Semiochemical-based alternatives to synthetic toxicant insecticides for pollen beetle management

There is an urgent need to develop sustainable pest management systems to protect arable crops in order to replace the current over-reliance on synthetic insecticides. Semiochemicals are insect- or plant-derived chemicals that are used by organisms as information signals. Integrated pest management tools are currently in development that utilise semiochemicals to manipulate the behaviour of pest insects and their natural enemies to provide effective control of pests within the crop. These innovative tools usually require fewer inputs and can involve multiple elements therefore reducing the likelihood of resistance developing compared with use of synthetic toxicants. We review here the life cycle of the pollen beetle Brassicogethes aeneus (previously known as Meligethes aeneus) which is a pest insect of oilseed rape (Brassica napus) and describe the current knowledge of any behaviour mediated by semiochemicals in this species. We discuss the behavioural processes where semiochemical-based control approaches may be appropriate and consider how these approaches could be integrated into an integrated pest management strategy for this important arable crop

Antiretroviral-naive and -treated HIV-1 patients can harbour more resistant viruses in CSF than in plasma

Objectives The neurological disorders in HIV-1-infected patients remain prevalent. The HIV-1 resistance in plasma and CSF was compared in patients with neurological disorders in a multicentre study. Methods Blood and CSF samples were collected at time of neurological disorders for 244 patients. The viral loads were >50 copies/mL in both compartments and bulk genotypic tests were realized. Results On 244 patients, 89 and 155 were antiretroviral (ARV) naive and ARV treated, respectively. In ARV-naive patients, detection of mutations in CSF and not in plasma were reported for the reverse transcriptase (RT) gene in 2/89 patients (2.2%) and for the protease gene in 1/89 patients (1.1%). In ARV-treated patients, 19/152 (12.5%) patients had HIV-1 mutations only in the CSF for the RT gene and 30/151 (19.8%) for the protease gene. Two mutations appeared statistically more prevalent in the CSF than in plasma: M41L (P = 0.0455) and T215Y (P = 0.0455). Conclusions In most cases, resistance mutations were present and similar in both studied compartments. However, in 3.4% of ARV-naive and 8.8% of ARV-treated patients, the virus was more resistant in CSF than in plasma. These results support the need for genotypic resistance testing when lumbar puncture is performe

Crystallization in multicomponent chiral systems : thermodynamic characterization and guidelines for chiral resolution of racemic compounds with cocrystallization

Chiral molecules are asymmetrical objects, and from this geometric property emerge enantiomers, that are a pair of non-superimposable mirror-image compounds. More than 50% of marketed drugs are chiral, and enantiomeric separation is a major research area. Enantiomers possess the same physical properties, but they interact differently with chiral receptors in the human body, which induces a different biological response. While one enantiomer has a desired therapeutic effect, its opposite-enantiomer can be inactive or produce unwanted side effects. Moreover, an inactive opposite-enantiomer in a racemic drug can be considered as an impurity representing up to 50% of the formulation, which presents economic consequences. Consequently, the manufacture of chiral active pharmaceutical ingredients (API) is regulated to prefer enantiopure drugs. Because enantioselective synthesis is not always possible, robust separation methods are required to achieve enantiomeric purity from racemic mixtures. Crystallization-based resolution processes are preferred at industrial scale because of more interesting costs. When a racemic mixture crystallizes as a stable racemic compound, one resolution strategy relies on the cocrystal engineering with an additional coformer molecule to prompt new thermodynamic equilibria more favorable. The work outlined in this thesis focuses on the thermodynamic characterization and understanding of multicomponent chiral systems to apply chiral resolution strategies of racemic compounds with cocrystallization. In Chapter 3, the detection of new cocrystals is discussed through the investigation of results obtained during a campaign aiming to find cocrystals to resolve the racemic compound of praziquantel. A total of 30 coformers are screened with four cocrystal screening methods, which are compared thoroughly by defining quantified parameters that help to review their strengths and weaknesses. The objective of this chapter is to conclude on screening methods’ efficiencies and convenience, with the view to provide relevant advice on the optimization of cocrystal screening method selection. Chapter 4 addresses the issue of chiral quantification in multicomponent systems and presents a novel chiral quantification method using ultraviolet circular dichroism spectroscopy and multivariate partial least square models. The method is used to understand the solid-liquid equilibria in the complex quaternary system of levetiracetam enantiomers with a chiral coformer in a solvent, through the accurate determination of the full quaternary phase diagram. The aim of this chapter is to propose a new approach for multicomponent chiral quantification in order to characterize complex systems and identify the conditions permitting a chiral separation process with crystallization. By using the acquired quaternary phase diagram, an enantioselective cocrystallization process is designed in Chapter 5 to recover levetiracetam from its racemic compound through the isolation of its enantiospecific cocrystal. This process is combined with a solvent-mediated transformation step that permits the retrieval of pure levetiracetam from its cocrystal. The objective of Chapter 5 is to propose guidelines to build and optimize chiral resolution processes with chiral cocrystallization from the understanding of phase diagram information. While cocrystallization provides a relevant collection of strategies for the chiral resolution of stable racemic compounds, several parameters must be considered to identify the best scenario permitting the resolution of a target compound. Therefore, in Chapter 6, the key points leading to a quick and efficient identification of the optimal resolution strategy are discussed, such as the racemic compound stability, the coformer selection methods and its chirality, and the identification of the thermodynamic equilibria compatible with a resolution. The aim of this chapter is to propose relevant guidelines for chiral resolution strategy identification with cocrystallization. The work in this thesis deepens the knowledge about chiral resolution of racemic compounds with cocrystallization by providing relevant new tools to this research area. New approaches are introduced to screen more efficiently for new cocrystals, to quantify complex multicomponent chiral systems, to design chiral resolution processes, and to identify the parameters for choosing the optimal resolution strategies. It is hoped that these methodologies will contribute to solve the challenges of enantiomers separation.Chiral molecules are asymmetrical objects, and from this geometric property emerge enantiomers, that are a pair of non-superimposable mirror-image compounds. More than 50% of marketed drugs are chiral, and enantiomeric separation is a major research area. Enantiomers possess the same physical properties, but they interact differently with chiral receptors in the human body, which induces a different biological response. While one enantiomer has a desired therapeutic effect, its opposite-enantiomer can be inactive or produce unwanted side effects. Moreover, an inactive opposite-enantiomer in a racemic drug can be considered as an impurity representing up to 50% of the formulation, which presents economic consequences. Consequently, the manufacture of chiral active pharmaceutical ingredients (API) is regulated to prefer enantiopure drugs. Because enantioselective synthesis is not always possible, robust separation methods are required to achieve enantiomeric purity from racemic mixtures. Crystallization-based resolution processes are preferred at industrial scale because of more interesting costs. When a racemic mixture crystallizes as a stable racemic compound, one resolution strategy relies on the cocrystal engineering with an additional coformer molecule to prompt new thermodynamic equilibria more favorable. The work outlined in this thesis focuses on the thermodynamic characterization and understanding of multicomponent chiral systems to apply chiral resolution strategies of racemic compounds with cocrystallization. In Chapter 3, the detection of new cocrystals is discussed through the investigation of results obtained during a campaign aiming to find cocrystals to resolve the racemic compound of praziquantel. A total of 30 coformers are screened with four cocrystal screening methods, which are compared thoroughly by defining quantified parameters that help to review their strengths and weaknesses. The objective of this chapter is to conclude on screening methods’ efficiencies and convenience, with the view to provide relevant advice on the optimization of cocrystal screening method selection. Chapter 4 addresses the issue of chiral quantification in multicomponent systems and presents a novel chiral quantification method using ultraviolet circular dichroism spectroscopy and multivariate partial least square models. The method is used to understand the solid-liquid equilibria in the complex quaternary system of levetiracetam enantiomers with a chiral coformer in a solvent, through the accurate determination of the full quaternary phase diagram. The aim of this chapter is to propose a new approach for multicomponent chiral quantification in order to characterize complex systems and identify the conditions permitting a chiral separation process with crystallization. By using the acquired quaternary phase diagram, an enantioselective cocrystallization process is designed in Chapter 5 to recover levetiracetam from its racemic compound through the isolation of its enantiospecific cocrystal. This process is combined with a solvent-mediated transformation step that permits the retrieval of pure levetiracetam from its cocrystal. The objective of Chapter 5 is to propose guidelines to build and optimize chiral resolution processes with chiral cocrystallization from the understanding of phase diagram information. While cocrystallization provides a relevant collection of strategies for the chiral resolution of stable racemic compounds, several parameters must be considered to identify the best scenario permitting the resolution of a target compound. Therefore, in Chapter 6, the key points leading to a quick and efficient identification of the optimal resolution strategy are discussed, such as the racemic compound stability, the coformer selection methods and its chirality, and the identification of the thermodynamic equilibria compatible with a resolution. The aim of this chapter is to propose relevant guidelines for chiral resolution strategy identification with cocrystallization. The work in this thesis deepens the knowledge about chiral resolution of racemic compounds with cocrystallization by providing relevant new tools to this research area. New approaches are introduced to screen more efficiently for new cocrystals, to quantify complex multicomponent chiral systems, to design chiral resolution processes, and to identify the parameters for choosing the optimal resolution strategies. It is hoped that these methodologies will contribute to solve the challenges of enantiomers separation

Multicomponent chiral quantification with UV circular dichroism spectroscopy : ternary and quaternary phase diagrams of Levetiracetam

Chiral molecules are challenging for the pharmaceutical industry because, although physical properties of the enantiomers are the same in achiral systems, they exhibit different effects in chiral systems, such as the human body. The separation of enantiomers is desired but complex, as enantiomers crystallize most often as racemic compounds. A technique to enable the chiral separation of racemic compounds is to create an asymmetry in the thermodynamic system by generating chiral cocrystal(s) using a chiral coformer and using the solubility differences to enable separation through crystallization from solution. However, such quaternary systems are complex and require analytical methods to quantify different chiral molecules in solution. Here we develop a new chiral quantification method using Ultraviolet-Circular Dichroism spectroscopy and multivariate Partial Least Squares calibration models, to build multicomponent chiral phase diagrams. Working on the quaternary system of (R)- and (S)-2-(2-oxopyrrolidin-1-yl)butanamide enantiomers with (S)-mandelic acid in acetonitrile, we measure accurately the full quaternary phase diagram for the first time. By understanding the phase stabilities of the racemic compound and the enantiospecific cocrystal, the chiral resolution of levetiracetam could be designed due to a large asymmetry in overall solubility between both sides of the racemic composition. This new method offers improvements for chiral molecule quantification in complex multicomponent chiral systems and can be applied to other chiral spectroscopy techniques

Simultaneous Chiral Resolution of Two Racemic Compounds by Preferential Cocrystallization

We tap into an unexplored area of preferential crystallization, being the first to develop simultaneous chiral resolution of two racemic compounds by preferential cocrystallization.We highlight how the two racemic compounds RS-mandelic acid (MAN) and RS-etiracetam (ETI) can be combined together as enantiospecific R-MAN:R-ETI and S-Man:S-ETI cocrystals forming a stable conglomerate system and subsequently develop a cyclic preferential crystallization allowing to simultaneous resolve both compounds. The developed process leads to excellent enantiopurity both for etiracetam (ee>98%) and mandelic acid (ee~95%) enantiomers </div

Simultaneous chiral resolution of two racemic compounds by preferential cocrystallization

We tap into an unexplored area of preferential crystallization, being the first to develop simultaneous chiral resolution of two racemic compounds by preferential cocrystallization. We highlight how the two racemic compounds RS-mandelic acid (MAN) and RS-etiracetam (ETI) can be combined together as enantiospecific R-MAN⋅R-ETI and S-MAN⋅S-ETI cocrystals forming a stable conglomerate system and subsequently develop a cyclic preferential crystallization allowing to simultaneous resolve both compounds. The developed process leads to excellent enantiopurity both for etiracetam (ee>98 %) and mandelic acid (ee≈95 %) enantiomers

Simultaneous Chiral Resolution of Two Racemic Compounds by Preferential Cocrystallization**

We tap into an unexplored area of preferential crystallization, being the first to develop simultaneous chiral resolution of two racemic compounds by preferential cocrystallization. We highlight how the two racemic compounds RS-mandelic acid (MAN) and RS-etiracetam (ETI) can be combined together as enantiospecific R-MAN:R-ETI and S-Man:S-ETI cocrystals forming a stable conglomerate system and subsequently develop a cyclic preferential crystallization allowing to simultaneous resolve both compounds. The developed process leads to excellent enantiopurity both for etiracetam (ee>98%) and mandelic acid (ee~95%) enantiomers

Co-crystals of non-steroidal anti-inflammatory drugs (NSAIDs) : insight toward formation, methods, and drug enhancement

Pharmaceutical co-crystals have been explored by many researchers as a strategy to optimize physicochemical properties of solid-state drugs. Their improvements of solubility, bioavailability, and the reduced tendency for phase transformation occurrence, are factors that highlight benefits of pharmaceutical co-crystals among other solid forms. According to the Biopharmaceutical Classification System (BCS), non-steroidal anti-inflammatory drugs (NSAIDs) are class II drugs, which have low aqueous solubility and therefore co-crystallization has the potential to optimize NSAID product properties. In this review, we highlight the recent progress made on NSAIDs co-crystals, their co-formers, synthesis, methods and use, while we underline some promising results on in vitro and in vivo co-crystal properties. A celecoxib-tramadol co-crystal reaches phase III clinical trials, showing greater analgesic activity than both individual APIs. The aqueous solubility of the co-crystal formed between L-proline and diclofenac is very high in comparison with the pure drug. Naproxen co-crystals with urea and thiourea have an increase of drug release of almost 60%. Co-crystal design brings a new perspective in drug development since the co-former used can also be a biologically active component allowing to combine different anti-inflammatory drugs, which have an incredible spectrum of application due to the analgesic, anti-pyretic and anti-inflammatory properties

Multicomponent Chiral Quantification with Ultraviolet Circular Dichroism Spectroscopy: Ternary and Quaternary Phase Diagrams of Levetiracetam

Chiral molecules are challenging for the pharmaceutical industry because although physical properties of the enantiomers are the same in achiral systems, they exhibit different effects in chiral systems, such as the human body. The separation of enantiomers is desired but complex, as enantiomers crystallize most often as racemic compounds. A technique to enable the chiral separation of racemic compounds is to create an asymmetry in the thermodynamic system by generating chiral cocrystal(s) using a chiral coformer and using the solubility differences to enable separation through crystallization from solution. However, such quaternary systems are complex and require analytical methods to quantify different chiral molecules in solution. Here, we develop a new chiral quantification method using ultraviolet-circular dichroism spectroscopy and multivariate partial least squares calibration models, to build multicomponent chiral phase diagrams. Working on the quaternary system of (R)- and (S)-2-(2-oxopyrrolidin-1-yl)butanamide enantiomers with (S)-mandelic acid in acetonitrile, we measure accurately the full quaternary phase diagram for the first time. By understanding the phase stabilities of the racemic compound and the enantiospecific cocrystal, the chiral resolution of levetiracetam could be designed due to a large asymmetry in overall solubility between both sides of the racemic composition. This new method offers improvements for chiral molecule quantification in complex multicomponent chiral systems and can be applied to other chiral spectroscopy techniques

Comparing and quantifying the efficiency of cocrystal screening methods for Praziquantel

Pharmaceutical cocrystals are highly interesting due to their effect on physicochemical properties and their role in separation technologies, particularly for chiral molecules. Detection of new cocrystals is a challenge and robust screening methods are required. As numerous techniques exist that differ in their crystallization mechanism, their efficiencies depend on the coformers investigated. The most important parameters characterizing the methods are the a) screenable coformers fraction, b) coformers success rate, c) ability to give several cocrystals per successful coformer, d) identification of new stable phases, e) experimental convenience. Based on these parameters, we compare and quantify the performance of three methods: liquid-assisted grinding, solvent evaporation, and saturation temperature measurements of mixtures. These methods were used to screen thirty molecules, predicted by a network-based link prediction algorithm (described in Crystal Growth & Design 2021 21 (6), 3428-3437) as potential coformers for the target molecule Praziquantel. The solvent evaporation method presented more drawbacks than advantages, liquid-assisted grinding emerged as the most successful and the quickest, while saturation temperature measurements provided equally good results in a slower route yielding additional solubility information relevant for future screenings, single-crystal growth and cocrystal production processes. Seventeen cocrystals were found, with fourteen showing stability, and twelve structures resolved