7 research outputs found
Leucopterin, the white pigment in butterfly wings: structural analysis by PDF fit, FIDEL fit, Rietveld refinement, solid-state NMR and DFT-D
Overcoming the Drawbacks of Sulpiride by Means of New Crystal Forms
This study aims at developing new multicomponent crystal forms of sulpiride, an antipsychotic drug. The main goal was to improve its solubility since it belongs to class IV of the BCS. Nine new adducts were obtained by combining the active pharmaceutical ingredient with acid coformers: a salt cocrystal and eight molecular salts. In addition, three novel co-drugs, of which two are molecular salts and one is a cocrystal, were also achieved. All samples were characterized in the solid state by complementary techniques (i.e., infrared spectroscopy, powder X-ray diffraction and solid-state NMR). For systems for which it was possible to obtain good-quality single crystals, the structure was solved by single crystal X-ray diffraction (SCXRD). SCXRD combined with solid-state NMR were used to evaluate the ionic or neutral character of the adducts. In vitro dissolution tests of the new crystal forms were performed and all the adducts display remarkable dissolution properties with respect to pure sulpiride
NAVIGATING THE COMPLEX SOLID FORM LANDSCAPE OF THE QUERCETIN FLAVONOID MOLECULE
Quercetin, a naturally occurring bioflavonoid substance widely used in the nutraceutical and food industries, exists in various solid forms that can have different physicochemical properties, thus impacting this compoundâs performance in various applications. In this work, we will clarify the complex solid-form landscape of this molecule. Two elusive isostructural solvates of quercetin were obtained from ethanol and methanol. The obtained crystals were characterized experimentally, but the crystallographic structure could not be solved due to their high instability. Nevertheless, the desolvated structure resulting from a high-temperature treatment (or prolonged storage at ambient conditions) of both these two labile crystals was characterized and solved via powder X-ray diffraction and solid-state nuclear magnetic resonance (SSNMR). This anhydrous crystal structure was compared with another anhydrous quercetin form obtained in our previous work, indicating that, at least, two different anhydrous polymorphs of quercetin exist. Navigating the solid-form landscape of quercetin is essential to ensure accurate control of the functional properties of food, nutraceutical, or pharmaceutical products containing crystal forms of this substance
Zwitterionic or Not? Fast and Reliable Structure Determination by Combining Crystal Structure Prediction and Solid-State NMR
When it comes to crystal structure determination, computational approaches such as Crystal Structure Prediction (CSP) have gained more and more attention since they offer some insight on how atoms and molecules are packed in the solid state, starting from only very basic information without diffraction data. Furthermore, it is well known that the coupling of CSP with solid-state NMR (SSNMR) greatly enhances the performance and the accuracy of the predictive method, leading to the so-called CSP-NMR crystallography (CSP-NMRX). In this paper, we present the successful application of CSP-NMRX to determine the crystal structure of three structural isomers of pyridine dicarboxylic acid, namely quinolinic, dipicolinic and dinicotinic acids, which can be in a zwitterionic form, or not, in the solid state. In a first step, mono- and bidimensional SSNMR spectra, i.e., 1H Magic-Angle Spinning (MAS), 13C and 15N Cross Polarisation Magic-Angle Spinning (CPMAS), 1H Double Quantum (DQ) MAS, 1H-13C HETeronuclear CORrelation (HETCOR), were used to determine the correct molecular structure (i.e., zwitterionic or not) and the local molecular arrangement; at the end, the RMSEs between experimental and computed 1H and 13C chemical shifts allowed the selection of the correct predicted structure for each system. Interestingly, while quinolinic and dipicolinic acids are zwitterionic and non-zwitterionic, respectively, in the solid state, dinicotinic acid exhibits in its crystal structure a âzwitterionic-non-zwitterionic continuum stateâ in which the proton is shared between the carboxylic moiety and the pyridinic nitrogen. Very refined SSNMR experiments were carried out, i.e., 14N-1H Phase-Modulated (PM) pulse and Rotational-Echo Saturation-Pulse Double-Resonance (RESPDOR), to provide an accurate NâH distance value confirming the hybrid nature of the molecule. The CSP-NMRX method showed a remarkable match between the selected structures and the experimental ones. The correct molecular input provided by SSNMR reduced the number of CSP calculations to be performed, leading to different predicted structures, while RMSEs provided an independent parameter with respect to the computed energy for the selection of the best candidate
Leucopterin, the white pigment in butterfly wings: structural analysis by PDF fit, FIDEL fit, Rietveld refinement, solid-state NMR and DFT-D
Leucopterin (C6H5N5O3) is the white pigment in the wings of Pieris brassicae butterflies, and other butterflies; it can also be found in wasps and other insects. Its crystal structure and its tautomeric form in the solid state were hitherto unknown. Leucopterin turned out to be a variable hydrate, with 0.5 to about 0.1 molecules of water per leucopterin molecule. Under ambient conditions, the preferred state is the hemihydrate. Initially, all attempts to grow single crystals suitable for X-ray diffraction were to no avail. Attempts to determine the crystal structure by powder diffraction using the direct-space method failed, because the trials did not include the correct, but rare, space group P2/c. Attempts were made to solve the crystal structure by a global fit to the pair distribution function (PDF-Global-Fit), as described by Prill and co-workers [Schlesinger et al. (2021). J. Appl. Cryst. 54, 776â786]. The approach worked well, but the correct structure was not found, because again the correct space group was not included. Finally, tiny single crystals of the hemihydrate could be obtained, which allowed at least the determination of the crystal symmetry and the positions of the C, N and O atoms. The tautomeric state of the hemihydrate was assessed by multinuclear solid-state NMR spectroscopy. 15N CPMAS spectra showed the presence of one NH2 and three NH groups, and one unprotonated N atom, which agreed with the 1H MAS and 13C CPMAS spectra. Independently, the tautomeric state was investigated by lattice-energy minimizations with dispersion-corrected density functional theory (DFT-D) on 17 different possible tautomers, which also included the prediction of the corresponding 1H, 13C and 15N chemical shifts in the solid. All methods showed the presence of the 2-amino-3,5,8-H tautomer. The DFT-D calculations also confirmed the crystal structure. Heating of the hemihydrate results in a slow release of water between 130 and 250â
°C, as shown by differential thermal analysis and thermogravimetry (DTA-TG). Temperature-dependent powder X-ray diffraction (PXRD) showed an irreversible continuous shift of the reflections upon heating, which reveals that leucopterin is a variable hydrate. This observation was also confirmed by PXRD of samples obtained under various synthetic and drying conditions. The crystal structure of a sample with about 0.2 molecules of water per leucopterin was solved by a fit with deviating lattice parameters (FIDEL), as described by Habermehl et al. [Acta Cryst. (2022), B78, 195â213]. A local fit, starting from the structure of the hemihydrate, as well as a global fit, starting from random structures, were performed, followed by Rietveld refinements. Despite dehydration, the space group remains P2/c. In both structures (hemihydrate and variable hydrate), the leucopterin molecules are connected by 2â4 hydrogen bonds into chains, which are connected by further hydrogen bonds to neighbouring chains. The molecular packing is very efficient. The density of leucopterin hemihydrate is as high as 1.909â
kgâ
dmâ3, which is one of the highest densities for organic compounds consisting of C, H, N and O only. The high density might explain the good light-scattering and opacity properties of the wings of Pieris brassicae and other butterflies
Type I Spinal Muscular Atrophy patients treated with nusinersen: 4 year follow-up of motor, respiratory and bulbar function
Background: We report the 4 year follow up in type I patients treated with nusinersen and the changes in motor, respiratory and bulbar function in relation to subtype, age and SMN2 copy number. Methods: The study included SMA 1 patients with at least one assessment after 12, 24 and 48 months from the first dose of nusinersen. The assessments used were Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) and the Hammersmith Infant Neurological Examination (HINE-2). Results: Forty-eight patients, with age ranging from 7âdays and 12âyears (mean 3.3, SD 3.6) were included in the study. The CHOP INTEND and HINE-II score significantly increased between baseline and 48 months (p<0.001). When age at starting treatment subgroups (<210âdays, <2âyears, 2-4âyears, 5-11âyears, >12âyears) were considered, the CHOP INTEND increased significantly in patients younger than 4âyears at treatment, while the HINE-2 increased significantly in patients younger than 2âyears at treatment. In a mixed model analysis, age, nutritional and respiratory status were predictive of changes on both scales while SMN2 copy number and decimal classification were not. Conclusions: Our results confirm the safety profile previously reported and support the durability of the efficacy of nusinersen at 4âyears with an overall stability or mild improvement and no evidence of deterioration over a long period of time
Onasemnogene abeparvovec in spinal muscular atrophy: predictors of efficacy and safety in naĂŻve patients with spinal muscular atrophy and following switch from other therapiesResearch in context
Summary: Background: Efficacy and safety of onasemnogene abeparvovec (OA) for Spinal Muscular Atrophy infants under 7 months and <8.5Â kg has been reported in clinical trials. This study examines efficacy and safety predictors in a wide age (22 daysâ72 months) and weight (3.2â17Â kg) range, also including patients previously treated with other drugs. Methods: 46 patients were treated for 12 months between January 2020 and March 2022. Safety profile was also available for another 21 patients with at least 6 month follow-up after OA infusion. 19/67 were treatment naĂŻve when treated with OA. Motor function was measured with the CHOP-INTEND. Findings: CHOP-INTEND changes varied among age groups. Baseline score and age at OA treatment best predicted changes. A mixed model post-hoc analysis showed that in patients treated before the age of 24 months the CHOP-INTEND changes were already significant 3 months after OA while in those treated after the age of 24 months the difference was only significant 12 months after OA. Adverse events occurred in 51/67. The risk for elevated transaminases serum levels was higher in older patients. This was also true for weight and for pre-treatment with nusinersen when analysed individually. A binomial negative regression analysis showed that only age at OA treatment had a significant effect on the risk of elevated transaminases. Interpretation: Our paper describes OA 12-month follow-up showing efficacy across various age and weight groups not targeted by clinical trials. The study identifies prognostic factors for safety and efficacy in treatment selection. Funding: None