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Determination of organic volatile impurities in Nepafenac by GC method

Mariola Mucha ,  Aleksandra Groman ,  Joanna Zagrodzka ,  Marcin Cybulski 

Pharmaceutical Research Institute, Rydygiera 8, Warsaw 01-793, Poland

The active substance Nepafenac is used to prevent and treat the pain and inflammation that can occur after an operation to remove a cataract from the eye and also to reduce the risk of macular oedema that can occur after cataract surgery. Nepafenac, is a ‘pro-drug’ of amfenac (a non-steroidal anti-inflammatory drug). It works by blocking an enzyme called cyclo-oxygenase, by reducing the production of prostaglandins in the eye. Nepafenac can reduce complications caused by eye surgery, such as inflammation, pain and swelling [1].

Several methods to control of residue solvents and reagent in active substance and the starting material purity were developed by using gas chromatography (very important and popular instrumental method in analytical chemistry). Our methods were validated according to the requirement of ICH (International Conference of Harmonization) validation guidelines Q2R1 [2] and  guideline for residual solvents Q3C [3].

In our original synthetic route 2-(methylthio)acetamide (NF1A) was used as starting material. Thus, the gas chromatography method with direct injection has been applied to control the quality of this material. The validation of this method (normalization method procedure) includes tests of specificity, system precision, detection limit and range at the area normalization.

Moreover it has been confirmed, that the gas chromatography methods with direct injection is effective technique  to control  of  triethylamine - reagent and NF1A in nepafenac by using limit test procedure. The validation of these methods includes the examination of specificity, system precision and detection  limit.
It has been demonstrated, that the gas chromatography methods with headspace injection may be develop to control of residual solvents from the first to the last synthetic step.
Residual acetone and 2-propanol (i.e. solvents from the final step of synthesis) - have been examined by using quantitative test procedure, and the validation of this method includes the examination of specificity and selectivity, system precision, repeatability, intermediate precision, accuracy, linearity, robustness as well as quantitation and detection limit.
Residual solvents from first step of synthesis and the staring material: methanol, toluene, dichloromethane and benzene - potential contaminant of acetone have been examined by using limit test procedure and the validation of these methods includes the examination of specificity, system precision and detection  limit.


The study was supported by European Union under European Regional Development Fund No. UDA-POIG.01.03.01-14-068/08 “Innovative technologies of ophthalmic  medicines of special therapeutic and social importance”.


[1] EMEA /H/C/000818 , EMA/366273/2013. EPAR summary for the public Nevanac/ Nepafenac

[2] ICH Harmonised Tripartite Guideline Validation of Analytical Procedures: Text and Methodology Q2(R1)
[3] ICH Harmonised Tripartite Guideline Impurities: Guideline for Residual Solvents Q3C(R5)

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Submitted: 2014-03-18 12:42
Revised:   2014-05-02 19:45