A Means of Establishing and Justifying Binary Ethanol/Water Mixtures as Simulating Solvents in Extractables Studies

Jenke, Dennis R.; Liu, Norman; Hua, Yousheng; Swanson, Steven; Bogseth, Roy

doi:10.5731/pdajpst.2015.01046

Cited by 16 publications

(5 citation statements)

References 21 publications

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“…In addition, partition coefficients 60% ethanol/40% water/LDPE for the identified blood simulant 60%ethanol/40% water were also calculated by using (Equation ( 3)). Equation (11) was applied for the calculations, where…”

Section: Case Study: Application Of the Approach For Risk Assessmentmentioning

confidence: 99%

“…With respect to MD in contact with the human body, CRM translates, for example, to various tissues, body fluids (e.g., blood) or the skin. To mimic the solubilization strength of a CRM, various concepts are described in literature, for example, related to binary ethanol in water mixtures 11,12 or mono-solvents. [13][14][15] The aim of such a solubilization strength alignment is to mimic the partitioning of a chemical i in the polymer/CRM system by a suitable polymer/solvent model system.…”

Section: Introductionmentioning

confidence: 99%

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Predicting partitioning from low density polyethylene to blood and adipose tissue by linear solvation energy relationship models

et al. 2023

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The variety of polymers utilized in medical devices demands for testing of extractables and leachables according to ISO 10993‐18:2020 in combination with ISO 10993‐1:2018. The extraction of the materials involves the use of organic solvents as well as aqueous buffers to cover a wide range of polarity and pH‐values, respectively. To estimate patient exposure to chemicals leaching from a polymer in direct body contact, simulating solvents are applied to best mimic the solubilization and partitioning behavior of the related tissue or body fluid. Here we apply linear solvation energy relationship (LSER) models to predict blood/water and adipose tissue/water partition coefficients. We suggest this predictive approach to project levels of potential leachables, design extraction experiments, and to identify the optimal composition of simulating extraction solvents. We compare our predictions to LSER predictions for commonly applied surrogates like ethanol/water mixtures, butanol, and octanol as well as olive oil, butanone, 1,4‐dioxane for blood and adipose tissue, respectively. We therefore selected a set of 26 experimentally determined blood/water partition coefficients and 33 adipose tissue/water partition coefficients, where we demonstrate that based on the root mean squared error rmse the LSER approach performs better than surrogates like octanol or butanol and equally well as 60:40 ethanol/water for blood. For adipose tissue/water partitioning, the experimentally determined octanol/water partition coefficient performs best but the rmse is at the same range as our LSER approach based on experimentally determined descriptors. Further, we applied our approach for 248 extractables where we calculated blood/low density polyethylene (LDPE) and adipose tissue/LDPE partition coefficients. By this approach, we successfully identified chemicals of potential interest to a toxicological evaluation based on the total risk score.

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Section: Case Study: Application Of the Approach For Risk Assessmentmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Predicting partitioning from low density polyethylene to blood and adipose tissue by linear solvation energy relationship models

et al. 2023

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“…Solvents most commonly used in extractable species profiling include alcoholwater mixtures and water-based buffers. Rarely is a very lipophilic solvent (e.g., hexane or dichloromethane) a suitable medium with relevance to the extraction propensity of a pharmaceutical product [21].…”

Section: Gc-ms Analysismentioning

confidence: 99%

Determination of Response Factors for Analytes Detected during Migration Studies, Strategy and Internal Standard Selection for Risk Minimization

Kritikos,

Bletsou,

Konstantinou

et al. 2023

Molecules

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Migration studies are one of the few domains of pharmaceutical analysis employing wide-scope screening methodologies. The studies involve the detection of contaminants within pharmaceutical products that arise from the interaction between the formulation and materials. Requiring both qualitative and quantitative data, the studies are conducted using Liquid Chromatography or Gas Chromatography coupled to a mass spectrometer (LC-MS and GC-MS). While mass spectrometry allows wide-scope analyte detection and identification at the very low Analytical Evaluation Threshold (AET) levels used in these studies, MS detectors are far from “universal response” detectors. Regulation brings the application of uncertainty factors into the picture to limit the risk of potential analytes detected escaping report and further evaluation; however, whether the application of a default value can cover any or all relevant applications is still debatable. The current study evaluated the response of species usually detected in migration studies, generating a suitable representative sample, analyzing said species, and creating a strategy and evaluation mechanism for acceptable classification of the detected species. Incorporating novel methodologies, i.e., Design of Experiments (DoE) for Design Space generation, the LC-MS-based methodology is also evaluated for its robustness in changes performed.

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“…A simulated extraction is accomplished by using extraction conditions, such as temperature and duration, that mimic the conditions of clinical use. Water with a proportion of ethanol (volume by volume) was demonstrated to be an appropriate simulating vehicle to extract comparable levels of the target leachables with respect to blood . An exaggerated extraction establishes the highest amount of leachable in a single extraction that most likely will be released by the medical device or material during clinical use .…”

Section: Introductionmentioning

confidence: 99%

“…Water with a proportion of ethanol (volume by volume) was demonstrated to be an appropriate simulating vehicle to extract comparable levels of the target leachables with respect to blood. 6 An exaggerated extraction establishes the highest amount of leachable in a single extraction that most likely will be released by the medical device or material during clinical use. 5 An exaggerated extraction is performed with elevated temperature, a duration that exceeds the duration of clinical use, and at a surface area/volume ratio that exceeded clinical use exposure.…”

Section: Introductionmentioning

confidence: 99%

Chemical Characterization of Leachables in Catheter Device

Wang

Tran

et al. 2022

ACS Omega

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Extractables or leachables of biomaterials or residues of additives used in the manufacturing process that are potentially released from a medical device may have an adverse effect on a patient. Chemical characterization of leachable chemicals and degradation products in a medical device is an important aspect of its overall biocompatibility assessment process, which helps to ensure that the therapeutical benefits exceed the potential biological risks associated with the use of the device or its components or materials. By evaluating the types and amounts of chemicals that may migrate from a device to a patient during clinical use, potential toxicological risks can be assessed. A semipolar solvent, 40% ethanol in water (v/v), an appropriate surrogate for blood and blood related substances, was used as an extraction medium to mimic the body fluid in contact with a medical device. The extraction was conducted at 37 °C for 24 h for limited exposure medical devices per ISO 10993-12:2021. From gas chromatography–mass spectrometry (GC–MS) and liquid chromatography–mass spectrometry (LC–MS) analysis, leachable chemicals of polylactams, linear polyamides, cyclic polytetramethylene ether (PTME), poly(tetramethylene ether) glycol (PTMEG), cyclic and linear poly(tetramethylene ether) glycol adipate (PTMEGA), cyclic and linear poly(tetramethylene ether) glycol adipamide (PTMEGAA) were structurally elucidated. The workflow presented in this study was proven to be a successful approach for rapid extractable and leachable profiling and identification with confidence.

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A Means of Establishing and Justifying Binary Ethanol/Water Mixtures as Simulating Solvents in Extractables Studies

Cited by 16 publications

References 21 publications

Predicting partitioning from low density polyethylene to blood and adipose tissue by linear solvation energy relationship models

Predicting partitioning from low density polyethylene to blood and adipose tissue by linear solvation energy relationship models

Determination of Response Factors for Analytes Detected during Migration Studies, Strategy and Internal Standard Selection for Risk Minimization

Chemical Characterization of Leachables in Catheter Device

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