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Pharmaceutical salts are ubiquitously present in the market given their benefits in optimizing the critical properties of an active pharmaceutical ingredient (API). Achieving these benefits requires careful selection and understanding of the salt form of choice. Stability is especially critical here, as salts are susceptible to disproportionation. Several studies have shown the impact of moisture on disproportionation, with more focus on external humidity (moisture coming from outside the system). This work, on the other hand, is systematically designed to study the impact of moisture generated in situ (moisture produced within the system). To that end, an in-house developed compound

One can confidently assign the absolute configuration of a chiral molecule using crystalline powders, via microcrystal electron diffraction (MicroED) analysis.

The absolute configuration of a clinically important drug candidate, SMTP-7, with only micron-sized powders available, is directly obtained via microcrystal electron diffraction (MicroED) analysis.

This paper introduces an interactive framework to guide decision-makers in a multi-criteria supplier selection process. State-of-the-art multi-criteria methods for supplier selection elicit the decision-maker’s preferences among the criteria by processing pre-collected data from different stakeholders. We propose a different approach where the preferences are elicited through an active learning loop. At each step, the framework optimally solves a combinatorial problem multiple times with different weights assigned to the objectives. Afterwards, a pair of solutions among those computed is selected using a particular query selection strategy, and the decision-maker expresses a preference between them. These two steps are repeated until a specific stopping criterion is satisfied. We also introduce two novel fast query selection strategies, and we compare them with a myopically optimal query selection strategy. Computational experiments on a large set of randomly generated instances are used to examine the performance of our query selection strategies, showing a better computation time and similar performance in terms of the number of queries taken to achieve convergence. Our experimental results also show the usability of the framework for real-world problems with respect to the execution time and the number of loops needed to achieve convergence.

Cuprizone is an amide compound that has been wildly used in various animal studies, such as in the investigation of remyelination in mouse model. It is important to control the amount of cuprizone dosed in animals to be consistent as different amounts may lead to different clinical observations. Cuprizone is usually administrated as a minor component (i.e., 0.3%) of a mixture with powdered or pelleted rodent chow. Its low content, combined with the complex nature of chow, represents a significant challenge for the quantification of cuprizone in the mixture. To the best of our knowledge, no method has been reported in the literature so far. In this study, a simple, selective, and sensitive hydrophilic interaction liquid chromatographic method was developed for the quantification of cuprizone in cuprizone pre-clinical formulations. The analytical method comprises a fast ultrasound assisted extraction with acetonitrile/water as a solvent followed by gradient separation using a Waters Xbridge HILIC column with 0.1% TFA in water and acetonitrile as mobile phases and UV detection at 220 nm. The specificity, linearity, accuracy, repeatability, and limit of quantitation (LOQ) of the method were established. The method was determined to be linear in the range of 10–200 μg/mL. Accuracy was assessed by spiking a chow placebo with various amounts of a cuprizone reference standard to achieve target concentration levels and the recoveries were within the acceptance criterion of 90–110% of the target concentrations. Repeatability was demonstrated at the nominal concentration of 100 µg/mL and LOQ level of 2.5 μg/mL. This method has been demonstrated to be suitable for its intended use and has been successfully applied to the quantification of low levels of cuprizone in chow formulations. It was found that the cuprizone content in chow could varied significantly between batches and the potential causes of the variability were investigated.

As a drug advances through the late stages of clinical development, formulation changes are common to meet clinical, manufacturing, and/or business needs. Since some formulation changes may alter in vivo drug absorption, it is critical to understand the impact of these changes on in vivo PK performances to support the transition between pre- and post-change formulations and ensure the drug's efficacy and safety. While clinical RBA/BE studies are time-consuming and expensive, other formulation bridging approaches that bring opportunities to expedite drug development by waiving clinical formulation bridging studies are summarized. This review discussed the current formulation bridging options based on in vitro dissolution, physiologically-based biopharmaceutics modeling (PBBM), in vitro - in vivo correlation (IVIVC), and risk-based assessment during the early and late stages of clinical development. By increasing the understanding of the opportunities and challenges associated with different formulation bridging approaches, this review helps with the selection/design of formulation bridging studies in a phase appropriate manner for formulation change during product development.

In this paper, we investigate the stability problem of the numeraire-based utility maximization problem in markets with transaction costs, where the stock price is not necessarily a semimartingale. Precisely, the static stability of primal and dual value functions as well as the convergence of primal and dual optimizers are presented when perturbations occur in the utility function and in the physical probability. Furthermore, this study focuses on the optimal dual process (ODP), which induces the dual optimizer and attains optimality for a dynamical dual problem. Properties of ODPs are discussed which are complement of the duality theory for this utility maximization problem. When the parameters of the market and the investor are slightly perturbed, both the dual optimizer and the associated optimal dual process are stable. Thus, a shadow price process is constructed based on the sequence of ODPs corresponding to problems with small misspecified parameters.

Chemical process development efforts leading to multikilogram production of BIIB068 hemiadipate are discussed. Process optimization resulted in (1) removal of transition metal from the process, (2)...

To utilize a particle engineering strategy to improve the manufacturability of a cohesive and poorly compactable API at high drug loading for direct compression of mini-tablets.A high-shear mixer was used for wet milling during the API manufacturing process to obtain target particle size distributions. The targeted particles were characterized and formulated into blends by mixing with excipients. The formulated blends were compressed directly into mini-tablets using a compaction simulator. The tablet hardness, weight variation, and friability of the mini-tablets were characterized and compared with mini-tablets prepared with hammer milled APIs.Compared to the hammer milled APIs, the wet milled APIs, had smoother surface, narrower particle size distributions and demonstrated a better flow properties. Moreover, the mini-tablets produced with the wet milled APIs exhibited better weight uniformity, robust tablet mechanical strength and ultimately better friability. In addition, unlike the hammer milled process, the wet milling process is controllable and easy to scale up.This study successfully implemented API particle engineering through a high shear wet milling process to produce particles suitable for robust drug product manufacturing.

Niya Hu,1,* Dongjiang Wang,2,* Yiqing Lin,1 Jun Zou,3 Yanling Liu,1 Zhigang Xiong,3 Jian Guo,2 Lingbing Zeng,1 Junming Li1 1Department of Clinical Laboratory, The First Affiliated Hospital of Nanchang University, Nanchang, People’s Republic of China; 2Department of Laboratory Medicine, Shanghai East Hospital, Tongji University, School of Medicine, Shanghai, People’s Republic of China; 3Department of Orthopedics, Jiangxi Provincial Children’s Hospital, Nanchang, People’s Republic of China*These authors contributed equally to this workCorrespondence: Lingbing Zeng; Junming Li Email lingbing_zeng@163.com; lisir361@163.comIntroduction: Tigecycline is one of the last resorts for carbapenem-resistant K. pneumoniae (CRKP) infections. Indeed, tigecycline-non-susceptible K. pneumoniae (TNSKP) strains are increasingly treated with the use of tigecycline. In this study, we attempted to better understand their epidemiological trends and characteristics. K. pneumoniae were collected from 2017 to 2020 at the First Affiliated Hospital of Nanchang University.Methods: Thirty-four TNSKP strains were selected during the study period, all of which were analyzed using antimicrobial susceptibility testing, multilocus sequence typing (MLST), and pulsed-field gel electrophoresis (PFGE). PCR and DNA sequencing were performed for the detection of β-lactamase genes and carbapenemase genes, and the mutation analysis of tet(A), tet(X), tet(L), tet(M), rpsJ, ramR, and oqxR, which are related to tigecycline resistance. Virulence gene and capsular genotype testing were conducted to identify whether the TNSKP strains were hypervirulent Klebsiella pneumoniae.Results: An epidemiology analysis showed that Klebsiella pneumoniae carbapenemase-2 (KPC-2) was the predominant carbapenemase in tigecycline non-susceptible carbapenem-resistant K. pneumoniae (TNSCRKP) (96.7%), and the dominant clone type was ST11-K14K64 (82.4%). Among them, 55.9% (19/34) of strains were from each department of ICU, particularly EICU and neurosurgery ICU. In order to further understand the molecular mechanisms of the TNSKP, a polymerase chain reaction of the resistant determinants was carried out. The results detected many tigecycline-resistant genes, such as tet(A) (97.1%), tet(X) (17.6%), rpsJ (97.1%), and ramR (8.8%).Conclusion: As the results of this study reveal, we should take effective measures to control the increase in TNSKP.Keywords: carbapenem-resistant, tigecycline-non-susceptible, Klebsiella pneumoniae

Sanguinarine has strong inhibitory effects against the cyanobacterium Microcystis aeruginosa. However, previous studies were mainly limited to laboratory tests. The efficacy of sanguinarine for mitigation of cyanobacterial blooms under field conditions, and its effects on aquatic microbial community structure remain unknown. To elucidate these issues, we carried out in situ cyanobacterial bloom mitigation tests. Our results showed that sanguinarine decreased population densities of the harmful cyanobacteria Microcystis and Anabaena. The inhibitory effects of sanguinarine on these cyanobacteria lasted 17 days, after which the harmful cyanobacteria recovered and again became the dominant species. Concentrations of microcystins in the sanguinarine treatments were lower than those of the untreated control except during the early stage of the field test. The results of community DNA pyrosequencing showed that sanguinarine decreased the relative abundance of the prokaryotic microorganisms Cyanobacteria, Actinobacteria, Planctomycetes and eukaryotic microorganisms of Cryptophyta, but increased the abundance of the prokaryotic phylum Proteobacteria and eukaryotic microorganisms within Ciliophora and Choanozoa. The shifting of prokaryotic microbial community in water column was directly related to the toxicity of sanguinarine, whereas eukaryotic microbial community structure was influenced by factors other than direct toxicity. Harmful cyanobacteria mitigation efficacy and microbial ecological effects of sanguinarine presented in this study will inform the broad application of sanguinarine in cyanobacteria mitigation.

This paper is concerned with the Black–Scholes–Barenblatt equation $\partial _{t}u+r(x\partial _{x}u-u)+G(x^{2}\partial _{xx}u)=0$ , where $G(\alpha )=\frac{1}{2}(\overline{\sigma}^{2}-\underline{\sigma}^{2})|\alpha |+\frac{1}{2}(\overline{\sigma}^{2}+\underline{\sigma}^{2})\alpha $ , $\alpha \in \mathbb{R}$ . This equation is usually used for derivative pricing in the financial market with volatility uncertainty. We discuss a strict comparison theorem for Black–Scholes–Barenblatt equations, and study strict sub-additivity of their solutions with respect to terminal conditions.