scholarly journals FORCED DEGRADATION STUDIES OF NILOTINIB HYDROCHLORIDE: ISOLATION, IDENTIFICATION & CHARACTERIZATION OF IMPURITIES

2020 ◽  
pp. 537-543
Author(s):  
JCMKNN Murty Singamsetti ◽  
Raghu Babu Korupolu ◽  
Himabindhu Gandham ◽  
Mahesh Kumar Reddy Geereddi ◽  
Muralidharan Kaliyaperumal ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Degradation Product ◽  
Kinase Inhibitor ◽  
Degradation Products ◽  
Myelogenous Leukemia ◽  
Forced Degradation ◽  
Molecular Formula ◽  
Forced Degradation Studies ◽  
Acidic Environments ◽  
Degradation Studies

Nilotinib hydrochloride is a tyrosine kinase inhibitor approved for the treatment of chronic myelogenous leukemia was subjected to forced degradation studies and the samples were analyzed by utilizing the LCMS compatible HPLC methods. Nilotinib Hydrochloride was subjected to thermal, hydrolytic, oxidative, acidic, basic and photolytic degradation conditions as per the regulatory guidelines. The drug was degraded in oxidative, basic and acidic environments and stable in photolytic and thermal conditions. The main degradation impurity components produced through the forced degradation study were isolated for the identification and quantification in presence of these impurities in the stability studies of drug substances as well as drug products. The identified degradation components were separated by mass assisted auto-purification technique and subjected for the characterization by NMR (13C-NMR, 1H-NMR, HMBC and HSQC), HRMS and FT-IR experimentations. Degradation products obtained from oxidative, basic and acidic environments were isolated and identified by the advanced techniques  as acid degradation product (DP-1) with molecular mass of 306.11 g/mol, empirical formula C17H14N4O2 with name as 4-methyl-3- (4 -(pyridine -3-yl) pyrimidin -2 -ylamino) benzoic acid. Base degradation product (DP-2) has molecular weight of 241.08 g/mol, molecular formula C11H10F3N3 with name as 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline.Oxidative degradation product (DP-3) has molecular weight of 545.18 g/mol, molecular formula C28H22F3N7O2 with name as 3-(2-(2-methyl-5-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenylcarbamoyl) phenylamino)pyrimidin-4-yl)pyridine1-oxide.  

scholarly journals Current Trend in Performance of Forced Degradation Studies for Drug Substance and Drug Product’s

2020 ◽  
Vol 10 (2-s) ◽  
pp. 149-155
Author(s):  
Rajveer Bhaskar ◽  
Monika Ola ◽  
Vinit Agnihotri ◽  
Arjun Chavan ◽  
Harpalsing Girase
Keyword(s):  
Degradation Product ◽  
Degradation Products ◽  
Drug Product ◽  
Current Trend ◽  
Forced Degradation ◽  
Regulatory Requirement ◽  
New Drug ◽  
Drug Substances ◽  
Forced Degradation Studies ◽  
Degradation Studies

The stability of a new drug substances and new drug products is a vital parameter which may affect purity, safety & potency. Changes in drug stability can threat patient safety by formation of toxic degradation products or deliver to lower dose than expected. Therefore it is to know the purity profile & behaviour of a drug substances under the various environmental condition.  Forced Degradation studies show the chemical behavior of the molecule which in turn helps in the  development of  new formulation & package . Degradation study is required to the design of a regulatory compliant stability program for the both drug substances & products, and formalized as a regulatory requirement in ICH Guideline Q1A in 1993. Forced degradation studies (chemical and physical stress testing) of new chemical entities and drug product which is required to develop and demonstrate the specificity i.e stability indicating method. Forced degradation studies used to determination of the degradation pathways and degradation product of drug substances i.e during storage, development, manufacturing and packaging Thus , this review discusses the current trends in performance of forced degradation studies by provide the information about strategy for conducting the studies of forced degradation Keywords: - Regulatory Guidelines (ICH, FDA, EMA), Degradation condition, Forced degradation, Degradation product.

scholarly journals RP-HPLC assay method development for Paracetamol and Lornoxicam in combination and characterization of oxidative degradation products of Lornoxicam

2013 ◽  
Vol 19 (4) ◽  
pp. 471-484
Author(s):  
Pritam Jain ◽  
Miketa Patel ◽  
Amar Chaudhari ◽  
Sanjay Surana
Keyword(s):  
Method Development ◽  
Degradation Products ◽  
Oxidative Degradation ◽  
Assay Method ◽  
Forced Degradation ◽  
Control Analysis ◽  
Reverse Phase ◽  
Solution Form ◽  
Forced Degradation Studies ◽  
Degradation Studies

A simple, specific, accurate and precise reverse phase high pressure liquid chromatographic method has been developed for the simultaneous determination of Paracetamol and Lornoxicam from tablets and to characterize degradation products of Lornoxicam by reverse phase C18 column (Inertsil ODS 3V C-18, 250 x 4.6 mm, 5 ?). The sample was analyzed using Buffer (0.02504 Molar): Methanol in the ratio of 45:55, as a mobile phase at a flow rate of 1.5 mL/min and detection at 290 nm. The retention time for Paracetamol and Lornoxicam was found to be 2.45 and 9.40 min respectively. The method can be used for estimation of combination of these drugs in tablets. The method was validated as per ICH guidelines. The linearity of developed method was achieved in the range of 249.09 - 747.29 ?g/mL (r2=0.9999) for Paracetamol and 4.0125 - 12.0375 ?g/mL (r2=0.9999) for Lornoxicam. Recoveries from tablets were between 98 and 102%. The method was validated with respect to linearity, accuracy, precision, robustness and forced degradation studies which further proved the stability-indicating power. During the forced degradation studies lornoxicam was observed to be labile to alkaline hydrolytic stress and oxidative stress (in the solution form). However, it was stable to the acid hydrolytic, photolytic and thermal stress (in both solid and solution form). The degraded products formed were investigated by electrospray ionization (ESI) time-of-flight mass spectrometry, NMR and IR spectroscopy. A possible degradation pathway was outlined based on the results. The method was found to be sensitive with a detection limit of 0.193 ?g/ml, 2.768 ?g/ml and a quantitation limit of 0.638 ?g/ml, 9.137 ?g/ml for lornoxicam and paracetamol, respectively. Due to these attributes, the proposed method could be used for routine quality control analysis of these drugs in combined dosage forms.

scholarly journals LC-MS/MS CHARACTERIZATION OF FORCED DEGRADATION PRODUCTS OF TUCATINIB, A NOVEL TYROSINE KINASE INHIBITOR: DEVELOPMENT AND VALIDATION OF RP-HPLC METHOD

2022 ◽  
pp. 58-66
Author(s):  
S. K. REEHANA ◽  
K. SUJANA
Keyword(s):  
Kinase Inhibitor ◽  
Degradation Products ◽  
Degradation Pathway ◽  
Hplc Method ◽  
Forced Degradation ◽  
Ich Guidelines ◽  
System Suitability ◽  
Forced Degradation Studies ◽  
Development And Validation

Objective: The current study focused on the development, validation, and characterization of forced degradation products using LC-MS/MS. Methods: A simple, selective, validated and well-defined isocratic HPLC methodology for the quantitative determination of Tucatinib at a wavelength of 239 nm. An isocratic elution of samples was performed on an Inertsil ODS (250x4.6 mm, 5m) column with a mobile phase of 70:30v/v Acetonitrile and formic acid (0.1%) delivered at a flow rate of 1.0 ml/min. MS/MS was used to characterize degradation products formed in the forced degradation study. The validation and characterization of forced degradation products were performed in accordance with ICH guidelines. Results: Over the concentration range of 5-100μg/ml, a good linear response was obtained. Tucatinib's LOD and LOQ were determined to be 0.05 and 0.5, respectively. According to standard guidelines, the method was quantitatively evaluated in terms of system suitability, linearity, precision, accuracy, and robustness, and the results were found to be within acceptable limits. The drug was degraded under acidic, alkaline, and reduction conditions in forced degradation studies. Conclusion: The method was found to be applicable for routine tucatinib analysis. Because no LC-MS/MS method for estimating tucatinib and its degradation products has been reported in the literature. There is a need to develop a method for studying the entire tucatinib degradation pathway.

A new stability indicating ultra-fast liquid chromatographic (RP-UFLC) method for the quantification of Nilotinib – A drug for blood cancer

2021 ◽  
pp. 2581-2586
Author(s):  
Paladugu Venkata Naveen ◽  
Seru Ganapaty
Keyword(s):  
Kinase Inhibitor ◽  
Myelogenous Leukemia ◽  
Forced Degradation ◽  
Chromatographic Study ◽  
Linear Regression Equation ◽  
Stability Indicating ◽  
Ich Guidelines ◽  
Forced Degradation Studies ◽  
Liquid Chromatographic ◽  
Alkaline Oxidation

Nilotinib hydrochloride monohydrate is a tyrosine kinase inhibitor approved for the treatment of chronic myelogenous leukemia. A new stability indicating ultra-fast liquid chromatographic (RP-UFLC) method was developed for the quantification of Nilotinib and validated. Mobile phase consisting of a mixture of sodium acetate (pH 5.0): acetonitrile (40: 60, v/v) was used with flow rate 0.8 mL/min (UV detection at 254 nm) for the chromatographic study. Nilotinib obeys Beer-Lambert’s law over the concentration range of 0.2-80 μg/mL (R2 = 0.9999) with linear regression equation y = 175336x +20675. The LOQ was found to be 0.1897 μg/mL and the LOD was found to be 0.0619 μg/mL. Forced degradation studies were performed such as acidic, alkaline, oxidation and thermal degradations and the method was validated as per ICH guidelines.

scholarly journals Chemometrics Approaches in Forced Degradation Studies of Pharmaceutical Drugs

Molecules ◽  
2019 ◽  
Vol 24 (20) ◽  
pp. 3804
Author(s):  
Benedito Roberto de Alvarenga Junior ◽  
Renato Lajarim Carneiro
Keyword(s):  
Degradation Products ◽  
Drug Product ◽  
Forced Degradation ◽  
Pharmaceutical Drugs ◽  
Know How ◽  
Pharmaceutical Ingredients ◽  
Physicochemical Stability ◽  
Forced Degradation Studies ◽  
Degradation Studies

Chemometrics is the chemistry field responsible for planning and extracting the maximum of information of experiments from chemical data using mathematical tools (linear algebra, statistics, and so on). Active pharmaceutical ingredients (APIs) can form impurities when exposed to excipients or environmental variables such as light, high temperatures, acidic or basic conditions, humidity, and oxidative environment. By considering that these impurities can affect the safety and efficacy of the drug product, it is necessary to know how these impurities are yielded and to establish the pathway of their formation. In this context, forced degradation studies of pharmaceutical drugs have been used for the characterization of physicochemical stability of APIs. These studies are also essential in the validation of analytical methodologies, in order to prove the selectivity of methods for the API and its impurities and to create strategies to avoid the formation of degradation products. This review aims to demonstrate how forced degradation studies have been actually performed and the applications of chemometric tools in related studies. Some papers are going to be discussed to exemplify the chemometric applications in forced degradation studies.

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