A METHOD FOR SALIFICATION IN THE TECHNOLOGY OF PREPARING THE INJECTABLE FORMULATIONS OF POORLY SOLUBLE ANTITUMOR COMPOUNDS

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DOI: https://doi.org/10.29296/25419218-2019-04-03
Issue: 
4
Year: 
2019

O.L. Orlova(1), L.L. Nikolaeva(1, 2), M.V. Dmitrieva(1), A.V. Lantsova(1), A.P. Polozkova(1), Z.S. Shprakh(1, 2), N.Yu. Kulbachevskaya(1), O.I. Konyaeva(1), N.A. Oborotova(1) 1-N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia, 24, Kashirskoe Shosse, Moscow 115478, Russian Federation; 2-I.M. Sechenov First Moscow State Medical University (Sechenov University), 8, Trubetskaya St., Build. 2, Moscow 119048, Russian Federation

Introduction. To design a drug is a complex multistep process that begins with studies of the physicochemical properties of an active pharmaceutical ingredient and with selection on an optimal formulation on the basis of the information obtained. Many biologically active substances, including antitumor agents, are poorly soluble in water and highly toxic. These compounds include the folic acid antagonist methotrexate that is widely used in the therapy of cancer and the new alkyl nitrosourea derivative ormustine. Salification is one of the most acceptable ways to overcome low solubility. Objective: to design injectable formulations of antitumor drugs, by converting the active ingredient into the salt formulation, in case of the Russian substance ormustine and a generic version of methotrexate. Material and methods. The investigation objects were methotrexate substance ser. EP 120813 (Hu Zhou Zhanwan Pharmaceutical Co., Ltd., China); ormustine substance (I.Ya. Postovsky Institute of Organic Synthesis, Ural Branch, Russian Academy of Sciences, Russia). Various chemicals, solvents, and reagents, which met the requirements of regulatory documents (GOST, TU, Russian and foreign pharmacopoeias) were used in the investigation. Results. Taking into account the physicochemical properties of antitumor substances, the investigators designed a parenteral ormustine formulation and reproduced a technology for obtaining methotrexate solutions. Water-soluble compounds were prepared through salification: by adding sodium hydroxide for methotrexate and by dissolving in 0.1 M hydrochloric acid for ormustine. Conclusion. Considering the properties of active pharmaceutical ingredients, the authors proposed a new original Ormustin lyophilisate formulation to prepare an injectable solution 125 mg and generic methotrexate injectable solutions 10 and 100 mg/ml.
Keywords: 
formulation
pharmaceutical technology
salification
methotrexate
ormustine
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