SIGNIFICANCE OF FORCED DEGRADATION STUDIES FOR DRUG SUBSTANCE AND DRUG PRODUCTS WITH REFERENCE TO ANTIHYPERTENSIVE AGENTS

INDIAN DRUGS ◽  
2016 ◽  
Vol 53 (01) ◽  
pp. 5-17
Author(s):  
J. G Modi ◽  
◽  
J. K Patel ◽  
N. A Gohel ◽  
K. G Modi ◽  
...  
Keyword(s):  
Degradation Products ◽  
Drug Product ◽  
Antihypertensive Agents ◽  
Active Pharmaceutical Ingredient ◽  
Pharmaceutical Product ◽  
Stress Conditions ◽  
Drug Substance ◽  
Forced Degradation ◽  
Degradation Study ◽  
Drug Products

Stability testing is used to provide evidence of how the quality of an Active Pharmaceutical Ingredient (API) or drug product varies with time under the infuence of a variety of environmental factors such as temperature, humidity and light. If drug product is not stable under various environmental conditions, it may affect the patient safety by formation of a toxic degradation product(s) or deliver a lower dose than expected. Stress testing of the API can help to identify the likely degradation products, which, in turn, can help to establish the degradation pathways and the intrinsic stability of the molecule. Forced degradation study is a process in which the natural degradation rate of a pharmaceutical product is increased by applying an additional stres by which stability of a drug substance or a drug product with effects on purity, potency and safety can be predicted. The present review summarizes the forced degradation study of antihypertensive agents, where degradation products for different stress conditions have been reported. As per review, maximum degradation products have been reported by alkaline, oxidative and photolytic stress conditions.

Identification and characterization of degradation products of indacaterol using liquid chromatography/mass spectrometry

2020 ◽  
Vol 26 (6) ◽  
pp. 425-431
Author(s):  
Naga Veera Yerra ◽  
S Babu Dadinaboyina ◽  
LSSN Vigjna Abbaraju ◽  
MVN Kumar Talluri ◽  
Jagadeshwar Reddy Thota
Keyword(s):  
Degradation Products ◽  
Thermal Conditions ◽  
Active Pharmaceutical Ingredient ◽  
Stress Conditions ◽  
Chronic Obstructive ◽  
Forced Degradation ◽  
Obstructive Pulmonary Disease ◽  
Guide Lines ◽  
Identification And Characterization

Indacaterol (IND), 5-[2-[(5,6-Diethyl-2,3-dihydro-1H-inden-2-yl)amino]-1-hydroxyethyl]-8-hydroxyquinolin-2(1H)-one, is an active pharmaceutical ingredient (API) which is used to treat chronic obstructive pulmonary disease (COPD). We followed the International Council for Harmonization (ICH) guide lines to study the degradation behavior of IND under various stress conditions. Stressed degradation of the drug was performed under hydrolytic (alkaline, acidic and neutral), photolytic, oxidative and thermal conditions. Identification and characterization of IND and its forced degradation products (DPs) were demonstrated by using LC-HRMS and MS/MS method. A total of three DPs (DP1-DP3) were identified and characterized. The IND was found to be stable under photolytic, oxidative and thermal conditions, whereas it produced three DPs in acidic, basic and neutral hydrolytic stress conditions.

Development and Validation of a Reversed-Phase Ultra-Performance Liquid Chromatographic Method for Assay of Lacidipine and Related Substances

2011 ◽  
Vol 94 (6) ◽  
pp. 1800-1806 ◽  
Author(s):  
Arivozhi Mohan ◽  
Hitesh B Patel ◽  
Dhandayutham Saravanan
Keyword(s):  
Degradation Products ◽  
Drug Product ◽  
Reversed Phase ◽  
Drug Substance ◽  
Forced Degradation ◽  
Related Substances ◽  
Forced Degradation Studies ◽  
Acetic Acid Buffer ◽  
Development And Validation ◽  
Liquid Chromatographic

Abstract A simple isocratic, RP-ultra-performance LC method was developed and validated for the determination of lacidipine, three process impurities formed during synthesis, and three degradation products present in drug substance and the drug product. An efficient chromatographic separation was achieved on an Acquity BEH C18 column using pH 4.5 ammonium acetate–acetic acid buffer–methanol (70 + 30, v/v) mobile phase. The monitoring wavelength was 240 nm, and the flow rate 0.25 mL/min. Forced degradation studies using acid, alkali, peroxide, water, heat, and light were conducted, and all impurities were separated. The method was validated successfully for specificity, precision, linearity, accuracy, LOD, LOQ, and robustness, according to International Conference on Harmonization guidelines. The linearity of the calibration curve for lacidipine and each impurity was found to be very good (r2 > 0.999). This method is shown to be suitable for analysis of lacidipine to evaluate the quality of drug substance and a drug product.

scholarly journals Identification of degradation impurity of TGR5 receptor agonist-ZY12201 by LC–MS technique during force degradation study

2021 ◽  
Vol 3 (6) ◽  
Author(s):  
Chandrakant Sojitra ◽  
Chintan Dholakia ◽  
Padmaja Sudhakar ◽  
Kumar K. Singh ◽  
Sameer Agarwal
Keyword(s):  
Degradation Products ◽  
Oxidative Degradation ◽  
Active Pharmaceutical Ingredient ◽  
Storage Conditions ◽  
Receptor Activation ◽  
Degradation Pathway ◽  
Forced Degradation ◽  
Degradation Study ◽  
Glucagon Like Peptide 1 ◽  
Orally Bioavailable

AbstractForced degradation study is a systemic characterization of degradation products of active pharmaceutical ingredient (API) at conditions which posses more harsh environment that accelerates degradation of API. Forced degradation and stability studies would be useful in selection of proper, packaging material and storage conditions of the API. These are also useful to demonstrate degradation pathways and degradation products of the API and further characterisation of the degradation products using mass spectrometry. TGR5 is a G protein-coupled receptor, activation of which promotes secretion of glucagon-like peptide-1 (GLP-1) and modulates insulin secretion. The potent and orally bioavailable TGR5 agonist, ZY12201, shows activation of TGR5 which increase secretion of GLP-1 and help in lowering blood glucose level in animal models. Hence it is necessary to establish and study degradation pathway and stability of API for better handling and regulatory approval. Force degradation studies of ZY12201 have shown presence of one oxidative impurity during oxidative degradation in HPLC analysis. The oxidized product is further characterized by LC–MS to elucidate structure of impurity and characterize its degradation pathway.

scholarly journals FORCED DEGRADATION STUDY OF STATINS: A REVIEW

2018 ◽  
Vol 10 (6) ◽  
pp. 38
Author(s):  
Rini Yulianita ◽  
Iyan Sopyan ◽  
Muchtaridi Muchtaridi
Keyword(s):  
Degradation Products ◽  
Storage Conditions ◽  
Lipid Lowering ◽  
Forced Degradation ◽  
Degradation Study ◽  
Drug Degradation ◽  
Drug Products ◽  
Drug Substances ◽  
Accelerated Stability ◽  
Forced Degradation Studies

Forced degradation study is the degradation of new drug substances and drug products in more severe conditions than accelerated conditions. Forced degradation study were conducted to demonstrate the specificity of stability-indicating methods, providing insight into degradation pathways and drug degradation products, assisting in the elucidation of degradation product structures, identifying degradation products that could be spontaneously generated during storage and use of drugs and to facilitate improvement in manufacturing process and formulation corresponding with accelerated stability studies. Statins, a class of lipid-lowering medications, are the most widely prescribed drugs and an example of an unstable drug. Statins are susceptible to hydrolysis in the presence of high temperatures and humidity. Therefore, the review discusses various studies of forced degradation studies in six statins drug (atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin) to describe the drug's intrinsic stability thus it can assist the selection of formulations and packaging as well as proper storage conditions.

Synthesis and Characterization of Potential and Degraded Impurities of Regadenoson

2020 ◽  
Vol 16 (8) ◽  
pp. 1130-1139
Author(s):  
Singaram Sathiyanarayanan ◽  
Chidambaram Subramanian Venkatesan ◽  
Senthamaraikannan Kabilan
Keyword(s):  
Mass Spectra ◽  
Degradation Products ◽  
Hplc Method ◽  
Forced Degradation ◽  
Spectroscopic Techniques ◽  
A2a Adenosine Receptor ◽  
Degradation Study ◽  
Related Substances ◽  
Adenosine Receptor Agonist

Background: Regadenoson is an A2A adenosine receptor agonist that is a coronary vasodilator and commonly used as a pharmacologic cardiac stressing agents. Methods: HPLC method was used for the analysis of related substances. The degraded impurities during the process were isolated and characterized by IR, Mass and NMR spectral analysis. Results: Forced degradation study of regadenoson under conditions of hydrolysis (neutral, acidic and alkaline) and oxidations suggested in the ICH Q1A(R2) was accomplished. The drug showed significant degradation under all the above conditions. On the whole, five novel degradation products were found under diverse conditions along with process related impurities which were not reported earlier. Conclusion: All the degradation products were well characterized by using advanced spectroscopic techniques like IR, 1H NMR, 13C NMR and Mass spectra. The identification of these impurities will be productive for the quality control during the production and stability behavior of the regadenoson drug substance.

scholarly journals On the Stability and Degradation Pathways of Venetoclax under Stress Conditions

Pharmaceutics ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 639
Author(s):  
Nina Žigart ◽  
Martin Črnugelj ◽  
Janez Ilaš ◽  
Zdenko Časar
Keyword(s):  
High Resolution Mass Spectrometry ◽  
Degradation Products ◽  
Single Agent ◽  
B Cell Lymphoma ◽  
Lymphocytic Leukemia ◽  
Stress Conditions ◽  
Forced Degradation ◽  
Degradation Pathways ◽  
Orally Bioavailable ◽  
The Stability

Venetoclax is an orally bioavailable, B-cell lymphoma-2 (BCL-2) selective inhibitor, used for the treatment of various types of blood cancers, such as chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). In this study we investigated the degradation of venetoclax under various stress conditions including acidic, basic, oxidative, photolytic and thermolytic conditions. We isolated and identified six of its main degradation products produced in forced degradation studies. The structures of the isolated degradation products were determined by using nuclear magnetic resonance (NMR) spectroscopy, high resolution mass spectrometry (HRMS) and infrared (IR) spectroscopy. Additionally, one oxidation degradation product was identified with comparison to a commercially obtained venetoclax impurity. We proposed the key degradation pathways of venetoclax in solution. To the best of our knowledge, no structures of degradation products of venetoclax have been previously published. The study provides novel and primary knowledge of the stability characteristics of venetoclax under stress conditions. Venetoclax is currently the only BCL-2 protein inhibitor on the market. In addition to single agent treatment, it is effective in combinational therapy, so future drug development involving venetoclax can be expected. A better insight into the stability properties of the therapeutic can facilitate future studies involving venetoclax and aid in the search of new similar therapeutics.

scholarly journals Understanding and Kinetic Modeling of Complex Degradation Pathways in the Solid Dosage Form: The Case of Saxagliptin

Pharmaceutics ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 452 ◽  
Author(s):  
Robnik ◽  
Likozar ◽  
Wang ◽  
Stanić Ljubin ◽  
Časar
Keyword(s):  
Relative Humidity ◽  
Degradation Product ◽  
Degradation Products ◽  
Drug Product ◽  
Degradation Kinetics ◽  
Dosage Forms ◽  
Drug Substance ◽  
Polymer Composition ◽  
Solid Dosage Forms ◽  
Solid Dosage

Drug substance degradation kinetics in solid dosage forms is rarely mechanistically modeled due to several potential micro-environmental and manufacturing related effects that need to be integrated into rate laws. The aim of our work was to construct a model capable of predicting individual degradation product concentrations, taking into account also formulation composition parameters. A comprehensive study was done on active film-coated tablets, manufactured by layering of the drug substance, a primary amine compound saxagliptin, onto inert tablet cores. Formulation variables like polyethylene glycol (PEG) 6000 amount and film-coat polymer composition are incorporated into the model, and are connected to saxagliptin degradation, via formation of reactive impurities. Derived reaction equations are based on mechanisms supported by ab initio calculations of individual reaction activation energies. Alongside temperature, relative humidity, and reactant concentration, the drug substance impurity profile is dependent on micro-environmental pH, altered by formation of acidic PEG degradation products. A consequence of pH lowering, due to formation of formic acid, is lower formation of main saxagliptin degradation product epi-cyclic amidine, a better resistance of formulation to high relative humidity conditions, and satisfactory tablet appearance. Discovered insights enhance the understanding of degradational behavior of similarly composed solid dosage forms on overall drug product quality and may be adopted by pharmaceutical scientists for the design of a stable formulation.

scholarly journals Determination of Rosuvastatin in the Presence of Its Degradation Products by a Stability-Indicating LC Method

2005 ◽  
Vol 88 (4) ◽  
pp. 1142-1147 ◽  
Author(s):  
Tushar N Mehta ◽  
Atul K Patel ◽  
Gopal M Kulkarni ◽  
Gunta Suubbaiah
Keyword(s):  
Degradation Products ◽  
Stability Study ◽  
Tablet Formulation ◽  
Assay Method ◽  
Forced Degradation ◽  
Degradation Study ◽  
Stability Indicating ◽  
Degraded Samples ◽  
Accelerated Stability

Abstract A forced degradation study was successfully applied for the development of a stability-indicating assay method for determination of rosuvastatin Ca in the presence of its degradation products. The method was developed and optimized by analyzing the forcefully degraded samples. Degradation of the drug was done at various pH values. Moreover, the drug was degraded under oxidative, photolytic, and thermal stress conditions. Mass balance between assay values of degraded samples and generated impurities was found to be satisfactory. The proposed method was able to resolve all of the possible degradation products formed during the stress study. The developed method was successfully applied for an accelerated stability study of the tablet formulation. The major impurities generated during the accelerated stability study of the tablet formulation were matches with those of the forced degradation study. The developed method was validated for determination of rosuvastatin Ca, and the method was found to be equally applicable to study the impurities formed during routine and forced degradation of rosuvastatin Ca.

Characterization of stress degradation products of blonanserin by UPLC-QTOF-tandem mass spectrometry

RSC Advances ◽  
2015 ◽  
Vol 5 (85) ◽  
pp. 69273-69288 ◽  
Author(s):  
Pradipbhai D. Kalariya ◽  
Prinesh N. Patel ◽  
Mahesh Sharma ◽  
Prabha Garg ◽  
R. Srinivas ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
High Resolution ◽  
Tandem Mass Spectrometry ◽  
Degradation Products ◽  
Structural Elucidation ◽  
Forced Degradation ◽  
Tandem Mass ◽  
Degradation Study ◽  
Stress Degradation

Forced degradation study of blonanserin and structural elucidation of its degradation products was performed using high resolution tandem mass spectrometry.

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