Absolute Purity Determination of a Hygroscopic Substance, Indocyanine Green, Using Quantitative NMR (qNMR)

Uchiyama, Nahoko; Hosoe, Junko; Sugimoto, Naotoshi; Ishizuki, Kyoko; Koide, Tatsuo; Murabayashi, Mika; Miyashita, Naoto; Kobayashi, Kengo; Fujimine, Yoshinori; Yokose, Toshiyuki; Ofuji, Katsuya; Shimizu, Hitoshi; Hasebe, Takashi; Asai, Yumi; Ena, Eri; Kikuchi, Junko; Kiyota, Kohei; Fujita, Kazuhiro; Makino, Yoshinobu; Yasobu, Naoko; Yamada, Yuko; Iwamoto, Yoshiaki; Miura, Toru; Mizui, Koji; Asakura, Katsuo; Suematsu, Takako; Kohama, Ai; Goda, Yukihiro

doi:10.1248/cpb.c20-00728

Cited by 11 publications

(10 citation statements)

References 5 publications

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“…7,8) We also established an optimized and reproducible 1 H-qNMR method for sample preparation of hygroscopic marker compounds for crude drugs, such as ginsenoside Rb1, 8) and hygroscopic chemical drugs, such as indocyanine green. 9) Through our series of studies, 19 reagents evaluated by 1 H-qNMR are listed as RSs for HPLC assays of 37 crude drugs and Kampo formula extract monographs up to the publication of JP 18 th Edition. 1) We established an optimized and reproducible 1 H-qNMR sample preparation method suitable for Chemical and Pharmaceutical Bulletin Advance Publication the various properties of the target compounds.…”

Section: Introductionmentioning

confidence: 99%

“…Our first 31 P-qNMR study with an organophosphorus anticancer drug, cyclophosphamide hydrate, revealed that the purity values determined by 31 P-qNMR agreed well with the values determined by the established 1 H-qNMR method in a validation study in multiple laboratories. 10) In a previous study, D2O was used as the dissolving solvent, and KH2PO4 or O-phosphorylethanolamine were used as RSs for 31 P-qNMR because of the chemical shift and solubility of cyclophosphamide hydrate. This demonstrates that selecting appropriate RSs and solvents is important for 31 P-qNMR measurements.…”

Section: Introductionmentioning

confidence: 99%

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Quantitative 31P-NMR for Purity Determination of Sofosbuvir and Method Validation

et al. 2022

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Quantitative 1 H-NMR ( 1 H-qNMR) is useful for determining the absolute purity of organic molecules; however, it is sometimes difficult to identify the target signal(s) for quantitation because of their overlap and complexity. Therefore, we focused on the 31 P nucleus because of the simplicity of its signals and previously reported 31 P-qNMR in D2O. Here we report 31 P-qNMR of an organophosphorus compound, sofosbuvir (SOF), which is soluble in organic solvents. Phosphonoacetic acid (PAA) and 1,4-BTMSB-d4 were used as reference standards for 31 P-qNMR and 1 H-qNMR, respectively, in methanol-d4. The purity of SOF determined by 31 P-qNMR was 100.63 ± 0.95%, whereas that determined by 1 H-qNMR was 99.07 ± 0.50%. The average half bandwidths of the 31 P signal of PAA and SOF were 3.38 ± 2.39 Hz and 2.22 ± 0.19 Hz, respectively, suggesting that the T2 relaxation time of the PAA signal was shorter than that of SOF and varied among test laboratories. This difference most likely arose from the instability in the chemical shift due to the deuterium exchange of the acidic protons of PAA, which decreased the integrated intensity of the PAA signal. Next, an aprotic solvent, DMSO-d6, was used as the dissolving solvent with PAA and DSS-d6 as reference standards for 31 P-qNMR and 1 H-qNMR, respectively. SOF purities determined by 31 P-qNMR and 1 H-qNMR were 99.10 ± 0.30% and 99.44 ± 0.29%, respectively. SOF purities determined by 31 P-qNMR agreed with the established 1 H-qNMR values, suggesting that an aprotic solvent is preferable for 31 P-qNMR because it is unnecessary to consider the effect of deuterium exchange.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Quantitative 31P-NMR for Purity Determination of Sofosbuvir and Method Validation

et al. 2022

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“…8 In this regard, contamination of qNMR calibrants by atmospheric moisture is of special concern for two reasons. 10 First, sample preparation for qNMR experiments is universally done in air (although the humidity of the air is sometimes controlled 11 ). Indeed, the accuracy of the weighing procedure for sample preparation 12 would be compromised by static electricity in the low-humidity environment of an inert atmosphere glovebox.…”

Section: ■ Introductionmentioning

confidence: 99%

Hygroscopic Tendencies of Substances Used as Calibrants for Quantitative Nuclear Magnetic Resonance Spectroscopy

Suiter

Widegren

2021

Anal. Chem.

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Atmospheric moisture can contaminate calibrants for quantitative nuclear magnetic resonance (qNMR) spectroscopy and cause systematic errors in qNMR measurements. Therefore, coulometric Karl Fischer (CKF) titration was used to evaluate the hygroscopic tendencies of several organic compounds that are commonly used as calibrants for qNMR spectroscopy: benzoic acid, dimethyl sulfone, 1,3,5-trimethoxybenzene, acetanilide, dimethyl terephthalate, and 1,2,4,5-tetramethylbenzene. Samples were placed in a sealed humidity chamber at 100% relative humidity (RH) and a temperature of 295.4 ± 0.9 K. Over the course of months, portions of each sample were analyzed by CKF titration. All the compounds except dimethyl sulfone were resistant to changes in water content and thus are good choices for qNMR experiments. In contrast, dimethyl sulfone absorbed about 25 mass % of water over 5 weeks at 100% RH; such behavior could compromise qNMR experiments under certain conditions.

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“…A comparison of absolute indocyanine green purities under three different humidity control revealed that using a constant temperature and humidity box resulted in the lowest variability. 15) As described above, we developed an optimal and reproducible 1 H-qNMR sample preparation method suitable for the respective properties of targeted compounds. However, depending on the purity and structure of the compound, selecting a quantitative signal can be difficult due to overlapping and complexity.…”

Section: Introductionmentioning

confidence: 99%

Purity Determination of Cyclophosphamide Hydrate by Quantitative 31P-NMR and Method Validation

et al. 2021

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Recently, quantitative NMR (qNMR), especially 1 H-qNMR, has been widely used to determine the absolute quantitative value of organic molecules. We previously reported an optimal and reproducible sample preparation method for 1 H-qNMR. In the present study, we focused on a 31 P-qNMR absolute determination method. An organophosphorus compound, cyclophosphamide hydrate (CP), listed in the Japanese Pharmacopeia 17th edition was selected as the target compound, and the 31 P-qNMR and 1 H-qNMR results were compared under three conditions with potassium dihydrogen phosphate (KH 2 PO 4 ) or O-phosphorylethanolamine (PEA) as the reference standard for 31 P-qNMR and DSS-d 6 as the standard for 1 H-qNMR. Condition 1: separate sample containing CP and KH 2 PO 4 for 31 P-qNMR or CP and DSS-d 6 for 1 H-qNMR. Condition 2: mixed sample containing CP, DSS-d 6 , and KH 2 PO 4 . Condition 3: mixed sample containing CP, DSS-d 6 , and PEA. As conditions 1 and 3 provided good results, validation studies at multiple laboratories were further conducted. The purities of CP determined under condition 1 by 1 H-qNMR at 11 laboratories and 31P-qNMR at 10 laboratories were 99.76±0.43% and 99.75±0.53%, respectively, and those determined under condition 3 at five laboratories were 99.66±0.08% and 99.61±0.53%, respectively. These data suggested that the CP purities determined by 31 P-qNMR are in good agreement with those determined by the established 1 H-qNMR method. Since the 31 P-qNMR signals are less complicated than the 1 H-qNMR signals, 31 P-qNMR would be useful for the absolute quantification of compounds that do not have a simple and separate 1 H-qNMR signal, such as a singlet or doublet, although further investigation with other compounds is needed.

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Absolute Purity Determination of a Hygroscopic Substance, Indocyanine Green, Using Quantitative NMR (qNMR)

Cited by 11 publications

References 5 publications

Quantitative <sup>31</sup>P-NMR for Purity Determination of Sofosbuvir and Method Validation

Quantitative <sup>31</sup>P-NMR for Purity Determination of Sofosbuvir and Method Validation

Hygroscopic Tendencies of Substances Used as Calibrants for Quantitative Nuclear Magnetic Resonance Spectroscopy

Purity Determination of Cyclophosphamide Hydrate by Quantitative <sup>31</sup>P-NMR and Method Validation

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