Identification of the acid‐induced degradation products of omeprazole and 5‐hydroxyomeprazole by high‐resolution mass spectrometry

Roberts, Joanne; McNaughtan, Moyra; Maclachlan, John T.; Hunter, Colin; Pahl, Ole

doi:10.1002/rcm.8120

Cited by 9 publications

(5 citation statements)

References 27 publications

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“…In 2019, ~35% of all vaccines in developing countries had to be discarded due to improper maintenance, leading to multiple countries reporting losses greater than $1,500,000 for compromised vaccines alone 3 . Perhaps more troubling, not only does the breakdown of biologics lead to reduced efficacy and economic losses, but in many cases loss of biologic integrity can result in ‘degradation products’ with detrimental, instead of health-inducing, effects 4 . Because of their inherent instability, the economic loss associated with their breakdown, and the risk of harmful effects being induced by breakdown products, it is essential that we employ reliable, effective, and economical means of stabilization for these life-saving medicines.…”

Section: Introductionmentioning

confidence: 99%

Natural and engineered mediators of desiccation tolerance stabilize Human Blood Clotting Factor VIII in a dry state

Packebush

Sánchez-Martínez

Biswas

et al. 2022

Preprint

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Biologics, pharmaceuticals containing or derived from living organisms, such as vaccines, antibodies, stem cells, blood, and blood products are a cornerstone of modern medicine. However, nearly all biologics have a major deficiency: they are inherently unstable, requiring storage under constant cold conditions. The so-called "cold-chain", while effective, represents a serious economic and logistical hurdle for deploying biologics in remote, underdeveloped, or austere settings where access to cold-chain infrastructure ranging from refrigerators and freezers to stable electricity is limited. To address this issue, we explore the possibility of using anhydrobiosis, the ability of organisms such as tardigrades to enter a reversible state of suspended animation brought on by extreme drying, as a jumping off point in the development of dry storage technology that would allow biologics to be kept in a desiccated state under ambient or even elevated temperatures. Here we examine the ability of different protein and sugar-based mediators of anhydrobiosis derived from tardigrades and other anhydrobiotic organisms to stabilize Human Blood Clotting Factor VIII under repeated dehydration/rehydration cycles, thermal stress, and long-term dry storage conditions. We find that while both protein and sugar-based protectants can stabilize the biologic pharmaceutical Human Blood Clotting Factor FVIII under all these conditions, protein-based mediators offer more accessible avenues for engineering and thus tuning of protective function. Using classic protein engineering approaches, we fine tune the biophysical properties of a protein-based mediator of anhydrobiosis derived from a tardigrade, CAHS D. Modulating the ability of CAHS D to form hydrogels made the protein better or worse at providing protection to Human Blood Clotting Factor VIII under different conditions. This study demonstrates the effectiveness of tardigrade CAHS proteins and other mediators of desiccation tolerance at preserving the function of a biologic without the need for the cold-chain. In addition, our study demonstrates that engineering approaches can tune natural products to serve specific protective functions, such as coping with desiccation cycling versus thermal stress. Ultimately, these findings provide a proof of principle that our reliance on the cold-chain to stabilize life-saving pharmaceuticals can be broken using natural and engineered mediators of desiccation tolerance.

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Section: Introductionmentioning

confidence: 99%

Natural and engineered mediators of desiccation tolerance stabilize Human Blood Clotting Factor VIII in a dry state

Packebush

Sánchez-Martínez

Biswas

et al. 2022

Preprint

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“…As seen in Figure 1, acid and oxidation cause significant degradation, however the degradants were well resolved from the omeprazole peak. There have been studies on the products from acid degradation of omeprazole 13,14 . One of the proposed degradation structures show fragmentation of the parent molecule where the S‐C bond linking the two ring structures is cleaved to give two smaller molecules 14 .…”

Section: Discussionmentioning

confidence: 99%

Stability of omeprazole in a commercial calcium carbonate based oral suspension at 2, 5 and 10 mg/mL stored under refrigeration (4°C) for 70 days

Low

Singh

Venkataya

et al. 2022

Pharmacy Practice and Res

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Background Omeprazole is a commonly prescribed proton pump inhibitor that acts to reduce gastric acid secretion. Liquid suspensions are preferred for paediatrics or patients with difficulty swallowing, however, are unstable. Aim This study reports on the stability of USP‐grade omeprazole, raw powder at 2, 5 and 10 mg/mL dosages suspended in Oral Mix Dry Alka SF (OMSF) stored at 4°C for 70 days. Method The omeprazole concentration in the suspensions were determined at the time of preparation and at 7, 14, 28, 42, 56 and 70 days by high performance liquid chromatography with photodiode array detection (HPLC‐PDA). The pH, homogeneity, colour, odour, and microbial levels were also determined. Results All the preparations are stable at 4°C for 70 days, with omeprazole concentration remaining within ±10% of the initial concentration. The pH showed a gradual decline from 9.0 to 7.7 over the study which is an acceptable change. The preparations passed microbial testing up to 70 days. Conclusion The 70 days stability achieved in OMSF far exceeds the 28 day beyond‐use‐date recommended by the Australian Pharmaceutical Formulary. The OMSF base provides compounding pharmacists with a convenient method to prepare omeprazole suspensions over a wide range of concentrations with extended dating, providing added convenience for the consumer and pharmacists.

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“…PPIs are sensitive to acidic environments, and inorganic acids are usually used to artificially accelerate the degradation of PPIs to allow for identification of the degradation products, some of which may have specific spectral properties. [21][22][23] Although a HTS method for screening omeprazole sulfide oxidase mutant libraries has been developed based on this principle, [24] the presence of the strong electron-withdrawing group trifluoroethoxy in lansoprazole may lead to fluorescence quenching, leaving no detectable fluorescent signal for acid-activated lansoprazole. Therefore, this HTS method is not suitable for the screening of lansoprazole sulfide and/or other prazole sulfides oxidase mutant libraries.…”

Section: Introductionmentioning

confidence: 99%

“…Unfortunately, this method failed in screening of variants for other prazole sulfides ( 1 a , 3 a – 5 a ) because the solubilities of the substrates were too low to form a uniform substrate layer on the agar plate. PPIs are sensitive to acidic environments, and inorganic acids are usually used to artificially accelerate the degradation of PPIs to allow for identification of the degradation products, some of which may have specific spectral properties [21–23] . Although a HTS method for screening omeprazole sulfide oxidase mutant libraries has been developed based on this principle, [24] the presence of the strong electron‐withdrawing group trifluoroethoxy in lansoprazole may lead to fluorescence quenching, leaving no detectable fluorescent signal for acid‐activated lansoprazole.…”

Section: Introductionmentioning

confidence: 99%

Colorimetric High‐Throughput Screening Method for Directed Evolution of Prazole Sulfide Monooxygenase

et al. 2022

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Baeyer‐Villiger monooxygenases (BVMOs) are important biocatalysts for the enzymatic synthesis of chiral sulfoxides, including chiral sulfoxide‐type proton pump inhibitors for the treatment of gastrointestinal diseases. However, native BVMOs are not yet suitable for practical application due to their unsatisfactory activity and thermostability. Although protein engineering approaches can help address these issues, few feasible high‐throughput methods are available for the engineering of such enzymes. Herein, a colorimetric detection method to distinguish sulfoxides from sulfides and sulfones was developed for prazole sulfide monooxygenases. Directed evolution enabled by this method has identified a prazole sulfide monooxygenase CbBVMO variant with improved activity and thermostability that catalyzes the asymmetric oxidation of lansoprazole sulfide. A 71.3 % increase in conversion and 6 °C enhancement in the melting point were achieved compared with the wild‐type enzyme. This new method is feasible for high‐throughput screening of prazole sulfide monooxygenase variants with improved activity, thermostability, and/or substrate specificity.

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Identification of the acid‐induced degradation products of omeprazole and 5‐hydroxyomeprazole by high‐resolution mass spectrometry

Cited by 9 publications

References 27 publications

Natural and engineered mediators of desiccation tolerance stabilize Human Blood Clotting Factor VIII in a dry state

Natural and engineered mediators of desiccation tolerance stabilize Human Blood Clotting Factor VIII in a dry state

Stability of omeprazole in a commercial calcium carbonate based oral suspension at 2, 5 and 10 mg/mL stored under refrigeration (4°C) for 70 days

Colorimetric High‐Throughput Screening Method for Directed Evolution of Prazole Sulfide Monooxygenase

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