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Development of forced degradation and stability indicating studies of drugs——A review

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Journal of Pharmaceutical Analysis 2014年第3期4卷 159-165页

作者： Blessy M Ruchi D.Patel Prajesh N.Prajapati Y.K.Agrawal Department of Pharmaceutical Analysis Institute of Research and DevelopmentGujarat Forensic Sciences University Sector-18ANr.Police BhavanGandhinagar 382007GujaratIndia

forced degradation is a degradation of new drug substance and drug product at conditions more severe than accelerated conditions. It is required to demonstrate specificity of stability indicating methods and also provides an insight into degradation pathways and degradation products of the drug substance and helps in elucidation of the structure of the degradation products. forced degradation studies show the chemical behavior of the molecule which in turn helps in the development of formulation and package. In addition, the regulatory guidance is very general and does not explain about the performance of forced degradation studies. Thus, this review discusses the current trends in performance of forced degradation studies by providing a strategy for conducting studies on degradation mechanisms and also describes the analytical methods helpful for development of stability indicating method.

关键词： degradation conditionsdegradation product forced degradation Stability indicatingmethod Stress testing

Identification, Isolation and Structure Confirmation of forced degradation Products of Sofosbuvir

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American Journal of Analytical Chemistry 2016年第11期7卷 797-815页

作者： Vasudev Pottabathini Vijayacharan Gugulothu Muralidharan Kaliyaperumal Satyanarayana Battu Department of Chemistry University College of Science Osmania University Hyderabad Telangana India GVK Bio Sciences Pvt. Ltd. Hyderabad Telangana India

A new stability indicating reverse phase chromatographic method was developed for the analysis of Heptisis C Drug Sofosbuvir. The developed UPLC method was superior in technology to conventional RP-HPLC with respect to resolution, speed, solvent consumption and analysis cost. Sofosbuvir was subjected to the thermal, hydrolytic, oxidative, and photolytic degradation, according to ICH guidelines. The drug depicted degradation in acidic, basic and oxidative conditions and it was stable to other stress conditions (thermal and photolytic). Identified degradation products were isolated using mass supported auto purification system and characterized by NMR techniques (1H NMR, D2O Exchange, 13C NMR, 31P NMR, 19F NMR, HSQC and HMBC) and HRMS experiments. Isolated acid degradation impurity was showing molecular weight of 416.08, molecular formula C16H18FN2O8P and its name as (R)-((2R, 3R, 4R, 5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methyl phenyl hydrogen phosphate. Isolated base degradation impurity-A was showing molecular weight of 453.13, molecular formula C16H25FN3O9P and its name as (S)-isopropyl 2-((R)-(((2R, 3R, 4R, 5R)-5-(2, 4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(hydroxy)phosphorylamino)propanoate. Isolated base degradation impurity-B was showing molecular weight of 411.08, molecular formula C13H19FN3O9 P and its name as (S)-2-((R)-(((2R, 3R, 4R, 5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methox-y)(hydroxy)phos-phorylamino)propanoic acid. In oxidative degradation study, degradation was observed very less and with obtained quantity (less than 2 mg) recorded 1H NMR and HRMS analysis. From the spectral

关键词： Sofosbuvir forced degradation Unknown Impurities Isolation Characterization

Investigation of the long-term stability and forced degradation of valtrate by high performance liquid chromatography coupled with triple quadrupole tandem mass spectrometry

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Journal of Chinese Pharmaceutical Sciences 2014年第12期23卷 850-857页

作者：王菲菲王明娟张聿梅王琰于健东王瑞忠程显龙汪祺郑笑为刘燕戴忠马双成 Erwin Adam 中国食品药品检定研究院北京100050 鲁汶大学药物分析实验室

Valtrate is the main drug quality control for the qualitative and quantitative analysis of Valerian medicines in the Chinese Pharmacopoeia 2010. However, valtrate is unstable under some conditions. We, for the first time, systemically evaluated the stability of two bath reference standards （RS） by high performance liquid chromatography coupled with a triple quadrupole mass spectrometer （HPLC-MS/MS）. The forced degradations of valtrate were performed to evaluate its optimal storage, transportation and experiment conditions according to ICH guideline. The developed HPLC method was validated to determine the degradation products. Valtrate RS was sensitive to alkaline and thermal conditions, but it was relatively stable under acidic, oxidation and photolysis conditions. A total of nine degradation components were identified under alkaline hydrolysis （N1-N4） and thermal degradation （B1-B5）. The information obtained in this work would be valuable to minimize the decomposition of valtrate during the processes of preparation, storage, distribution and utilization. It was highly suggested to store valtrate with a single dose packing in brown closed ampoule at -20℃. Under the above-mentioned storage condition, valtrate could be stable for up to 3 years.

关键词： Valtrate Stability Long-term stability forced degradation Tandem mass spectrometry

Taxifolin stability: In silico prediction and in vitro degradation with HPLC-UV/UPLCe ESI-MS monitoring

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Journal of Pharmaceutical Analysis 2021年第2期11卷 232-240页

作者： Fernanda Cristina Stenger Moura Carmem Lúciados Santos Machado Favero Reisdorfer Paula Angelica Garcia Couto Maurizio Ricci Valdir Cechinel-Filho Tiago J.Bonomini Louis P.Sandjo Tania Mari Belle Bresolin Pharmaceutical Sciences Graduate Program School of Health SciencesCourse of PharmacyUniversidade do Vale do ItajaíItajaíSC88302-202Brazil Laboratory of Research and Development of Drugs Pharmaceutical Sciences Graduate ProgramSchool of Health SciencesCourse of PharmacyUniversidade Federal do PampaUruguaianaRS97500-970Brazil Department of Pharmaceutical Science Universita degli Studi di PerugiaPerugiaPG06123Italy Chemistry Department Universidade Federal de Santa CatarinaTrindadeFlorian opolisSC88040-900Brazil

Taxifolin has a plethora of therapeutic activities and is currently isolated from the stem bark of the tree Larix gmelinni(Dahurian larch). It is a flavonoid of high commercial interest for its use in supplements or in antioxidant-rich functional foods. However, its poor stability and low bioavailability hinder the use of flavonoid in nutritional or pharmaceutical formulations. In this work, taxifolin isolated from the seeds of Mimusops balata, was evaluated by in silico stability prediction studies and in vitro forced degradation studies(acid and alkaline hydrolysis, oxidation, visible/UV radiation, dry/humid heating) monitored by high performance liquid chromatography with ultraviolet detection(HPLC-UV) and ultrahigh performance liquid chromatography-electrospray ionization-mass spectrometry(UPLC-ESI-MS). The in silico stability prediction studies indicated the most susceptible regions in the molecule to nucleophilic and electrophilic attacks, as well as the sites susceptible to oxidation. The in vitro forced degradation tests were in agreement with the in silico stability prediction, indicating that taxifolin is extremely unstable(class 1) under alkaline hydrolysis. In addition, taxifolin thermal degradation was increased by *** the other hand, with respect to photosensitivity, taxifolin can be classified as class 4(stable).Moreover, the alkaline degradation products were characterized by UPLC-ESI-MS/MS as dimers of taxifolin. These results enabled an understanding of the intrinsic lability of taxifolin, contributing to the development of stability-indicating methods, and of appropriate drug release systems, with the aims of preserving its stability and improving its bioavailability.

关键词： Dihydroquercetin In silico stability prediction forced degradation

Isolation and characterization of a degradation product in leflunomide and a validated selective stability-indicating HPLC-UV method for their quantification

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Journal of Pharmaceutical Analysis 2015年第3期5卷 207-212页

作者： Balraj Saini Gulshan Bansal Department of Pharmaceutical Sciences and Drug Research Punjabi University

Leflunomide （LLM） is subjected to forced degradation under conditions of hydrolysis, oxidation, dry heat, and photolysis as recommended by International Conference on Harmonization guideline Q1A（R2）. In total, four degradation products （I-IV） were formed under different conditions. Products I, II and IV were formed in alkaline hydrolytic, acidic hydrolytic and alkaline photolytic conditions. LLM and all degradation products were optimally resolved by gradient elution over a C18 column. The major degradation product （IV） formed in hydrolytic alkaline conditions was isolated through column chromatography. Based on its IH NMR, IR and mass spectral data, it was characterized as a British Pharmacopoeial impurity B. The HPLC method was found to be linear, accurate, precise, sensitive, specific, rugged and robust for quantification of LLM as well as product IV. Finally, the method was applied to stability testing of the commercially available LLM tablets.

关键词： Leflunomide Characterization forced degradation degradation product HPLC-UV

Stability-indicating assay method for determination of actarit,its process related impurities and degradation products:Insight into stability profile and degradation pathways

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Journal of Pharmaceutical Analysis 2014年第6期4卷 374-383页

作者： A.Abiramasundari Rahul P.Joshi Hitesh B.Jalani Jayesh A.Sharma Dhaivat H.Pandya Amit N.Pandya Vasudevan Sudarsanam Kamala K.Vasu Department of Medicinal Chemistry B.V. Pat el PERD Centre Ahmedcibad Gujarat 380054 India

The stability of the drug actarit was studied under different stress conditions like hydrolysis（acid,alkaline and neutral）,oxidation,photolysis and thermal degradation as recommended hy International Conference on Harmonization（ICH） *** was found to be unstable in acidic,basic and photolytic conditions and produced a common degradation product while oxidative stress condition produced three additional degradation *** was impassive to neutral hydrolysis,dry thermal and accelerated stability *** products were identified,isolated and characterized by different spectroscopic *** and the degradation products were synthesized by a new route using green *** chromatographic separation of the drug and its impurities was achieved in a phenomenex luna C18 column employing a step gradient elution by high performance liquid chromatography coupled to photodiode array and mass spectrometry detectors（HPLC-PDAMS）.A specilic and sensitive stability-indicating assay method for the simultaneous determination of the drug *** process related impurities and degradation products was developed and validated.

关键词： Actarit forced degradation Stability-indicating assay method

Stability indicating high performance thin-layer chromatographic method for simultaneous estimation of pantoprazole sodium and itopride hydrochloride in combined dosage form

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Journal of Pharmaceutical Analysis 2011年第4期1卷 275-283页

作者： Deepak Bageshwar Vineeta Khanvilkar Vilasrao Kadam Bharati Vidyapeeth's College of Pharmacy Sector-8CBD BelapurNavi Mumbai 400614India

A specific, precise and stability indicating high-performance thin-layer chromatographic method for simultaneous estimation of pantoprazole sodium and itopride hydrochloride in pharmaceutical formulations was developed and validated. The method employed TLC aluminium plates precoated with silica gel 60F254 as the stationary phase. The solvent system consisted of methanol：water：ammonium acetate; 4.0：1.0：0.5 （v/v/v）. This system was found to give compact and dense spots for both itopride hydrochloride （Rf value of 0.55__＋0.02） and pantoprazole sodium （Rf value of 0.85＋0.04）. Densitometric analysis of both drugs was carried out in the reflectance- absorbance mode at 289 nm. The linear regression analysis data for the calibration plots showed a good linear relationship with R2=0.9988___0.0012 in the concentration range of 100--400 ng for pantoprazole sodium. Also, the linear regression analysis data for the calibration plots showed a good linear relationship with R2=0.9990_＋0.0008 in the concentration range of 200-1200 ng for itopride hydrochloride. The method was validated for specificity, precision, robustness and recovery. Statistical analysis proves that the method is repeatable and selective for the estimation of both the said drugs. As the method could effectively separate the drug from its degradation products, it can be employed as a stability indicating method.

关键词： Gastroesophageal refluxdisease (GERD) Itopride hydrochtoride Pantoprazole sodium High performance thinlayer chromatography(HPTLC) Stability indicating forced degradation

Identification, Isolation and Characterization of Unknown Acid degradation Product of Nevirapine

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American Journal of Analytical Chemistry 2016年第9期7卷 663-678页

A Novel stability indicating RP-UPLC chromatographic method was developed for analysis of Nevirapine in pharmaceutical formulations. The developed RP-UPLC method is superior in technology to conventional RP-HPLC with respect to speed, resolution, solvent consumption and cost of analysis. Nevirapine was subjected to the stress conditions like acid, base, thermal, oxidative and photolytic degradation. Nevirapine was found to degrade significantly in acid and thermal degradation. In acid degradation relative retention time with 0.42 is found as unknown impurity. New impurity was identified, isolated using mass based auto purification system and characterized by 1H NMR (1D and 2D) and HRMS experiments. Isolated impurity was showing molecular weight of 244.10, molecular formula C12H12N4O2 and its name as 2-(3-Amino-4-methylpyridin-2-ylamino)nicotinic acid. The calibration graph was linear and the method showed less deviation in accuracy results. The test solution was found to be stable for 20 days when stored in the refrigerator between 2°C to 8°C. The developed RP-UPLC method was validated and meets the requirements delineated by the International Conference on Harmonization (ICH) guidelines. The intra-day and inter-day variation was less than 1%. The method was reproducible and selective for the estimation of Nevirapine. Because the method could effectively separate the drug from its degradation products, it can be employed as a stability-indicating method.

关键词： Nevirapine Method Development Validation forced degradation Unknown Impurity Isolation Characterization NMR HRMS

Drug-Excipient Interaction of Methylphenidate with Glycerin in Methylphenidate Oral Solution and Identification of its Transesterification Products by UPLC-MS/MS

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American Journal of Analytical Chemistry 2016年第2期7卷 151-164页

作者： Kishore Kumar Hotha Swapan Roychowdhury Veerappan Subramanian Novel Laboratories Inc. Somerset NJ USA

Reactions between active drug substances and excipients are of interest in the drug formulation process should be checked for the interactions during the storage conditions. Some excipients react with certain chemical groups in drug substances which will form new impurities in the finished product formulations. In the present paper transesterification reaction of methylphenidate with glycerin to form different structural isomeric products was described. These impurities identified in forced degradation studies, excipient compatibility studies and stability analysis of the finished product. Stability samples were analyzed and observed that about ~0.6% of the Methylphenidate content was transformed into methylphenidate-glycerin isomers within 3 Months at 40°C/75% RH and 18 Months at 25°C/60% RH conditions. Analysis of two lots of marketed preparations having expiry dates in 2012 and 2013 showed content of the Methylphenidate esters corresponding to ~0.6% of the declared Methylphenidate content. The samples of this impurity were investigated by HPLC, UPLC-MS/MS to generate the mechanism of the impurity formation.

关键词： Methylphenidate Oral Solution Glycerin Transesterification Excipient Interactions forced degradation