Mechanistic In Situ and Ex Situ Studies of Phase Transformations in Molecular Co-Crystals.

Co-crystallisation is widely explored as a route to improve the physical properties of pharmaceutical active ingredients, but little is known about the fundamental mechanisms of the process. Herein, we apply a hyphenated differential scanning calorimetry-X-ray diffraction technique to mimic the commercial hot melt extrusion process, and explore the heat-induced synthesis of a series of new co-crystals containing isonicotinamide. These comprise a 1:1 co-crystal with 4-hydroxybenzoic acid, 2:1 and 1:2 systems with 4-hydroxyphenylacetic acid and a 1:1 crystal with 3,4-dihydroxyphenylactic acid. The formation of co-crystals during heating is complex mechanistically. In addition to co-crystallisation, conversions between polymorphs of the co-former starting materials and co-crystal products are also observed. A subsequent study exploring the use of inkjet printing and milling to generate co-crystals revealed that the synthetic approach has a major effect on the co-crystal species and polymorphs produced.

Gaseous "nanoprobes" for detecting gas-trapping environments in macroscopic films of vapor-deposited amorphous ice.

Vapor-deposited amorphous ice, traditionally called amorphous solid water (ASW), is one of the most abundant materials in the universe and a prototypical material for studying physical vapor-deposition processes. Its complex nature arises from a strong tendency to form porous structures combined with complicated glass transition, relaxation, and desorption behavior. To gain further insights into the various gas-trapping environments that exist in ASW and hence its morphology, films in the 25-100 µm thickness range were codeposited with small amounts of gaseous "nanoprobes" including argon, methane, helium, and carbon dioxide. Upon heating in the 95-185 K temperature range, three distinct desorption processes are observed which we attribute to the gas desorption out of open cracks above 100 K, from internal voids that collapse due to the glass transition at ∼125 K and finally from fully matrix-isolated gas induced by the irreversible crystallization to stacking disordered ice (ice Isd) at ∼155 K. Nanoscale films of ASW have only displayed the latter desorption process which means that the first two desorption processes arise from the macroscopic dimensions of our ASW films. Baffling the flow of water vapor toward the deposition plate greatly reduces the first desorption feature, and hence the formation of cracks, but it significantly increases the amount of matrix-isolated gas. The complex nature in which ASW can trap gaseous species is thought to be relevant for a range of cosmological processes.

Drug repurposing in neurological diseases: an integrated approach to reduce trial and error.

Identifying effective disease-modifying therapies for neurological diseases remains an important challenge in drug discovery and development. Drug repurposing attempts to determine new indications for pre-existing compounds and represents a major opportunity to address this clinically unmet need. It is potentially more cost-effective and time-efficient than de novo drug development and has yielded notable successes in neurological disorders. However, across all medical disciplines, only 30% of repurposed drugs, and 10% of novel candidate molecules, gain market approval. One potentially significant contributor towards this limited success rate is an incomplete knowledge of the exposure-response relationships for the compounds of interest, and how these relate to the new indication, prior to commencing a new trial. We provide an overview of the current approach to early-stage drug repurposing and consider the issues contributing to inconclusive, or possibly falsely negative, Phase II and III trial outcomes in neurological diseases by highlighting examples that illustrate the limitations of empirical evidence generation without a strong scientific basis for the dose rationale. We conclude with a framework suggesting a translational, iterative approach, that integrates pharmacological, pharmaceutical and clinical expertise, towards preclinical and early clinical drug development. This ensures appropriate dosing regimen, route of administration and/or formulation are selected for the new indication before their evaluation in prospective clinical trials.

Polymorphic Phase Transitions in Carbamazepine and 10,11-Dihydrocarbamazepine.

Temperature-induced phase transitions in carbamazepine (CBZ) and 10,11-dihydrocarbamazepine (DHC) were studied by simultaneous differential scanning calorimetry-X-ray diffraction in this work. The transitions generally involve a transitional melt phase which is quickly followed by recrystallisation. The expansions of the unit cell as a function of temperature could be quantified and allow us to determine a directional order of stability in relation to the lattice constants. Dihydrocarbamazepine form II undergoes a conversion to form I by a localised melt phase. Carbamazepine (CBZ) form IV converts to form I at 182 °C, again by a localised intermediate melt phase. CBZ form II converted to form I at 119 °C by a pathway that appears to have included some melting, and form III underwent a part melt-recrystallisation and a part sublimation-recrystallisation to form I.