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Nitrosation of dimethylamine by nitrite esters in aqueous basic media","volume":"117","author":"Casado","year":"1986","journal-title":"Monatsh. Chem"},{"key":"10.1016\/j.xphs.2025.104067_bib0040","first-page":"381","article-title":"Nitrosation mechanisms","volume":"19","author":"Williams","year":"1983","journal-title":"Adv Phys Org Chem"},{"issue":"1","key":"10.1016\/j.xphs.2025.104067_bib0041","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/S0278-6915(82)80013-6","article-title":"Inhibition of nitrosation of amines by thiols, alcohols and carbohydrates","volume":"20","author":"Williams","year":"1982","journal-title":"Fd Chem Toxicol"},{"key":"10.1016\/j.xphs.2025.104067_bib0042","doi-asserted-by":"crossref","first-page":"1021","DOI":"10.1039\/p29810001021","article-title":"Alkyl nitrites as nitrosating agents. Kinetics and mechanism of reactions of propyl nitrite in propan-1-ol","volume":"2","author":"Aldred","year":"1981","journal-title":"J Chem Soc Perkin Trans"},{"key":"10.1016\/j.xphs.2025.104067_bib0043","unstructured":"See the ESI for a description of the saturating solubility models used herein. It is assumed that the excipients present in the drug product don\u2019t significantly impact amine solubility. If solubility measurements are to be carried out, they should be carried out at or near the pH of the saturated solution layer being used in the model."},{"key":"10.1016\/j.xphs.2025.104067_bib0044","doi-asserted-by":"crossref","DOI":"10.1039\/J19690001212","article-title":"Thermodynamics of proton ionization in dilute aqueous solution. Part XI. pK, \u0394H\u00b0, and \u0394S\u00b0 values for proton ionization from protonated amines at 25\u00b0","author":"Christensen","year":"1969","journal-title":"J Chem Soc A Inorganic Physical Theoretical"},{"key":"10.1016\/j.xphs.2025.104067_bib0045","unstructured":"Advanced Chemistry Developments Inc. ACD\/Percepta, ACD\/pKa classic, ACD\/Labs release 2020.2.0 (Build 3435. 16 Jan 2021). Available at: www.acdlabs.com."},{"key":"10.1016\/j.xphs.2025.104067_bib0046","series-title":"Pka Prediction For Organic Acids and Bases","first-page":"16","author":"Perrin","year":"1981"},{"key":"10.1016\/j.xphs.2025.104067_bib0047","unstructured":"An example of a diamine with two pKas is used in the discussion and details of the model may be found in the ESI."},{"key":"10.1016\/j.xphs.2025.104067_bib0048","unstructured":"A description of the penalizing temperature dependence term used in the models described herein may be found in the ESI. A discussion of the rationale behind the temperature dependence term may be found in reference 17."},{"key":"10.1016\/j.xphs.2025.104067_bib0049","series-title":"Solvents and Solvent Effects in Organic Chemistry","first-page":"147","author":"Reichardt","year":"2003"},{"issue":"10","key":"10.1016\/j.xphs.2025.104067_bib0050","doi-asserted-by":"crossref","first-page":"1714","DOI":"10.1021\/acs.oprd.3c00073","article-title":"A consideration of the extent that tertiary amines can form N-nitroso dialkylamines in pharmaceutical products","volume":"27","author":"Ashworth","year":"2023","journal-title":"Org Process Res Dev"},{"key":"10.1016\/j.xphs.2025.104067_bib0051","unstructured":"European Medicines Agency. Carcinogenic potency categorisation approach for N-nitrosamines, EMA. 451665\/2023, October 12, 2023. Available at: https:\/\/www.ema.europa.eu\/system\/files\/documents\/other\/appendix_2_carcinogenic_potency_categorisation_approach_for_n-nitrosamines_en.pdf Accessed May 27, 2025."},{"key":"10.1016\/j.xphs.2025.104067_bib0052","series-title":"Aqueous Acid-Base Equilibria and Titrations","first-page":"9","author":"De Levie","year":"1999"},{"key":"10.1016\/j.xphs.2025.104067_bib0053","unstructured":"The predicted pH of 4.98 was used for the simulations discussed herein as that will lead the model to predict a lower rate, which is appropriate when demonstrating that it overpredicts the rate of nitrosation. In the context of a risk assessment the lower value measured for the solution would be taken as this is more conservative. The solubility was measured by slurrying an excess of 4-phenyl piperidine HCl in water, which means that any excess HCl present in the entire sample used will have dissolved resulting in a low solution pH. Full details of the solution to the proton condition may be found in the ESI."},{"key":"10.1016\/j.xphs.2025.104067_bib0054","unstructured":"Details of the models used in this work may be found in the ESI."},{"key":"10.1016\/j.xphs.2025.104067_bib0055","unstructured":"Berkeley Madonna Version 8.3.14, Robert I. Macey & George F. Oster, www.berkeley-madonna.myshopify.com."},{"key":"10.1016\/j.xphs.2025.104067_bib0056","unstructured":"A shorter step size can be used and simply leads to a slower simulation, which takes minutes to run rather than the less than a minute usually achieved on a standard business laptop. very small step sizes can lead to an impractical number of data points being calculated."},{"key":"10.1016\/j.xphs.2025.104067_bib0057","unstructured":"The nitrite levels used were calculated based on upper limit measured values from the Lhasa excipient nitrite database for the excipients present in the drug product. If the highest value for an excipient was a LOD value this value was ignored and the highest measured value in the database used."},{"key":"10.1016\/j.xphs.2025.104067_bib0058","unstructured":"See Table S1 for a comparison of simulation results at obtained at 25\u00b0C to the measured levels of 4-nitroso piperidine formation."},{"key":"10.1016\/j.xphs.2025.104067_bib0059","series-title":"Advances in Inorganic Chemistry and Radiochemistry","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/S0065-2792(08)60080-1","article-title":"Reaction mechanisms of inorganic nitrogen compounds","volume":"22","author":"Stedman","year":"1979"},{"issue":"3","key":"10.1016\/j.xphs.2025.104067_bib0060","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1021\/ja02216a004","article-title":"The equilibrium between nitric acid, nitrous acid and nitric oxide","volume":"33","author":"Lewis","year":"1911","journal-title":"J Am Chem Soc"},{"key":"10.1016\/j.xphs.2025.104067_bib0061","unstructured":"See Figure S2 for the effect of reactant availability upon the rate of nitrosation by ClNO and protonated nitrous acid."},{"key":"10.1016\/j.xphs.2025.104067_bib0062","series-title":"Accelerated Predictive Stability","first-page":"33","article-title":"Theory and fundamentals of accelerated predictive stability (APS) studies","author":"Scrivens","year":"2018"},{"issue":"8","key":"10.1016\/j.xphs.2025.104067_bib0063","doi-asserted-by":"crossref","first-page":"1443","DOI":"10.1021\/acs.oprd.0c00166","article-title":"A structured approach to cope with impurities during industrial crystallization development","volume":"24","author":"Unwin","year":"2020","journal-title":"Org Process Res Dev"},{"issue":"4","key":"10.1016\/j.xphs.2025.104067_bib0064","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1021\/acs.oprd.3c00009","article-title":"Prevalence of impurity rejection mechanisms in pharmaceutical crystallizations","volume":"27","author":"Nordstrom","year":"2023","journal-title":"Org Process Res Dev"},{"issue":"5","key":"10.1016\/j.xphs.2025.104067_bib0065","doi-asserted-by":"crossref","first-page":"1746","DOI":"10.1016\/j.xphs.2018.12.003","article-title":"Degradation rate observation as a function of drug load in solid-State drug products","volume":"108","author":"Baertschi","year":"2019","journal-title":"J Pharm Sci"},{"key":"10.1016\/j.xphs.2025.104067_bib0066","unstructured":"Baertschi et al. analyzed reactivity in terms of percentage conversion of the active ingredient. This does not equate to absolute rate in terms of number of molecules reacted, which may be a more meaningful metric in some scenarios."},{"issue":"12","key":"10.1016\/j.xphs.2025.104067_bib0067","doi-asserted-by":"crossref","first-page":"3075","DOI":"10.1016\/j.xphs.2023.06.013","article-title":"Bumetanide as a model NDSRI substrate: n-nitrosobumetanide impurity formation and its inhibition in Bumetanide tablets","volume":"112","author":"Shakleya","year":"2023","journal-title":"J Pharm Sci"},{"key":"10.1016\/j.xphs.2025.104067_bib0068","doi-asserted-by":"crossref","DOI":"10.1016\/j.ijpharm.2024.124832","article-title":"Nitrosamine mitigation: NDMA impurity formation and its inhibition in metformin hydrochloride tablets","volume":"666","author":"Shakleya","year":"2024","journal-title":"Int J Pharmaceutics"},{"issue":"10","key":"10.1016\/j.xphs.2025.104067_bib0069","doi-asserted-by":"crossref","first-page":"1784","DOI":"10.1021\/acs.oprd.3c00084","article-title":"Approaches and considerations for the investigation and synthesis of N-nitrosamine drug substance-related impurities (NDSRIs)","volume":"27","author":"Ashworth","year":"2023","journal-title":"Org Process Res Dev"},{"key":"10.1016\/j.xphs.2025.104067_bib0070","unstructured":"See Figure S3 for comparisons of the rate constants for dialkylamine nitrosation by N2O3 and BrNO as a function of amine pKa which support the assumptions made in the general model of amine nitrosation (see reference 17)."},{"key":"10.1016\/j.xphs.2025.104067_bib0071","unstructured":"See figure S1 for the formation of NNO-1 and NNO-2 over three years at 25\u00b0C between pH 7 and 12."},{"key":"10.1016\/j.xphs.2025.104067_bib0072","unstructured":"This may not be true for products with a low drug loading, where caution should be employed in applying competition-based models."},{"key":"10.1016\/j.xphs.2025.104067_bib0073","unstructured":"A pKa of 11.2 was taken from reference 44 for DIPA."},{"key":"10.1016\/j.xphs.2025.104067_bib0075","unstructured":"European Medicines Agency. Appendix 1: Acceptable Intakes Established for N-Nitrosamines, EMA\/165331\/2025\/Rev. 9. 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