Development of a purity control strategy for pemetrexed disodium and validation of associated analytical methodology

Warner, Anne M.; Piraner, Irina; Weimer, Heather; White, Kevin

doi:10.1016/j.jpba.2014.11.032

Cited by 16 publications

(9 citation statements)

References 8 publications

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“…Compounds 6 and 7 were mentioned previously, but without full characterization [12,13]. Detailed HPLC analyses for 6 , 8 , 10 were also described [14].…”

Section: Resultsmentioning

confidence: 99%

Synthesis and Physicochemical Characterization of the Impurities of Pemetrexed Disodium, an Anticancer Drug

et al. 2015

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Abstract:A physicochemical characterization of the process-related impurities associated with the synthesis of pemetrexed disodium was performed. The possibility of pemetrexed impurities forming has been mentioned in literature, but no study on their structure has been published yet. This paper describes the development of the synthesis methods for these compounds and discusses their structure elucidation on the basis of two-dimensional NMR experiments and MS data. The identification of these impurities should be useful for the quality control during the production of the pemetrexed disodium salt.

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“…Compounds 6 and 7 were mentioned previously, but without full characterization [12,13]. Detailed HPLC analyses for 6 , 8 , 10 were also described [14].…”

Section: Resultsmentioning

confidence: 99%

Synthesis and Physicochemical Characterization of the Impurities of Pemetrexed Disodium, an Anticancer Drug

et al. 2015

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“…The forced degradation behavior of pemetrexed under various stress conditions, such as thermal stress degradation, acidic and basic hydrolyses, and peroxide and photo-induced oxidations, was evaluated in the aqueous state. Identification of the impurities in the forced degradation samples was performed according to the relative retention time (RRT) between each impurity and pemetrexed [7,8]. The RRT of the representative degradation products obtained in this study and reported previously is shown in Table 4.…”

Section: Forced Degradation Testmentioning

confidence: 96%

“…The hydrolytic pathway can occur in acidic conditions ( Figure 1c); the des-glutamate and glutamic acid are formed from the acid-catalyzed hydrolysis of the amide linkage of pemetrexed. This hydrolytic degradation product could be proceeded to further degradation by oxidation [7,8]. As NaOH was added, oxidation became the dominant degradation mechanism, with the oxidative dimers being the major degradation products detected under these conditions (Figure 1d).…”

Section: Forced Degradation Testmentioning

confidence: 99%

“…Most of the degradation products formed under thermal stressed conditions are supposed to result from the oxidative mechanism, but a relatively large increase in the opened-ring keto-amide, which can be generated from heating, was observed as compared to the other samples ( Figure 1b) [8]. Predicting the degree to which heat could accelerate oxidation is difficult because of the inverse relationship between the amount of dissolved oxygen and the temperature [29].…”

Section: Forced Degradation Testmentioning

confidence: 99%

“…In addition, the chemical and physical stability of the reconstituted pemetrexed solution has been demonstrated to last only for up to 24 h after the reconstitution of the original vial, when stored at controlled room temperature [4,5]. Owing to the disadvantages of such a lyophilized injection, there has been a requirement for the development of a ready to use (RTU) pemetrexed liquid injection; however, the relatively rapid formation of degradants has been the main challenging factor so far in developing it as a commercially available final drug product [6][7][8][9].…”

Section: Introductionmentioning

confidence: 99%

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Effect of Formulation Factors and Oxygen Levels on the Stability of Aqueous Injectable Solution Containing Pemetrexed

Won

Park

et al. 2020

Pharmaceutics

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The aim of this study was to investigate the effects of various parameters at each control strategy in drug product degradation on the stability of pemetrexed in injectable aqueous solution. A forced degradation study confirmed that oxidation is the main mechanism responsible for the degradation of pemetrexed in aqueous solutions. As control strategies, the antioxidant levels, drug concentration, pH of the control formulation, dissolved oxygen (DO) levels in the control process, and headspace oxygen levels in the control packaging were varied, and their effects on the stability of pemetrexed were evaluated. Sodium sulfite was found to be particularly effective in preventing the color change, and N-acetylcysteine (NAC) had a significant effect in preventing chemical degradation. The sulfite and NAC were found to stabilize pemetrexed in the aqueous solution by acting as sacrificial reductants. A pH below 6 caused significant degradation. The stability of pemetrexed in the solution increased as the concentration of the drug increased from 12.5 to 50 mg/mL. In addition, the DO levels in the solution were controlled by nitrogen purging, and the oxygen levels in headspace were controlled by nitrogen headspace, which also had significant positive effects in improving the stability of the pemetrexed solution; thus, it was confirmed that molecular oxygen is involved in the rate-limiting oxidation step. Based on these results obtained by observing the effects of various control strategies, the optimal formulation of an injectable solution of pemetrexed is suggested as follows: sodium sulfite at 0.06 mg/mL, as an antioxidant for prevention of color change; NAC at 1.63 mg/mL, as an antioxidant for prevention of chemical degradation; pH range 7–8; DO levels below 1 ppm; and headspace oxygen levels below 1%. In conclusion, it can be suggested that this study, which includes well-designed control strategies, can lead to a better understanding of the complex degradation mechanism of pemetrexed; thus, it can lead to the development of an injectable solution formulation of pemetrexed, with improved stability.

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Charged Aerosol Detection

Acworth

Kopaciewicz

2017

Charged Aerosol Detection for Liquid Chromatography and Related Separation Techniques

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Development of a purity control strategy for pemetrexed disodium and validation of associated analytical methodology

Cited by 16 publications

References 8 publications

Synthesis and Physicochemical Characterization of the Impurities of Pemetrexed Disodium, an Anticancer Drug

Synthesis and Physicochemical Characterization of the Impurities of Pemetrexed Disodium, an Anticancer Drug

Effect of Formulation Factors and Oxygen Levels on the Stability of Aqueous Injectable Solution Containing Pemetrexed

Charged Aerosol Detection

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