Transmission Low-Frequency Raman Spectroscopy for Quantification

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Transmission Low-Frequency Raman Spectroscopy for Quantification of Crystalline Polymorphs in Pharmaceutical Tablets Motoki Inoue, Hiroshi Hisada, Tatsuo Koide, Toshiro Fukami, Anjan Roy, James Carriere, and Randy Heyler Anal. Chem., Just Accepted Manuscript • Publication Date (Web): 03 Jan 2019 Downloaded from http://pubs.acs.org on January 3, 2019

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Analytical Chemistry

Transmission Low-Frequency Raman Spectroscopy for Quantification

of

Crystalline

Polymorphs

in

Pharmaceutical Tablets Motoki Inoue1*, Hiroshi Hisada1, Tatsuo Koide2, Toshiro Fukami1, Anjan Roy3, James Carriere3, Randy Heyler3 1Department

of Molecular Pharmaceutics, Meiji Pharmaceutical University, 2-522-1, Noshio,

Kiyose, Tokyo 204-8588, JAPAN 2Division

of Drugs, National Institute of Health Sciences, 3-25-26, Tonomachi, Kawasaki-ku,

Kawasaki, Kanagawa 210-9501, JAPAN 3Ondax

Inc., 850E, Duarte Road, Monrovia, California 91016, USA

*Corresponding author: Motoki INOUE, Ph.D. Department of Molecular Pharmaceutics, Meiji Pharmaceutical University 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan TEL. & FAX: +81-42-495-8915, Email: [email protected]

KEYWORDS: Transmission; Low-Frequency Raman Spectroscopy; THz-Raman; Quantification; Crystalline Polymorph; Carbamazepine; Pharmaceutical Tablets

ACS Paragon Plus Environment

Analytical Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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The purpose of this study was to quantify polymorphs of active pharmaceutical ingredients in pharmaceutical tablets using a novel transmission low-frequency Raman spectroscopy method. We developed a novel transmission geometry for low-frequency Raman spectroscopy and compared quantitative ability in transmission mode versus backscattering mode using chemometrics. We prepared two series of tablets: 1) containing different weight-based contents of carbamazepine form III and 2) including different ratios of carbamazepine polymorphs (forms I/ III). From the relationship between the contents of carbamazepine form III and partial least squares (PLS) predictions in the tablets, correlation coefficients in transmission mode (R2= 0.98) were found to be higher than in backscattering mode (R2= 0.97). The root mean square error of cross-validation (RMSECV) of the transmission mode was 3.9 compared to 4.9 for the backscattering mode. The tablets containing a mixture of carbamazepine (I/ III) polymorphs were measured by transmission low-frequency Raman spectroscopy, and it was found that the spectral shape changed according to the ratio of polymorphs: the relationship between the actual content and the prediction showed high correlation. These findings indicate that transmission low-frequency Raman spectroscopy possess the potential to complement existing analytical methods for the quantification of polymorphs.


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1. INTRODUCTION Selecting the crystalline form of active pharmaceutical ingredients (APIs) is an important aspect of optimizing drug performance.1 The different crystalline forms, including polymorphs and solvates, possess varying physicochemical properties, such as packing, thermodynamics, kinetics, and surface and mechanical properties.2 Crystalline transformations during pharmaceutical manufacturing are well-known as processing-induced transformations (PITs).3,4 It is important to confirm whether the intended crystalline form remains in the final products because prediction and control of PITs is complicated.5-7 In general, the crystalline form of API in pharmaceutical tablets is evaluated using crystallographic study8, thermal analysis9, and spectroscopic methods10-12. Powder X-ray diffraction (PXRD) patterns are especially easy to obtain; therefore, this method is widely used for identifying the crystalline form. In pharmaceutical manufacturing, rapid, noninvasive and nondestructive analytical techniques on tablets are important. Therefore, we focused on Raman spectroscopy, which can be used as a complementary method that is also amenable to high-throughput screening. Raman spectroscopy can detect molecular information in a short time, and the method is both noncontact and nondestructive.13-15 In general, backscattering (180° geometry) Raman spectroscopy irradiates only a small portion of the sample; therefore, it represents a localized area, rather than the entire pharmaceutical tablet.16 To overcome this limitation, many Raman sampling methods have been developed: 1) averaging of Raman spectra collected at many different locations on the sample,17 2) spectral collection via sample rotation and temporal averaging of the acquired data,18 and 3) wide area illumination (WAI),19 which makes use of a dispersive Raman probe constituting multiple optical fibers known as a pharmaceutical area testing (PhAT) probe.20 These geometries are complicated, and data processing is required for each sample. For the analysis of pharmaceutical tablets, it is often difficult to obtain information from a tablet’s interior (bulk) due to interference from the coating on the tablet or capsule material. In contrast, transmission (forward scattering) Raman spectroscopy is an average of bulk spectra without surface interference from either the coating of the tablet or capsule.21,22



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Transmission Raman spectroscopy is an ideal analytical method for quantification of compounds in pharmaceutical tablets because it has the potential to provide rapid structural and chemical information on the bulk content of pharmaceutical formulations, including intact tablets.22-27 In the case of conventional Raman spectroscopy, hydrogen bonds differ among polymorphs; in some cases, it is difficult to distinguish differences within only the fingerprint region28,29. Raman spectra in lowfrequency regions have functioned as complementary general analytical methods.28-36 The vibrational modes in the region of 0 to 100 cm-1 are generated by global fluctuations and phonons, while those in the region from 100 to 200 cm-1 are generated by localized intermolecular interactions.37-39 The authors have previously reported a method of monitoring the crystalline transformation of API and the transition of cocrystals between different stoichiometric situations using low-frequency Raman spectroscopy assisted by chemometrics.40,41 In this study, we propose low-frequency Raman spectroscopy as a proof-of-concept that can quantify crystalline polymorphs. In this paper, transmission and backscattering low-frequency Raman spectroscopy are quantitatively compared, and the benefits of transmission over backscattering mode are discussed.

2. EXPERIMENTAL SECTION 2.1. Materials Carbamazepine (Figure 1) (as a model API) and D-mannitol were purchased from Tokyo Chemical Industry (Tokyo, Japan). Microcrystalline cellulose (Ceolus UF-702) was kindly donated by Asahi Kasei Co., Ltd. (Tokyo, Japan). Carbamazepine form III was used as received and then heated at 170 °C for 3 h to prepare form I. All materials were sieved under 100 μm before use. 2.2. Tablet preparation The powdery materials were mixed by hand in a mortar and pestle. The resultant mixture was compressed at 0.79 kN for 5 seconds using a single-punch press to obtain a disk that was 10 mm in diameter.


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2.3. Raman spectroscopy Low-frequency Raman spectra were measured using an 853 nm laser with a power of 50 mW. Both in backscattering and transmission geometry, the spectral range included both the Stokes and antiStokes scattering in the -800 to 800 cm-1 region with an exposure time of 300 seconds. A schematic of the instrumental setup for both transmission and backscattering Raman spectroscopy is shown in Figure 2. When the laser excitation is incident upon one side of a tablet, transmission Raman scattering is simultaneously collected from the opposite side. The spectrometer with a spectral resolution of 4 cm−1 includes a holographic transmission grating (RXN2, Kaiser Optical Systems Inc., Ann Arbor, MI, USA) and a probe head that has been adapted to couple to a THz-Raman® Probe system (Ondax Inc., Monrovia, CA, USA). The probe system includes a frequency stabilized laser with spectrally matched ultranarrow band notch filters. Tablets were placed onto a sample holder with a 9 mm aperture and secured by a clasp. Raman spectra were corrected for the dark condition. 2.4. Spectroscopy data analysis All spectra were normalized using standard normal variate (SNV) transformation using Grams/AI8.0 software (Thermo Fisher Scientific, Inc., MA, USA). Contents of crystalline carbamazepine were scored by partial least squares (PLS) analysis using Grams IQ (Thermo Fisher Scientific, Inc.). In PLS regression, model selection has also been commonly performed using leave-one-out cross validation.42

3. RESULTS 3.1. Transmission low-frequency Raman spectra To compare transmission and backscattering low-frequency Raman spectra, 1 mm thick tablets containing carbamazepine forms I and III were measured. Figure 3 shows the transmission and backscattering low-frequency Raman spectra obtained from carbamazepine forms I and III. All spectra correspond well with previously reported spectra.41 The transmission Raman spectrum also corresponds well with the backscattering spectrum. One noteworthy observation is that the Rayleigh



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peak is further diminished in transmission mode. 3.2. Optimization of tablet thickness for transmission measurement The effect of tablet thickness on transmission low-frequency Raman intensity was investigated by changing the weight of carbamazepine form III (80-200 mg). Figure 4 shows the low-frequency Raman signal for the carbamazepine form III peaks at 39 cm-1. In the backscattering geometry, Raman intensity increased upon increasing tablet thickness up to 1.7 mm and then remained constant. This phenomena was similar to reported by Wang and coworkers.43 They stated that the Raman intensity increased with tablet thickness until a critical thickness is reached beyond which the intensity is unchanged. In our case, the critical thickness was corresponded to 1.7 mm. Conversely, in the transmission mode, Raman signals from a 1.2 mm thickness tablet showed maximum intensity and then decreased with tablet thickening. This result indicated that 1.2 mm thick tablets are best suited for transmission Raman experiments; this size was exclusively used for further experiments. 3.3. Quantitative comparison between transmission mode and backscattering mode Carbamazepine form III of 0-75% (w/w), mannitol 10% (w/w) and microcrystalline cellulose (MCC) were mixed to obtain a total weight of 100 mg as shown in Table 1. Predicted form III contents were calculated with PLS regression using the spectral range of 10 to 200 cm-1. Figure 5 shows the relationship between weight-based contents of carbamazepine form III in tablets and PLS predictions of the carbamazepine content. Figure 6 shows that the loading scores of both the transmission mode and backscattering mode were similar to the pure spectrum of form III. From Figure 5, a good linear relationship was obtained for transmission mode (R2 = 0.98) and backscattering mode (R2 = 0.97). The calibration statistics between transmission mode and backscattering mode were compared in detail. Leave-one-out cross-validation (CV) is a statistical method to evaluate the stability of a model. CV involves using single observations as the validation set and the remaining observations as the training set. This is repeated in all combinations to cut the original sample on a validation set of N observations and a training set. The root means square error of cross-validation (RMSECV) was defined as


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follows,44 𝑛

RMSECV =

∑𝑖 = 1(𝑦𝑖 ― ŷ𝑐𝑣,𝑖)2 𝑁

where yi is the reference measurement result for the ith sample, ŷcv,i is the estimated result for the ith sample when the model is constructed with the ith sample removed, and N is the number of samples. RMSECV of transmission mode and backscattering mode is 3.9 and 4.9, respectively. It was indicated that the correlation between the actual contents and predicted contents using the transmission mode was higher than that when using backscattering mode. Table 2 represented the predicted errors of this study.

3.4. Quantification of carbamazepine polymorph contents in tablets We quantified tablets which consisted only of carbamazepine polymorphs, which were difficult to distinguish in conventional region Raman spectra.45 To clarify the limit of detection of polymorphs of carbamazepine, the transmission Raman spectra were obtained and the ratios of polymorphs were calculated. Tablet formulations, with different contents of carbamazepine polymorphs being normalized to 100 mg total mixture weights, were summarized in Table 3. In this section, we used tablets with different ratios of forms I and III. Figure 7 shows transmission mode low-frequency Raman spectra of carbamazepine with different ratios and the relationship between contents and predicted ratios of form I to form III. Low-frequency Raman spectra changed according to the ratio of polymorph contents of forms I and III (Figure 7 (a)). As seen in Figure 7 (b), the ratio of polymorphs corresponded to the PLS predicted contents. The performance of the model was evaluated by root mean square error (RMSE) calculated using the following equations: 𝑛

RMSE =

∑𝑖 = 1(𝑦𝑖 ― ŷ𝑖)2 𝑁

where yi represents the reference value, ŷi the calculated value and N is the number of samples. Limit



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of detection (LOD) was calculated using the following equation: LOD =

3.3𝜎 𝑆

where σ is the standard deviation of the lowest constituent concentration and S is the slope of the calibration curve. From the above result, the RMSE = 0.94 and LOD = 3.2 for transmission mode were calculated, respectively.

4. DISCUSSION Quantification of polymorphs in pharmaceutical tablets requires measurements under solid-state, and there are numerous available analytical techniques.46 Powder X-ray diffraction (PXRD) is the most popular technique because it can directly detect crystal lattice information.9 Gordon and coworkers have compared quantified binary polymorphic carbamazepine mixtures using both powder X-ray diffraction and Raman spectroscopy.47 In the study, these researchers stated that Raman spectra appeared to be a more reliable quantification method because such problems as different particle size, morphology, and spatial distribution of the binary solid-state forms of the drug seemed to have no significant influence on Raman scattering. Croker and coworkers also supported the assertion that spectral methods are more suitable than PXRD for quantitative analysis of polymorphic mixtures.48 PXRD is a well-known method to analyze crystals; however, it requires at least several tens of minutes to obtain spectra with high signal-to-noise ratio (SNR). Additionally, the sample needs to be a uniform powder with manual placement of the crystals on the sampling plate, resulting in significant sample preparation time. Since Raman spectroscopy enables rapid, noninvasive testing, it is more suitable than PXRD for rapid/high-throughput tablet analysis. Burley and coworkers have reported the quantification of polymorphic contents using commercially available transmission Raman spectrometers, measuring spectra in the 30-2000 cm-1 range.49 However, some crystalline polymorphs only exhibit spectral differences in the 10-30 cm-1 spectral range. In the case of sulfathiazole, it is difficult to distinguish form III from form IV as the difference in Raman spectra is observed in the


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low-frequency region, between 23 and 27 cm-1. In our previous study, we have reported that polymorphs of sulfathiazole were discriminated and quantified using the low-frequency Raman spectra with averaging of Raman spectra collected at different locations on the sample.50 In the present study, the quantitative analysis of crystal polymorphism was carried out using novel transmission lowfrequency Raman spectroscopy within the spectral region below 30 cm-1. Interestingly, the Rayleigh peak was much weaker in the transmission mode than in the backscattering mode. This feature is useful for analysis of compounds that manifest peaks at extremely low Raman shift, due to the negligible interference by the Rayleigh peak. We studied the different thickness of tablets: the intensity of specific peaks increased up to 2 mm and then showed a constant value in backscattering mode. We hypothesized that increasing Raman scattering was derived from deeper penetration of the excitation laser. Conversely, in the case of transmission mode, the maximum value was shown at 1.2 mm thickness. Therefore, there is a trade-off relationship between the intensity of transmitted Raman scattering and exposure laser. In other words, though the resulting Raman scattering increases with tablet thickening, it is more likely to be reflected in tablets. In the transmission mode, Raman intensity are influenced by various factors including particle size, material density, diameter and thickness of a tablet.43,51 Since tablet thickness is the most influential factor, we investigated optimum thickness for measurements. 1.2 mm-thickness tablet showed the highest signal. In this study, we chose to match the optimized transmission Raman signal. Comparison of the accuracy of quantitative analysis between transmission and backscattering showed that the R2 value when using transmission mode (0.98) was slightly higher than that of the backscattering mode (0.97). Additionally, the RMSECV of transmission is 3.9, which is approximately a 20% improvement compared to backscattering mode (4.9). These findings indicate that transmission mode is superior to quantify crystallinity of API in the pharmaceutical tablet. The backscatter spot size is small compared to the grain size of the various components within the tablet, depending on the position of the spot on the surface of the tablet even if the total tablet had an equal mix of both



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components. Contrary, transmission mode creates a volumetric average of the composition of the entire tablet and eliminates all the spatial effects that can create uncertainty in backscatter geometry. Detailed optical differences between backscattering and transmission geometries were added to Figure S1 in the supporting information. Sample heterogeneity was confirmed using low-frequency Raman imaging. Chemical image of the prepared tablet (I/III= 50/50) is represented as Figure S2 in the supporting information. The mapping was performed over a 1 × 1 mm region consisting of 400 points (x: 20, y: 20 points). The image shows the distribution of I and III crystals as red and green, respectively. The area ratio of I and III is 48/52, which almost corresponded with the predicted concentration calculated by PLS. The authors therefore considered that the difference of predicted error is due to the penetration depth of the excitation laser in the sample tablet and sample geometry. Since the penetration depths of a laser into the tablets vary by the type of sample tablets, this aspect is difficult to discuss. Despite the fact that similar spectra have been obtained in both transmission and backscattering modes, the intensity of the Raman spectra in the transmission mode was weaker than that of backscattering. This tendency is also observed in the case of conventional region transmission Raman spectra.22 The author inferred that the accuracy of transmission mode is higher than backscattering mode as follows. 1) The obtained Raman scattering is higher in transmission mode than that in backscattering mode. This is because the transmission mode involves tablet thickness while backscattering mode can only be obtained from a surface area of the tablets. 2) The random scattering of photons inside the tablets, i.e., the long optical path lengths, are longer in transmission mode than in backscattering mode.52 The long optical path length is obviously an advantage since the apparent cross-section for Raman conversion is also increased. Similar results were also obtained by only one scan, and spectral change corresponding to charged ratio was obtained (Fig. 7a). Using PLS analysis, the charged value and the predicted value almost agreed. The variances observed in the CBZ (form III) concentration plots for backscattering measurements are attributed to the small sampling area per measurement. It is suspected that variations tend to occur due to the inhomogeneity in dispersion


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within these tablets. Validation of analytical procedures including aspects of precision, linearity, and repeatability are shown in Figure S3 in the supporting information. The predicted errors were calculated at I/III = 33.3/66.7, 50/50, and 66.7/33.3 for each drug concentration, while correlation coefficients and RMSE of lines for each day were R2=0.999 and 0.89 - 1.86, respectively. Intermediate precisions were represented using a calibration curve as external validation standards. The standard deviations during each day were small (0.02 - 2.2). However, the standard deviations among 3 days showed large values (2.4 - 4.1). This is due to the spectrometer and unstable laser power; we are currently improving these apparatuses. Thus, it is necessary to calibrate the instrument and measure samples within the same day. A prototype with an excitation laser output of 50 mW was employed, which can easily be increased. To apply this method to real-time release testing (RTRt), it is necessary to decrease the measurement time. To study tablets with larger thickness, we are now developing systems with a higher power laser and reflection using a mirror in addition to general improvements of the light collecting optics. However, since this study is a “proof of concept” study of transmission low-frequency Raman spectroscopy, we utilized a prototype geometry with low excitation laser power.

5. CONCLUSIONS In this study, we demonstrated that transmission low-frequency Raman spectroscopy can be used for the quantitative analysis of crystalline polymorphs in pharmaceutical tablets. Furthermore, this technique can be used to analyze whether the intended crystalline form remains in the final form of the pharmaceutical tablets. Further study must shorten the measurement time by adjustment of the laser power and the sensitivity of the detector. It can be expected that this analysis can be used as an analysis method for RTRt.

Acknowledgements



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The authors thank Kaiser Optical Systems Inc. for their instrumental support. This work was supported by JSPS KAKENHI Grant Number 16K18867 (M.I.).

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Table 1 Tablet formulations for quantification comparison study between transmission and backscattering mode. Carbamazepine III No. MCC (w/w%) D-Mannitol (w/w%) (w/w%) 1 0 90 10 2 1 89 10 3 5 85 10 4 10 80 10 5 15 75 10 6 20 70 10 7 8 9 10

30 40 50 75

60 50 40 15


10 10 10 10

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Table 2 Summarized obtained and predicted errors. Raman mode

R2

RMSECV

Transmission Backscattering

0.98 0.97

3.9 4.9



Table 3 Tablet formulations with different contents of carbamazepine polymorphs. No. Form I (w/w%) Form III (w/w%) 1 0 100 2 1 99 3 5 95 4 10 90 5 25 75 6 50 50 7 75 25 8 90 10 9 95 5 10 99 1 11 100 0


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Figure captions Figure 1 Chemical structure of carbamazepine. Figure 2 Schematic diagram showing the setup for (a) transmission and (b) backscattering Raman spectroscopy. Figure 3 Comparison of transmission mode and backscattering low-frequency Raman spectra of carbamazepine (a) form I and (b) form III. These spectra were obtained the same collection parameters. Figure 4 Raman signal for the form III peak intensity at 39 cm-1 in both transmission (〇) and backscattering mode (●). Figure 5 Regression line between weight-base and predicted content of carbamazepine form III. Comparison of (a) transmission mode and (b) backscattering mode. Figure 6 Loading plot form PLS model of low-frequency Raman data in (a) transmission and (b) backscattering mode. These two score plots are quite similar to the pure spectrum of form III. Figure 7 Carbamazepine with different mixing ratios of form I and III (a) transmission lowfrequency Raman spectra, (b) relationship between contents and predicted ratio of form I/III.


Analytical Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47


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1

2 3

Figure 1 Chemical structure of carbamazepine.

4



1 2

Figure 2 Schematic diagram showing the setup for (a) transmission and (b) backscattering Raman

3

spectroscopy.

4 5


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1 2

Figure 3 Comparison of transmission mode and backscattering low-frequency Raman spectra of

3

carbamazepine (a) form I and (b) form III. These spectra were obtained the same collection parameters.

4



1

2 3

Figure 4 Raman signal for the form III peak intensity at 39 cm-1 in both transmission (〇)

4

and backscattering mode (●).

5


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1 2

Figure 5 Regression line between weight-base and predicted content of carbamazepine form III.

3

Comparison of (a) transmission mode and (b) backscattering mode.



1 2

Figure 6 Loading plot form PLS model of low-frequency Raman data in (a) transmission and (b)

3

backscattering mode. These two score plots are quite similar to the pure spectrum of form III.

4


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1 2

Figure 7 Carbamazepine with different mixing ratios of form I and III (a) transmission low-

3

frequency Raman spectra, (b) relationship between contents and predicted ratio of form I/III.


Transmission Low-Frequency Raman Spectroscopy for Quantification

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