Conventional solid oral dosage form development is not typically challenged by reliance on an amorphous drug substance as a direct ingredient in the drug product, as this may result in product development hurdles arising from process design and scale-up, control of physical quality attributes, drug product processability and stability. Here, we present the Chemistry, Manufacturing and Controls development journey behind the successful commercialization of an amorphous drug substance, Elagolix Sodium, a first-in-class, orally active gonadotropin-releasing hormone antagonist. The reason behind the lack of crystalline state was assessed via Molecular Dynamics (MD) at the molecular and inter-molecular level, revealing barriers for nucleation due to prevalence of intra-molecular hydrogen bond, repulsive interactions between API molecules and strong solvation effects. To provide a foundational basis for the design of the API manufacturing process, we modeled the solvent-induced plasticization behavior experimentally and computationally via MD for insights into molecular mobility. In addition, we applied material science tetrahedron concepts to link API porosity to drug product tablet compressibility. Finally, we designed the API isolation process, incorporating computational fluid dynamics modeling in the design of an impinging jet mixer for precipitation and solvent-dependent glass transition relationships in the cake wash, blow-down and drying process, to enable the consistent manufacture of a porous, non-sintered amorphous API powder that is suitable for robust drug product manufacturing.

Cellulose, an abundant biopolymer in nature as a structural component of plant cell walls, has a native semi-crystalline structure in which the arrangement of amorphous-crystalline domains governs its key properties such as mechanical and physico-chemical properties. The performance of the material in different situations is shaped by molecular mobility, which affects attributes such as mechanical properties, chemical reactivity, and water absorption. Nevertheless, it is difficult to investigate experimentally the structural and dynamic properties of cellulose-rich materials. This is especially the case for the glass transition, which impacts its quality and properties. This experimental challenge is notably evidenced by the considerable variability in data across the literature. The purpose of this study is to offer a comprehensive multi-scale exploration of dynamics within cellulose-rich materials, emphasizing literature data on cellulose glass transition and molecular relaxations, and providing insights into methods for characterizing their physical state and underscoring the impact of water-cellulose interactions on molecular mobility in these systems. The promising results obtained using multiple approaches bring out the importance of combining methods to achieve a more accurate and detailed understanding of the complex thermal transition in cellulose materials, particularly when considering the influence of water on their thermal dynamics and properties.

Glassy hybrid metal halides have emerged as promising materials in recent years due to their high structural adjustability and low melting points, offering unique merits that overcome the limitations of their crystalline and polycrystalline counterparts as well as other conventional amorphous semiconductors. This review article comprehensively explores the structural characteristics, electronic properties, and chemical coordination of hybrid metal halides, emphasizing their role in the glass transition from the crystalline phase to the amorphous phase. We examine the intrinsic disorder within the amorphous phase that facilitates light transmission and discuss recent advances in device architecture and interface engineering by optimizing the charge transport of glassy hybrid metal halides for high-quality applications. With full theoretical understanding and rational structural design, potential applications in displays, information storage, X-ray imaging, and sensing are highlighted, underscoring the transformative impact of glassy hybrid metal halides in the fields of materials science and information science.

Analyses of ancient DNA typically involve sequencing the surviving short oligonucleotides and aligning to genome assemblies from related, modern species. Here, we report that skin from a female woolly mammoth (†Mammuthus primigenius) that died 52,000 years ago retained its ancient genome architecture. We use PaleoHi-C to map chromatin contacts and assemble its genome, yielding 28 chromosome-length scaffolds. Chromosome territories, compartments, loops, Barr bodies, and inactive X chromosome (Xi) superdomains persist. The active and inactive genome compartments in mammoth skin more closely resemble Asian elephant skin than other elephant tissues. Our analyses uncover new biology. Differences in compartmentalization reveal genes whose transcription was potentially altered in mammoths vs. elephants. Mammoth Xi has a tetradic architecture, not bipartite like human and mouse. We hypothesize that, shortly after this mammoth\'s death, the sample spontaneously freeze-dried in the Siberian cold, leading to a glass transition that preserved subfossils of ancient chromosomes at nanometer scale.

Densely packed, motile bacteria can adopt collective states not seen in conventional, passive materials. These states remain in many ways mysterious, and their physical characterization can aid our understanding of natural bacterial colonies and biofilms as well as materials in general. Here, we overcome challenges associated with generating uniformly growing, large, quasi-two-dimensional bacterial assemblies by a membrane-based microfluidic device and report the emergence of glassy states in two-dimensional suspension of Escherichia coli. As the number density increases by cell growth, populations of motile bacteria transition to a glassy state, where cells are packed and unable to move. This takes place in two steps, the first one suppressing only the orientational modes and the second one vitrifying the motion completely. Characterizing each phase through statistical analyses and investigations of individual motion of bacteria, we find not only characteristic features of glass such as rapid slowdown, dynamic heterogeneity, and cage effects, but also a few properties distinguished from those of thermal glass. These distinctive properties include the spontaneous formation of micro-domains of aligned cells with collective motion, the appearance of an unusual signal in the dynamic susceptibility, and the dynamic slowdown with a density dependence generally forbidden for thermal systems. Our results are expected to capture general characteristics of such active rod glass, which may serve as a physical mechanism underlying dense bacterial aggregates.

Preserving microbial ecosystems obtained from traditional cheese-making processes is crucial to safeguarding the biodiversity of microbial cheese communities and thus ensuring that the high flavor quality of traditional cheeses is maintained. Few protocols have been proposed for the long-term storage of microbial consortia. This work aimed to develop preservation methods to stabilize the entire microbial community in smear-ripened cheese without multiplication or isolation. A simplified microbial community, capable of reproducing the metabolic pattern of cheese maturation, was used in three independent cheese productions. Cheese samples were taken before and after the ripening step, mixed with maltodextrin or saline solution, and subjected to different stabilization conditions including freezing and freeze-drying, followed by 1 month of storage. Microbial survival was quantified using the colony-forming unit assay. Differential scanning calorimetry was used to relate the physical events occurring within the samples to the microbial storage stability. Freezing at -80 °C resulted in the lowest loss of culturability (<0.8 log unit), followed by freezing at -20 °C and freeze-drying. The ripening bacteria appeared as the most sensitive microorganisms within the community. Moreover, a successful cheese production using the best-stabilized community showed the possibility of preserving and re-using an entire microbial community of interest.

This study investigated the thermal properties of potato and hop pollen for cryopreservation and subsequent cross-breeding. Phase transitions and frozen water content in selected pollen samples were measured using a differential scanning calorimeter (DSC). Unlike hop pollen, potato pollen showed high variability in thermal properties and water content. Three specific types of pollen samples based on their thermal characteristics and water content were distinguished by DSC in potato: (1) \'glassy\', with a water content lower than 0.21 g water per g dry matter; (2) \'transient\', with a water content between 0.27 and 0.34 g of water per g of dry matter; (3) \'frozen\', with a water content higher than 0.34 g of water per g of dry matter. Only the \'glassy\' pollen samples with a low water content showed suitable properties for its long-term storage using cryopreservation in potato and hops. Cryopreservation of pollen did not significantly reduce its viability, and cryopreserved pollen was successfully used to produce both potato and hop hybrids. The results indicate that cryopreservation is a feasible technique for the preservation and utilization of pollen of these crops in the breeding process.

The aim of this work was to investigate wheat gluten protein network structure throughout the deep-frying process and evaluate its contribution to frying-induced micro- and macrostructure development. Gluten polymerization, gluten-water interactions, and molecular mobility were assessed as a function of the deep-frying time (0 - 180 s) for gluten-water model systems of differing hydration levels (40 - 60 % moisture content). Results showed that gluten protein extractability decreased considerably upon deep frying (5 s) mainly due to glutenin polymerization by disulfide covalent cross-linking. Stronger gliadin and glutenin protein-protein interactions were attributed to the formation of covalent linkages and evaporation of water interacting with protein chains. Longer deep-frying (> 60 s) resulted in progressively lower protein extractabilities, mainly due to the loss in gliadin protein extractability, which was associated with gliadin co-polymerization with glutenin by thiol-disulfide exchange reactions. The mobility of gluten polymers was substantially reduced during deep-frying (based on the lower T2 relaxation time of the proton fraction representing the non-exchanging protons of gluten) and gluten proteins gradually transitioned from the rubbery to the glassy state (based on the increased area of said protons). The sample volume during deep-frying was strongly correlated to the reduced protein extractability (r = -0.792, p < 0.001) and T2 relaxation time of non-exchanging protons of gluten proteins (r = -0.866, p < 0.001) thus demonstrating that the extent of gluten structural expansion as a result of deep-frying is dictated both by the polymerization of proteins and the reduction in their molecular mobility.

We report an intriguing example of enantioselectivity in the formation of new multicomponent crystalline solid containing vinpocetine and malic acid. Several experimental data sets confirmed that the multicomponent system presents a clear enantiospecific crystallisation behaviour both in the solid-state and in solution: only the system consisting of vinpocetine and L-malic acid produces a free-flowing solid consisting of a new crystalline form, while the experiments with D-malic acid produced an amorphous and often deliquescent material. The new vinpocetine-L-malic system crystallizes in the monoclinic space group of P21 and in a 1:1 molar ratio, where the two molecules are linked through intermolecular hydrogen bonds in the asymmetric unit. The vinpocetine-DL-malic system was partially crystalline (with also traces of unreacted vinpocetine) with diffraction peaks corresponding to those of vinpocetine-L-malic acid. Solid-state NMR experiments revealed strong ionic interactions in all the three systems. However, while vinpocetine-L-malic acid system was a pure and crystalline phase, the other two systems persistently showed the presence of unreacted vinpocetine. This resulted in a significant worsening of the dissolution profile with respect to the pure vinpocetine-L-malic crystalline salt, whose dissolution kinetics appeared superior.

Water-soluble carbohydrates commonly exist in an amorphous state in foods and undergo glass-rubber transition (glass transition) at the glass transition temperature (Tg). The critical water content (Wc) and critical water activity (awc) are the water content and water activity (aw) at which the glass transition occurs at 298 K (typical ambient temperature), respectively. For amorphous water-soluble carbohydrates, Wc can be predicted from the Tg of anhydrous solid (Tgs) using previously reported equations. However, an approach for predicting awc is still lacking. This study aimed to establish an awc-predictive approach for amorphous water-soluble carbohydrates based on Tgs. First, the water sorption isotherms of four hydrogenated starch hydrolysates were investigated, and the results were analyzed using the Guggenheim-Anderson-de Boer (GAB) model. Second, the effect of Tgs on the GAB parameters (C, K, and Wm) was evaluated using the Tgs values reported in previous literatures. C and Wm decreased and increased logarithmically, respectively, with increasing 1/Tgs. K was fixed to 1 (constant), as it showed little variation. These results enabled the prediction of the GAB parameters from Tgs. The GAB model could then predict awc from Wc, which was determined using the previously established equations. The predicted awc values were in good agreement with the experimentally determined awc. Additionally, we demonstrated that this awc-prediction approach is also applicable to amorphous water-soluble electrolytes and partially water-insoluble carbohydrates. Thus, this approach can be used for the quality control of amorphous water-soluble carbohydrates and carbohydrate-based foods.