Methylprednisolone and its related substances in freeze-dried powders for injections

Abstract

In this work, the behavior of the active pharmaceutical substances methylprednisolone (in a form of methylprednisolone sodium succinate) in finished pharmaceutical dosage form, i.e., freeze-dried powder for injections, was examined. The goal was to evaluate the chemical stabilities of methylprednisolone sodium succinate packaged in a dual chamber vial, as a specific container closure system. The effect of different parameters: temperature, moisture and light were monitored. The method proposed by United States Pharmacopeia was used to determine concentrations of methylprednisolone, as the sum of the concentration of methylprednisolone esters (17-hydrogen succinate and 21-hydrogen succinate) and free methylprednisolone. The HPLC method was used for stability evaluation of the active substance and determination of related substances. Four main degradation products were registered. Temperature has a major impact on the degradation process with the appearance of 3 degradation products (impurities B, C and D), while the presence of light caused an increasing content of impurity A. Identification of impurity B, C and D has been realized using mass and NMR spectroscopy. All three substances are substances related to methylprednisolone.

U ovom radu ispitivane su osobine farmakološki aktivne supstance metilprednizolona (u obliku metilprednizolon-natrijum-sukcinata) u gotovom proizvodu - liofilizatu za rastvor za injekcije. Cilj rada je ispitivanje hemijske stabilnosti metilpredni-zolon-natrijum-sukcinata u dvokomornoj bočici, kao specifičnom sistemu kontaktnog pakovanja. Ispitan je efekat različitih parametara: temperature, vlage i svetlosti. Za određivanje koncentracije metilprednizolona, kao zbirne koncentracije metilprednizolon estara (17-hidrogen-sukcinata i 21-hidrogen-sukcinata) i slobodnog metilprednizolona, korišćena je metoda opisana u Američkoj farmakopeji. Za ispitivanje srodnih supstanci primenjena je HPLC metoda. Uočena su 4 degradaciona proizvoda. Dokazano je da povećanje temperature ima najveći značaj na proces degradacije i utiče na povećanje sadržaja nečistoća B, C i D, dok prisustvo svetlosti dovodi do povećanja sadržaja nečistoće A. Nečistoće B, C i D su identifikovane primenom masene i NMR spektroskopije. Sve tri nečistoće su identifikovane kao srodne supstance metilprednizolona.