching mode of NH2 groups, which are free of interactions with other functional groups [45]. This suggests that while the number of interaction-
Heat flow (mW) 0 -2 -4 100 90 80 70 60 50
Temperature (°C)
2
40 30 (a) (b)
5
10 15 20 25 30 35 2θ (degree)
Fig. 1. XRD-DSC profiles obtained upon application of heat at a rate of 1 °C/min. The XRD patterns of initial materials are shown for NA(a) and IBF (b).
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free NH2 groups of NA decreased, the number of interacting NH2 groups increased upon heating. The other peak observed at 3162 cm−1 may be attributed to the NH2 symmetric stretching mode of the amide groups [45]. The three sharp peaks found at around 2900 cm−1 are due to the C\\H stretching mode of CH3. The intensity of these peaks was enhanced and sharpened upon heating, suggesting that the microenvironment around CH3, such as density, may have changed. In the lower wavenumber range of the IR spectra, several peaks due to amide and carboxyl groups were found. In this range, the most intensive peak at 1702 cm−1 is assigned to the C_O stretching mode of the carboxyl groups belonging to IBF [46]. The other two peaks at 1737 and 1674 cm−1 are also assigned to the C_O stretching mode of IBF and NA, respectively. The peak at 1702 cm−1 is due to the C_O stretching of interacting carboxyl group in the cocrystal [38,39,41] and the other peaks are due to the interaction-free functional groups. The peak changes are representative of either the associations and dissociations between carboxyl and amino groups upon heating. To decompose the obtained IR spectra and further dissect the cocrystallization process, MCR-ALS was carried out. In Fig. 2 are shown the changes in the source amount of each component. Here, we adopted a 4-component analysis including initial mixture, cocrystal, melted IBF, and crystalline NA, on the basis that XRD-DSC showed that the initial mixture transitioned into a cocrystal, and that melted IBF and crystalline NA were among the final products upon further heating. As shown in Fig. 2 (I), the amount of first component moderately increased with increasing temperature. The second and third components respectively decreased and increased at around the melting temperature of IBF. Then the third component inversely decreased when the fourth component increased. The variations between components suggest that the second component is the initial mixture, that the first and fourth components are the final states and the third component is the intermediate product. In Fig. 3 are shown the source spectra of each component and IR spectra of the materials. As expected, the spectrum of the second component matched the spectrum of the initial physical mixture; hence, the second component was correctly attributed to the initial state of
0.06
(I)
0.03
Source amount
0.2
(II)
0.1 0 0.1 0 0.2
(III)
(IV)
0.1 0 65
70 75 80 Temperature (°C)
85
Fig. 2. Changes in the source amounts of individual components calculated from the MCRALS analysis of IR spectra. Amount profiles of the first, second, third, and fourth components are shown in (I) – (IV), respectively.
3
(I) (II) (III) (IV) (a) (b) (c) 3300 3000 1800 1600 1400 1200 Wavenumber (cm-1) Fig. 3. Source spectra resulting from the MCR-ALS analysis of IR spectra: the spectra (I) (IV) correspond to the source component shown in Fig. 2 (I) – (IV), respectively. The other spectra indicate the measured IR spectra obtained for the initial physical mixture (a), IBF (b), and NA (c).
the sample. The source spectrum of the third component was similar to that of the first component; however, except for a sharp peak at 1702 cm−1. We attributed this sharp peak to the stretching mode of the interacting carboxyl groups of IBF. The association of the hydrogen bonds of IBF was represented by the increase in the third component upon heating. The hydrogen bonds between the carboxyl groups of IBF and the amide groups of NA is reflective of the formation of a cocrystal structure hence the increase in the source amount of the third component, which subsequently turns into melted IBF and crystalline NA [34]. As represented in Fig. 2, the cocrystal shifted to first and fourth components. The first component spectrum presents a peak at 1728 cm−1, which is attributed to the interaction-free carboxyl group in contrast to the peak observed at 1702 cm−1. Additionally, there are no peaks around 3400 cm−1 which is classically assigned to amide groups. This suggests that the first component is a material with no amide groups and present fewer interactions; hence, the first component corresponds to the melted IBF. The spectral similarities suggest that the fourth component corresponds to crystalline NA. The decomposition by MCR-ALS successfully resulted in (I) amorphous IBF, (II) initial mixture, (III) cocrystal, and (IV) crystalline NA for the first, second, third, and fourth components, respectively. To confirm the hypothesis that a dynamic competition exists between the cocrystal and the amorphous states, the XRD patterns were subjected to MCR-ALS analysis. In Fig. 4 are represented the changes in the amount of each component upon heating. The XRD patterns were decomposed into four components similarly to the IR spectra. The temperature-dependent changes coincide with the changes shown in Fig. 2. The amount of first component shown in Fig. 4 (i) moderately increased, while the amount of second and third components decreased at first. This confirms our previous conclusions that the second and third components represent the initial mixture and the intermediate state, respectively. When comparing the first and fourth components, the amount of the first component changed prior to the increase in the fourth component and dropped at around 85 °C. Similarly to the ALS-MCR analysis of the IR spectra, the intermediate state competitively transitioned between the first and fourth component. However, there is a difference in the profile of the first component compared to the results from IR spectroscopy. According to the DSC profile, the temperatures of increment and decrement in the first component correspond to the first and second
4
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8000
(i)
4000 0
Source amount
8000
(ii)
4000
The fourth component predominantly displays a halo pattern matching the amorphous solid and several weak positive and negative peaks. The positive and negative peaks on the halo pattern is assigned to the diffraction peaks due to NA and IBF crystal solids, respectively. Positive peaks reflect increment in the component. Hence, the spectra suggest the growth of both amorphous IBF and crystalline NA upon melting of crystalline IBF and cocrystal. In conclusion, the MCR-ALS analysis of the XRD patterns led to the identification of four components respectively assigned to (i) cocrystal, (ii) initial mixture, (iii) intermediate state, and (iv) mixture of amorphous IBF and crystalline NA.
0 8000
(iii)
4000 0 8000 4000
(iv)
0 30 40 50 60 70 80 90 Temperature (°C) Fig. 4. Changes in the source amount of individual components calculated from the MCRALS analysis of XRD patterns. The profiles (i) – (iv) indicate the amount profiles of the first, second, third, and fourth components, respectively.
endothermic events, respectively. Additionally, its source component (Fig. 5) corresponds to the XRD pattern of the cocrystal. Hence, the first component was correctly attributed to the cocrystal structure. The third component represents the intermediate between initial mixture and cocrystal, which was not detected by IR spectroscopy. When comparing the source profiles between the second and third components (Fig. 5), these peaks are very similar albeit a slight peak shift. The differences between these two components is due to the distance differences between molecules in the crystalline structure. In practice, the diffraction peak of the third component appear at lower angle than those of the second component, which means more largely-spaced diffraction planes should be observed in the intermediate state. It is likely that the slight difference in distance does not significantly affect the interactions between molecules and hence is not detectable on the IR spectra.
(i)
4. Discussion As a result of the MCR-ALS decomposition analysis, we determined that a cocrystal structure is achieved via the formation of an intermediate state, and the transition to an amorphous IBF and crystalline NA structure. Kakuda et al. also reported similar findings based on the ALS analysis of XRD-DSC simultaneous measurements [47]. They investigated the crystalline structural change in poly(ethylene imine) film and reported that the polymer film resulted in the transition into an amorphous state upon heat. Structural differences between the initial and intermediate states may be estimated based on the IR spectra and XRD patterns. During the MCR-ALS analysis of XRD patterns, the third component was associated with diffraction peaks occurring at 16.6°, 20.2°, and 22.3° attributed to the IBF crystal, and corresponding to the (210), (012), and (202) diffraction planes, respectively [48]. In the crystalline structure, these planes are nearly perpendicularly-oriented along the hydrogen bonds between carboxyl groups. Hence, the lower diffraction peaks seen in the intermediate state refer to largely-spaced planes or carboxyl groups. The larger spacing induces rearrangement in the hydrogen bonds between carboxyl and amide groups. In the crystal structure reported by Bàthori et al. [49], hydrogen bonds between NA molecules are absent, while the cocrystal structure of IBF-NA reported by Berry et al. [34] presents hydrogen bonds between the amide groups of NA molecules. In the present study, our results revealed that the process of IBF-NA cocrystal formation results from a phase separation between amorphous IBF and crystalline NA upon heating. Cocrystal formation progressed under non-isothermal conditions and the cocrystal state was determined to be a non-equilibrium state. To prepare high purity cocrystal solids, it is hence necessary to optimize the processing temperatures to reach isothermal conditions. Based on our results, we propose that the optimal temperature required for cocrystal formation is restricted to a narrow range. The IR spectra suggested that a temperature of 70 °C could prevent changes to an amorphous state, while the XRD measurements suggested that the optimal temperature ranged between 65 and 70 °C. At temperatures above 70 °C, corresponding to the melting point of IBF, phase separation was shown to be more predominant than cocrystal formation (Fig. 4).
(ii) (iii)
5. Conclusion
(iv) (a) (b)
5
10
15
20 25 2θ (°)
30
35
Fig. 5. Source patterns of individual components calculated from the MCR-ALS analysis of XRD patterns. The patterns (i) – (iv) are the individual components corresponding to the profiles (i) – (iv) shown in Fig. 4, respectively. The other patterns are the measured XRD patterns of the cocrystal (a) and initial samples (b), respectively.
IBF and NA cocrystals were prepared using the melting method. The cocrystal formation process was analyzed by XRD and IR measurements, and the data subjected to MCR-ALS. Our results showed that cocrystal formation entailed expansion of IBF and NA crystal structure, dissociation of hydrogen bonds between IBF molecules, and interactions between NA and IBF molecules. Upon heating, amorphization of IBF and crystallization of NA occurred subsequently to cocrystal formation. Our study highlights the importance of optimizing the processing temperature for the preparation of a high purity cocrystal state. We also report that MCR-ALS is a powerful approach to fragment a complex dataset into a more coherent ensemble.
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MCR-ALS analysis of IR spectroscopy and XRD for the investigation of ibuprofen - nicotinamide cocrystal formation Sae Ishihara a, Yusuke Hattori a,b, Makoto Otsuka a,b,⁎ a b
Faculty of Pharmacy, Musashino University, 1-1-20 Shin-machi, Nishi-Tokyo city, Tokyo 202-8585, Japan Research Institute of Pharmaceutical Sciences, Musashino University, 1-1-20 Shin-machi, Nishi-Tokyo City, Tokyo 202-8585, Japan
a r t i c l e
i n f o
Article history: Received 28 March 2019 Received in revised form 7 May 2019 Accepted 17 May 2019 Available online 18 May 2019 Keywords: MCR-ALS Cocrystal Ibuprofen Nicotinamide IR spectroscopy XRD
a b s t r a c t To improve aqueous solubility, a poorly water-soluble active ingredient is classically combined with a conformer to form cocrystals. Hot melt extrusion is one preparation method for the formation of cocrystal solids. The aim of our study was to determine the optimal temperature conditions for the formation of ibuprofen and nicotinamide cocrystals using real-time infrared (IR) and X-ray diffraction (XRD) measurements. IR spectra and XRD patterns were subjected to multivariate curve resolution alternating least squares (MCR-ALS) analysis and decomposed into several components. Each component was descriptive of a specific step in the formation of the cocrystal. Cocrystal formation was followed by a separation phase between amorphous ibuprofen and crystalline nicotinamide. Our results suggest that, when using the hot melt exclusion method, careful consideration should be made towards optimizing processing temperatures in order to prevent amorphization and promote control over the process of cocrystal formation. © 2019 Published by Elsevier B.V.
1. Introduction More than 70% of candidates currently in development exhibit poor water solubility [1]. The insolubility has hampered the pharmaceutical development of compounds with superior pharmacological properties. The Biopharmaceutical Classification System (BCS) categorizes active pharmaceutical ingredients (API) on the basis of water solubility and membrane permeability [2]. More than 30% of currently marketed drugs are classified as class II [3]. APIs classified as BCS class II are membrane permeable but present poor water solubility. A number of methods have been investigated to increase water solubility hence bioavailability of class II API. Several methods have been reported, and the following have been proposed: micronization [4], nanoisation [5], amorphization [6], solid dispersion [7,8], self-emulsifying drug delivery system [9], inclusion with other substances [10], salt formation [11], and cocrystalization [12]. Since 2000, the process of cocrystal solid formation has been actively studied, especially from the perspective of its crystalline structure, using primarily X-ray diffraction measurements [12]. Similarly to salts, a cocrystal exhibits different physical characteristics that are different from a pure crystal [13–15]. Because salts are formed on the basis of acid-base interactions and ionic bonds, salt formation can only be
⁎ Corresponding author at: Faculty of Pharmacy, Musashino University, 1-1-20 Shinmachi, Nishi-Tokyo City, Tokyo 202-8585, Japan. E-mail address: [email protected] (M. Otsuka).
https://doi.org/10.1016/j.saa.2019.117142 1386-1425/© 2019 Published by Elsevier B.V.
applied to APIs presenting dissociable ionic groups. On the other hand, cocrystals formed by an API and a conformer is reliant on weaker interactions such as hydrogen bond or van der Waals forces; hence, cocrystal formation is preferred when considering the use of APIs containing neutral functional groups. Cocrystals may be prepared using procedures such as co-grinding [16,17], solvent evaporation [18,19], slurry method [20,21], hot melt extrusion [22–24], or the antisolvent method [25]. More recently, supercritical fluid, solvent-mediated phase transition, and ultrasonic methods have also been described [26–28]. In a previous report, we reported that the purity of carbamazepine – nicotinamide cocrystal was dependent on the preparation methods [29]. For example, a solvent evaporation method provides cocrystal solids with a more highly ordered structure than a co-grinding method. As a result the disordered cocrystal obtained from the co-grinding method dissolved faster than the ordered cocrystal [29]. As such, the crystallinity of a cocrystal contributes significantly to the dissolution of API. Therefore, understanding of the mechanisms and kinetics of cocrystal formation allows for closer control and monitoring. There has been few reports on the kinetics of cocrystal formation. R, S-ibuprofen (IBF) [2- (4-isobutylphenyl) propanoic acid] is a nonsteroidal anti-inflammatory drug (NSAIDs) and is widely used for the treatment of arthritis and fever on the basis of its antipyretic and analgesic effects. NSAIDs, including IBF, are known to delay cognitive decline, reduce the incidence of Alzheimer's dementia and provide neuroprotection [30–32]. Nicotinamide (NA) is an amide derivative of niacin, it belongs to the vitamin B group, and was documented to restore cognitive function [33].
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IBF and NA are capable of forming cocrystals [34–41] and as such, may offer more benefits for the treatment of dementia disorders e.g., Alzheimer's disease [34]. The preparation of IBF-NA cocrystal solids was previously reported via solvent evaporation [35,37–39,41], slurry [35], and hot-melt [34,36,40] methods. Kelly et al. previously reported the use of hot-melt extrusion method for the synthesis of cocrystal and described the monitoring of cocrystal formation using in-line near-infrared spectroscopy and partial least squares regression method [36]. Processing temperature is a critical parameter to consider for the optimization of formation ratio and prevention of molecule decomposition. Soares et al. investigated cocrystal formation by evaporation and slurry methods using in-line Raman spectroscopic data and multivariate curve resolution alternating least squares (MCR-ALS) analysis [35]. MCR-ALS is one of the most chemometric methods, used globally for the analysis of spectral data such as IR [42] and Raman [43] spectra. MCR-ALS relies on the decomposition analysis of the corrected spectra of a mixture into the spectra of each individual component. In this study, we aimed to investigate the formation process of IBFNA cocrystal obtained by the hot-melt method with a focus on the processing temperature, using real-time IR and X-ray diffraction measurements. To decompose spectral patterns into single components, IR spectra and XRD patterns were subjected to MCR-ALS analysis. 2. Material and methods 2.1. Materials IBF was kindly provided by BASF Japan (Tokyo, Japan) while NA (3pyridinecarboxamide) was purchased from Wako Pure Chemical Industries (Osaka, Japan). The purity of both compounds was higher than 98.0%. An equimolecular mixture was prepared by mixing IBF (3.14 g, 15.2 mmol) and NA (1.86 g, 15.2 mmol) using a mortar and pestle. All subsequent measurements (detailed below) were made on this mixture. 2.2. Methods 2.2.1. Simultaneous measurements of X-ray diffraction and differential scanning calorimetry (XRD-DSC) XRD-DSC measurements were preformed using a DSC unit (DSC8230, Rigaku, Tokyo) equipped with an X-ray diffractometer (RINT-Ultima III, Rigaku). The XRD patterns were corrected with a Cu Kα radiation (1.54056 Å) with anode at a voltage of 40 kV and current of 40 mA. The XRD patterns and DSC curve of the physical mixture were measured using approximately 15 mg of specimen in a 7 mm- aluminum square pan with a 0.5 mm depth. Aluminum oxide (Al2O3) was used as the reference material. The measurements were performed within the temperature range of 25–100 °C at 1 °C/min heating rate under a nitrogen atmosphere. The diffraction angles were scanned from 5° to 35° in 2θ with 15°/min of scan speed, and thirty-eight patterns were collected. 2.2.2. ATR Fourier-transform infrared (FT-IR) spectroscopy IR spectra were recorded using a Fourier transform infrared spectrophotometer (FT/IR-4100, JASCO, Tokyo) with a temperature controlled attenuated total reflectance (ATR) attachment (Golden gate, Specac, Kent, UK). Approximately 20 mg of the physical mixture was placed on ATR prism of diamond and pressed down to the prism. The mixture was heated from 65 °C to 100 °C, and the spectra were continuously collected with an interval of 50 s upon heating the sample at 1 °C/min. Forty-three spectra were obtained within the spectral range of 600–3500 cm−1. 2.2.3. Non-isothermal kinetic analysis The collected XRD patterns and IR spectra were processed using MCR-ALS analysis to determine the conversion ratio when transitioning
from a state of physical mixture to a cocrystal. The MCR-ALS was carried out using Unscrambler X (CAMO Analytics, Oslo, Norway). Prior to the MCR-ALS calculation, both XRD patterns and IR spectra were processed by smoothing using the Savitzky-Golay method and were normalized to the peak area. Forty-three IR spectra within the spectral range of 600–2070 cm−1 and 2480–3450 cm−1 were used to remove the IR bands due to CO2 gas. For the calculation of XRD patterns, thirty-eight patterns were used within the 2θ range of 5–35°. 3. Results Simultaneously measured XRD-DSC profiles are shown in Fig. 1. The DSC curve showed two endothermic peaks i.e. at 67.9 and 88.6 °C. The DSC curves obtained for IBF and NA as pure materials denoted a single endothermic peak reflective of their melting behavior (data not shown). Since the melting temperatures of IBF and NA are 78.7 °C and 131.7 °C, respectively, the endothermic event observed at 67.9 °C corresponds to the depressed melting point of IBF due to the mixing with NA. The second peak is likely due to the melting of the other solid state. In the XRD patterns, the characteristic peak at 6.0° in 2θ of IBF disappeared with increasing temperature higher than 65 °C, and the peaks at 13.3°, 14.8° due to NA remained at higher temperatures than 65 °C. The changes observed in the XRD patterns also suggest that the former endothermic peak is due to the melting of crystalline IBF while NA is still in a crystalline state. The latter endothermic peak is representative of cocrystal melting, which is line with previous report by Müllers [44]. The diffraction peaks observed at 16.1° and 17.6° correspond to the peak characteristic of the cocrystal state between IBF and NA. These peaks disappeared at a temperature above the melting temperature of 88.6 °C. On the other hand, crystalline NA remained present at higher temperature due to its high melting temperature compared to the second endothermic event. In the mixture IR spectra, several peaks can be observed but they vary as the temperature increases (data not shown). In the higher wavenumber range, the peak observed at 3367 cm−1 decreased upon heating, which may be attributed to the antisymmetric stretching mode of NH2 groups, which are free of interactions with other functional groups [45]. This suggests that while the number of interaction-
Heat flow (mW) 0 -2 -4 100 90 80 70 60 50
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40 30 (a) (b)
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Fig. 1. XRD-DSC profiles obtained upon application of heat at a rate of 1 °C/min. The XRD patterns of initial materials are shown for NA(a) and IBF (b).
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free NH2 groups of NA decreased, the number of interacting NH2 groups increased upon heating. The other peak observed at 3162 cm−1 may be attributed to the NH2 symmetric stretching mode of the amide groups [45]. The three sharp peaks found at around 2900 cm−1 are due to the C\\H stretching mode of CH3. The intensity of these peaks was enhanced and sharpened upon heating, suggesting that the microenvironment around CH3, such as density, may have changed. In the lower wavenumber range of the IR spectra, several peaks due to amide and carboxyl groups were found. In this range, the most intensive peak at 1702 cm−1 is assigned to the C_O stretching mode of the carboxyl groups belonging to IBF [46]. The other two peaks at 1737 and 1674 cm−1 are also assigned to the C_O stretching mode of IBF and NA, respectively. The peak at 1702 cm−1 is due to the C_O stretching of interacting carboxyl group in the cocrystal [38,39,41] and the other peaks are due to the interaction-free functional groups. The peak changes are representative of either the associations and dissociations between carboxyl and amino groups upon heating. To decompose the obtained IR spectra and further dissect the cocrystallization process, MCR-ALS was carried out. In Fig. 2 are shown the changes in the source amount of each component. Here, we adopted a 4-component analysis including initial mixture, cocrystal, melted IBF, and crystalline NA, on the basis that XRD-DSC showed that the initial mixture transitioned into a cocrystal, and that melted IBF and crystalline NA were among the final products upon further heating. As shown in Fig. 2 (I), the amount of first component moderately increased with increasing temperature. The second and third components respectively decreased and increased at around the melting temperature of IBF. Then the third component inversely decreased when the fourth component increased. The variations between components suggest that the second component is the initial mixture, that the first and fourth components are the final states and the third component is the intermediate product. In Fig. 3 are shown the source spectra of each component and IR spectra of the materials. As expected, the spectrum of the second component matched the spectrum of the initial physical mixture; hence, the second component was correctly attributed to the initial state of
0.06
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0.1 0 0.1 0 0.2
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(IV)
0.1 0 65
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Fig. 2. Changes in the source amounts of individual components calculated from the MCRALS analysis of IR spectra. Amount profiles of the first, second, third, and fourth components are shown in (I) – (IV), respectively.
3
(I) (II) (III) (IV) (a) (b) (c) 3300 3000 1800 1600 1400 1200 Wavenumber (cm-1) Fig. 3. Source spectra resulting from the MCR-ALS analysis of IR spectra: the spectra (I) (IV) correspond to the source component shown in Fig. 2 (I) – (IV), respectively. The other spectra indicate the measured IR spectra obtained for the initial physical mixture (a), IBF (b), and NA (c).
the sample. The source spectrum of the third component was similar to that of the first component; however, except for a sharp peak at 1702 cm−1. We attributed this sharp peak to the stretching mode of the interacting carboxyl groups of IBF. The association of the hydrogen bonds of IBF was represented by the increase in the third component upon heating. The hydrogen bonds between the carboxyl groups of IBF and the amide groups of NA is reflective of the formation of a cocrystal structure hence the increase in the source amount of the third component, which subsequently turns into melted IBF and crystalline NA [34]. As represented in Fig. 2, the cocrystal shifted to first and fourth components. The first component spectrum presents a peak at 1728 cm−1, which is attributed to the interaction-free carboxyl group in contrast to the peak observed at 1702 cm−1. Additionally, there are no peaks around 3400 cm−1 which is classically assigned to amide groups. This suggests that the first component is a material with no amide groups and present fewer interactions; hence, the first component corresponds to the melted IBF. The spectral similarities suggest that the fourth component corresponds to crystalline NA. The decomposition by MCR-ALS successfully resulted in (I) amorphous IBF, (II) initial mixture, (III) cocrystal, and (IV) crystalline NA for the first, second, third, and fourth components, respectively. To confirm the hypothesis that a dynamic competition exists between the cocrystal and the amorphous states, the XRD patterns were subjected to MCR-ALS analysis. In Fig. 4 are represented the changes in the amount of each component upon heating. The XRD patterns were decomposed into four components similarly to the IR spectra. The temperature-dependent changes coincide with the changes shown in Fig. 2. The amount of first component shown in Fig. 4 (i) moderately increased, while the amount of second and third components decreased at first. This confirms our previous conclusions that the second and third components represent the initial mixture and the intermediate state, respectively. When comparing the first and fourth components, the amount of the first component changed prior to the increase in the fourth component and dropped at around 85 °C. Similarly to the ALS-MCR analysis of the IR spectra, the intermediate state competitively transitioned between the first and fourth component. However, there is a difference in the profile of the first component compared to the results from IR spectroscopy. According to the DSC profile, the temperatures of increment and decrement in the first component correspond to the first and second
4
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8000
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4000 0
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The fourth component predominantly displays a halo pattern matching the amorphous solid and several weak positive and negative peaks. The positive and negative peaks on the halo pattern is assigned to the diffraction peaks due to NA and IBF crystal solids, respectively. Positive peaks reflect increment in the component. Hence, the spectra suggest the growth of both amorphous IBF and crystalline NA upon melting of crystalline IBF and cocrystal. In conclusion, the MCR-ALS analysis of the XRD patterns led to the identification of four components respectively assigned to (i) cocrystal, (ii) initial mixture, (iii) intermediate state, and (iv) mixture of amorphous IBF and crystalline NA.
0 8000
(iii)
4000 0 8000 4000
(iv)
0 30 40 50 60 70 80 90 Temperature (°C) Fig. 4. Changes in the source amount of individual components calculated from the MCRALS analysis of XRD patterns. The profiles (i) – (iv) indicate the amount profiles of the first, second, third, and fourth components, respectively.
endothermic events, respectively. Additionally, its source component (Fig. 5) corresponds to the XRD pattern of the cocrystal. Hence, the first component was correctly attributed to the cocrystal structure. The third component represents the intermediate between initial mixture and cocrystal, which was not detected by IR spectroscopy. When comparing the source profiles between the second and third components (Fig. 5), these peaks are very similar albeit a slight peak shift. The differences between these two components is due to the distance differences between molecules in the crystalline structure. In practice, the diffraction peak of the third component appear at lower angle than those of the second component, which means more largely-spaced diffraction planes should be observed in the intermediate state. It is likely that the slight difference in distance does not significantly affect the interactions between molecules and hence is not detectable on the IR spectra.
(i)
4. Discussion As a result of the MCR-ALS decomposition analysis, we determined that a cocrystal structure is achieved via the formation of an intermediate state, and the transition to an amorphous IBF and crystalline NA structure. Kakuda et al. also reported similar findings based on the ALS analysis of XRD-DSC simultaneous measurements [47]. They investigated the crystalline structural change in poly(ethylene imine) film and reported that the polymer film resulted in the transition into an amorphous state upon heat. Structural differences between the initial and intermediate states may be estimated based on the IR spectra and XRD patterns. During the MCR-ALS analysis of XRD patterns, the third component was associated with diffraction peaks occurring at 16.6°, 20.2°, and 22.3° attributed to the IBF crystal, and corresponding to the (210), (012), and (202) diffraction planes, respectively [48]. In the crystalline structure, these planes are nearly perpendicularly-oriented along the hydrogen bonds between carboxyl groups. Hence, the lower diffraction peaks seen in the intermediate state refer to largely-spaced planes or carboxyl groups. The larger spacing induces rearrangement in the hydrogen bonds between carboxyl and amide groups. In the crystal structure reported by Bàthori et al. [49], hydrogen bonds between NA molecules are absent, while the cocrystal structure of IBF-NA reported by Berry et al. [34] presents hydrogen bonds between the amide groups of NA molecules. In the present study, our results revealed that the process of IBF-NA cocrystal formation results from a phase separation between amorphous IBF and crystalline NA upon heating. Cocrystal formation progressed under non-isothermal conditions and the cocrystal state was determined to be a non-equilibrium state. To prepare high purity cocrystal solids, it is hence necessary to optimize the processing temperatures to reach isothermal conditions. Based on our results, we propose that the optimal temperature required for cocrystal formation is restricted to a narrow range. The IR spectra suggested that a temperature of 70 °C could prevent changes to an amorphous state, while the XRD measurements suggested that the optimal temperature ranged between 65 and 70 °C. At temperatures above 70 °C, corresponding to the melting point of IBF, phase separation was shown to be more predominant than cocrystal formation (Fig. 4).
(ii) (iii)
5. Conclusion
(iv) (a) (b)
5
10
15
20 25 2θ (°)
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35
Fig. 5. Source patterns of individual components calculated from the MCR-ALS analysis of XRD patterns. The patterns (i) – (iv) are the individual components corresponding to the profiles (i) – (iv) shown in Fig. 4, respectively. The other patterns are the measured XRD patterns of the cocrystal (a) and initial samples (b), respectively.
IBF and NA cocrystals were prepared using the melting method. The cocrystal formation process was analyzed by XRD and IR measurements, and the data subjected to MCR-ALS. Our results showed that cocrystal formation entailed expansion of IBF and NA crystal structure, dissociation of hydrogen bonds between IBF molecules, and interactions between NA and IBF molecules. Upon heating, amorphization of IBF and crystallization of NA occurred subsequently to cocrystal formation. Our study highlights the importance of optimizing the processing temperature for the preparation of a high purity cocrystal state. We also report that MCR-ALS is a powerful approach to fragment a complex dataset into a more coherent ensemble.
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