DEREK deals with diabetes drug degradation products

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  • Published: Mar 1, 2018
  • Author: Ryan De Vooght-Johnson
  • Channels: Laboratory Informatics / Chemometrics & Informatics
thumbnail image: DEREK deals with diabetes drug degradation products

Degradation studies needed on canagliflozin

Degradation studies on active pharmaceutical ingredients (APIs) are important both for optimising a pharmaceutical’s formulation and deciding on the expiry date that needs to be placed on its packaging. Degradation studies are frequently carried out under forcing conditions, looking at the effects of acids, bases, oxidants, light and heat.

Canagliflozin is an important anti-diabetic drug, usually sold under the trade name Invokana. Little information on its degradation products is publically available, which prompted the researchers from Hyderabad and S.A.S Nagar to begin their own studies. They used UHPLC-MS to separate and identify degradation products, and then used toxicological software packages to examine the likely toxicity of these products. TOPKAT (toxicity prediction by komputer assisted technology) is a software program that uses QSTRs (quantitative structure–toxicity relationships) to predict the likely toxicity of a compound from its structure. DEREK (deductive estimate of risk from existing knowledge) is another software program that is based largely on the application of various rules to published toxicity data.

Canagliflozin degraded under a variety of conditions

The degradation of canagliflozin was carried out under the following conditions: acidic hydrolysis with HCl in aqueous acetonitrile, acidic hydrolysis with HCl in aqueous methanol, basic hydrolysis with aqueous NaOH, neutral hydrolysis with aqueous acetonitrile (all at 75 °C), oxidation with aqueous hydrogen peroxide at room temperature, photolysis with a fluorescent lamp at 45 °C, UV photolysis at 45 °C, and heating the solid at 50 °C. These conditions were in line with the International Conference on Harmonisation (ICH) guidelines.

After the stress tests, the acidic and basic samples were neutralised. All the samples were dissolved in aqueous acetonitrile and filtered through a membrane filter prior to chromatography. UHPLC was carried out using a Waters UPLC system; initial runs were carried out with a BEH C18 column, but an Acquity CSH C18 gave better resolution. The aqueous phase was 0.1% formic acid, while the organic phase was 70:30 v/v acetonitrile : methanol. The amount of organic phase was taken from 20 to 90% in a series of gradients. Mass spectroscopy employed an Agilent G6540B Q-TOF (quadrupole time-of-flight) instrument with electrospray ionisation (ESI); accurate mass determination allowed the structures of the degradation products to be determined.

Canagliflozin proved to be stable under most of the conditions studied, but gave some degradation products with the oxidative conditions (hydrogen peroxide) and with acids. Two oxidative products were noted, DP1 and DP2. The former had two extra oxygens, one on the thiophene sulphur atom and one on the phenyl group with the fluorine on it. The second oxidative product, DP2, had one extra oxygen, giving a 3-ketothiophene. The acidic degradation products were both pseudo degradation products, formed by reacting with the solvents present: DP3 was an acetyl derivative, formed by reaction with acetonitrile, while DP4 was a methyl ether, formed by reaction with methanol.

The structures of the degradation products were entered into the TOPKAT and DEREK software packages. DP1 was flagged up as a possible skin sensitiser by DEREK, while DP2 and DP3 were given as possible eye irritants by TOPKAT.

Degradation studies and toxicological software provide useful information

The forced degradation experiments gave good indications of canagliflozin’s stability under a variety of conditions. The formation of pseudo degradation products from solvent reactions is potentially a problem since in theory they might mask the presence of peaks from real degradation products (i.e. those not involving the solvent). Toxicological packages such as DEREK and TOPKAT can help to reduce the need for animal testing, which is an important goal for both financial and ethical reasons.

Related Links

Rapid Communications in Mass Spectroscopy, 2018, 32, 212-220. Baira et al. Characterization of forced degradation products of canagliflozine by liquid chromatography/quadrupole time-of-flight tandem mass spectrometry and in silico toxicity predictions.

Chemical Research in Toxicology, 2016, 29, 810-822. Bhhatarai et al. Evaluation of TOPKAT, Toxtree, and Derek Nexus in Silico Models for Ocular Irritation and Development of a Knowledge-Based Framework To Improve the Prediction of Severe Irritation.

Journal of Pharmaceutical Analysis, 2014, 4, 159-165. Blessy et al. Development of forced degradation and stability indicating studies of drugs—A review.

Article by Ryan De Vooght-Johnson

The views represented in this article are solely those of the author and do not necessarily represent those of John Wiley and Sons, Ltd.

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