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The objective of this study was to improve the solubility and inhibit the crystallisation during the gastric-to-intestinal transfer of Erlotinib (ERL), a small molecule kinase inhibitor (smKI) compound class, which is classified as class II drug in the Biopharmaceutical Classification System (BCS). A screening approach combining different parameters (solubility in aqueous media, inhibitory effect of drug crystallisation from supersaturated drug solutions) was applied to selected polymers for the development of solid amorphous dispersions of ERL. ERL solid amorphous dispersions formulations were then prepared with 3 different polymers (Soluplus®, HPMC-AS-L, HPMC-AS-H) at a fixed drug: polymer ratio (1:4) by two different production methods (spray drying and hot melt extrusion). The spray-dried particles and cryo-milled extrudates were characterized by thermal properties, shape and particle size, solubility and dissolution behavior in aqueous media. The influence of the manufacturing process on these solid characteristics was also identified during this study. Based on the obtained results, it is concluded that the cryo-milled extrudates of HPMC-AS-L displayed better performance (enhanced solubility, reduced ERL crystallization during the simulated gastric-to-intestinal transfer) and represents a promising amorphous solid dispersion formulation for oral administration of ERL. [ABSTRACT FROM AUTHOR]

The emergence and spread of Plasmodium falciparum resistance to first-line antimalarials creates an imperative to identify and develop potent preclinical candidates with distinct modes of action. Here, we report the identification of MMV688533, an acylguanidine that was developed following a whole-cell screen with compounds known to hit high-value targets in human cells. MMV688533 displays fast parasite clearance in vitro and is not cross-resistant with known antimalarials. In a P. falciparum NSG mouse model, MMV688533 displays a long-lasting pharmacokinetic profile and excellent safety. Selection studies reveal a low propensity for resistance, with modest loss of potency mediated by point mutations in PfACG1 and PfEHD. These proteins are implicated in intracellular trafficking, lipid utilization, and endocytosis, suggesting interference with these pathways as a potential mode of action. This preclinical candidate may offer the potential for a single low-dose cure for malaria., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

A high throughput phenotypic screening against Mycobacterium smegmatis led us to the discovery of a new class of bacteriostatic, highly hydrophobic antitubercular quinazolinones that potently inhibited the in vitro growth of either extracellular or intramacrophagic M. tuberculosis (Mtb), via modulation of an unidentified but yet novel target. Optimization of the initial hit compound culminated in the identification of potent but poorly soluble Mtb growth inhibitors, three of which were progressed to in vivo efficacy studies. Despite nanomolar in vitro potency and attractive PK properties, none of these compounds was convincingly potent in our in vivo mouse tuberculosis models. This lack of efficacy may be linked to the poor drug-likeness of the test molecules and/or to the properties of the target., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Rasburicase (Fasturtec/Elitek) is a new generation of recombinant urate oxidase administred therapeutically by intravenous infusion for the prevention or treatment of hyperuricemia during chemotherapy. To ensure a long storage period, a freeze-dried formulation was developed to guarantee the molecular integrity and enzyme activity. Screening of potential excipients was the first stage of the preformulation study. The selection was based on stability results (rasburicase solution with excipient) obtained with the isoelectric focusing profiles and residual enzyme activity. The different excipients were classified as stabilising, neutral or destabilising. A stability study was then carried out on different freeze-dried formulations containing the usual bulking agents for freeze-drying, excipients with a high glass transition temperature or competitive enzyme inhibitors having a stabilising effect. A mannitol/alanine mixture in phosphate buffer was selected from these preliminary results. Finally, the optimal content of mannitol and alanine in the freeze-dried powder was determined by an experimental design study. The water content and the appearance of the "cake", the osmolality, pH, clarity, and enzyme activity of the reconstituted solution were assessed. The formula with a mannitol/alanine ratio of 0.7 was found to be the best composition. Differential scanning calorimetry and ThermoStimulated Current technique experiments were carried out to study the amorphous phase. A glass transition temperature of about 45-500 degrees C was found. Glassy state is known to preserve stability, which was verified by the real stability data. X-ray diffraction studies have shown that alanine is in a crystallised state and that mannitol remains amorphous. Crystallised excipients participate in forming the structure of the powder and therefore help to prevent any collapse. Amorphous mannitol creates a surrounding medium favourable to the stability of the protein.

Two crystalline forms and the amorphous state of irbesartan, a pharmaceutical drug chosen as a model, were analyzed by Thermally Stimulated Current (TSC) spectroscopy, a powerful technique currently used in polymer science to investigate the molecular dynamics of heterogeneous and complex materials. Whereas no specific dielectric response was noted for the B crystalline form, the A form of irbesartan exhibited molecular motions localized inside its channel structure. The dynamics involved in the dielectric glass transition of amorphous samples followed a compensation law characteristic of highly cooperative relaxation processes. Concerning the amorphous content in physical mixtures, a calibration curve and a limit of detection (2.5%) were established. The limit of detection could be improved by optimizing the TSC experimental parameters. The amorphous sample recrystallized at a single temperature was interpreted by the "idealized one-state model" defined here to describe systems composed of identical semicrystalline particles in which amorphous and crystalline phases are independent of each other (i.e., no chemical and physical interaction between the two phases). Therefore, the idealized one-state model may be simulated by a two-state model, which is representative of the two-phase model. Other samples recrystallized through a complex annealing stage were explained by the classical one-state model in agreement with the three-phase model used to describe bulk semicrystalline systems. These results demonstrate that, as for polymers, the semicrystalline state of pharmaceutical drugs should not be considered as a single state but as a more complex system that can be described as an idealized one-state model or a one-state model depending on the applied thermal treatment. These results give a new view that should be taken into account in the development of amorphous pharmaceutical drugs and formulations., (Copyright 2002 Wiley-Liss, Inc.)