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RSF thanks the Royal Society for receipt of a URF, EPSRC (EP/N509668/1), and the University of Glasgow for funding. IDHO and MRW thank EPSRC for funding (EP/N015401/1). We acknowledge Diamond Light Source for time on I19-2 under proposal CY24020. ZHD thanks the ERC (Advanced Grant 787073 ADOR) for studentship funding. CLH thanks UKRI for a Future Leaders Fellowship (MR/V026070/1) and the University of Edinburgh for a Chancellor’s Fellowship. SAM acknowledges the support of the Australian Research Council (ARC) from a Future Fellowship (FT200100243) and Discovery Project (DP 220103690). Postsynthetic modification of metal-organic frameworks (MOFs) has proven a hugely powerful tool to tune physical properties and introduce functionality, by exploiting reactive sites on both the MOF linkers and their inorganic secondary building units (SBUs), and so has facilitated a wide range of applications. Studies into the reactivity of MOF SBUs have focussed solely on removal of neutral coordinating solvents, or direct exchange of linkers such as carboxylates, despite the prevalence of ancillary charge-balancing oxide and hydroxide ligands found in many SBUs. Herein, we show that the µ2-OH ligands in the MIL-53 topology Sc MOF, GUF-1, are labile, and can be substituted for µ2-OCH3 units through reaction with pore-bound methanol molecules in a very rare example of pressure-induced postsynthetic modification. Using comprehensive solid-state NMR spectroscopic analysis, we show an order of magnitude increase in this cluster anion substitution process after exposing bulk samples suspended in methanol to a pressure of 0.8 GPa in a large volume press. Additionally, single crystals compressed in diamond anvil cells with methanol as the pressure-transmitting medium have enabled full structural characterisation of the process across a range of pressures, leading to a quantitative single-crystal to single-crystal conversion at 4.98 GPa. This unexpected SBU reactivity – in this case chemisorption of methanol – has implications across a range of MOF chemistry, from activation of small molecules for heterogeneous catalysis to chemical stability, and we expect cluster anion substitution to be developed into a highly convenient novel method for modifying the internal pore surface and chemistry of a range of porous materials. Publisher PDF

How can we improve the current, often iterative tablet formulation process?

AIM: To build fundamental understanding of salt "water bridge" propensity, creation, stability, and structure-property relationships. OBJECTIVE: Use data driven approaches to identify features that promote water bridge formation; characterize the structural features and mechanism of extended stability; discover and characterize new salt water bridge forms to confirm design approaches

The use of high pressure has been shown to be a highly effective route to the discovery and isolation of new solid forms. Typically this is achieved within a diamond anvil cell (DAC) with a single crystal subject to compression, or grown from a compressed solution. Single crystal studies are ideal to elucidate structural changes with pressure; however, bulk properties of the sample material, i.e. a powder, can not be readily obtained. In our lab, we have an additional capability to perform high pressure experiments in a large volume press (LVP), capable of providing ~ 1GPa pressure to materials on the gram scale. These two sample environments can be used to study the effect of high pressure on crystal structure and also the bulk material properties e.g. phase composition, rheology and dissolution.

CO2 isotherms for FMOF-1 reveal 11.0 mol L–1 max uptake and suggest framework expansion, substantiated by in situ neutron diffraction and GCMC simulations., FMOF-1 is a flexible, superhydrophobic metal–organic framework with a network of channels and side pockets decorated with –CF3 groups. CO2 adsorption isotherms measured between 278 and 313 K and up to 55 bar reveal a maximum uptake of ca. 6.16 mol kg–1 (11.0 mol L–1) and unusual isotherm shapes at the higher temperatures, suggesting framework expansion. We used neutron diffraction and molecular simulations to investigate the framework expansion behaviour and the accessibility of the small pockets to N2, O2, and CO2. Neutron diffraction in situ experiments on the crystalline powder show that CO2 molecules are favourably adsorbed at three distinct adsorption sites in the large channels of FMOF-1 and cannot access the small pockets in FMOF-1 at 290 K and oversaturated pressure at 61 bar. Stepped adsorption isotherms for N2 and O2 at 77 K can be explained by combining Monte Carlo simulations in several different crystal structures of FMOF-1 obtained from neutron and X-ray diffraction under different conditions. A similar analysis is successful for CO2 adsorption at 278 and 283 K up to ca. 30 bar; however, at 298 K and pressures above 30 bar, the results suggest even more substantial expansion of the FMOF-1 framework. The measured contact angle for water on an FMOF-1 pellet is 158°, demonstrating superhydrophobicity. Simulations and adsorption measurements also show that FMOF-1 is hydrophobic and water is not adsorbed in FMOF-1 at room temperature. Simulated mixture isotherms of CO2 in the presence of 80% relative humidity predict that water does not influence the CO2 adsorption in FMOF-1, suggesting that hydrophobic MOFs could hold promise for CO2 capture from humid gas streams.

Understanding the mechanism of interaction between pharmaceutical molecules (APIs) and impurities on crystal surfaces is a key concept in understanding purification and for the design of pharmaceutical crystallization processes. Several techniques may be used to study crystal surface properties, such as scanning electron microscopy (SEM) and X-ray photoelectron spectroscopy (XPS), which provide detailed imaging and elemental surface characterization. Time of flight secondary ion mass spectrometry (TOF-SIMS) is valuable in determining molecular identity and distribution. By combining TOF-SIMS, SEM, and optical (OM) and Raman microscopies, we can evaluate the usefulness of TOF-SIMS as a surface characterization technique for pharmaceutical crystals. 4-Nitrophenol has been selected as an impurity that can be incorporated during crystallization of acetaminophen (paracetamol). This study explores the distribution of impurity and its concentration on the different crystal faces of samples obtained by crystallization over a range of impurity loadings and supersaturation conditions. Raman maps of paracetamol single crystal faces were analyzed using the characteristic Raman peak intensity of 4-nitrophenol to identify regions where it accumulated; Raman maps of three single crystals produced in the presence of 4-nitrophenol using different crystallization procedures highlight how it can be difficult to detect very low concentrations of similar chemical species. In contrast, the 4-nitrophenol monoisotopic mass obtained via TOF-SIMS was shown to be detectable in all the three single crystals produced. This indicates that TOF-SIMS can be a valuable technique for single crystal impurity distribution mapping even when the impurity concentration is very low.

The understanding and optimisation of particle morphologies is a common objective for particle engineering approaches either to improve material-handling in the manufacturing process or to influence Critical Quality Attributes (CQAs) linked to product performance. This study demonstrates the rational development of pharmaceutical formulations by conducting single particle experiments to investigate the range of achievable particle attributes across a pragmatic design space. An acoustic levitator was employed to provide a container-less particle design environment for single droplet drying experiments with starting droplet volumes between 10 ul – 80 ul. The temperature and humidity was controlled by an enclosure. The system gave access to characterise the particle formation and subsequent drying process using thermal and high speed imaging techniques. The dried particles were subject to visual and quantitative analysis using nano-focused x-ray tomography to allow a three-dimensional structural description. Extracted morphological descriptors of each particle have been related to solid phase nucleation and growth kinetics. Special emphasis of this study is the evaluation of the solid phase porosity, structural thickness and crystallinity influenced by the solidification from solution and with an impact on key particle performance attributes such as mechanical stability, manufacturability, solubility and solid state stability. Formulations of an active pharmaceutical ingredient with polymeric excipients have been developed to address challenges of a highly crystalline solid with large elongated primary particles. The formulated particles exhibited significantly improved structural modifications leading to an increased mechanical stability, (partially) suppressed crystallinity and tailored dissolution rates. The overall observed diversity of particle properties obtained from single droplet experiments for changing compound systems expressed the importance of an in-depth characterisation of the solidification process prior to process implementation. In summary this study combined the capabilities of an acoustic levitation system and a nano-focused x-ray tomograph to provide a platform to investigate the particle formation and allows a morphological characterisation on a single droplet scale. A comprehensive study enables the development of a mechanistic understanding for a rational particle design approach of novel compound systems targeting critical particle properties influencing particle performance. The fundamental knowledge gained from this method can then be transferred to develop a design space for process applications involving particle formation and drying such as spray drying.