From molecular crystals to salt co-crystals of barbituric acid via the carbonate ion and an improvement of the solid state properties

Co-crystals formed by neutral barbituric acid (HBA) molecules and alkaline barbiturate salts have been prepared by solvent-free mechanochemical treatment of solid HBA and alkaline carbonates or bicarbonates. During the reaction the carbonate salts release CO2 and H2O, affording the corresponding barbiturate salts which then co-crystallize with the neutral molecule. These "salt co-crystals" have the general formula M x+(BA-)x\ub7HBA\ub7nH 2O with (M = Na and K). The compounds can be obtained in a single step, by directly grinding HBA with M2CO3 (4:1 ratio) or MHCO3 (2:1 ratio), or, alternatively, in two steps: the preparation of the BA salt followed by a further grinding process or crystallization of the resulting salts with a stoichiometric amount of neutral HBA. All compounds have been characterized by means of single-crystal and powder XRD, solid-state NMR (1H MAS, 13C and 15N CPMAS), vibrational spectroscopies and thermal methods (DSC and TGA). A series of BA- salts (either hydrated or anhydrous) of formula Mx +(BA-)x\ub7nH2O (M = Na, K, Mg and Ca) have also been prepared and reported for comparison

Using salt cocrystals to improve the solubility of niclosamide

This Article reports the solvent-free synthesis and characterization of a number of different crystal forms of niclosamide (HNic), which is an API belonging to the Salicilamide class. The synthesized compounds are four new salt cocrystals (KNic.HNic.H2O, KNic.HNic.3H(2)O, NaNic.HNic.3H(2)O, NaNic.HNic.2H(2)O), a classic cocrystal with imidazole (IM) (HNic.IM), and two sodium salts, (NaNic.DMSO.H2O and NaNic.DMSO.2H(2)O). The peculiarity of these salt cocrystals is the APIs concomitant presence as both a neutral component and as a salt coformer and the fact that they interact via hydrogen bond formation. HNics poor aqueous solubility makes the enhancement of its dissolution rate via the modulation of its physical properties extremely important. All samples have been investigated using a combination of solid-state experimental techniques which provide complementary information on powdered samples. These techniques are X-ray powder diffraction, solid-state NMR, IR, and Raman. Single crystals were only obtained for KNic.HNic.H2O and NaNic.DMSO.2H(2)O. The nature of the adducts (whether salt or cocrystal), their stoichiometry and the presence of independent molecules in the unit cell of the other samples were thus all determined by means of solid-state NMR and the comparative analysis of C-13 and N-15 CPMAS (Cross-Polarization Magic Angle Spinning) and 1H MAS spectra. Furthermore, differential scanning calorimetry, thermogravimetric analysis and intrinsic dissolution rate measurements completed the characterization and enabled us to evaluate the effects of microscopic changes (molecular packing, weak interactions, conformations, etc.) on the macroscopic properties (thermal stability and bioavailability) of the multicomponent forms. The results obtained indicate that the formation of salt cocrystals provides a reliable method with which to improve the HNic intrinsic dissolution rate

Continuous vs intermittent Non-Invasive blood pressure MONitoring in preventing postoperative organ failure (niMON): study protocol for an open-label, multicenter randomized trial

Background: Blood pressure has become one of the most important vital signs to monitor in the perioperative setting. Recently, the Italian Society of Anesthesia Analgesia Resuscitation and Intensive Care (SIAARTI) recommended, with low level of evidence, continuous monitoring of blood pressure during the intraoperative period. Continuous monitoring allows for early detection of hypotension, which may potentially lead to a timely treatment. Whether the ability to detect more hypotension events by continuous noninvasive blood pressure (C-NiBP) monitoring can improve patient outcomes is still unclear. Here, we report the rationale, study design, and statistical analysis plan of the niMON trial, which aims to evaluate the effect of intraoperative C-NiBP compared with intermittent (I-NiBP) monitoring on postoperative myocardial and renal injury. Methods: The niMon trial is an investigator-initiated, multicenter, international, open-label, parallel-group, randomized clinical trial. Eligible patients will be randomized in a 1:1 ratio to receive C-NiBP or I-NiBP as an intraoperative monitoring strategy. The proportion of patients who develop myocardial injury in the first postoperative week is the primary outcome; the secondary outcomes are the proportions of patients who develop postoperative AKI, in-hospital mortality rate, and 30 and 90 postoperative days events. A sample size of 1265 patients will provide a power of 80% to detect a 4% absolute reduction in the rate of the primary outcome. Conclusions: The niMON data will provide evidence to guide the choice of the most appropriate intraoperative blood pressure monitoring strategy. Clinical trial registration: Clinical Trial Registration: NCT05496322, registered on the 5th of August 2023