Identification of Pseudopolymorphism of Magnesium Stearate by

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Identification of Pseudopolymorphism of Magnesium Stearate by Using Low Frequency Raman Spectroscopy Tatsuo Koide, Toshiro Fukami, Hiroshi Hisada, Motoki Inoue, James Carriere, Randy Heyler, Noriko Katori, Haruhiro Okuda, and Yukihiro Goda Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.6b00199 • Publication Date (Web): 27 Oct 2016 Downloaded from http://pubs.acs.org on October 30, 2016

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Organic Process Research & Development

Identification of Pseudopolymorphism of Magnesium Stearate by Using Low Frequency Raman Spectroscopy

Tatsuo Koide1*, Toshiro Fukami2, Hiroshi Hisada2,3, Motoki Inoue2, James Carriere4, Randy Heyler4, Noriko Katori1, Haruhiro Okuda1, Yukihiro Goda1

1

Division of Drugs, National Institute of Health Sciences, 1-18-1 Kamiyoga,

Setagaya-ku, Tokyo, Japan, 158-8501 2

Department of Molecular Pharmaceutics, Meiji Pharmaceutical University, Kiyose,

Tokyo 204-8588 Japan 3

TEK Analysis Inc. Neyagawa, Osaka 572-0020 Japan

4

Ondax Inc. 850 Duarte Rd, Monrovia, CA 91016 USA

*Correspondence

to:

Tatsuo

Koide

(Telephone:

+81-03-3707-6950; E-mail: [email protected] )

1

ACS Paragon Plus Environment

+81-03-3700-8694;

Fax:


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Abstract Magnesium stearate (Mg-St) currently available on the market has a wide variety of properties, including: pseudopolymorphism, relative content of stearic acid in fatty acid, and particle size. These properties of Mg-St influence manufacturing processes of pharmaceutical products, therefore it is necessary to control the quality of Mg-St from suppliers. The purpose of this study was to evaluate the low frequency region of Raman spectroscopy for identification of pseudopolymorphism in Mg-St.

Ten samples of Mg-St

obtained from different suppliers were measured by powder X-ray diffraction (PXRD) and thermogravimetry and

differential

thermal

analysis

(TG-DTA)

to

identify the

pseudopolymorphism of Mg-St. Then we investigated the relationship between their Raman spectra including the low frequency region and pseudopolymorphism. The results were categorized as four types of Mg-St, namely, mono-, di-, tri-hydrate and their mixture. The conventional region (greater than 200 cm-1) of the Raman spectrum was able to identify pseudopolymorphism to a certain degree, however it was not easy to completely distinguish pseudopolymorphism for the mixture of Mg-St. Whereas, the low frequency region (below than 200 cm-1) of the Raman spectrum was able to clearly distinguish them. These data suggest that Raman spectroscopy, especially low frequency Raman is an effective method for rapid identification of pseudopolymorphism in Mg-St.

Key words: Raman spectroscopy; Magnesium stearate; Low frequency Raman; Pseudopolymorphism 2


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Introduction Magnesium stearate (Mg-St) is an essential additive as a lubricant for manufacturing of pharmaceutical tablets. In reality, most Mg-St is composed of magnesium salt and a mixture of fatty acid including mainly stearic acid. Relative content of stearic acid in fatty acid is extensively regulated, by more than 40% according to the pharmacopoeia of principal countries. Physical properties of Mg-St, for example, particle size, pseudopolymorphism and crystallinity, may be different depending on suppliers. The differences in pseudopolymorphism of Mg-St, mono-, di- and tri-hydrates are well known, and have an influence on pharmaceutical manufacturing processes such as mixing and tableting1-5). Previous studies3-5) presented that powder lubrication, densification, and flowability were different between mono-hydrate and di-hydrate of Mg-St. It suggests that we have to employ different manufacturing conditions such as mixing time if we use different pseudopolymorphism of Mg-St. For manufacturing high quality products, it is important to obtain Mg-St with constant physical properties like pseudopolymorphism. Although specified in the pharmacopoeia, identification of magnesium salt, relative content of stearic acid by gas chromatography and water content are not enough to ensure the pseudopolymorphism of Mg-St. Moreover supply routes of materials for pharmaceutical manufacturing are now progressing towards globalization6). Importing materials from countries in which Good Manufacturing Practice (GMP) does not function well, involves the risk of receiving inferior quality. In this case, it is necessary to test the quality of

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materials in each container. Infrared spectroscopy, which is used most widely in identification testing, requires sampling and pre-treatment such as KBr. These treatments are however not suitable for the large sample test required for each container, therefore an alternative technique is desired. Similar to infrared spectroscopy, Raman spectroscopy is an analytical technique for observing the change in energy such as with molecular vibrations7), that occurs when light is irradiated onto samples. Application research of Raman spectroscopy is progressing in the field of pharmaceutical quality control, focusing on qualitative and quantitative analysis of materials such as polymorphism8-10), screening of counterfeit medicine11-13), chemical mapping of pharmaceutical dosage forms14,15) and real time monitoring in a manufacturing process16,17). Additionally, the low frequency region of the Raman spectrum reflects lattice vibrations that are related to the physical structure of the molecule. Therefore this region is superior in identification of polymorphism and co-crystals18). Moreover recent advances in ultra-narrow-band notch filter technology enable one to conveniently obtain high-quality low frequency Raman spectra19), and it increases the opportunity to utilize Raman spectroscopy in the pharmaceutical field20-23). Thus previous research has shown that Raman spectroscopy is useful for various cases of pharmaceutical analysis, and for this reason the method has attracted much attention as a pharmaceutical quality control technique.

Identification

testing

using

Raman

spectroscopy

does

not

require

pre-measurement treatment, and the measurements can be rapidly performed. Therefore

4


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Raman spectroscopy enables the treatment of a large number of samples. However, as far as we know, there are no Raman spectral comparison data between differences of pseudopolymorphism of Mg-St. In this study, identification of Mg-St by Raman spectroscopy has been investigated with a focus on identification of pseudopolymorphism.

Material and Methods 1. Materials Ten samples of Mg-St acquired from different suppliers were used in this study. First grade (W1), Japanese pharmacopoeia grade (WM), and plant-derived (WP) Mg-St were purchased from Wako Pure Chemical Industries, Ltd. (Osaka, Japan). Technical grade (SG) Mg-St was purchased from Sigma-Aldrich Co. LLC. (St. Louis, USA). Cica-grade (KT) Mg-St was purchased from Kanto Chemical Co., Inc. (Tokyo, Japan). Japanese pharmacopoeia grade (TH) was purchased from Taihei Chemical Industries Co., Ltd. (Osaka, Japan). Two types for manufacturing (M2, MM) and plant-derived (MP) Mg-St were purchased from Mallinckrodt Inc. (St. Louis, USA). Reagent grade (AL) Mg-St was purchased from Alfa Aesar (Heysham, UK).

2. Evaluation of the physical properties of Mg-St Pseudopolymorphism of Mg-St was measured by powder X-ray diffraction

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(PXRD) method. The diffractometer used was a Rigaku Miniflex (Rigaku Corp., Tokyo, Japan). PXRD was performed at a voltage of 30 kV, a current of 15 mA, scanning angles in the range 5–35°, a scan speed of 4° min–1 and a Cu Kα radiation source. Thermogravimetry and differential thermal analysis (TG-DTA) was performed using a TG-8120 (Rigaku Corp.). Samples were placed in an open aluminum pan and measured at a scan speed of 5°C min–1 from ambient temperature to 150°C without air flow. The measurement was conducted three times, and an average value was calculated. Relative content of stearic acid in fatty acid was measured by gas chromatography according to the monograph conditions of Mg-St in the Japanese Pharmacopoeia. Gas chromatography measurements were made using a HP 6890 gas chromatograph (Agilent Technologies, Santa Clara, CA) equipped with a 30 m × 0.32 mm × 0.25 µm HP-INNOWax column (Agilent Technologies).

3. Measurement of Raman spectrum A Raman Work Station (Kaiser Optical Systems Inc, Ann Arbor, MI USA) was used for measurement of the Raman spectrum in the conventional frequency region. Measurements were performed with an excitation wavelength of 785 nm, laser power of 300mW, frequency region between 200 and 2000 cm-1, frequency resolution about 4 cm-1 and exposure time of 20 seconds. The low frequency region of the Raman spectrum was measured with a TR-Probe system (Ondax Inc, Monrovia, CA USA) having an excitation

6


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wavelength of 853nm and the same Raman Work Station, resulting in a shifted collection region of -850 cm-1 to +850cm-1. Measurement of the low frequency region between -200 and 200 cm-1, had a frequency resolution about 4 cm-1 and exposure time for 60 seconds. The obtained spectra were analyzed with Isys version 5.0 (Malvern Instruments, Ltd., Worcestershire, UK) data analysis software.

Results 1. Pseudopolymorphism of Mg-St PXRD patterns of the ten samples of Mg-St are shown in Fig. 1. WM, WP, SG, KT, TH, MP, and MM had similar PXRD patterns. The PXRD patterns of the other three samples, M2, W1 and AL were different from the rest. When the PXRD patterns of these samples were compared with those that were previously reported in the literature3), the results indicated these seven samples were mono-hydrate Mg-St and M2 and W1 were di-hydrate and tri-hydrate respectively. The PXRD pattern of AL showed characteristics of both mono-hydrate and tri-hydrate, suggesting AL was a mixture of mono-hydrate and tri-hydrate. The results of thermal analysis of Mg-St samples are shown in Figs. 2, 3 and Table 1. The results of thermogravimetry of WM, WP, SG, KT, TH, MP and MM showed a large weight loss around 100-110°C(Fig. 2). The total mass decrease of these samples was

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between 3.4 and 3.8% (Table 1). The breakdown of the weight loss was a very gentle mass decrease until 100°C, and between 2.6 and 2.8% around 100-110°C which was close to the theoretical value of mono-hydrate (approximately 3.0%). In the results of M2 and W1, a weight loss occurred around 80-90°C and 60-80°C, respectively, and mass decreases were about 5.4 and 7.3%, respectively. These values were very close to the theoretical values (approximately 5.7 and 8.4%, respectively). In the case of AL, weight loss occurred in two steps, around 60-80°C and 100-110°C. It also suggested that AL was a mixture of mono-hydrate and tri-hydrate. The results of the differential thermal analysis (Fig. 3) generally supported the results of PXRD. However WM, WP, KT and TH which were identified as mono-hydrate by PXRD exhibited a small endothermic peak around 80°C, suggesting that a small amount of di-hydrate was contained in these samples.

2. Raman spectrum of pseudopolymorphism of Mg-St in the conventional region Raman spectra for the ten samples of Mg-St in the conventional region are shown in Fig 4, and Fig. 5 shows an enlarged view. Although similar spectra were obtained in the ten samples, there were slight differences around 950 cm-1 and 1440 cm-1 depending on the types of hydrate. Mono-hydrate had a broad peak around 950 cm-1. While M2 (di-hydrate), had a sharp peak at 945 cm-1, and W1 (tri-hydrate), had a peak at 952 cm-1. On the other hand, spectra of M2 and W1 exhibited a small peak shift (about 4 cm-1) around the peak at 1440 cm-1 compared with that of monohydrate. The spectrum of AL, which was a mixture

8


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of mono-hydrate and tri-hydrate, showed no difference around 950 cm-1, however a peak shift of 2cm-1 near 1440 cm-1 (about half of that of di-hydrate or tri-hydrate) was also observed.

3. Raman spectrum of pseudopolymorphism of Mg-St in the low frequency region Raman spectra for the ten samples of Mg-St in the low frequency region are shown in Fig. 6, and Fig. 7 shows enlarged and overlapped normalized spectra of some samples of Mg-St. Large spectral differences were observed between 30 and 60 cm-1 and between 100 and 180 cm-1 depending on the hydration types. The spectra of mono-hydrate had a sharp peak at 49 cm-1 and a broad peak near 156 cm-1. While the spectra of M2 (di-hydrate) has a sharp peak at 44 cm-1 and a peak near 129 cm-1. The spectra of W1 (tri-hydrate) had a sharp peak at 39 cm-1 and a peak near 118 cm-1. The spectra of AL had broad peaks at 39 cm-1, 49 cm-1, 118 cm-1 and 156 cm-1. These peaks were characteristic of both mono-hydrate and tri-hydrate.

4. The content of stearic acid in Mg-St and its Raman spectrum The content of stearic acid in fatty acid for the ten samples of Mg-St is shown in Table 2. The contents of stearic acid in the seven samples of mono-hydrate of Mg-St showed WM, WP, SG, KT and TH were between 65 and 68%, while the contents in MM and MP were lower, at 53 and 58%, respectively. The seven samples of mono-hydrate of

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Mg-St exhibited similar Raman spectra, although the relative content of stearic acid in fatty acid in these samples differed largely from 53 to 68%. On the other hand, the contents in AL, M2 and W1 were 43%, 71% and 99%, respectively. AL and W1 were largely different from the others. However a noticeable difference in the conventional region of their Raman spectra was not observed. Thus the relationship between the content of stearic acid and Raman spectra of Mg-St was not observed.

Discussion In this study, ten samples of Mg-St acquired from different suppliers were used, and it was shown that various pseudopolymorphs and mixtures were available on the market. Although most of the samples were mono-hydrate, some of them contained small amounts of di-hydrate according to the results of thermal analysis. However the di-hydrate content levels were estimated to be a few percent or less, and these values were considered permissible to regard them as mono-hydrate. AL, M2 and W1 were different accorrding to TG-DTA and PXRD data from those seven samples of Mg-St and the principal component of M2 and W1 was not mono-hydrate. Moreover W1 does not fit the specification of the principal pharmacopoeia where the water content is prescribed as 6% or lower. The principal component of AL was mono-hydrate, but it contained a considerable amount of try-hydrate, which was clearly detected by TG-DTA and PXRD. W1 and AL were provided

10


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as reagents that were not intended for use in pharmaceutical manufacturing. And recently some suppliers have stopped providing M2, therefore M2 is rarely distributed on the market today. For these reasons, M2, W1 and AL have not been distributed for pharmaceutical manufacturing, and currently mono-hydrate is mainly used. However, substances imported from the regions in which have deficient regulation systems have a possibility to obtain undesired substances, for example wrong hydrated Mg-St or hydrated mixture. In these situations of pharmaceutical manufacturing, Mg-St is distinguished two categories, general mono-hydrate and others. Therefore discrimination between mono-hydrate and other hydrates is a more important issue for pharmaceutical manufacturing. In this study, ten samples of Mg-St acquired from different suppliers were categorized by PXRD and described kinds of hydrates in Table 1. The PXRD results and characteristic peaks of Raman scattering were presented in Table 3. Identification of pseudopolymorphism of Mg-St with the conventional region of Raman spectroscopy was considered possible to a certain degree by comparing spectra around 950 cm-1 and 1440 cm-1. The degree of the peak shift at 1440 cm-1 was not much different and not differentiable between di-hydrate and tri-hydrate. And a peak at 950 cm-1 could not easily discriminate a mixture such as AL, because mono-, di- and tri- hydrate peaks all overlap each other around 950 cm-1. Therefore the utility of the low frequency region of Raman spectroscopy for discrimination of pseudopolymorphism of Mg-St was examined. When each pseudopolymorph of Mg-St was measured using the low frequency region, there were differences in peaks between 30 and

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60 cm-1 and between 100 and 180 cm-1. In particular, a peak in the spectrum of each hydrate was clearly separated between 100 and 180 cm-1 region and it demonstrated that discrimination between mono-hydrate and other hydrates was possible even if Mg-St was a mixture of pseudopolymorphs. We need to obtain Mg-St with constant quality for establishment of robust pharmaceutical manufacturing processes because the physical property of Mg-St has an influence on the pharmaceutical manufacturing process. However there is a possibility that various kinds of pseudopolymorphs of Mg-St are obtained in internationalized supply routes. Moreover information on pseudopolymorphism of Mg-St was not usually indicated on the container labels and was not identified for any of the Mg-St samples acquired in this study. It was not until we measured Mg-St by PXRD and thermal analysis that we obtained information about pseudopolymorphism. These analytical techniques are often used for evaluation of pseudopolymorphism in Mg-St, however they were not suitable for rapid identification testing of each container. The low frequency region of Raman spectrum reflects low energy molecular interaction and it indicates mainly physical information such as polymorphism, whereas conventional region indicates chemical information such as chemical bonding. The difference among the pseudopolymorphism corresponds low frequency region like that of a polymorphism. That is a reason low frequency region of Raman spectrum was more effective to identify the pseudopolymorphism of Mg-St than the conventional region. Therefore a rapid and nondestructive technique such as Raman

12


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spectroscopy, and especially the low frequency region, is useful to identify the pseudopolymorphism of Mg-St.

Conclusion In this study, Raman spectroscopy was able to identify mono-, di- and tri-hydrate of Mg-St acquired from various suppliers. In particular, the low frequency Raman region more clearly discriminated pseudopolymorphism of Mg-St than the conventional region. It was demonstrated that Raman spectroscopy including the low frequency region was useful in rapidly identifying pseudopolymorphism of Mg-St.

ACKNOWLEDGEMENTS The authors thank Kaiser Optical Systems Inc. for their instrumental support, and Mr. Akinori Okuyama and Ms. Rie Ishii for their experimental efforts.

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REFERENCES 1) Ertel, K. D.; Carstensen, J. T. J. Pharm. Sci. 1988, 77(7), 625-629. 2) Bracconi, P.; Andrès, C.; N’diaye, A.; Pourcelot, Y. Thermochimica acta 2005, 429(1), 43-51. 3) Yonemochi, E. Pharm Tech Japan 2013, 29(4), 37-50. 4) Rao, K. P.; Chawla, G.; Kaushal, A. M.; Bansal, A. K. Pharm. Dev. Technol. 2005, 10(3), 423-437. 5) Okoye, P.; Wu, S. H. Pharmaceutical Technology 2007, 31(9), 116-129. 6) Okuda, H. J. Pharm. Sci. Tech. Jpn. 2014, 74(5), 341-344. 7) Vankeirsbilck, T.; Vercauteren, A.; Baeyens, W.; Van der Weken, G.; Verpoort, F.; Vergote, G.; Remon, J. P. TrAC Trends Anal. Chem. 2002, 21(12), 869-877. 8) McGoverin, C. M.; Hargreaves, M. D.; Matousek, P.; Gordon, K. C. J. Raman Spectrosc. 2012, 43(2), 280-285. 9) Croker, D. M.; Hennigan, M. C.; Maher, A.; Hu, Y.; Ryder, A. G.; Hodnett, B. K.; J. Pharm. Biomed. Anal. 2012, 63, 80-86. 10) Carron, K.; Cox, R, Anal. Chem. 2010, 82(9), 3419-3425. 11) De Veij,; M. Deneckere, A.; Vandenabeele, P.; De Kaste, D.; Moens, L. J. Pharm. Biomed. Anal. 2008, 46(2), 303-309. 12) Ricci, C.; Nyadong, L.; Yang, F.; Fernandez, F.M.; Brown, C. D.; Newton, P. N.; Kazarian, S. G. Anal. Chim. Acta 2008, 623(2), 178-186.

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13) Kwok, K.; Taylor, L. S. J. Pharm. Biomed. Anal. 2012, 66, 126-135. 14) Kano, T.; Yoshihashi, Y.; Yonemochi, E.; Terada, K. Int. J. Pharm. 2014, 461(1), 495-504. 15) Yamashita, M.; Sasaki, H.; Moriyama, K. J. Pharm. Sci. 2015, 104(12), 4093-4098. 16) Burggraeve, A.; Monteyne, T.; Vervaet, C.; Remon, J. P.; De Beer, T. Eur. J. Pharm. Biopharm. 2013, 83(1), 2-15. 17) Müller, J.; Knop, K.; Wirges, M.; Kleinebudde, P. J. Pharm. Biomed. Anal. 2010, 53(4), 884-894. 18) Larkin, P. J.; Dabros, M.; Sarsfield, B.; Chan, E.; Carriere, J. T.; Smith, B. C. Appl. Spectrosc. 2014, 68, 758-776. 19) Carriere, J.; Heyler, R.; Smith, B. Raman Technology for Today’s Spectroscopists 2013, June, 44-50. 20) Hisada, H.; Inoue, M.; Koide, T.; Carriere, J.; Heyler, R.; Fukami, T. Org. Process Res. Dev. 2015, 19(11), 1796-1798. 21) Wang, H.; Boraey, M. A.; Williams, L.; Lechuga-Ballesteros, D.; Vehring, R. Int. J. Pharm. 2014, 469(1), 197-205. 22) Mah, P. T.; Fraser, S. J.; Reish, M. E.; Rades, T.; Gordon, K. C.; Strachan, C. J. Vib. Spectrosco. 2015, 77, 10-16. 23) Roy, S.; Chamberlin, B,; Matzger, A. J.; Org. Process Res. Dev. 2013, 17(7), 976-980.

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Figure Captions

Fig. 1

X-ray powder diffraction patterns of Mg-St a) WM, b) W1, c) WP, d) SG, e) KT, f) AL, g) TH, h) M2, i) MP, j) MM

Fig. 2

Thermogravimetry curves of Mg-St a) WM, b) W1, c) WP, d) SG, e) KT, f) AL, g) TH, h) M2, i) MP, j) MM

Fig. 3

Differential thermal analysis curves of Mg-St a) WM, b) W1, c) WP, d) SG, e) KT, f) AL, g) TH, h) M2, i) MP, j) MM

Fig. 4

Conventional region Raman spectra of Mg-St a) WM, b) W1, c) WP, d) SG, e) KT, f) AL, g) TH, h) M2, i) MP, j) MM

Fig. 5

Enlarged figure of the conventional region Raman spectra of Mg-St a) WM, b) W1, c) WP, d) SG, e) KT, f) AL, g) TH, h) M2, i) MP, j) MM

Fig. 6

Low frequency region Raman spectra of Mg-St a) WM, b) W1, c) WP, d) SG, e) KT, f) AL, g) TH, h) M2, i) MP, j) MM

Fig. 7

Enlarged figure of the normalized low frequency region Raman spectra of Mg-St Red : WM,

Green : W1, Blue : AL,

Black : M2,

Table 1 Results of PXRD and TG-DTA of Mg-St obtained from different suppliers

Table 2 Contents of Stearic acid in Mg-St obtained from different suppliers

Table 3 PXRD and Raman characteristics peaks of Pseudopolymorphism of Mg-St

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Table 1

Samples

Pseudopolymorphism

Loss on weight (%)

Range of weight loss (°C)

PXRD

TG

TG

WM

Mono-hydrate

3.56

100-110°C

W1

Tri- hydrate

7.31

60-80°C

WP

Mono-hydrate

3.45

100-110°C

SG

Mono-hydrate

3.62

100-110°C

KT

Mono-hydrate

3.73

100-110°C

AL

Mono- and Tri- hydrate

4.88

60-110°C

TH

Mono-hydrate

3.63

100-110°C

M2

Di-hydrate

5.40

80-90°C

MP

Mono-hydrate

3.51

100-110°C

MM

Mono-hydrate

3.49

100-110°C

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Table 2

Samples

Stearic acid(%) GC

WM

65.2

W1

98.9

WP

66.8

SG

68.5

KT

68.3

AL

42.7

TH

66.0

M2

71.0

MP

57.6

MM

53.2

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Table 3

Pseudopolymorphism

Mono-hydrate

Samples

WM, WP, SG,

PXRD

Raman shift

Raman shift

(deg.)

Conventional

Low Frequency

(cm-1)

(cm-1)

21.5, 21.8, 22.8

1436

49, 156

KT, TH, MP, MM Di-hydrate

M2

22.8, 23.4, 25.2

945, 1440

44, 129

Tri- hydrate

W1

19.8, 23.6

952, 1440

39, 118

Mixture

AL

19.8, 21.5, 21.8,

1438

39, 49, 118, 156

(Mono- and Tri-

22.8, 23.6

hydrate)

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Fig. 1 (a (b (c (d (e (f (g (h (i (j

5

10

15

20

25

2theta (deg.) ACS Paragon Plus Environment

30

35

Page 21 of 27

Fig. 2 (a (b

Weight Loss (%)

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


(c (d (e (f (g (h (i (j 40

60

80

100

Temp. (ºC) ACS Paragon Plus Environment

120

140


Fig. 3 (a (b (c (d (e

Endothermic

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

Page 22 of 27

(f (g (h (i (j 40

60

80

100

Temp. (ºC) ACS Paragon Plus Environment

120

140

Page 23 of 27

Fig. 4

(a (b (c

Raman intensity

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


(d (e (f

(g (h (i (j

800

900

1000

1100

1200

1300

Raman Shift (cm-1) ACS Paragon Plus Environment

1400

1500

1600


Fig. 5

(a (a (b

(b (c

(c

Raman intensity

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

Page 24 of 27

(d (e (f

(d (e

(g

(f

(h (i

(g (h

(j

(i (j

850 900 950

1380

1420

1460

Raman Shift (cm-1) ACS Paragon Plus Environment

1500

Page 25 of 27

Fig. 6

(a (b

Raman Intensity

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


(c (d (e (f (g (h (i (j

30

80

130

180

Raman Shift (cm-1)



Fig. 7

Raman Intensity

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

Page 26 of 27

20 40 60 80 100 120 140 160 180 200

Raman Shift (cm-1)


Page 27 of 27

Graphical Abstract

Raman Intensity

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


5

10

15

20

25

2theta (deg.)

30

35

30 80 130 180 Raman Shift (cm-1)

PXRD Pattern and Low Frequency Raman Spectra of Magnesium Stearate Available on the Market


Identification of Pseudopolymorphism of Magnesium Stearate by

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