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•Solubility of the benzoate, hydrochloride, malonate, and nicotinate new salts of bedaquiline delineated.•Predictability of the experimental solubilities of the new bedaquiline ...salts.•Relative contributions of the crystallinity and hydrophobicity of the salts to their solubilities.•CCDC reference numbers for the benzoate, hydrochloride, malonate, and nicotinate salts of bedaquiline.
Determining the solubility of a compound is important for predicting its oral bioavailability, the medium to be used for dissolution, and solvents for cleaning during manufacturing. The solubilities of the newly synthesized benzoate, hydrochloride, nicotinate, and malonate salts of bedaquiline were elucidated, and the plausible reasons for the differences observed in their experimental aqueous solubilities were highlighted.
The shake flask method was used to determine the experimental solubilities of the bedaquiline free base and all the salts in water, 0.01 N HCl, and pH 6.8 buffer. The molar and mole fraction solubility estimates of the salts were determined using equations for ideal and non-ideal situations. Furthermore, the relative contribution of the lattice and activity coefficient to the overall aqueous solubility of the salts were predicted graphically.
The new salts ranked hydrochloride 0.6437 mg/mL > malonate 0.0268 mg/ml > nicotinate 0.0024 mg/mL > benzoate 0.0004 mg/mL, showed improved aqueous solubility over the free base. The general solubility equation GSE, fairly predicted the solubilities for the benzoate and malonate salts, but the ideal solubility equations provided poor estimates of their experimental values. Based on the ideal solubility estimates, the crystal lattice contributions of all salts were malonate > nicotinate > HCl > benzoate. However, using the activity coefficient values, the order of hydrophobicity of the bedaquiline salts was: benzoate > nicotinate > malonate > HCl.
The salts forms of bedaquiline offered additional solubility as a function of their crystallinity and hydrophobicity.
Levothyroxine tablets, although highly prescribed in the United States, have been one of the most frequently recalled products. Because of the importance of the medication, several efforts have been ...put in place by the United States Food and Drug Administration (US FDA) to control the quality of levothyroxine tablets available to patients using the drug. The choice of excipients used in the formulation has been shown to impact the hygroscopicity and microenvironment, and ultimately the stability of the levothyroxine tablets formulations. Based on information generated from the US FDA Enforcement Report database, one of the main reasons for recalls is the low potency of different batches of the product. The yearly product recall trends for levothyroxine formulations were determined using the FDA Enforcement Report database. Three brands of levothyroxine tablets were selected with excipient lists similar to those products that have been historically recalled. The samples were placed at ambient (~23 °C), accelerated stability (40 °C/75% RH), and stress (50 °C/75% RH) conditions for up to 6 months. Sample potencies were determined at 0, 1.5, 3, and 6 months using the methods for assay and impurities in the United States Pharmacopeia (USP) monograph for levothyroxine tablets. Additional sample monitoring was conducted by overlaying the initial powder X-ray diffractograms (PXRD) of the samples from 0 months with the patterns generated thereafter. There has been a decline in the number of levothyroxine tablets recalled over the years. The highest numbers of recalls were recorded in the years 2013 33 and 2020 23; no recalls occurred in the years 2019 and 2022. All of the brands evaluated met the USP 95.0-105.0% assay requirements at 1.5 months under accelerated conditions; only one of the brands complied at 3 months. Under ambient conditions, two brands were stable at 6 months, with borderline assay results. For stability, levothyroxine was found in microgram quantities in the formulations and PXRD could not detect changes at these low levels. However, we found some distinguishing data for samples under stress conditions.
Science educators report that students struggle with understanding, using, and evaluating the evidence underpinning scientific knowledge. However, there are not many studies focused on helping ...instructors address those difficulties. Here, we report on a laboratory instructor's scaffolding of students' evidentiary reasoning with and about evidence for evolutionary trees with guidance from the Conceptual Analysis of Disciplinary Evidence (CADE) framework, which links biological knowledge with epistemic considerations. To consider both domain-general and discipline-specific aspects of evidence, CADE was implemented to inform scaffolds in two ways: (1) generic evidence scaffolds (GES) reminded students of general epistemic considerations; (2) disciplinary evidence scaffolds (DES) explicitly reminded students of the disciplinary knowledge of relevance for considering biological evidence. An instructor's lab discussions were compared before and after they had a workshop with CADE. CADE helped the lab instructor facilitate students' evidentiary reasoning about evolutionary trees. In comparison to baseline, both GES and DES discussions covered more aspects and relationships among types of evidence for evolutionary tree-thinking and the instructor prompted more kinds of general epistemic considerations and biological knowledge. DES discussions emphasized the importance of disciplinary knowledge for research design. The CADE framework guided planning and implementation of intentional scaffolding aimed at guiding evidentiary reasoning.
The online version contains supplementary material available at 10.1007/s11191-023-00435-6.
High numbers of drug recalls persist despite the tremendous time and effort invested by pharmaceutical organizations and regulatory bodies such as the Food and Drug Administration (FDA) to ensure the ...quality of safe and effective medicines for the patient. It is imperative to better understand the underlying risk factors of drug formulation-based recalls to best protect the patient from poor quality drugs. Increased knowledge of underlying factors of formulation risk can also help inform the future design and development of drugs. In this study, we used a text mining technique with Python to parse the data and examine drug recalls from the aspect of administration route, dosage form, release mechanism, market type, pharmacologic class, and excipients. Observational analysis of the recalls revealed both high- and low-risk factors for the formulation-based recalls. Higher risk, or an increased probability of a formulation-based recall, was associated with factors such as extended release mechanism, capsule dosage form, oral route of administration, and an increased number of excipients, while lower risk of formulation-based recalls was associated with other factors including the new drug application market type, immediate release mechanism, and solution dosage form. In addition, the factors did not work independently, and we observed interactions among variables. For example, the release mechanism modified the effect of market type, administration route, and dosage form. This study will help inform the future design of quality drug products by pharmaceutical organizations and assist risk-based oversight by regulatory organizations, such as FDA, to ensure patient safety.
Pharmaceutical companies use the quality by design (QbD) approach to build high-quality drug products. A thorough understanding of risk factors is required to successfully employ QbD. In order to ...better understand risk factors that potentially impact drug product quality and inform future QbD approaches, we hypothesized root causes of drug product recalls based on publicly available data and a retroactive analysis of drug products recalled by the United States Food and Drug Administration (USFDA) from 2012 to 2018. We focused on two categories of drug products that pose unique regulatory challenges and an increased risk of shortage that could hinder the adequate supply of quality medicine to the patient. Knowing the significant risk factors from previous drug product recalls can help inform QbD and avoid future recalls. Quality recall reasons were studied individually to find risk factors associated with each recall category. Logistical regression statistical tests were done in R using a significance level of 0.05 to find correlations between a recalled product and its manufacturing information such as excipients and manufacturing steps. The results showed significant positive and negative correlations, such as products containing magnesium stearate are more likely to be recalled for impurities and degradation. This information could be used in the future to inform the design and manufacturing of drug products, ensuring consumers receive high-quality products with a low risk of recall.
People living in Africa face a heavy and wide-ranging burden of disease that takes an incalculable toll on social and economic development as well as shortening life expectancy (life expectancy in ...Tanzania is about 60 vs. about 80 in the United States and Europe. Further, the pharmaceutical market in developing countries is immature and may not support quality medicines. In many cases, a tender system is used, and medicines are bought by the government at the lowest price. In addition to access to medicines, a number of pharmaceutical sciences problems are apparent. The availability of infrastructure and especially standard instruments such as HPLC and X-ray diffraction is minimal. Additionally, there is an important need to increase access to advanced education for men and women in Africa, especially access to state-of-the-art scientific education. Utilizing the mandate of Nelson Mandela, Purdue's conceptual approach has been to utilize education to combat these problems.
The number and severity of nonconformities generated during an audit of a medicine testing laboratory indicates its level of quality compliance. Quality standards are established and maintained to ...ensure the reliability of laboratory test reports. The National Medicines Regulatory Authority (NMRA) Quality Control laboratories assess the quality of medicines used by the populace as part of their regulatory function. Although countries desire to have reliable medicine testing facilities, accrediting a national laboratory to international standards poses financial and technical challenges for many low-income countries. Sharing the benefits of laboratory accreditation could help more countries within sub-Saharan Africa overcome existing challenges to achieve accreditation and robust quality systems. This study investigated the impact of ISO/IEC 17025 accreditation on the performance of an NMRA Quality Control laboratory to provide evidence of improved quality compliance within a low-resource setting.
Pre- and post- accreditation audits of nonconformities for management and technical requirements of the ISO/IEC17025:2005 standards were evaluated from a Quality Control laboratory in the National Agency for Food and Drug Administration and Control (NAFDAC), located in Nigeria, West Africa. The following research questions were addressed: "does accreditation impact the adherence to quality standards?" and "does accreditation decrease the severity of nonconformities in Quality Control laboratory audits?"
Statistical analysis of the pre- to post- accreditation audits from the years 2013 through 2017 revealed a significant decrease in the total number of nonconformities (χ
= 74, p-value = 9.99e-05, r = 0.67). Further examination of audits from the years 2013 through 2018 audits also revealed a reduction in the number of nonconformities (χ
= 53, p-value = 9.99e-05, r = 0.62). A reduction in the number of major observations and a decrease in the severity of nonconformities was also observed.
A higher level of quality compliance was exhibited for the laboratory during the post-accreditation years. Overall, ISO/IEC 17025 accreditation of the NMRA Quality Control laboratory resulted in improved reliability of test reports and enhancement of the laboratory quality system.
Celotno besedilo
Dostopno za:
CEKLJ, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The development and implementation of varied assessment practices is a major focus in higher education. Assessment benefits both students and teachers; it informs teachers about students' learning ...and misconceptions, thereby helping teachers improve teaching practices and students assess their current state of understanding. In general, the field lacks a rubric or an assessment model for assessing students' understanding of science content and their representations, which was the impetus for this study. The rubric developed in this study will help instructors assess students' representational competence in a course-based research experience (CURE) and could also be adapted to assess students' understanding of other scientific concepts and misconceptions. The rubric will enable teachers to collect evidence of students' understanding so they can make their science teaching more authentic, support students' learning of the core scientific concepts, and provide an opportunity for teachers to modify their instruction accordingly across science disciplines, benefitting science teaching and learning overall.
Crystal structures of salts of bedaquiline Okezue, Mercy; Smith, Daniel; Zeller, Matthias ...
Acta crystallographica. Section C, Structural chemistry,
November 2020, Letnik:
76, Številka:
11
Journal Article
Recenzirano
Odprti dostop
Bedaquiline systematic name: 1‐(6‐bromo‐2‐methoxyquinolin‐3‐yl)‐4‐(dimethylamino)‐2‐(naphthalen‐1‐yl)‐1‐phenylbutan‐2‐ol, C32H31BrN2O2 is one of two important new drugs for the treatment of ...drug‐resistant tuberculosis (TB). It is marketed in the US as its fumarate salt {systematic name: 4‐(6‐bromo‐2‐methoxyquinolin‐3‐yl)‐3‐hydroxy‐3‐(naphthalen‐1‐yl)‐4‐phenylbutyldimethylazanium 3‐carboxyprop‐2‐enoate, C32H32BrN2O2+·C4H3O4−}, and about a dozen other salts of bedaquiline have been described in patent literature, but none have so far been structurally described. In a first communication, we present the crystal structure of bedaquilinium fumarate and of two new benzoate salts, as well as that of a degradation product of the reaction of bedaquilinium fumarate with sodium ethoxide, 3‐benzyl‐6‐bromo‐2‐methoxyquinoline, C17H14BrNO. The fumarate and benzoate salts both feature cations monoprotonated at the dimethylamino group. The much less basic quinoline N atom remains unprotonated. Both salts feature a 1:1 cation‐to‐anion ratio, with the fumarate being present as monoanionic hydrofumarate. The conformations of the cations are compared to that of free base bedaquiline and with each other. The flexible backbone of the bedaquiline structure leads to a landscape of conformations with little commonalities between the bedaquiline entities in the various structures. The conformations are distinctively different for the two independent molecules of the free base, the two independent molecules of the hydrofumarate salt, and the one unique cation of the benzoate salt. Packing of the salts is dominated by hydrogen bonding. Hydrogen‐bonding motifs, as well as the larger hydrogen‐bonded entities within the salts, are quite similar for the salts, despite the vastly differing conformations of the cations, and both the hydrofumarate and the benzoate structure feature chains of hydrogen‐bonded anions that are surrounded by and hydrogen bonded to the larger bedaquilinium cations, leading to infinite broad ribbons of anions, cations, and (for the benzoate salt) water molecules. The benzoate salt was isolated in two forms: as a 1.17‐hydrate (C32H32BrN2O2+·C7H5O2−·1.166H2O), obtained from acetone or propanol solution, with one fully occupied water molecule tightly integrated into the hydrogen‐bonding network of anions and cations, and one partially occupied water molecule refined occupancy 16.6 (7)%, only loosely hydrogen bonded to the quinoline N atom. The second form is an acetonitrile solvate (C32H32BrN2O2+·C7H5O2−·0.742CH3CN·H2O), in which the partially occupied water molecule is replaced by a 74.2 (7)%‐occupied acetonitrile molecule. The partial occupancy induces disorder for the benzoate phenyl ring. The acetonitrile solvate is unstable in atmosphere and converts into a form not distinguishable by powder XRD from the 1.17‐hydrate.
The single‐crystal structures of three salts of bedaquiline, a drug used for the treatment of drug‐resistant tuberculosis (TB), are described.
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