Evaluation of a Novel LC-MS/MS Based Analytical Method for the Risk Assessment of Nitrosamines in Pharmaceutical Products and Packaging Materials.

The detection of nitrosamine impurities, particularly small dialkyl types, which are frequently known to be potent mutagenic carcinogens, in some Sartan group active pharmaceutical ingredients (APIs) and finished drug products caused global regulatory organizations to have concerns. Accordingly, Registration Holders/Applicants, API manufacturers, and their raw material suppliers are required to check the presence of nitrosamines in their products and carry out risk assessments using the quality risk management principles specified in the ICH Q9 guide. In this context, a new LC-MS/MS method has been developed and validated for the simultaneous determination of NDMA, NDEA, NMBA, NDIPA, NEIPA, NDBA, and MeNP nitrosamine compounds in API and finished products as well as in primary packaging materials, one of the risk sources. This validated method was applied to check the nitrosamine content may occur from canister, blister, printed aluminum foil, nasal spray, and eye drop packaging materials as part of the Extractables & Leachables studies arising from interactions between the product and the primary packaging. For the determination and quality control of nitrosamines in sartan group pharmaceutical products and packaging materials, the developed LC-MS/MS analytical method offers highly reliable, fast, high accuracy, good sensitivity and simultaneous detection even at low concentrations.

Simultaneous quantification of tiotropium bromide impurities G + H in capsule formulation by LC-MS/MS.

Tiotropium Bromide is a long-acting bronchodilator that is used in the treatment of chronic obstructive pulmonary disease (COPD) and asthma bronchodilator or bronchiolitis, which are substances that expand the bronchi and reduce resistance in the respiratory tract and increase airflow to the lungs. For Tiotropium Bromide found in inhaler capsules to treat COPD, determining the relevant impurities G and H, which are not UV active, is crucial. For this purpose, a new and sensitive liquid chromatography triple-quadrupole mass spectrometry (LC-MS/MS) detection with electrospray ionization by using multiple reaction monitoring in the positive mode method was developed and validated. The identity of the compounds was supported by using LC-Q/TOF. All chromatographic studies were performed with a Zorbax Eclipse XDB-C8 (150 mm x 4.6 mm, 5.0 µm) column with a total injection time of 13 min at a flow rate of 0.4 ml/min as a gradient. The limit of detection (LOD) and limit of quantitation (LOQ) in the current study range were determined as 1.0 ppb and 2.5 ppb, respectively. The results of the validation parameters following the ICH Q2(R1) guideline were determined within the acceptance criteria.

Validation of Stability-Indicating RP-HPLC Method and Determination of Impurities by LC-QTOF-MS for Adenosine in Eye Drops.

BACKGROUND: Presently, there is no validated method for stability-indicating related substances of adenosine used in the treatment of cataracts and found in different combined eye drop products. OBJECTIVE: A stability-indicating related substances analytical method for adenosine used in the treatment of cataracts and found in different combined eye drop products should be developed and validated. METHOD: A new reverse phase-HPLC method of determination for adenosine-related compounds has been developed and validated according to the International Council for Harmonisation. In this method, all impurities were easily detected for adenosine, which is found in combination with different active ingredients such as nicotinic acid and nicotinamide. The impurities obtained by a stress test were purified and their structures were characterized by mass spectroscopy (LC-QTOF-MS). RESULTS: The concentration range for linearity was evaluated as 0.06-4.27 µg/mL for adenosine, 0.15-4.27 µg/mL for uridine, 0.15-4.17 µg/mL for inosine, 0.13-4.35 µg/mL for guanosine, and 0.12-4.26 µg/mL for adenine. Good linearity was achieved for each component, and it was determined that the correlation coefficient (r) met the acceptance criterion r ≥ 0.99. The accuracy of the method was good-to-excellent recoveries at each concentration level (from LOQ to 120% of the specification limit) were achieved within the limit range of 80.0-120.0%, and RSD of recoveries was found below 10.0% for both formulations. CONCLUSIONS: With this economical and simple method validated in accordance with the ICH Q2 (R1) guideline, a new method has been created for adenosine, which is suitable for routine analysis. HIGHLIGHTS: The validated method is a very simple and suitable method for green chemistry without any pre-processing, and the structure of the impurities obtained as a result of stress studies was confirmed by LC-QTOF-MS.