Evaluation of Hydroperoxides in Common Pharmaceutical Excipients

Wasylaschuk, Walter; Harmon, Paul A.; Wagner, Gabriella; Harman, Amy B.; Templeton, Allen C.; Xu, Hui; Reed, Robert A.

doi:10.1002/jps.20726

Cited by 172 publications

(101 citation statements)

References 27 publications

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“…There are two reasons for this: i) unavailability of the ROOH standards because of their thermally unstable nature (Bach et al, 1996), and ii) the lack of appropriate analytical techniques. So far, the analysis of ROOH in the condensed phase has mainly been done by means of chemical assays, such as the iodometric (Docherty et al, 2005;Banerjee and Budke, 1964), triphenylphosphine (Nakamura and Maeda, 1996), ferrous oxidation-10 xylenol orange (Wasylaschuk et al, 2007), and horseradish peroxidase approaches (Walker et al, 2006;Hong et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Identification of Organic Hydroperoxides and Peroxy Acids Using Atmospheric Pressure Chemical Ionization – Tandem Mass Spectrometry (APCI-MS/MS): Application to Secondary Organic Aerosol

Zhou¹,

Rivera-Rios²,

Keutsch³

et al. 2018

Preprint

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Abstract.Molecules with hydroperoxide functional groups are of extreme importance to both the atmospheric and biological 10 chemistry fields. In this work, an analytical method is presented for the identification of organic hydroperoxides and peroxy and peracetic acid), as well as the ROOH formed from the reactions of H 2 O 2 with aldehydes (i.e. acetaldehyde, hexanal, glyoxal and methylglyoxal). This new ROOH detection method was applied to methanol extracts of secondary organic aerosol (SOA) material generated from ozonolysis of α-pinene, indicating a number of ROOH molecules in the SOA material. While the full scan mass spectrum of SOA demonstrates the presence of monomers (m/z=80-250), dimers (m/z=250-450) and trimers (m/z=450-600), the neutral loss scan shows that the ROOH products all have masses less than 20 300 Da, indicating that ROOH molecules may not contribute significantly to the SOA oligomeric content. We anticipate this method could also be applied to biological systems with considerable value.

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Section: Introductionmentioning

confidence: 99%

Identification of Organic Hydroperoxides and Peroxy Acids Using Atmospheric Pressure Chemical Ionization – Tandem Mass Spectrometry (APCI-MS/MS): Application to Secondary Organic Aerosol

Zhou¹,

Rivera-Rios²,

Keutsch³

et al. 2018

Preprint

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“…The alkyl polyoxyethylene side chains of polysorbates undergo autooxidation resulting in formation of hydroperoxides, side-chain cleavage, and eventually formation of short-chain acids such as formic acid; all of which can affect the stability of the product (16). Oxidative degradation leads to loss of drug potency over time and may challenge formulation development and reduce shelf life (17). Oxidation is one of the major chemical degradation pathways for protein pharmaceuticals.…”

Section: Introductionmentioning

confidence: 99%

Effect of Polysorbate 80 Concentration on Thermal and Photostability of a Monoclonal Antibody

et al. 2012

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Abstract. Polysorbate 80 is widely used in protein formulations to protect protein against agitationinduced aggregation. In this study, we address concerns about residual peroxide present in Polysorbate 80 on protein stability. Residual peroxide may oxidize active pharmaceutical ingredients leading to reduced stability and may ultimately lead to lower potency and efficacy. The effect of Polysorbate 80 concentration on thermal and photostability of monoclonal antibody of the IgG1 subclass (MAb1) was evaluated at Polysorbate 80 concentrations ranging from 0.00% to 1.00% (w/v). MAb1 samples at 5 mg/ mL with various Polysorbate 80 concentrations were subjected to accelerated thermal stress by incubation at 25°C, 40°C, and 50°C for a period of 4 weeks and light stress per ICH guideline Q1B, option 1. Our results show that Polysorbate 80 concentration of 1.00% (w/v) adversely affected thermal and photostability of MAb1. This study demonstrates the importance of carefully choosing Polysorbate 80 concentration in protein formulations to prevent destabilizing effect of Polysorbate 80 on thermal and photostability.

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“…Unlike the previous report, 7) wherein substantial amount of N-oxide derivative It has been reported that Tween 80 contains appreciable amounts of hydroperoxide in the range of 1100 to 3900 nmol/g depending the source of Tween 80 while magnesium stearate and lactose usually contain Ͻ100 nmol/g of peroxides by a more sensitive ferrous oxidation-xylenol orange (FeOX2) method reported recently. 8) The degradation of raloxifene HCl is an example of two electron nucleophilic reaction that can occur between the peroxide and the drug substance. Low levels of peroxide content, as reported for magnesium stearate and lactose, may also be sufficient to participate is peroxy radical chain propagation, which could have been initiated at higher temperatures as used in the study.…”

Section: Resultsmentioning

confidence: 99%

Role of Excipients on N-Oxide Raloxifene Generation from Raloxifene-Excipients Binary Mixtures

Yarkala

Sivakumar

Rao³

et al. 2009

CHEMICAL & PHARMACEUTICAL BULLETIN

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Raloxifene HCl (RHCl) is known to be susceptible to oxidation and forms the corresponding N-oxide derivative as the primary degradation product. The purpose of this study was to evaluate the role of excipients on the generation of the N-oxide derivative from the corresponding RHCl-excipient binary mixtures. Binary mixtures of RHCl with crospovidone, povidone, magnesium stearate, Tween 80 and anhydrous lactose in drug: excipients ratio of 1 : 1 (crospovidone and povidone); 10 : 1 (Tween 80 and magnesium stearate) and 1 : 5 (anhydrous lactose) were prepared by both dry blending (trituration) and wet blending (to improve contact between drug and excipients). The prepared binary mixtures were then stored at 25, 40, 75 and 125°C and generation of the N-oxide derivative was monitored over six months using a validated HPLC method. Pure drug and excipients stored similarly acted as controls. Further, all the individual excipients (used as control) were monitored for peroxide impurity generation using an in-house colorimetric method. The results showed that N-oxide generation was observed from all binary mixtures and the amount of N-oxide derivative formed were always higher from the mixtures prepared by wet blending and the amount of N-oxide derivative formed was dependent on storage temperature. This study thus shows that the presence of peroxide in the excipient and its role in oxidative degradation of drug substance calls for monitoring of the peroxide impurity present in the excipients used for formulating of drug sensitive to oxidation as used herein.Key words raloxifene HCl; excipient; N-oxide-raloxifene; povidone; crospovidone Incompatibility between drugs and excipients can alter the stability and bioavailability of drugs, thus affecting its safety and efficacy. Study of drug-excipient compatibility is an important and integral process in the development of a stable dosage form. Many reports are available in the literature that has deliberated the importance of this issue and various methods of compatability testing have been discussed. [1][2][3][4][5] Raloxifene HCl (RHCl), is a selective estrogen receptor modulator shown to be effective in the prevention of osteoporosis, 6) which could be a potential substitute for long-term female hormone replacement therapy. Raloxifene is available as 60 mg tablet under the brand of Evista (Eli-Lilly) and contains 12.5% w/w RHCl, 5% povidone, 6% crospovidone and a combination of other excipients including anhydrous lactose, lactose monohydrate, Tween 80 and magnesium stearate. In an earlier published report, 7) it was disclosed that raloxifene forms a N-oxide derivative as a degradation product when the tablets were stored in sealed bottles and open containers at both 30°C/60% relative humidity (RH) and at 40°C/75% RH. Stability studies on binary mixtures of RHCl with primary excipients used in the tablet (Evista) were reported, 7) wherein the binary mixtures were stored at 125°C for a period of 31 d. The results showed that maximum amount of N-oxide derivative generation we...

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Evaluation of Hydroperoxides in Common Pharmaceutical Excipients

Cited by 172 publications

References 27 publications

Identification of Organic Hydroperoxides and Peroxy Acids Using Atmospheric Pressure Chemical Ionization – Tandem Mass Spectrometry (APCI-MS/MS): Application to Secondary Organic Aerosol

Identification of Organic Hydroperoxides and Peroxy Acids Using Atmospheric Pressure Chemical Ionization – Tandem Mass Spectrometry (APCI-MS/MS): Application to Secondary Organic Aerosol

Effect of Polysorbate 80 Concentration on Thermal and Photostability of a Monoclonal Antibody

Role of Excipients on N-Oxide Raloxifene Generation from Raloxifene-Excipients Binary Mixtures

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