Seguimiento del medicamento Ranitidina, desde la innovación a la retirada del mercado debido a la formación de N-Nitrosodimetilamina: Un caso de estudio sobre la importancia del monitoreo y control de calidad por parte del Químico Farmacéutico

Ranitidina, un antagonista de los receptores H₂ de histamina, fue ampliamente utilizada para tratar trastornos gástricos hasta que en 2019 se detectó la impureza N-nitrosodimetilamina (NDMA), un compuesto potencialmente cancerígeno. Esto llevó a su retiro definitivo del mercado en 2020 por parte de...

Full description

Autores:
Rubiano Jaimes, Ilenee Estefanía
Sánchez Arévalo, Oriana
Tipo de recurso:
https://purl.org/coar/resource_type/c_7a1f
Fecha de publicación:
2025
Institución:
Universidad El Bosque
Repositorio:
Repositorio U. El Bosque
Idioma:
spa
OAI Identifier:
oai:repositorio.unbosque.edu.co:20.500.12495/14353
Acceso en línea:
https://hdl.handle.net/20.500.12495/14353
Palabra clave:
Ranitidina
N-nitrosodimetilamina
Técnicas cromatográficas
Plan de gestión de riesgos
Guías de calidad e impurezas
615.19
Ranitidine
N-Nitrosodimethylamine
Chromatographic techniques
risk management plan
Quality guidelines and impurities
Rights
License
Attribution-ShareAlike 4.0 International
id UNBOSQUE2_0158815e11f57d502c2e968564a24d02
oai_identifier_str oai:repositorio.unbosque.edu.co:20.500.12495/14353
network_acronym_str UNBOSQUE2
network_name_str Repositorio U. El Bosque
repository_id_str
dc.title.none.fl_str_mv Seguimiento del medicamento Ranitidina, desde la innovación a la retirada del mercado debido a la formación de N-Nitrosodimetilamina: Un caso de estudio sobre la importancia del monitoreo y control de calidad por parte del Químico Farmacéutico
dc.title.translated.none.fl_str_mv Follow-up of the drug Ranitidine, from innovation to market withdrawal due to the formation of N-Nitrosodimethylamine: A case study on the importance of monitoring and quality control by the Pharmaceutical Chemist
title Seguimiento del medicamento Ranitidina, desde la innovación a la retirada del mercado debido a la formación de N-Nitrosodimetilamina: Un caso de estudio sobre la importancia del monitoreo y control de calidad por parte del Químico Farmacéutico
spellingShingle Seguimiento del medicamento Ranitidina, desde la innovación a la retirada del mercado debido a la formación de N-Nitrosodimetilamina: Un caso de estudio sobre la importancia del monitoreo y control de calidad por parte del Químico Farmacéutico
Ranitidina
N-nitrosodimetilamina
Técnicas cromatográficas
Plan de gestión de riesgos
Guías de calidad e impurezas
615.19
Ranitidine
N-Nitrosodimethylamine
Chromatographic techniques
risk management plan
Quality guidelines and impurities
title_short Seguimiento del medicamento Ranitidina, desde la innovación a la retirada del mercado debido a la formación de N-Nitrosodimetilamina: Un caso de estudio sobre la importancia del monitoreo y control de calidad por parte del Químico Farmacéutico
title_full Seguimiento del medicamento Ranitidina, desde la innovación a la retirada del mercado debido a la formación de N-Nitrosodimetilamina: Un caso de estudio sobre la importancia del monitoreo y control de calidad por parte del Químico Farmacéutico
title_fullStr Seguimiento del medicamento Ranitidina, desde la innovación a la retirada del mercado debido a la formación de N-Nitrosodimetilamina: Un caso de estudio sobre la importancia del monitoreo y control de calidad por parte del Químico Farmacéutico
title_full_unstemmed Seguimiento del medicamento Ranitidina, desde la innovación a la retirada del mercado debido a la formación de N-Nitrosodimetilamina: Un caso de estudio sobre la importancia del monitoreo y control de calidad por parte del Químico Farmacéutico
title_sort Seguimiento del medicamento Ranitidina, desde la innovación a la retirada del mercado debido a la formación de N-Nitrosodimetilamina: Un caso de estudio sobre la importancia del monitoreo y control de calidad por parte del Químico Farmacéutico
dc.creator.fl_str_mv Rubiano Jaimes, Ilenee Estefanía
Sánchez Arévalo, Oriana
dc.contributor.advisor.none.fl_str_mv Muñoz Cárdenas, Monica del Pilar
Gónzalez Chacón, Fernando Alexis
dc.contributor.author.none.fl_str_mv Rubiano Jaimes, Ilenee Estefanía
Sánchez Arévalo, Oriana
dc.subject.none.fl_str_mv Ranitidina
N-nitrosodimetilamina
Técnicas cromatográficas
Plan de gestión de riesgos
Guías de calidad e impurezas
topic Ranitidina
N-nitrosodimetilamina
Técnicas cromatográficas
Plan de gestión de riesgos
Guías de calidad e impurezas
615.19
Ranitidine
N-Nitrosodimethylamine
Chromatographic techniques
risk management plan
Quality guidelines and impurities
dc.subject.ddc.none.fl_str_mv 615.19
dc.subject.keywords.none.fl_str_mv Ranitidine
N-Nitrosodimethylamine
Chromatographic techniques
risk management plan
Quality guidelines and impurities
description Ranitidina, un antagonista de los receptores H₂ de histamina, fue ampliamente utilizada para tratar trastornos gástricos hasta que en 2019 se detectó la impureza N-nitrosodimetilamina (NDMA), un compuesto potencialmente cancerígeno. Esto llevó a su retiro definitivo del mercado en 2020 por parte de la FDA. Este estudio analiza la evolución del medicamento, los métodos de detección de NDMA y el rol del Químico Farmacéutico en la farmacovigilancia. Para la cuantificación de NDMA, se evaluaron técnicas como la cromatografía de gases acoplada a espectrometría de masas (GC-MS) y la cromatografía líquida de alta resolución acoplada a espectrometría de masas (HPLC-MS). Los resultados mostraron que, aunque la GC-MS es altamente sensible, puede inducir artificialmente la formación de NDMA debido a la degradación térmica de la Ranitidina, mientras que la HPLC-MS demostró ser más precisa y reproducible. Este caso evidencia la importancia del monitoreo activo de los medicamentos para prevenir riesgos en la salud pública. El Químico Farmacéutico desempeña un papel esencial en el control de calidad, la implementación de estrategias analíticas y el seguimiento de los medicamentos a lo largo de su ciclo de vida, garantizando la detección temprana de impurezas y la seguridad del paciente.
publishDate 2025
dc.date.accessioned.none.fl_str_mv 2025-05-15T17:46:05Z
dc.date.available.none.fl_str_mv 2025-05-15T17:46:05Z
dc.date.issued.none.fl_str_mv 2025-05
dc.type.coar.fl_str_mv http://purl.org/coar/resource_type/c_7a1f
dc.type.local.none.fl_str_mv Tesis/Trabajo de grado - Monografía - Pregrado
dc.type.coar.none.fl_str_mv https://purl.org/coar/resource_type/c_7a1f
dc.type.driver.none.fl_str_mv info:eu-repo/semantics/bachelorThesis
dc.type.coarversion.none.fl_str_mv https://purl.org/coar/version/c_ab4af688f83e57aa
format https://purl.org/coar/resource_type/c_7a1f
dc.identifier.uri.none.fl_str_mv https://hdl.handle.net/20.500.12495/14353
dc.identifier.instname.spa.fl_str_mv Universidad El Bosque
dc.identifier.reponame.spa.fl_str_mv reponame:Repositorio Institucional Universidad El Bosque
dc.identifier.repourl.none.fl_str_mv repourl:https://repositorio.unbosque.edu.co
url https://hdl.handle.net/20.500.12495/14353
identifier_str_mv Universidad El Bosque
reponame:Repositorio Institucional Universidad El Bosque
repourl:https://repositorio.unbosque.edu.co
dc.language.iso.fl_str_mv spa
language spa
dc.relation.references.none.fl_str_mv 1. Arnold I. https://www.arnolditkin.com/blog/product-liability/history-of-zantac-ranitidine-/. 2020. History of Zantac (Ranitidine). Disponible en: https://www.arnolditkin.com/blog/product-liability/history-of-zantac-ranitidine-/
2. De la garza J. Retiro de Zantac. The de la garza law group [Internet]. 2023. Disponible en: https://dlgtriallaw.com/espanol/productos-defectuosos/retiro-de-zantac/
3. Reuters T. How Zantac went from world’s best-selling drug to being pulled from store shelves [Internet]. 2019. Disponible en: https://www.cbc.ca/news/health/How Zantac went from world’s best-selling drug to being pulled from store shelves | CBC Newszantac-heartburn-timeline-1.5330575
4. Food And Drug Administratrion. Statement alerting patients and health care professionals of NDMA found in samples of ranitidine [Internet]. 2019. Disponible en: https://www.fda.gov/news-events/press-announcements/statement-alerting-patients-and-health-care-professionals-ndma-found-samples-ranitidine
5. Palmer E. Novartis is first to recall generic Zantac after confirming suspected carcinogen. Fierce Pharma [Internet]. 2019. Disponible en: https://www.fiercepharma.com/manufacturing/novartis-first-to-recall-generic-zantac-after-confirming-suspected-carcinogen
6. Food And Drug Administration. FDA Requests Removal of All Ranitidine Products (Zantac) from the Market [Internet]. 2020. Disponible en: https://www.fda.gov/news-events/press-announcements/fda-requests-removal-all-ranitidine-products-zantac-market
7. Pro Doc Ltée. Ranitidine Tablets USP Product Monograph. En: United States Pharmacopeia. 2018.
8. Agencia Española de Medicamentos y Productos Sanitarios. Ficha Técnica Ranitidina Arafarma Group 300 mg Comprimidos Recubiertos EFG [Internet]. 2013. Disponible en: https://cima.aemps.es/cima/dochtml/ft/63821/FichaTecnica_63821.html
9. Pediamécum. Ranitidina [Internet]. 2021. Disponible en: https://www.aeped.es/pediamecum/generatepdf/api?n=83833#:~:text=V%C3%ADa%20oral%3A%20Tratamiento%3A%204%2D,6%2D8%20horas%3B%20m%C3%A1x
10. Daly MJ, Humphray JM, Stables R. Antagonism of Vasodepressor and Gastric Secretory Responses To Histamine by the H2-Receptor Antagonists, Ranitidine and Cimetidine, In the Anaesthetized Dog. Br J Pharmacol [Internet]. 1981;72. Disponible en: https://api.semanticscholar.org/CorpusID:12996722
11. Aronson J. Ranitidine. En: Aronson JK, editor. Meyler’s Side Effects of Drugs (Sixteenth Edition) [Internet]. Sixteenth Edition. Oxford: Elsevier; 2016. p. 74-6. Disponible en: https://www.sciencedirect.com/science/article/pii/B9780444537171013913
12. Caitlin C. Nugent, Samuel R. Falkson, Jamie M. Terrell. H2 Blockers. National Library of Medicine [Internet]. 2024; Disponible en: https://www.ncbi.nlm.nih.gov/books/NBK525994/
13. Soleymani J, Djozan D, Martínez F, Jouyban A. Solubility of ranitidine hydrochloride in solvent mixtures of PEG 200, PEG 400, ethanol and propylene glycol at 25°C. J Mol Liq [Internet]. 2013;182:91-4. Disponible en: https://www.sciencedirect.com/science/article/pii/S0167732213000962
14. Hohnjec M, Kuftinec J, Malnar M, Škreblin M, Kajfež F, Nagl A, et al. Ranitidine. En: Florey K, editor. Academic Press; 1986. p. 533-61. (Analytical Profiles of Drug Substances; vol. 15). Disponible en: https://www.sciencedirect.com/science/article/pii/S0099542808604232
15. Home Sunshine Pharma. Clorhidrato de Ranitidina [Internet]. 2025. Disponible en: https://www.hspchem.com/apis-and-intermediates/ranitidine-hydrochloride-cas-66357-35-5.html
16. Xiangya School of Pharmaceutical Sciences. ADMETLab 3.0 [Internet]. 2025. Disponible en: https://admetlab3.scbdd.com/server/evaluationCal
17. Bethasda M. Histamine Type-2 Receptor Antagonists (H2 Blockers) [Internet]. 2012. Disponible en: https://www.ncbi.nlm.nih.gov/books/
18. Mills J, Koch K, Webster C, Sirgo M, Fitzgerald K, Wood J. The safety of ranitidine in over a decade of use. Aliment Pharmacol Ther [Internet]. 2008;11(1):129-37. Disponible en: https://onlinelibrary.wiley.com/doi/epdf/10.1046/j.1365-2036.1997.136312000.x
19. Schunack W. What are the differences between the H2-receptor antagonists? Aliment Pharmacol Ther [Internet]. 1987;493s-503s. Disponible en: https://pubmed.ncbi.nlm.nih.gov/2908767/
20. Vardanyan RS, Hruby VJ. 16 - Antihistamine Drugs. En: Vardanyan RS, Hruby VJ, editores. Synthesis of Essential Drugs [Internet]. Amsterdam: Elsevier; 2006. p. 219-35. Disponible en: https://www.sciencedirect.com/science/article/pii/B9780444521668500169
21. Daly MJ, Humphray JM, Stables R. Some in vitro and in vivo actions the new Histamine H2-Receptor Antagonist, Ranitidina. Br J Pharmacol [Internet]. 1981;72(1):49-54. Disponible en: https://bpspubs.onlinelibrary.wiley.com/doi/abs/10.1111/j.1476-5381.1981.tb09103.x
22. Daly MJ, Humphray JM, Bunce KT, Stables R. The effect of ranitidine on gastric acid secretory response curves to histamine, pentagastrin or bethanechol in the dog with a heidenhain pouch. Agents Actions [Internet]. 1981;11:160-4. Disponible en: https://api.semanticscholar.org/CorpusID:19458248
23. Scarpignato C, Tramacere R, Pezzetta A. Effect of famotidine and ranitidine on gastric secretion and emptying in the rat. Drug Dev Res [Internet]. 1987;11(1):37-43. Disponible en: https://analyticalsciencejournals.onlinelibrary.wiley.com/doi/abs/10.1002/ddr.430110105
24. Decktor DL, Pendleton RG, Kellner A, Davis MA. Acute effects of ranitidine, famotidine and omeprazole on plasma gastrin in the rat. J Pharmacol Exp Ther [Internet]. 1989;249 1:1-5. Disponible en: https://api.semanticscholar.org/CorpusID:32649835
25. Gough KR, Bardhan KD, Crowe JP, Korman MG, Lee FI, Reed PI, et al. RANITIDINE AND CIMETIDINE IN PREVENTION OF DUODENAL ULCER RELAPSE: A Double-blind, Randomised, Multicentre, Comparative Trial. The Lancet [Internet]. 1984;324(8404):659-62. Disponible en: https://www.sciencedirect.com/science/article/pii/S0140673684912248
26. Sabesin S. Safety issues relating to long-term treatment with histamine H2-receptor antagonists. Aliment Pharmacol Ther. 1993;7(2):35-40.
27. Pipkin GA, Mills JG, Kler L, Dixon JS, Wood JR. The Safety of Ranitidine Bismuth Citrate in Controlled Clinical Studies. Pharmacoepidemiol Drug Saf [Internet]. 1 de noviembre de 1996;5(6):399-407. Disponible en: https://doi.org/10.1002/(SICI)1099-1557(199611)5:6<399::AID-PDS243>3.0.CO
28. Galmiche JP, Shi G, Simon B, Casset-Semanaz F, Slama A. On-demand treatment of gastro-oesophageal reflux symptoms: a comparison of ranitidine 75 mg with cimetidine 200 mg or placebo. Aliment Pharmacol Ther [Internet]. 1 de septiembre de 1998;12(9):909-17. Disponible en: https://doi.org/10.1046/j.1365-2036.1998.00384.x
29. Sirgo MA, Mills R, Euler AR, Walker S. The Safety of Ranitidine in Elderly Versus Non-Elderly Patients. The Journal of Clinical Pharmacology [Internet]. 1993;33(1):79-83. Disponible en: https://accp1.onlinelibrary.wiley.com/doi/abs/10.1002/j.1552-4604.1993.tb03908.x
30. Pappa W, Williams J, Payne K, Buaron R, Mussari R, Ciociola A. A double-blind, placebo-controlled study of the efficacy and safety of non-prescription ranitidine 75 mg in the prevention of meal-induced heartburn. Aliment Pharmacol Ther [Internet]. 1999;13(4):467-73. Disponible en: https://onlinelibrary.wiley.com/doi/abs/10.1046/j.1365-2036.1999.00505.x
31. Orenstein S, Blumer J, Faessel H, McGuire J, Fung K, Li B, et al. Ranitidine, 75 mg, over-the-counter dose: pharmacokinetic and pharmacodynamic effects in children with symptoms of gastro-oesophageal reflux. Aliment Pharmacol Ther [Internet]. 2002;16(5):899-907. Disponible en: https://pubmed.ncbi.nlm.nih.gov/11966498/
32. Rose U. European Pharmacopoeia Activities on Control of Nitrosamines and other DNA-Reactive Impurities. J Pharm Sci [Internet]. 1 de mayo de 2023;112(5):1163-5. Disponible en: https://doi.org/10.1016/j.xphs.2022.11.015
33. Comisión Farmacopea Argentina. Tabletas de Clorhidrato de Ranitidina. Séptima. Vol. 3. Farmacopea Argentina; 2003. 351-352 p.
34. Comisión de la Farmacopea Británica. Tabletas de Clorhidrato de Ranitidina. Onceava. Vol. 3. Farmacopea Británica; 2020. 1208-1209 p.
35. Novaković J. High-performance thin-layer chromatography for the determination of ranitidine hydrochloride and famotidine in pharmaceuticals. J Chromatogr A [Internet]. 1999;846(1):193-8. Disponible en: https://www.sciencedirect.com/science/article/pii/S0021967399005105
36. Basavaiah K, Nagegowda P. Determination of ranitidine hydrochloride in pharmaceutical preparations by titrimetry and visible spectrophotometry using bromate and acid dyes. Il Farmaco [Internet]. 2004;59(2):147-53. Disponible en: https://www.sciencedirect.com/science/article/pii/S0014827X03003082
37. Walash M, Sharaf El Din M, Metwalli M, RedaShabana M. Spectrophotometric determination of nizatidine and ranitidine through charge transfer complex formation. Arch Pharm Res. 1 de agosto de 2004;27:720-6.
38. Weston DJ, Bateman RHK, Wilson ID, Wood T, Creaser CS. Direct analysis of pharmaceutical drug formulations using ion mobility spectrometry/quadrupole-time-of-flight mass spectrometry combined with desorption electrospray ionization. Anal Chem [Internet]. 2005;77 23:7572-80. Disponible en: https://api.semanticscholar.org/CorpusID:24877633
39. El-Bayoumi A, El-Shanawany AA, El-Sadek M, El-Sattar AA. Stability indicating spectrodensitometric determination of ranitidine hydrochloride using linear and non-linear regression. J Pharm Biomed Anal [Internet]. 1999;21 4:867-73. Disponible en: https://api.semanticscholar.org/CorpusID:42679870
40. Ficarra P, Ficarra R, Tommasini A. High-performance liquid chromatography of ranitidine in pharmaceuticals. J Pharm Biomed Anal [Internet]. 1984;2(1):119-23. Disponible en: https://www.sciencedirect.com/science/article/pii/0731708584800977
41. Beaulieu N, Lacroix P, Sears R, Lovering E. High-performance liquid chromatographic methods for the determination of ranitidine and related substances in raw materials and tablets. J Pharm Sci [Internet]. 1988;77(10):889-92. Disponible en: https://pubmed.ncbi.nlm.nih.gov/3236234/
42. Arayne M, Sultana N, Zuberi M, Siddiqui F. Simultaneous determination of metformin, cimetidine, famotidine, and ranitidine in human serum and dosage formulations using HPLC with UV detection. J Chromatogr Sci [Internet]. 2010;48(9):721-5. Disponible en: https://pubmed.ncbi.nlm.nih.gov/20875233/
43. Food and Drug Administration. La FDA anuncia el retiro voluntario del mercado de varios medicamentos que contienen valsartán, tras la detección de una impureza [Internet]. 2018. Disponible en: https://www.fda.gov/news-events/comunicados-de-prensa/la-fda-anuncia-el-retiro-voluntario-del-mercado-de-varios-medicamentos-que-contienen-valsartan-tras
44. Organización Mundial de la Salud (OMS). Nota informativa de la OMS. Actualización sobre las impurezas de Nitrosaminas [Internet]. 2010. Disponible en: https://www.who.int/docs/default-source/essential-medicines/medical-alert-2019/information-note-nitrosamine-impurities-nov2019-esp.pdf?sfvrsn=d189497f_21
45. Agencia para Sustancias Tóxicas y el Registro de Enfermedades (ATSDR). Resumen de la Salud Pública. N-Nitrosodimetilamina [Internet]. 1989. Disponible en: https://www.atsdr.cdc.gov/es/phs/es_phs141.pdf
46. International Council for Harmonisation (ICH). Impurities in new drug products (Q3B(R2) [Internet]. 2006. Disponible en: https://database.ich.org/sites/default/files/Q3B%28R2%29%20Guideline.pdf
47. Johnson GE, Dobo K, Gollapudi B, Harvey J, Kenny J, Kenyon M, et al. Permitted daily exposure limits for noteworthy N-nitrosamines. Environ Mol Mutagen [Internet]. 1 de junio de 2021;62(5):293-305. Disponible en: https://doi.org/10.1002/em.22446
48. Fisher scientific. N-Nitrosodimetilamina [Internet]. 2025. Disponible en: https://www.fishersci.es/shop/products/n-nitrosodimethylamine-spex-certiprep/12989314
49. Gobierno de España. N-nitrosodimetilamina [Internet]. 2018. Disponible en: https://chemicalsafety.ilo.org/dyn/icsc/showcard.display?p_card_id=0525&p_version=2&p_lang=es
50. New Jersey department of health. Hoja informativa sobre sustancias peligrosas: N-nitrosodimetilamina. [Internet]. 2012. Disponible en: https://nj.gov/health/eoh/rtkweb/documents/fs/1405sp.pdf
51. Council of Europe. N-nitroso-dimethylamine (solution in Methanol) Fichas de Datos de Seguridad [Internet]. 2023. Disponible en: https://sds.edqm.eu/pdf/SDS/EDQM_202000236_1.0_SDS_ES.pdf?ref=1623847776
52. Agencia para Sustancias Tóxicas y el Registro de Enfermedades (ATSDR). N-nitrosodimetilamina (N-nitrosodimethylamine) [Internet]. 2023. Disponible en: https://www.atsdr.cdc.gov/es/toxfaqs/es_tfacts141.html
53. Ray SD, Mehendale HM. N-Nitrosodimethylamine. En: Wexler P, editor. Encyclopedia of Toxicology (Second Edition) [Internet]. New York: Elsevier; 2005. p. 255-8. Disponible en: https://www.sciencedirect.com/science/article/pii/B012369400000661X
54. Yoon HJ, Kim JH, Seo GH, Park H. Risk of Cancer Following the Use of N-Nitrosodimethylamine (NDMA) Contaminated Ranitidine Products: A Nationwide Cohort Study in South Korea. J Clin Med [Internet]. 2021;10(1). Disponible en: https://www.mdpi.com/2077-0383/10/1/153
55. Liu YD, Selbes M, Zeng C, Zhong R, Karanfil T. Formation Mechanism of NDMA from Ranitidine, Trimethylamine, and Other Tertiary Amines during Chloramination: A Computational Study. Environ Sci Technol [Internet]. 5 de agosto de 2014;48(15):8653-63. Disponible en: https://doi.org/10.1021/es500997e
56. Harmon P. Ranitidine: A Proposed Mechanistic Rationale for NDMA Formation and a Potential Control Strategy. J Pharm Sci [Internet]. 2023;112(5):1220-4. Disponible en: https://www.sciencedirect.com/science/article/pii/S0022354922005214
57. Abe Y, Yamamoto E, Yoshida H, Usui A, Tomita N, Kanno H, et al. Temperature-Dependent Formation of N-Nitrosodimethylamine during the Storage of Ranitidine Reagent Powders and Tablets. Chem Pharm Bull (Tokyo). 8 de agosto de 2020;68.
58. Agilent. Análisis de nitrosaminas en productos farmacéuticos [Internet]. 2021. Disponible en: https://www.agilent.com/cs/library/brochures/brochure-nitrosamine-in-pharma-gc-ms-5994-2979es-es-agilent.pdf
59. Turner D. GC-MS Principle, Instrument and Analyses and GC-MS/MS [Internet]. 2024. Disponible en: https://www.technologynetworks.com/analysis/articles/gc-ms-principle-instrument-and-analyses-and-gc-msms-362513
60. Giménez-Campillo C, Pastor-Belda M, Campillo N, Hernández-Córdoba M, Viñas P. Development of a new methodology for the determination of N-nitrosamines impurities in ranitidine pharmaceuticals using microextraction and gas chromatography-mass spectrometry. Talanta [Internet]. 2021;223:121659. Disponible en: https://www.sciencedirect.com/science/article/pii/S0039914020309504
61. Manchuri KM, Shaik MA, Gopireddy VSR, Naziya S, Gogineni S. Analytical Methodologies to Detect N-Nitrosamine Impurities in Active Pharmaceutical Ingredients, Drug Products and Other Matrices. Chem Res Toxicol [Internet]. 2024;37(9):1456-83. Disponible en: https://doi.org/10.1021/acs.chemrestox.4c00234
62. Lim H hee, Oh YS, Shin HS. Determination of N-nitrosodimethylamine and N-nitrosomethylethylamine in drug substances and products of sartans, metformin and ranitidine by precipitation and solid phase extraction and gas chromatography–tandem mass spectrometry. J Pharm Biomed Anal. 1 de julio de 2020;189:113460.
63. Alshehri Y, Aldawsari F, Alghamdi T. HS-SPME-GC-MS as an alternative method for NDMA analysis in ranitidine products. J Pharm Biomed Anal. 2020;
64. Shinde V. Veeprho. 2020. Difference Between LC, LC-MS, LC-MS-MS, and HR-MS. Disponible en: https://veeprho.com/difference-between-lc-lc-ms-lc-ms-ms-and-hr-ms/
65. Food and Drug Administration. Liquid Chromatography-High Resolution Mass Spectrometry (LC-HRMS) Method for the Determination of NDMA in Ranitidine Drug Substance and Drug Product. 2019; Disponible en: https://www.fda.gov/media/130801/download
66. Maziarz M, Rainville P. Reliable HPLC/UV Quantification of  Nitrosamine Impurities in Valsartan and  Ranitidine Drug Substances. Waters Technology Brief 720006738EN. 2019;
67. Health Sciences Authority. Determination of NDMA in Ranitidine Products By LC-MS/MS. Pharmaceutical Laboratory, Applied Sciences Group, Health Sciences Authority. 2019;
68. Schmaler J. Test method for the determination of NDMA by LC-MS/MS in Ranitidine Drug Substance and Film Coated Tablets . Chemisches und Veterinäruntersuchungsamt Karlsruhe. 2019;
69. Angrish P, Mani C, Banerjee S. Development of a Validated Method of Testing for NDMA in Ranitidine. Pharmaceutical Technology. 2020;44:42-7.
70. Xiang Z, Qian P. Detection and analysis of N-nitrosodimethylamine in ranitidine by using Q Exactive Focus High Resolution Mass Spectrometry. Thermo Fisher Scientific [Internet]. 2020; Disponible en: https://assets.thermofisher.com/TFS-Assets/CMD/Application-Notes/an-73411-hrms-ndma-raniditine-an73411-en.pdf
71. Banerjee S. Determination of NDMA Impurity in Ranitidine Using the Agilent 6470 Triple Quadrupole LC/MS. En 2020. Disponible en: https://api.semanticscholar.org/CorpusID:211016423
72. Yang H, Bardsley J, Du M, Scheibner O. HRAM LC-MS method for the determination of nitrosamine impurities in drugs. Thermo Fisher Scientific. 2020.
73. Maziarz M, Rainville P. Quick Analysis of N-nitrosodimethylamine (NDMA) in Ranitidine Drug Substance and Drug Product by HPLC/UV. Waters Corporation. 2020.
74. Liu J, Zhao Z, Yang X, Jin Y, Liu X, Wang C, et al. Determination of N-nitrosodimethylamine in Ranitidine Dosage Forms by ESI-LC-MS/MS. Iran J Pharm Res. 2021;255-64.
75. Sun Z, Xing J, Minarni A, Zhan Z. Quantitative Determination of NDMA Impurity in Ranitidine Drug Products – Examples of Actual Samples Analysis by LCMS-8060 with APCI. Shimadzu Group. 2021.
76. Nascimiento V, Murgu M, Mullin L. Selective and Specific Quantitation of NDMA in Ranitidine with the Xevo G2-XS QTof. Waters Corporation. 2021.
77. Rao G, Ramadevi D, Rao B, Rajana N, Basavaiah K. Novel stability indicating LC-MS method for N-Nitroso dimethyl amine genotoxic impurity quantification in ranitidine drug substance and drug product. J Appl Pharm Sci. 2022.
78. Nimje H, Shirsath A, Pawar S, Deodhar M. Liquid Chromatography with Tandem Mass Spectrometric Method Development and Validation Study for the Estimation of N-Nitrosodimethylamine in Ranitidine Tablets. Indian J Pharm Sci. 2024.
79. Schweikart F, Hulthe G. HPLC–UV–MS Analysis: A Source for Severe Oxidation Artifacts. Anal Chem [Internet]. 5 de febrero de 2019;91(3):1748-51. Disponible en: https://doi.org/10.1021/acs.analchem.8b05845
80. Pacific biolabs. LC/MS AND LC/MS/MS [Internet]. 2022. Disponible en: https://pacificbiolabs.com/lc-ms/
81. Crutchfield CA, Clarke W. High resolution accurate mass (HRAM) mass spectrometry. En: Nair H, Clarke W, editores. Mass Spectrometry for the Clinical Laboratory [Internet]. San Diego: Academic Press; 2017. p. 247-59. Disponible en: https://www.sciencedirect.com/science/article/pii/B9780128008713000122
82. Allen D, McWhinney B. Quadrupole Time-of-Flight Mass Spectrometry: A Paradigm Shift in Toxicology Screening Applications. Clin Biochem Rev. 2019;135-46.
83. Nováková L, Svoboda P, Pavlík J. Ultra-high performance liquid chromatography. En: Fanali S, Haddad PR, Poole CF, Riekkola ML, editores. Liquid Chromatography (Second Edition) [Internet]. Elsevier; 2017. p. 719-69. Disponible en: https://www.sciencedirect.com/science/article/pii/B9780128053935000294
84. López R, Romero R, Garrido A. Ultrahigh-pressure liquid chromatography-mass spectrometry: An overview of the last decade. TrAC Trends in Analytical Chemistry [Internet]. 2019;118:170-81. Disponible en: https://www.sciencedirect.com/science/article/pii/S0165993619301700
85. Thibodeaux S, Yurek D, McGee J. HPLC-MS/MS for Hit Generation. Eli Lilly & Company and the National Center for Advancing Translational Sciences [Internet]. 2017; Disponible en: https://www.ncbi.nlm.nih.gov/books/NBK126175/
86. Moser J, Schlingemann J, Saal C. N-Nitrosamines Impurities in Pharmaceuticals The Abrupt Challenges that Resulted, the Evolving Science, and the Regulatory Framework. J Pharm Sci [Internet]. 1 de mayo de 2023;112(5):1161-2. Disponible en: https://doi.org/10.1016/j.xphs.2023.01.016
87. Wood I, Goyret A. Situación actual sobre la calidad, comercialización y disponibilidad de Ranitidina. Boletín Farmacológico. 2023;7-7.
88. Horne S, Vera MD, Nagavelli LR, Sayeed VA, Heckman L, Johnson D, et al. Regulatory Experiences with Root Causes and Risk Factors for Nitrosamine Impurities in Pharmaceuticals. J Pharm Sci [Internet]. 2023;112(5):1166-82. Disponible en: https://www.sciencedirect.com/science/article/pii/S0022354922006141
89. Paglialunga S, van Haarst A. The Impact of N-nitrosamine Impurities on Clinical Drug Development. J Pharm Sci [Internet]. 2023;112(5):1183-91. Disponible en: https://www.sciencedirect.com/science/article/pii/S0022354923000199
dc.rights.en.fl_str_mv Attribution-ShareAlike 4.0 International
dc.rights.coar.fl_str_mv http://purl.org/coar/access_right/c_abf2
dc.rights.uri.none.fl_str_mv http://creativecommons.org/licenses/by-sa/4.0/
dc.rights.local.spa.fl_str_mv Acceso abierto
dc.rights.accessrights.none.fl_str_mv https://purl.org/coar/access_right/c_abf2
rights_invalid_str_mv Attribution-ShareAlike 4.0 International
http://creativecommons.org/licenses/by-sa/4.0/
Acceso abierto
https://purl.org/coar/access_right/c_abf2
http://purl.org/coar/access_right/c_abf2
dc.format.mimetype.none.fl_str_mv application/pdf
dc.publisher.program.spa.fl_str_mv Química Farmacéutica
dc.publisher.grantor.spa.fl_str_mv Universidad El Bosque
dc.publisher.faculty.spa.fl_str_mv Facultad de Ciencias
institution Universidad El Bosque
bitstream.url.fl_str_mv https://repositorio.unbosque.edu.co/bitstreams/861b66a5-2557-4ad8-9312-0b096ce79b78/download
https://repositorio.unbosque.edu.co/bitstreams/9b151a3f-e29e-41d4-8aff-16c07e3313a1/download
https://repositorio.unbosque.edu.co/bitstreams/f8557449-a31c-46e1-811d-b18292c17789/download
https://repositorio.unbosque.edu.co/bitstreams/3d03751c-f689-4dbe-92f0-7c0055feeabd/download
https://repositorio.unbosque.edu.co/bitstreams/43b1bc33-3e05-4851-b758-1659f6cdcb28/download
https://repositorio.unbosque.edu.co/bitstreams/141a4857-f565-4559-9ad4-b9f96f8a12de/download
https://repositorio.unbosque.edu.co/bitstreams/5d1b2a51-ce68-4169-a464-948f5aae3c34/download
bitstream.checksum.fl_str_mv 108c15d5b341fb0eb9a9f111fe8e2a09
17cc15b951e7cc6b3728a574117320f9
306d66892e61961b653b9b968875a7f1
da1fcfd94900aab3f0ba211fc7c03688
adb7af3ef071a784ffe1b544b9a344ab
b1594f1f1b117d3818f6e170db30d54c
e4962fea336e8498fbf426e46e8739b8
bitstream.checksumAlgorithm.fl_str_mv MD5
MD5
MD5
MD5
MD5
MD5
MD5
repository.name.fl_str_mv Repositorio Institucional Universidad El Bosque
repository.mail.fl_str_mv bibliotecas@biteca.com
_version_ 1834107999161942016
spelling Muñoz Cárdenas, Monica del PilarGónzalez Chacón, Fernando AlexisRubiano Jaimes, Ilenee EstefaníaSánchez Arévalo, Oriana2025-05-15T17:46:05Z2025-05-15T17:46:05Z2025-05https://hdl.handle.net/20.500.12495/14353Universidad El Bosquereponame:Repositorio Institucional Universidad El Bosquerepourl:https://repositorio.unbosque.edu.coRanitidina, un antagonista de los receptores H₂ de histamina, fue ampliamente utilizada para tratar trastornos gástricos hasta que en 2019 se detectó la impureza N-nitrosodimetilamina (NDMA), un compuesto potencialmente cancerígeno. Esto llevó a su retiro definitivo del mercado en 2020 por parte de la FDA. Este estudio analiza la evolución del medicamento, los métodos de detección de NDMA y el rol del Químico Farmacéutico en la farmacovigilancia. Para la cuantificación de NDMA, se evaluaron técnicas como la cromatografía de gases acoplada a espectrometría de masas (GC-MS) y la cromatografía líquida de alta resolución acoplada a espectrometría de masas (HPLC-MS). Los resultados mostraron que, aunque la GC-MS es altamente sensible, puede inducir artificialmente la formación de NDMA debido a la degradación térmica de la Ranitidina, mientras que la HPLC-MS demostró ser más precisa y reproducible. Este caso evidencia la importancia del monitoreo activo de los medicamentos para prevenir riesgos en la salud pública. El Químico Farmacéutico desempeña un papel esencial en el control de calidad, la implementación de estrategias analíticas y el seguimiento de los medicamentos a lo largo de su ciclo de vida, garantizando la detección temprana de impurezas y la seguridad del paciente.PregradoQuímico FarmacéuticoRanitidine, a histamine H₂ receptor antagonist, was widely used to treat gastric disorders until the impurity N-nitrosodimethylamine (NDMA), a potentially carcinogenic compound, was detected in 2019. This led to its definitive withdrawal from the market in 2020 by the FDA. This study analyzes the evolution of the drug, NDMA detection methods and the role of the Pharmaceutical Chemist in pharmacovigilance. For NDMA quantification, techniques such as Gas chromatography-mass spectrometry (GC-MS) and high performance liquid chromatography-mass spectrometry (HPLC-MS) were evaluated. The results showed that, although GC-MS is highly sensitive, it can artificially induce the formation of NDMA due to thermal degradation of Ranitidine, while HPLC-MS proved to be more accurate and reproducible. This case evidences the importance of active drug monitoring to prevent public health risks. The Pharmaceutical Chemist plays an essential role in quality control, implementation of analytical strategies and monitoring of drugs throughout their life cycle, ensuring early detection of impurities and patient safety.application/pdfAttribution-ShareAlike 4.0 Internationalhttp://creativecommons.org/licenses/by-sa/4.0/Acceso abiertohttps://purl.org/coar/access_right/c_abf2http://purl.org/coar/access_right/c_abf2RanitidinaN-nitrosodimetilaminaTécnicas cromatográficasPlan de gestión de riesgosGuías de calidad e impurezas615.19RanitidineN-NitrosodimethylamineChromatographic techniquesrisk management planQuality guidelines and impuritiesSeguimiento del medicamento Ranitidina, desde la innovación a la retirada del mercado debido a la formación de N-Nitrosodimetilamina: Un caso de estudio sobre la importancia del monitoreo y control de calidad por parte del Químico FarmacéuticoFollow-up of the drug Ranitidine, from innovation to market withdrawal due to the formation of N-Nitrosodimethylamine: A case study on the importance of monitoring and quality control by the Pharmaceutical ChemistQuímica FarmacéuticaUniversidad El BosqueFacultad de CienciasTesis/Trabajo de grado - Monografía - Pregradohttps://purl.org/coar/resource_type/c_7a1fhttp://purl.org/coar/resource_type/c_7a1finfo:eu-repo/semantics/bachelorThesishttps://purl.org/coar/version/c_ab4af688f83e57aa1. Arnold I. https://www.arnolditkin.com/blog/product-liability/history-of-zantac-ranitidine-/. 2020. History of Zantac (Ranitidine). Disponible en: https://www.arnolditkin.com/blog/product-liability/history-of-zantac-ranitidine-/2. De la garza J. Retiro de Zantac. The de la garza law group [Internet]. 2023. Disponible en: https://dlgtriallaw.com/espanol/productos-defectuosos/retiro-de-zantac/3. Reuters T. How Zantac went from world’s best-selling drug to being pulled from store shelves [Internet]. 2019. Disponible en: https://www.cbc.ca/news/health/How Zantac went from world’s best-selling drug to being pulled from store shelves | CBC Newszantac-heartburn-timeline-1.53305754. Food And Drug Administratrion. Statement alerting patients and health care professionals of NDMA found in samples of ranitidine [Internet]. 2019. Disponible en: https://www.fda.gov/news-events/press-announcements/statement-alerting-patients-and-health-care-professionals-ndma-found-samples-ranitidine5. Palmer E. Novartis is first to recall generic Zantac after confirming suspected carcinogen. Fierce Pharma [Internet]. 2019. Disponible en: https://www.fiercepharma.com/manufacturing/novartis-first-to-recall-generic-zantac-after-confirming-suspected-carcinogen6. Food And Drug Administration. FDA Requests Removal of All Ranitidine Products (Zantac) from the Market [Internet]. 2020. Disponible en: https://www.fda.gov/news-events/press-announcements/fda-requests-removal-all-ranitidine-products-zantac-market7. Pro Doc Ltée. Ranitidine Tablets USP Product Monograph. En: United States Pharmacopeia. 2018.8. Agencia Española de Medicamentos y Productos Sanitarios. Ficha Técnica Ranitidina Arafarma Group 300 mg Comprimidos Recubiertos EFG [Internet]. 2013. Disponible en: https://cima.aemps.es/cima/dochtml/ft/63821/FichaTecnica_63821.html9. Pediamécum. Ranitidina [Internet]. 2021. Disponible en: https://www.aeped.es/pediamecum/generatepdf/api?n=83833#:~:text=V%C3%ADa%20oral%3A%20Tratamiento%3A%204%2D,6%2D8%20horas%3B%20m%C3%A1x10. Daly MJ, Humphray JM, Stables R. Antagonism of Vasodepressor and Gastric Secretory Responses To Histamine by the H2-Receptor Antagonists, Ranitidine and Cimetidine, In the Anaesthetized Dog. Br J Pharmacol [Internet]. 1981;72. Disponible en: https://api.semanticscholar.org/CorpusID:1299672211. Aronson J. Ranitidine. En: Aronson JK, editor. Meyler’s Side Effects of Drugs (Sixteenth Edition) [Internet]. Sixteenth Edition. Oxford: Elsevier; 2016. p. 74-6. Disponible en: https://www.sciencedirect.com/science/article/pii/B978044453717101391312. Caitlin C. Nugent, Samuel R. Falkson, Jamie M. Terrell. H2 Blockers. National Library of Medicine [Internet]. 2024; Disponible en: https://www.ncbi.nlm.nih.gov/books/NBK525994/13. Soleymani J, Djozan D, Martínez F, Jouyban A. Solubility of ranitidine hydrochloride in solvent mixtures of PEG 200, PEG 400, ethanol and propylene glycol at 25°C. J Mol Liq [Internet]. 2013;182:91-4. Disponible en: https://www.sciencedirect.com/science/article/pii/S016773221300096214. Hohnjec M, Kuftinec J, Malnar M, Škreblin M, Kajfež F, Nagl A, et al. Ranitidine. En: Florey K, editor. Academic Press; 1986. p. 533-61. (Analytical Profiles of Drug Substances; vol. 15). Disponible en: https://www.sciencedirect.com/science/article/pii/S009954280860423215. Home Sunshine Pharma. Clorhidrato de Ranitidina [Internet]. 2025. Disponible en: https://www.hspchem.com/apis-and-intermediates/ranitidine-hydrochloride-cas-66357-35-5.html16. Xiangya School of Pharmaceutical Sciences. ADMETLab 3.0 [Internet]. 2025. Disponible en: https://admetlab3.scbdd.com/server/evaluationCal17. Bethasda M. Histamine Type-2 Receptor Antagonists (H2 Blockers) [Internet]. 2012. Disponible en: https://www.ncbi.nlm.nih.gov/books/18. Mills J, Koch K, Webster C, Sirgo M, Fitzgerald K, Wood J. The safety of ranitidine in over a decade of use. Aliment Pharmacol Ther [Internet]. 2008;11(1):129-37. Disponible en: https://onlinelibrary.wiley.com/doi/epdf/10.1046/j.1365-2036.1997.136312000.x19. Schunack W. What are the differences between the H2-receptor antagonists? Aliment Pharmacol Ther [Internet]. 1987;493s-503s. Disponible en: https://pubmed.ncbi.nlm.nih.gov/2908767/20. Vardanyan RS, Hruby VJ. 16 - Antihistamine Drugs. En: Vardanyan RS, Hruby VJ, editores. Synthesis of Essential Drugs [Internet]. Amsterdam: Elsevier; 2006. p. 219-35. Disponible en: https://www.sciencedirect.com/science/article/pii/B978044452166850016921. Daly MJ, Humphray JM, Stables R. Some in vitro and in vivo actions the new Histamine H2-Receptor Antagonist, Ranitidina. Br J Pharmacol [Internet]. 1981;72(1):49-54. Disponible en: https://bpspubs.onlinelibrary.wiley.com/doi/abs/10.1111/j.1476-5381.1981.tb09103.x22. Daly MJ, Humphray JM, Bunce KT, Stables R. The effect of ranitidine on gastric acid secretory response curves to histamine, pentagastrin or bethanechol in the dog with a heidenhain pouch. Agents Actions [Internet]. 1981;11:160-4. Disponible en: https://api.semanticscholar.org/CorpusID:1945824823. Scarpignato C, Tramacere R, Pezzetta A. Effect of famotidine and ranitidine on gastric secretion and emptying in the rat. Drug Dev Res [Internet]. 1987;11(1):37-43. Disponible en: https://analyticalsciencejournals.onlinelibrary.wiley.com/doi/abs/10.1002/ddr.43011010524. Decktor DL, Pendleton RG, Kellner A, Davis MA. Acute effects of ranitidine, famotidine and omeprazole on plasma gastrin in the rat. J Pharmacol Exp Ther [Internet]. 1989;249 1:1-5. Disponible en: https://api.semanticscholar.org/CorpusID:3264983525. Gough KR, Bardhan KD, Crowe JP, Korman MG, Lee FI, Reed PI, et al. RANITIDINE AND CIMETIDINE IN PREVENTION OF DUODENAL ULCER RELAPSE: A Double-blind, Randomised, Multicentre, Comparative Trial. The Lancet [Internet]. 1984;324(8404):659-62. Disponible en: https://www.sciencedirect.com/science/article/pii/S014067368491224826. Sabesin S. Safety issues relating to long-term treatment with histamine H2-receptor antagonists. Aliment Pharmacol Ther. 1993;7(2):35-40.27. Pipkin GA, Mills JG, Kler L, Dixon JS, Wood JR. The Safety of Ranitidine Bismuth Citrate in Controlled Clinical Studies. Pharmacoepidemiol Drug Saf [Internet]. 1 de noviembre de 1996;5(6):399-407. Disponible en: https://doi.org/10.1002/(SICI)1099-1557(199611)5:6<399::AID-PDS243>3.0.CO28. Galmiche JP, Shi G, Simon B, Casset-Semanaz F, Slama A. On-demand treatment of gastro-oesophageal reflux symptoms: a comparison of ranitidine 75 mg with cimetidine 200 mg or placebo. Aliment Pharmacol Ther [Internet]. 1 de septiembre de 1998;12(9):909-17. Disponible en: https://doi.org/10.1046/j.1365-2036.1998.00384.x29. Sirgo MA, Mills R, Euler AR, Walker S. The Safety of Ranitidine in Elderly Versus Non-Elderly Patients. The Journal of Clinical Pharmacology [Internet]. 1993;33(1):79-83. Disponible en: https://accp1.onlinelibrary.wiley.com/doi/abs/10.1002/j.1552-4604.1993.tb03908.x30. Pappa W, Williams J, Payne K, Buaron R, Mussari R, Ciociola A. A double-blind, placebo-controlled study of the efficacy and safety of non-prescription ranitidine 75 mg in the prevention of meal-induced heartburn. Aliment Pharmacol Ther [Internet]. 1999;13(4):467-73. Disponible en: https://onlinelibrary.wiley.com/doi/abs/10.1046/j.1365-2036.1999.00505.x31. Orenstein S, Blumer J, Faessel H, McGuire J, Fung K, Li B, et al. Ranitidine, 75 mg, over-the-counter dose: pharmacokinetic and pharmacodynamic effects in children with symptoms of gastro-oesophageal reflux. Aliment Pharmacol Ther [Internet]. 2002;16(5):899-907. Disponible en: https://pubmed.ncbi.nlm.nih.gov/11966498/32. Rose U. European Pharmacopoeia Activities on Control of Nitrosamines and other DNA-Reactive Impurities. J Pharm Sci [Internet]. 1 de mayo de 2023;112(5):1163-5. Disponible en: https://doi.org/10.1016/j.xphs.2022.11.01533. Comisión Farmacopea Argentina. Tabletas de Clorhidrato de Ranitidina. Séptima. Vol. 3. Farmacopea Argentina; 2003. 351-352 p.34. Comisión de la Farmacopea Británica. Tabletas de Clorhidrato de Ranitidina. Onceava. Vol. 3. Farmacopea Británica; 2020. 1208-1209 p.35. Novaković J. High-performance thin-layer chromatography for the determination of ranitidine hydrochloride and famotidine in pharmaceuticals. J Chromatogr A [Internet]. 1999;846(1):193-8. Disponible en: https://www.sciencedirect.com/science/article/pii/S002196739900510536. Basavaiah K, Nagegowda P. Determination of ranitidine hydrochloride in pharmaceutical preparations by titrimetry and visible spectrophotometry using bromate and acid dyes. Il Farmaco [Internet]. 2004;59(2):147-53. Disponible en: https://www.sciencedirect.com/science/article/pii/S0014827X0300308237. Walash M, Sharaf El Din M, Metwalli M, RedaShabana M. Spectrophotometric determination of nizatidine and ranitidine through charge transfer complex formation. Arch Pharm Res. 1 de agosto de 2004;27:720-6.38. Weston DJ, Bateman RHK, Wilson ID, Wood T, Creaser CS. Direct analysis of pharmaceutical drug formulations using ion mobility spectrometry/quadrupole-time-of-flight mass spectrometry combined with desorption electrospray ionization. Anal Chem [Internet]. 2005;77 23:7572-80. Disponible en: https://api.semanticscholar.org/CorpusID:2487763339. El-Bayoumi A, El-Shanawany AA, El-Sadek M, El-Sattar AA. Stability indicating spectrodensitometric determination of ranitidine hydrochloride using linear and non-linear regression. J Pharm Biomed Anal [Internet]. 1999;21 4:867-73. Disponible en: https://api.semanticscholar.org/CorpusID:4267987040. Ficarra P, Ficarra R, Tommasini A. High-performance liquid chromatography of ranitidine in pharmaceuticals. J Pharm Biomed Anal [Internet]. 1984;2(1):119-23. Disponible en: https://www.sciencedirect.com/science/article/pii/073170858480097741. Beaulieu N, Lacroix P, Sears R, Lovering E. High-performance liquid chromatographic methods for the determination of ranitidine and related substances in raw materials and tablets. J Pharm Sci [Internet]. 1988;77(10):889-92. Disponible en: https://pubmed.ncbi.nlm.nih.gov/3236234/42. Arayne M, Sultana N, Zuberi M, Siddiqui F. Simultaneous determination of metformin, cimetidine, famotidine, and ranitidine in human serum and dosage formulations using HPLC with UV detection. J Chromatogr Sci [Internet]. 2010;48(9):721-5. Disponible en: https://pubmed.ncbi.nlm.nih.gov/20875233/43. Food and Drug Administration. La FDA anuncia el retiro voluntario del mercado de varios medicamentos que contienen valsartán, tras la detección de una impureza [Internet]. 2018. Disponible en: https://www.fda.gov/news-events/comunicados-de-prensa/la-fda-anuncia-el-retiro-voluntario-del-mercado-de-varios-medicamentos-que-contienen-valsartan-tras44. Organización Mundial de la Salud (OMS). Nota informativa de la OMS. Actualización sobre las impurezas de Nitrosaminas [Internet]. 2010. Disponible en: https://www.who.int/docs/default-source/essential-medicines/medical-alert-2019/information-note-nitrosamine-impurities-nov2019-esp.pdf?sfvrsn=d189497f_2145. Agencia para Sustancias Tóxicas y el Registro de Enfermedades (ATSDR). Resumen de la Salud Pública. N-Nitrosodimetilamina [Internet]. 1989. Disponible en: https://www.atsdr.cdc.gov/es/phs/es_phs141.pdf46. International Council for Harmonisation (ICH). Impurities in new drug products (Q3B(R2) [Internet]. 2006. Disponible en: https://database.ich.org/sites/default/files/Q3B%28R2%29%20Guideline.pdf47. Johnson GE, Dobo K, Gollapudi B, Harvey J, Kenny J, Kenyon M, et al. Permitted daily exposure limits for noteworthy N-nitrosamines. Environ Mol Mutagen [Internet]. 1 de junio de 2021;62(5):293-305. Disponible en: https://doi.org/10.1002/em.2244648. Fisher scientific. N-Nitrosodimetilamina [Internet]. 2025. Disponible en: https://www.fishersci.es/shop/products/n-nitrosodimethylamine-spex-certiprep/1298931449. Gobierno de España. N-nitrosodimetilamina [Internet]. 2018. Disponible en: https://chemicalsafety.ilo.org/dyn/icsc/showcard.display?p_card_id=0525&p_version=2&p_lang=es50. New Jersey department of health. Hoja informativa sobre sustancias peligrosas: N-nitrosodimetilamina. [Internet]. 2012. Disponible en: https://nj.gov/health/eoh/rtkweb/documents/fs/1405sp.pdf51. Council of Europe. N-nitroso-dimethylamine (solution in Methanol) Fichas de Datos de Seguridad [Internet]. 2023. Disponible en: https://sds.edqm.eu/pdf/SDS/EDQM_202000236_1.0_SDS_ES.pdf?ref=162384777652. Agencia para Sustancias Tóxicas y el Registro de Enfermedades (ATSDR). N-nitrosodimetilamina (N-nitrosodimethylamine) [Internet]. 2023. Disponible en: https://www.atsdr.cdc.gov/es/toxfaqs/es_tfacts141.html53. Ray SD, Mehendale HM. N-Nitrosodimethylamine. En: Wexler P, editor. Encyclopedia of Toxicology (Second Edition) [Internet]. New York: Elsevier; 2005. p. 255-8. Disponible en: https://www.sciencedirect.com/science/article/pii/B012369400000661X54. Yoon HJ, Kim JH, Seo GH, Park H. Risk of Cancer Following the Use of N-Nitrosodimethylamine (NDMA) Contaminated Ranitidine Products: A Nationwide Cohort Study in South Korea. J Clin Med [Internet]. 2021;10(1). Disponible en: https://www.mdpi.com/2077-0383/10/1/15355. Liu YD, Selbes M, Zeng C, Zhong R, Karanfil T. Formation Mechanism of NDMA from Ranitidine, Trimethylamine, and Other Tertiary Amines during Chloramination: A Computational Study. Environ Sci Technol [Internet]. 5 de agosto de 2014;48(15):8653-63. Disponible en: https://doi.org/10.1021/es500997e56. Harmon P. Ranitidine: A Proposed Mechanistic Rationale for NDMA Formation and a Potential Control Strategy. J Pharm Sci [Internet]. 2023;112(5):1220-4. Disponible en: https://www.sciencedirect.com/science/article/pii/S002235492200521457. Abe Y, Yamamoto E, Yoshida H, Usui A, Tomita N, Kanno H, et al. Temperature-Dependent Formation of N-Nitrosodimethylamine during the Storage of Ranitidine Reagent Powders and Tablets. Chem Pharm Bull (Tokyo). 8 de agosto de 2020;68.58. Agilent. Análisis de nitrosaminas en productos farmacéuticos [Internet]. 2021. Disponible en: https://www.agilent.com/cs/library/brochures/brochure-nitrosamine-in-pharma-gc-ms-5994-2979es-es-agilent.pdf59. Turner D. GC-MS Principle, Instrument and Analyses and GC-MS/MS [Internet]. 2024. Disponible en: https://www.technologynetworks.com/analysis/articles/gc-ms-principle-instrument-and-analyses-and-gc-msms-36251360. Giménez-Campillo C, Pastor-Belda M, Campillo N, Hernández-Córdoba M, Viñas P. Development of a new methodology for the determination of N-nitrosamines impurities in ranitidine pharmaceuticals using microextraction and gas chromatography-mass spectrometry. Talanta [Internet]. 2021;223:121659. Disponible en: https://www.sciencedirect.com/science/article/pii/S003991402030950461. Manchuri KM, Shaik MA, Gopireddy VSR, Naziya S, Gogineni S. Analytical Methodologies to Detect N-Nitrosamine Impurities in Active Pharmaceutical Ingredients, Drug Products and Other Matrices. Chem Res Toxicol [Internet]. 2024;37(9):1456-83. Disponible en: https://doi.org/10.1021/acs.chemrestox.4c0023462. Lim H hee, Oh YS, Shin HS. Determination of N-nitrosodimethylamine and N-nitrosomethylethylamine in drug substances and products of sartans, metformin and ranitidine by precipitation and solid phase extraction and gas chromatography–tandem mass spectrometry. J Pharm Biomed Anal. 1 de julio de 2020;189:113460.63. Alshehri Y, Aldawsari F, Alghamdi T. HS-SPME-GC-MS as an alternative method for NDMA analysis in ranitidine products. J Pharm Biomed Anal. 2020;64. Shinde V. Veeprho. 2020. Difference Between LC, LC-MS, LC-MS-MS, and HR-MS. Disponible en: https://veeprho.com/difference-between-lc-lc-ms-lc-ms-ms-and-hr-ms/65. Food and Drug Administration. Liquid Chromatography-High Resolution Mass Spectrometry (LC-HRMS) Method for the Determination of NDMA in Ranitidine Drug Substance and Drug Product. 2019; Disponible en: https://www.fda.gov/media/130801/download66. Maziarz M, Rainville P. Reliable HPLC/UV Quantification of  Nitrosamine Impurities in Valsartan and  Ranitidine Drug Substances. Waters Technology Brief 720006738EN. 2019;67. Health Sciences Authority. Determination of NDMA in Ranitidine Products By LC-MS/MS. Pharmaceutical Laboratory, Applied Sciences Group, Health Sciences Authority. 2019;68. Schmaler J. Test method for the determination of NDMA by LC-MS/MS in Ranitidine Drug Substance and Film Coated Tablets . Chemisches und Veterinäruntersuchungsamt Karlsruhe. 2019;69. Angrish P, Mani C, Banerjee S. Development of a Validated Method of Testing for NDMA in Ranitidine. Pharmaceutical Technology. 2020;44:42-7.70. Xiang Z, Qian P. Detection and analysis of N-nitrosodimethylamine in ranitidine by using Q Exactive Focus High Resolution Mass Spectrometry. Thermo Fisher Scientific [Internet]. 2020; Disponible en: https://assets.thermofisher.com/TFS-Assets/CMD/Application-Notes/an-73411-hrms-ndma-raniditine-an73411-en.pdf71. Banerjee S. Determination of NDMA Impurity in Ranitidine Using the Agilent 6470 Triple Quadrupole LC/MS. En 2020. Disponible en: https://api.semanticscholar.org/CorpusID:21101642372. Yang H, Bardsley J, Du M, Scheibner O. HRAM LC-MS method for the determination of nitrosamine impurities in drugs. Thermo Fisher Scientific. 2020.73. Maziarz M, Rainville P. Quick Analysis of N-nitrosodimethylamine (NDMA) in Ranitidine Drug Substance and Drug Product by HPLC/UV. Waters Corporation. 2020.74. Liu J, Zhao Z, Yang X, Jin Y, Liu X, Wang C, et al. Determination of N-nitrosodimethylamine in Ranitidine Dosage Forms by ESI-LC-MS/MS. Iran J Pharm Res. 2021;255-64.75. Sun Z, Xing J, Minarni A, Zhan Z. Quantitative Determination of NDMA Impurity in Ranitidine Drug Products – Examples of Actual Samples Analysis by LCMS-8060 with APCI. Shimadzu Group. 2021.76. Nascimiento V, Murgu M, Mullin L. Selective and Specific Quantitation of NDMA in Ranitidine with the Xevo G2-XS QTof. Waters Corporation. 2021.77. Rao G, Ramadevi D, Rao B, Rajana N, Basavaiah K. Novel stability indicating LC-MS method for N-Nitroso dimethyl amine genotoxic impurity quantification in ranitidine drug substance and drug product. J Appl Pharm Sci. 2022.78. Nimje H, Shirsath A, Pawar S, Deodhar M. Liquid Chromatography with Tandem Mass Spectrometric Method Development and Validation Study for the Estimation of N-Nitrosodimethylamine in Ranitidine Tablets. Indian J Pharm Sci. 2024.79. Schweikart F, Hulthe G. HPLC–UV–MS Analysis: A Source for Severe Oxidation Artifacts. Anal Chem [Internet]. 5 de febrero de 2019;91(3):1748-51. Disponible en: https://doi.org/10.1021/acs.analchem.8b0584580. Pacific biolabs. LC/MS AND LC/MS/MS [Internet]. 2022. Disponible en: https://pacificbiolabs.com/lc-ms/81. Crutchfield CA, Clarke W. High resolution accurate mass (HRAM) mass spectrometry. En: Nair H, Clarke W, editores. Mass Spectrometry for the Clinical Laboratory [Internet]. San Diego: Academic Press; 2017. p. 247-59. Disponible en: https://www.sciencedirect.com/science/article/pii/B978012800871300012282. Allen D, McWhinney B. Quadrupole Time-of-Flight Mass Spectrometry: A Paradigm Shift in Toxicology Screening Applications. Clin Biochem Rev. 2019;135-46.83. Nováková L, Svoboda P, Pavlík J. Ultra-high performance liquid chromatography. En: Fanali S, Haddad PR, Poole CF, Riekkola ML, editores. Liquid Chromatography (Second Edition) [Internet]. Elsevier; 2017. p. 719-69. Disponible en: https://www.sciencedirect.com/science/article/pii/B978012805393500029484. López R, Romero R, Garrido A. Ultrahigh-pressure liquid chromatography-mass spectrometry: An overview of the last decade. TrAC Trends in Analytical Chemistry [Internet]. 2019;118:170-81. Disponible en: https://www.sciencedirect.com/science/article/pii/S016599361930170085. Thibodeaux S, Yurek D, McGee J. HPLC-MS/MS for Hit Generation. Eli Lilly & Company and the National Center for Advancing Translational Sciences [Internet]. 2017; Disponible en: https://www.ncbi.nlm.nih.gov/books/NBK126175/86. Moser J, Schlingemann J, Saal C. N-Nitrosamines Impurities in Pharmaceuticals The Abrupt Challenges that Resulted, the Evolving Science, and the Regulatory Framework. J Pharm Sci [Internet]. 1 de mayo de 2023;112(5):1161-2. Disponible en: https://doi.org/10.1016/j.xphs.2023.01.01687. Wood I, Goyret A. Situación actual sobre la calidad, comercialización y disponibilidad de Ranitidina. Boletín Farmacológico. 2023;7-7.88. Horne S, Vera MD, Nagavelli LR, Sayeed VA, Heckman L, Johnson D, et al. Regulatory Experiences with Root Causes and Risk Factors for Nitrosamine Impurities in Pharmaceuticals. J Pharm Sci [Internet]. 2023;112(5):1166-82. Disponible en: https://www.sciencedirect.com/science/article/pii/S002235492200614189. Paglialunga S, van Haarst A. The Impact of N-nitrosamine Impurities on Clinical Drug Development. J Pharm Sci [Internet]. 2023;112(5):1183-91. Disponible en: https://www.sciencedirect.com/science/article/pii/S0022354923000199spaORIGINALTrabajo de grado.pdfTrabajo de grado.pdfapplication/pdf1331918https://repositorio.unbosque.edu.co/bitstreams/861b66a5-2557-4ad8-9312-0b096ce79b78/download108c15d5b341fb0eb9a9f111fe8e2a09MD51LICENSElicense.txtlicense.txttext/plain; charset=utf-82000https://repositorio.unbosque.edu.co/bitstreams/9b151a3f-e29e-41d4-8aff-16c07e3313a1/download17cc15b951e7cc6b3728a574117320f9MD53Carta de autorizacion.pdfapplication/pdf122099https://repositorio.unbosque.edu.co/bitstreams/f8557449-a31c-46e1-811d-b18292c17789/download306d66892e61961b653b9b968875a7f1MD55Anexo 1 acta de aprobacion.pdfapplication/pdf20235440https://repositorio.unbosque.edu.co/bitstreams/3d03751c-f689-4dbe-92f0-7c0055feeabd/downloadda1fcfd94900aab3f0ba211fc7c03688MD56CC-LICENSElicense_rdflicense_rdfapplication/rdf+xml; charset=utf-81154https://repositorio.unbosque.edu.co/bitstreams/43b1bc33-3e05-4851-b758-1659f6cdcb28/downloadadb7af3ef071a784ffe1b544b9a344abMD54TEXTTrabajo de grado.pdf.txtTrabajo de grado.pdf.txtExtracted texttext/plain101699https://repositorio.unbosque.edu.co/bitstreams/141a4857-f565-4559-9ad4-b9f96f8a12de/downloadb1594f1f1b117d3818f6e170db30d54cMD57THUMBNAILTrabajo de grado.pdf.jpgTrabajo de grado.pdf.jpgGenerated Thumbnailimage/jpeg5297https://repositorio.unbosque.edu.co/bitstreams/5d1b2a51-ce68-4169-a464-948f5aae3c34/downloade4962fea336e8498fbf426e46e8739b8MD5820.500.12495/14353oai:repositorio.unbosque.edu.co:20.500.12495/143532025-05-16 05:07:06.211http://creativecommons.org/licenses/by-sa/4.0/Attribution-ShareAlike 4.0 Internationalopen.accesshttps://repositorio.unbosque.edu.coRepositorio Institucional Universidad El Bosquebibliotecas@biteca.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

Publicaciones similares