Selective scavenging of the genotoxic impurity methyl p-toluenesulfonate from pharmaceutical formulations

Keçili, Rüstem; Billing, Johan; Leeman, Mats; Nivhede, David; Sellergren, Börje; Rees, Anthony T.; Yilmaz, Ecevit

doi:10.1016/j.seppur.2012.09.028

Cited by 25 publications

(11 citation statements)

References 14 publications

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“…As expected, they were removed at nearly the same rate and the final GTI concentration decreased to below 5 ppm, satisfying the typical target level of 10 ppm. 25,44 Although the yield was low, the advantage of membrane processes over affinity-based purification technologies (e.g. resin, chromatography) was clearly demonstrated in this system: GTIs from different chemical classes can be removed simultaneously; usually affinity-based purifications would require specific selective agents for each chemical class of impurities.…”

Section: Membrane Selection and Single Stage Diafiltration (Ssd)mentioning

confidence: 97%

Increasing the sustainability of membrane processes through cascade approach and solvent recovery—pharmaceutical purification case study

et al. 2014

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Membrane processes suffer limitations such as low product yield and high solvent consumption, hindering their widespread application in the pharmaceutical and fine chemicals industries. In the present work, the authors propose an efficient purification methodology employing a two-stage cascade configuration coupled to an adsorptive solvent recovery unit, which addresses the two limitations. The process has been validated on purification of active pharmaceutical ingredient (API) from genotoxic impurity (GTI) using organic solvent nanofiltration (OSN). The model system selected for study comprises roxithromycin macrolide antibiotic (Roxi) with 4-dimethylaminopyridine (DMAP) and ethyl tosylate (EtTS) as API and GTIs, respectively. By implementing a two-stage cascade configuration for membrane diafiltration, the process yield was increased from 58% to 95% while maintaining less than 5 ppm GTI in the final solution. Through this yield enhancement, the membrane process has been "revamped" from an unfeasible process to a highly competitive unit operation when compared to other traditional processes. The advantage of size exclusion membranes over other separation techniques has been illustrated by the simultaneous removal of two GTIs from different chemical classes. In addition, a solvent recovery step has been assessed using charcoal as a non-selective adsorbent, and it has been shown that pure solvent can be recovered from the permeate. Considering the costs of solvent, charcoal, and waste disposal, it was concluded that 70% solvent recovery is the cost-optimum point. Conventional single-stage diafiltration (SSD) and two-stage diafiltration (TSD) configurations were compared in terms of green metrics such as cost, mass and solvent intensity, and energy consumption. It was calculated that implementation of TSD, depending on the batch scale, can achieve up to 92% cost saving while reducing the mass and solvent intensity up to 73%. In addition, the advantage of adsorptive solvent recovery has been assessed revealing up to 96% energy reduction compared to distillation and a 70% reduction of CO 2 footprint.

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Section: Membrane Selection and Single Stage Diafiltration (Ssd)mentioning

confidence: 97%

Increasing the sustainability of membrane processes through cascade approach and solvent recovery—pharmaceutical purification case study

et al. 2014

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“…The main operating parameters studied to reach the target objective will be diavolumes (D) and amount of adsorber (m), respectively, for OSN and adsorption operations. The model uses a discrete number of parameters with values within a given range (described below), selected according to previous works [6,10,15,16,23] and/or literature [12,13]. The main parameters considered, for each solute (API and GTI) were membrane rejection and isotherm adsorption constants, respectively, for OSN and adsorption operations.…”

Section: Set-up and Boundariesmentioning

confidence: 99%

“…Removal of 80% of GTI was achieved with API losses about 15-20% using 50 mgMIP/mL of solution. Kecili et al studied MPTS (5µg/mL) removal from 21-chloro-diflorasone (500 µg/mL) solutions using several polystyrene-divinylbenzene and silica based scavengers in 2-propanol [12]. The authors obtained 100% GTI removal with silica based Si-Trisamine and macroporous polystyrene-divinylbenzene based MP-Trisamine resin, using 150 mgResin/mL, with no API loss after using 2-propanol:THF (1:1) for API recovery.…”

Section: Api Loss (%) Low Highmentioning

confidence: 99%

“…OSN and PBI adsorbers will There are several strategies in place to mitigate the presence of GTIs in API formulations. However, some are expensive and time consuming (chromatography, solvent exchange), others are not adequate for thermal sensitive APIs (distillation), may lead to high API losses (recrystallization [10,11]) or face challenging working conditions (commercial resins designed to perform in aqueous media, but API synthesis takes place in organic solvents) [5,[12][13][14]. Furthermore, none of these techniques targets the selective removal of the impurity, and therefore, losses of the desired product occur [10].…”

Section: Introductionmentioning

confidence: 99%

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Comparison and Combination of Organic Solvent Nanofiltration and Adsorption Processes: A Mathematical Approach for Mitigation of Active Pharmaceutical Ingredient Losses during Genotoxin Removal

et al. 2020

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Active pharmaceutical ingredients (API) are synthesized using highly reactive reagents, catalysts, and solvents. Some of those persist as impurities in the final product and are genotoxic or carcinogenic. The conventional processes used for API purification and isolation are able to achieve the limits imposed by regulatory agencies, but at the expense of significant API losses. Here we report the development of a model to aid in the decision of which dedicated purification process, membrane or adsorption, is most suitable for removal of genotoxic impurities (GTIs), according with a small set of key intrinsic parameters. A hybrid process was developed, combining these two unit operations, to be applied when the use of OSN or adsorption alone result on non-acceptable API losses. Membrane solute rejection and solvent flux was used as parameter for OSN. In the case of adsorption, two isotherm models, Langmuir and Freundlich, were considered. The effect of the recirculation stream and amount of adsorber used on the hybrid process was investigated. Case studies were experimentally validated, confirming that combining the two unit operations can reduce API loss from 24.76% in OSN to 9.76% in a hybrid process. Economic and environmental analyses were performed.

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“…The removal of GTIs from (active pharmaceutical ingredients) APIs is of particular importance for the pharmaceutical industry and in the context of API safety assessment. Several processes have therefore been assessed to address this problem, including adequate chemical process design, solid phase extraction, preparative column chromatography, recrystallization and phase exchanges, and fractional distillation ( Szekely et al, 2012 ; Kecili et al, 2013 ; Schülé et al, 2014 ).…”

Section: Introductionmentioning

confidence: 99%

Trace Level Quantification of 4-Methyl-1-nitrosopiperazin in Rifampicin Capsules by LC-MS/MS

et al. 2022

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Rifampicin is a first-line anti-tuberculosis drug. However, in August 2020, the presence of 1-methyl-4-nitrosopiperazine (MNP), a nitrosamine impurity, was detected by the United Stated Food and Drug Administration (US FDA) in rifampicin capsules. Consequently, the development of efficient methods for the detection of MNP is an important objective. In this study, the MNP present in rifampicin capsules was detected using LC-MS/MS. A total of 27 batches from nine manufacturers in the Chinese market were tested, with MNP (0.33–2.36 ppm) being detected in all samples at levels exceeding the maximum acceptable intake limit of 0.16 ppm initially set by the FDA. However, after considering the associated benefits and risks, the FDA-approved limit was revised to 5 ppm; hence, all the samples examined herein exhibited MNP levels well below the required limit. Furthermore, the results of forced degradation experiments suggest that MNP is formed by the thermal degradation of rifampicin.

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Selective scavenging of the genotoxic impurity methyl p-toluenesulfonate from pharmaceutical formulations

Cited by 25 publications

References 14 publications

Increasing the sustainability of membrane processes through cascade approach and solvent recovery—pharmaceutical purification case study

Increasing the sustainability of membrane processes through cascade approach and solvent recovery—pharmaceutical purification case study

Comparison and Combination of Organic Solvent Nanofiltration and Adsorption Processes: A Mathematical Approach for Mitigation of Active Pharmaceutical Ingredient Losses during Genotoxin Removal

Trace Level Quantification of 4-Methyl-1-nitrosopiperazin in Rifampicin Capsules by LC-MS/MS

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