Determination of minor quantities of linezolid polymorphs in a drug substance and tablet formulation by powder X-ray diffraction technique

Abstract

Linezolid (LZD) is one of the first commercially available synthetic oxazolidinone antibiotics and is widely used for the treatment of multidrug-resistant Gram-positive bacterial infection. LZD was found to have five polymorphic forms. The most stable and commercialized polymorphs are known as forms II and IV. Trace content of form II in LZD form IV will cause to transition LZD form IV to II rapidly. Powder X-ray diffraction (PXRD) methods were evaluated for the determination of the polymorphic content of the drug substance and drug product. The estimated limit of detection values of the single peak method for LZD polymorph form II in drug substance and tablet formulation were 0.4 and 0.6%, respectively, while the limit of detection value of Rietveld Refinement (full-profile fitting) evaluated LZD polymorph form II in drug substance was 0.2%. The results clearly show that levels <1 wt.% (in active pharmaceutical ingredients) and 2 wt.% (in tablets) LZD form II in form IV can be detected and quantified by PXRD. Validation of the analytical method proved that the method is repeatable, sensitive, and accurate.

A practical guide to pharmaceutical analyses using X-ray powder diffraction

“…Numerous cases are cited where detection limits using laboratory equipment are 0.1 wt.% for crystalline materials and 1 wt.% for amorphous materials (Beckers, 2015). Recently published data on the API linezolid (Sun et al , 2017) demonstrate <1% detection limits for polymorph II using a laboratory diffractometer. The three largest global diffractometer manufacturers have all demonstrated <1% detection of crystalline pharmaceutical materials with their laboratory units.…”

X-ray Diffraction Analysis of Linezolid Crystalline Forms as Part of Quality Control

“…Мы делаем заключение, что только формы II и IV являются различными полиморфными модификациями линезолида. Термостабильной является форма IV, поэтому Управление по контролю за каче-ством продуктов питания и лекарственных средств (Food and Drug Administration, FDA) с 2000 г. рекомендует использовать именно эту форму при производстве различных лекарственных средств, содержащих линезолид [10].…”

“…Следует отметить, что наличие в коммерческом образце субстанции линезолида (форма IV) примеси формы II описано авторами работы [10]. Исследуя методом РФА полиморфные модификации II и IV линезолида, M. Sun с соавт.…”

“…4 264 ОРИГИНАЛЬНЫЕ СТАТЬИ / ORIGINAL ARTICLES 1 https://extranet.who.int/prequal/sites/default/files/TB299part6v1.pdf для производства таблеток линезолида, присутствует около 1 % (по массе) формы II. Авторы также утверждают, что присутствие в фармакопейной субстанции линезолида примеси формы II даже в небольшом количестве способствует конформационной конверсии субстанции из формы IV в форму II [10].…”

Determination of minor quantities of linezolid polymorphs in a drug substance and tablet formulation by powder X-ray diffraction technique – ADDENDUM

“…When originally published, the article by Sun et al . (2017) did not include supplementary material. The data files of the linezolid polymorph forms II and IV can now be viewed as supplemental files to the original article.…”