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Identification and characterization of unknown oxidation degradation products of Rimegepant by HPLC and triple quadrupole mass spectrometry

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EUROPEAN JOURNAL OF MASS SPECTROMETRY 2025年第1-2期31卷 38-50页

作者： Godi, Narayana Reddy Dodda, Sireesha Vanga, Nagavardhana Reddy ummiti, kumarswamy Anurag Univ Sch Pharm Dept Pharmaceut Anal Hyderabad 500088 Telangana India GITAM Deemed Be Univ Ind Chem Prod Dev & Anal Ctr GITAM Sch Sci Dept Chem Bengaluru Campus Bengaluru Karnataka India Koneru Lakshmaiah Educ Fdn Coll Engn Dept Chem Guntur Andhra Pradesh India

Rimegepant is a calcitonin gene-related peptide receptor antagonist that has been licensed for migraine headache treatment in the United States, the European Union, the United Kingdom, Hong Kong, Australia, and Kuwait. The oxidation stress study of the Rimegepant drug substance revealed the presence of five impurities. Rimegepant degraded by 5% under the selected oxidation conditions, meeting regulatory expectations. Four out of five impurities are enhanced by more than 1%. This research aims to characterize these oxidation degradation products utilizing the triple quadrupole mass spectroscopic technique. The Rimegepant oxidation degradation products were identified using an optimized chromatographic method that relies on reverse-phase HPLC with PDA detection. This technique utilized a Waters Xbridge C18 column with an eluent mixture of acetonitrile and 0.1% formic acid in water. The oxidation products of Rimegepant have been effectively separated, with a resolution above 3.0. Triple quadrupole mass spectrometry analysis characterized the five degradation products, which showed three N-oxide impurities with masses m/z 566, m/z 550, and m/z 548, as well as two hydrolysis products with masses, m/z 218, m/z 290. These new impurities deserve special attention because the drug's potency and related impurity levels determine any pharmaceutical medication product's quality, safety, and effectiveness.

关键词： Rimegepant oxidation stress study degradation products HPLC TQ-MS

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Evaluation of temperature, excipients impact on the primary structure of Ganirelix in an injectable formulation, and comparison with Orgalutran® using MALDI-TOF/TOF-MS

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JOURNAL OF MASS SPECTROMETRY 2020年第10期55卷 e4610-e4610页

作者： ummiti, kumarswamy Kumar, J. V. Shanmukha Koneru Lakshmaiah Univ Dept Chem Guntur Andhra Pradesh India

Ganirelix is a linear polypeptide consisting of covalently bonded 10 amino acid residues. The amino acid sequence in a peptide determines the properties of the molecule. The slightest change in the primary structure (amino acid sequence) of therapeutic peptides can significantly impact its safety, efficacy, and immunogenicity. Hence, the primary structure analysis of therapeutic peptides is regarded as a critical quality attribute (CQA). A vast array of analytical techniques can be used to capture the primary structure of the peptide. In this study, we applied matrix-assisted laser desorption ionization (MALDI)/tandem time of flight mass spectroscopic (TOF/TOF MS) method to demonstrate the primary structure of Ganirelix in an injectable formulation. The apparent monoisotopic molecular mass of Ganirelix is 1,568.9 Da. The attained primary amino acid sequence of Ganirelix in temperature-stressed generic product matched with the theoretical sequence and showed homology with those of the reference listed drug (RLD).

关键词： amino acid sequence Ganirelix acetate MALDI-TOF TOF MS mass interpretation temperature effect

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Establishment of validated stability indicating purity method based on the stress degradation behavior of gonadotropin-releasing hormone antagonist (ganirelix) in an injectable formulation using HPLC and LC-MS-QTOF

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EUROPEAN JOURNAL OF MASS SPECTROMETRY 2021年第2-4期27卷 126-140页

作者： ummiti, kumarswamy Kumar, J. V. Shanmukha Koneru Lakshmaiah Educ Fdn Dept Chem Guntur 522502 Andhra Pradesh India

Stress study of a drug substance or pharmaceutical drug product provides a vision into degradation pathways and degradation products of the active pharmaceutical ingredient and helps in interpretation of the chemical structure of the degradation impurities. In the current study, Ganirelix active ingredient presented in the Orgalutran (R) was stressed with acidic and alkali hydrolysis, photolysis, thermal and oxidation conditions as per the guidelines of International Conference on Harmonization (ICH) Q1A (R2). Ganirelix was found to be labile under thermal and alkali hydrolytic stress conditions, while it was stable to acid hydrolytic, oxidative and photolytic stress. All degradation products were separated with a resolution > 1.5 on a C18 column (2.6 mu m, 25 cmx4.6 mm) using a hydrophilic ion pair such as sodium perchlorate, at a concentration <0.04 M. In total, four major degradant impurities were found during stress study. These impurities were fractionated and desalted by flash chromatography for identification of chemical structures. LC-MS-QTOF analysis revealed that two degradation products are diastereomers of Ganirelix, one degradation product is a deamination compound and other degradation product result from the insertion of a new amino acid residue in the Ganirelix peptide sequence. The developed method is sensitive enough to quantify the related substances of Ganirelix at the 0.04% level with that of Ganirelix test concentration.

关键词： Ganirelix HPLC-PDA forced degradation degradation products LC-MS-QTOF validation

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ISOLATION, IDENTIFICATION, AND CHARACTERIZATION OF 17-OXO DEXAMETHASONE, AN OXIDATIVE DEGRADATION IMPURITY OF DEXAMETHASONE USING FLASH CHROMATOGRAPHY AND NMR/HRMS/IR

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JOURNAL OF LIQUID CHROMATOGRAPHY & RELATED TECHNOLOGIES 2014年第17期37卷 2403-2419页

作者： ummiti, kumarswamy Vakkala, Sudhakar Panuganti, Venkatesh Annarapu, Malleswara Reddy Dr Reddys Labs Ltd Gener Analyt Res & Dev Hyderabad Andhra Pradesh India

Some formulations of dexamethasone available in the market require gamma-radiation sterilized dexamethasone active pharmaceutical ingredient (API). A new impurity was detected in the gamma-radiation sterilized dexamethasone API and determined using gradient ultra performance liquid chromatography (UPLC) method with UV detection. This impurity was identified as the major peroxide degradation impurity of dexamethasone. This impurity standard was consequently isolated via oxidative degradation followed by flash liquid chromatography (LC) method. Using high-resolutionmass spectrometry (HRMS), nuclear magnetic resonance (NMR), and infrared (IR) study the impurity was identified as 17-oxo dexamethasone (dexamethasone 17-ketone). In this method, about 600 mg of relatively pure 17-oxo dexamethasone impurity (chromatographic purity: 99.34% w/w by LC) was obtained with 1000 mg of extract loaded. This isolated 17-oxo dexamethasone impurity served as external standard for determination of percentage amounts of this impurity present in dexamethasone API and various formulation of dexamethasone. Several HPLC methods were developed and reported for the determination of dexamethasone and its related substances using UV detection. But till now there are no reports on isolation and characterization of 17-oxo dexamethasone formed during c-radiation sterilized dexamethasone API.

关键词： 17-oxo dexamethasone (dexamethasone 17-ketone) flash chromatography HRMS IR NMR UPLC validation

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Determination of Amino Acid Composition of Ganirelix Acetate in an Injectable Formulation by Pre-column Derivatization with 6-Aminoquinolyl-N-hydroxysuccinimidyl Carbamate

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JOURNAL OF CHROMATOGRAPHIC SCIENCE 2020年第8期58卷 687-694页

作者： ummiti, kumarswamy Kumar, J. V. Shanmukha Koneru Lakshmaiah Univ Guntur 522502 Andhra Pradesh India

Ganirelix is a synthetic decapeptide linked with nine different amino acids. To understand the peptide amino acid sequence or primary structure, the first step is to determine the amino acid composition of the peptide which can be a determining factor for the peptide immunogenicity. Edman degradation is not a suitable analytical technique to identify amino acid sequence present in Ganirelix due to the absence of uncharged N-terminal amino group. To address this challenge, a pre-column derivatization method was developed with 6-aminoquinolyl-N-hydroxysuccinimidyl carbamate reagent. In the present work, the Ganirelix active pharmaceutical ingredient present in the injectable formulation was isolated by fraction collection and further purified by flash chromatography. The amino acid composition of Ganirelix is assayed by carrying out acid hydrolysis with 6 mol L-1 hydrochloric acid solution containing 1% phenol at 100 degrees C for 24 h and derivatization with 6-aminoquinolyl-N-hydroxysuccinimidyl carbamate reagent solution, followed by determination of individual amino acids by reverse-phase chromatography using a C18 column. High resolution was achieved for the nine amino acid mixture. The amino acid composition results of temperature-stressed Ganirelix generic product and reference listed drug are in good agreement with the theoretical molar ratio of label information.

关键词： Peptides

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Development of a Stability-Indicating Purity Method for Ubrogepant Through Stress Degradation Analysis, Extraction, and Characterization of Unidentified Degradation Products Using Flash Chromatography, NMR, IR, and LC-MS

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JOURNAL OF AOAC INTERNATIONAL 2024年第5期107卷 761-773页

作者： Vanga, Nagavardhana Reddy Ratnam, K. Venkata ummiti, kumarswamy Ratnakaram, Venkata Nadh GITAM Deemed Univ Ind Chem Prod Dev & Anal Ctr Dept Chem Bengaluru Campus Bengaluru 561203 Karnataka India Koneru Lakshmaiah Educ Fdn Coll Engn Dept Chem Guntur 522502 Andhra Pradesh India

Background Ubrogepant is a prescription medication used to prevent migraine headaches. It is currently available in tablet *** The goal of this work is to investigate the drug degradation profile of ubrogepant, as well as to isolate and characterize undiscovered ubrogepant degradation products by utilizing LC-MS, NMR, and IR spectroscopic analytical techniques and, furthermore, to develop a high-resolution, sensitive, stability-indicating analytical approach for detecting and quantifying ubrogepant degradation products in its pharmaceutical *** To identify and quantify the degradation products of ubrogepant in pharmaceutical products, a novel gradient reverse-phase HPLC (RP-HPLC) technique with a photo diode array (PDA) detector was developed by utilizing a C18 stationary phase column. The eluent comprised a mixture of acetonitrile and water with 0.1% (v/v) ortho-phosphoric acid. To establish the intrinsic stability of the ubrogepant pharmaceutical product, it was stress-tested under various degradation conditions, including water, alkaline, acid hydrolysis, photolytic, oxidative, and thermal. Flash chromatography was used to isolate the two major degradants, and the structures were determined using NMR (1H, 13C, distortionless enhancement by polarisation transfer-DEPT-135), IR, and LC-MS *** The ubrogepant medication was relatively more degradable in alkaline and acidic conditions, and two unique degradation products were discovered. Based on spectroscopic and chromatographic evidence, it was conclusively demonstrated that these unique compounds were ubrogepant hydrolysis products. All degradation products were separated with a resolution greater than 2.0. The peak purity data showed that the ubrogepant peak in all of the stress samples examined was pure. Under all stress environments, ubrogepant achieved a minimum mass balance of 95%. The validated approach developed was sensitive enough to quantify ubrogepant degradation pro

关键词： Hydrolysis

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Evaluation of effects of temperature and humidity on the secondary structure of Ganirelix in an injectable formulation and comparison with Orgalutran® using circular dichroism spectroscopy

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CHIRALITY 2023年第7期35卷 427-434页

作者： ummiti, kumarswamy Kumar, J. V. Shanmukha Prasad, M. Muni Subbappa, Praveen Kumar Koneru Lakshmaiah Educ Fdn Coll Engn Dept Engn Chem Guntur India DK Govt Degree Coll Women Dept Chem Nellore India Slayback Pharm LLC Princeton NJ USA Koneru Lakshmaiah Educ Fdn Guntur 522502 Andhra Pradesh India

Ganirelix, a drug used in in vitro fertilization (IVF), prevents ovulation in women who are not ready to have children by inhibiting a gene that produces gonadotropin. Peptides are macromolecules that are able to preserve a predetermined shape while carrying out the structural and regulatory roles for which they were originally intended. Peptide structures can be altered in the production and storage processes. Therapeutic peptides' biological activity can be drastically altered by even small modifications in their primary and secondary structures. The molecules' secondary structures can be monitored by subjecting them to different processing or storage conditions. In our investigation, we used circular dichroism (CD) spectroscopy with two different software programs for secondary structure evaluation to look at how environmental factors like temperature and humidity affected the secondary structure of Ganirelix in an injectable formulation. The CD results revealed that the alpha-helical (regular and distorted), beta-sheet, beta-strands (regular and distorted), beta-turn, and random coil structures of temperature and humidity stressed generic drug products are comparable to reference-listed drug.

关键词： circular dichroism (CD) spectroscopy ganirelix acetate humidity secondary structure temperature

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DETERMINATION OF RESIDUAL CHLORIDE IN SEVELAMER CARBONATE USING HIGH PERFORMANCE LIQUID CHROMATOGRAPHY

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JOURNAL OF LIQUID CHROMATOGRAPHY & RELATED TECHNOLOGIES 2014年第2期37卷 187-194页

作者： ummiti, kumarswamy Chennuru, Kalyan Reddy Vakkala, Sudhakar Dama, Venugopal Annarapu, Malleswara Reddy Dr Reddys Labs Ltd Gener Analyt Res & Dev Hyderabad Andhra Pradesh India

Sevelamer carbonate is the active ingredient of Renvela tablets;a cross-linked polymeric amine that binds phosphate. It was developed as a pharmaceutical alternative to sevelamer hydrochloride (Renagel). Renvela is indicated for the control of hyperphosphatemia in patients with end-stage renal disease (ESRD). Sevelamer carbonate is manufactured from sevelamer hydrochloride, in which carbonate replaces chloride as the counter ion. Therefore, chloride is one of the impurities present in sevelamer carbonate. A number of suitable analytical techniques are available for chloride estimation, including titration, colorimetry, electrochemical chromatography, indirect photochemical detection, and ion chromatography. Limits of detection range from 50g/L for colorimetry to 5mg/L for titration. The specification limit of chloride content in sevelamer carbonate is not more than 0.05%. As a result, accurate determination of this residual chloride in sevelamer carbonate is not possible with colorimetry and titration. In the case of electrochemical detectors, the electrode response could drift with time. Indirect photometric detection is a more time consuming method. A novel isocratic reverse phase HPLC method has been developed in order to detect and quantify the residual chloride. This method involves mixing the drug (polymer) with water, filtering off the solution, and quantitating the water soluble chloride by HPLC using refractive index detector. The method was validated with respect to specificity, precision, linearity, and robustness. The presented method provides equal sensitivity with ion chromatography, specific, and inexpensive analytical procedure and, therefore, is highly suitable for detection and quantification of the residual chloride in sevelamer carbonate API.

关键词： chloride HPLC refractive index detector renvela sevelamer carbonate

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