Metformin impurity amount, theoretically 1/90 of Ranitidine

MFDS "Total calculated '1/90' level of Ranitidine as a result of toxicity calculation. Cause of creation requires overhaul , Overhaul required

Agilent reports show similar results, 'Ranithidine 90%, Nizatidine 5%, Metformin 1% or less'

Molecular structure of Metformin

With Metformin, issues of impurity detection have been raised, and it is possible that N-nitrosodimethylamine (NDMA) will be detected much less than earlier Ranitidine or Nizatidine.

 

According to officials at the MFDS on Dec 9, a qualitative structure activity relationship (QSAR) is used as a simple test to determine the toxicity of a substance.

 

It is a test method that compares and predicts physical and chemical properties by similarity of intrinsic chemical structure.

 

Since the properties of a substance are closely related to its molecular structure, it is a principle that similar physical structures have similar physical properties and toxicity.

 

In fact, the results of predicting the toxicity of Ranitidine-Nizatidine in this way are nearly identical to the actual detection of NDMA in both formulations, according to the MFDS official.

 

According to the official, the results of Ranitidine and Nizatidine QSAR were 90 and 5, respectively.

 

The actual detection amounts were 53.50 ppm and 1.43 ppm based on the maximum values.

 

A MFDS official said, "On this extension, Metformin's QSAR test results are only around 1." It is expected that the possibility of actual detection is much lower than that of Ranitidine or Nizatidine.

 

◆'Ranithidine 90%, Nizatidine 5%, Metformin 1% or less' This is in line with the findings of Agilent, a US material analysis company.

 

Agilent conducted an experiment in May 2017 to investigate the effects of discarded drugs and chemicals on water pollution.

 

Agilent

66 substances were selected for the survey.

 

It includes Ranitidine and Nizatidine, and Metformin.

 

Among the various substances, it is explained that a substance that is likely to be transformed into DMA (dimethylamine) is selected.

 

DMA, together with nitrite, is one of the two materials of NDMA Experimental results showed that the rate of NDMA formation was 60-90% for Ranitidine.

 

Of the 100 ranitidine molecules, 60 to 90 change to NDMA.

 

5% to Nizatidine.

 

Metformin was found to be less than 1%.

 

This is consistent with the description of the MFDS official.

 

However, as in the case of Valsartan, it is not possible to exclude the possibility that NDMA is generated due to reaction of a specific solvent in the manufacturing process.

 

In the case of Valsartan, dimethylamine was formed as a decomposition product during the high temperature process of dimethylformamide (DMF), which was used as a solvent, and the dimethylamine reacted with nitrite under acidic conditions, leading to NDMA formation.

 

An official from the MFDS explained, “It is difficult to identify the cause of NDMA in Metformin right away, and we have to chop up the molecules of Metformin into small pieces to closely examine the similarity with Ranitidine and the toxicity of the substance itself”.

 

"As a result of the QSAR test, Ranitidine was 90 and Metformin was 1, and A detailed survey of Metformin will be performed and it will be compared with the QSAR test results" said the official.