Two different multi-component crystals consisting of papaverine [1-(3,4-dimethoxybenzyl)-6,7-dimethoxyisoquinoline, C20H21NO4] and fumaric acid [C4H4O4] were obtained. Single-crystal X-ray structure analysis revealed that one, C20H21NO4·1.5C4H4O4 (I), is a salt co-crystal composed of salt-forming and non-salt-forming molecules, and the other, C20H21NO4·0.5C4H4O4 (II), is a salt–co-crystal intermediate (i.e., in an intermediate state between a salt and a co-crystal). In this study, one state (crystal structure at 100 K) within the salt–co-crystal continuum is defined as the ‘intermediate’.

2022-08-01·Journal of Pharmaceutical Sciences3区 · 医学

Impact of Poloxamer 188 Material Attributes on Proteinaceous Visible Particle Formation in Liquid Monoclonal Antibody Formulations

3区 · 医学

Article

作者: Hashimoto, Daisuke ; Oltra, Nuria Sancho ; Arai, Kengo ; Duboeuf, Jeremy ; Yamanaka, Yuji ; Fukuda, Masakazu ; Saitoh, Satoshi ; Kishore, Ravuri S K ; Imai, Hirotaka ; Soeda, Kohei ; Takahashi, Masaya

Surfactants such as Poloxamer 188 (PX188) play an important role in controlling particle formation in biotherapeutic formulations due to interfacial stresses. This study demonstrates for the first time that hydrophobicity of PX188 is a potential critical material attribute (CMA) as far as control of visible particle (VP) formation is concerned. We have found that within PX188 lots satisfying pharmacopeial specifications, there is variability in material attributes such as hydrophobicity, as determined from their reversed-phase high-performance liquid chromatography profiles. However, it currently remains unknown how such variability in hydrophobicity of PX188 affects surfactant function and VP formation. Here, we compared the effect of seven PX188 lots in two monoclonal antibody drug product formulations under various stress conditions. Notably, proteinaceous VP formation was reduced while using a PX188 lot with higher hydrophobicity. Our findings emphasize the importance of monitoring lot-to-lot variability of PX188 and provide insight into potential CMA for improving and controlling material attributes of PX188 for use in liquid biotherapeutic formulations.

2021-07-01·Chemical and Pharmaceutical Bulletin4区 · 医学

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

4区 · 医学

Article

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

Recently, quantitative NMR (qNMR), especially ¹H-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 ¹H-qNMR. In the present study, we focused on a ³¹P-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 ³¹P-qNMR and ¹H-qNMR results were compared under three conditions with potassium dihydrogen phosphate (KH₂PO₄) or O-phosphorylethanolamine (PEA) as the reference standard for ³¹P-qNMR and sodium 4,4-dimethyl-4-silapentanesulfonate-d₆ (DSS-d₆) as the standard for ¹H-qNMR. Condition 1: separate sample containing CP and KH₂PO₄ for ³¹P-qNMR or CP and DSS-d₆ for ¹H-qNMR. Condition 2: mixed sample containing CP, DSS-d₆, and KH₂PO₄. Condition 3: mixed sample containing CP, DSS-d₆, 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 ¹H-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 ³¹P-qNMR are in good agreement with those determined by the established ¹H-qNMR method. Since the ³¹P-qNMR signals are less complicated than the ¹H-qNMR signals, ³¹P-qNMR would be useful for the absolute quantification of compounds that do not have a simple and separate ¹H-qNMR signal, such as a singlet or doublet, although further investigation with other compounds is needed.

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