Calculation formula of Related substances by area normalization

Discussion about the topics related to pharmaceutical research and development (R&D).

Any one can suggest how to calculate RS by area normalization method in a single component formulation and a double component formulation.
example : Levocetrizine di HCl and montelukast sodium tablet RS by % area normalization method.

1 Like

Dear Yogesh,
When it comes to calculate the % impurity by area normalization one can do it by taking the individual area of the impurity divided by the total area and multiply that by 100 to get the % of impurity.
Coming to the query of yours w.r.t calculation of the impurity in drug product, it is possible for a single component drug product but will become complicated for a combination product as the characteristics of the drug will be all together different with different impurities involved.
The example you have itself has the answer, both the products LDhcL API monograph and Mont Sodium tablets monograph is available in USP and Forum you can refer that.
Both the drugs have different column chemistries, the wavelengths are different and many other parameters.
My suggestion will be always to develop an external standard methods for RS by well establishing the RRF’s for each known impurities may it be single or muliple drug combination. This approach with proper justifications and required validations is well accepted by the regulatory bodies world wide.
Hope this clarifies your doubt.
Thanks

1 Like

@vishu8
Hi, please let me know how to impurities limit are decided for any in-house products. Like single, total, specified, unspecified etc. Is there any article for understanding their calculation…
Please help me to understand this concept of impurities.
Thanks to you in advance.

Dear Manish,

Good morning,

The limits for impurities are set as per the maximum daily dose administered in one day i.e. in a 24 hour cycle.

To respond to your question related to the setting of impurities limits w. r. t the synthetic drug substances, in general you follow the ICH Q3 series of guidelines. Irrespective of the market the limits are set in line to these guidelines. The calculation parts are given at the end of each guideline to follow.

These guidelines tell about how to set the limits (reporting threshold limit, limits for setting known and unknown impurities) for drug substance Q3A, drug product Q3B, Residual solvents Q3C and Elemental impurities Q3D.

Hope these clarifies you doubt, go through these guidelines and you will definitely understand.

Thanks

Dear Yogesh

Area Normalization method can only be used for single component drug produc. Degradents only adds up to 100% including main peak.
Area Normalization = Imp area/Total Area*100

Where as major RRF difference is there for impurities then also Area normalization can apply with RRF.
In some cases external standard method can’t apply where the excipients dilutes with diluent and reduces the recovery. In this case diluted test sample method has to be adopt to nullify dilution error. But it is also acceptable if the impurities limit is below 2% where as higher impurities main peak degrades high abs we calculate degraded diluted test sample and reports higher impuritie. In this case area normalization will be more accurate and demand test solution linearity. In diluted test sample method calculation shall be done against degraded sample where as area normalization against 100% including main peak and degradents.
Area normalization with RRF
=(Imp Area/Total Area)*(1/RRF)*100

Total Area=Main peak area+(Imp Area/Imp RRF)+sum of all unspecified impurities

Where all known impurities shall be corrected with RRF and has to be add