Demonstrating a Quartz Crystal Microbalance with Dissipation (QCMD) to Enhance the Monitoring and Mechanistic Understanding of Iron Carbonate Crystalline Films.

This paper reports the real time monitoring of siderite deposition, on both Au- and Fe-coated surfaces, using the changes in frequency and dissipation of quartz crystal microbalance with dissipation (QCMD). In an iron chloride solution saturated with carbon dioxide, buffered with sodium bicarbonate to pH 6.8, roughly spherical particles of siderite formed within 15 min, which subsequently deposited on the QCMD crystal surface. Imaging of the surface showed a layer formed from particles ca. < 0.5 µm in diameter. Larger particles are clearly deposited on top of the lower layer; these larger particles are >1 µm in diameter. Monitoring of the frequency clearly differentiates the formation of the lower layer from the larger crystals deposited on top at later times. The elastic moduli calculated from QCMD data showed a progressive dissipation increase; the modeling of the solid-liquid interface using a flat approximation resulted in a poor estimation of elastic and storage moduli. Rather, the impedance modeled as a viscoelastic layer in contact with a semi-infinite liquid, where a random bumpy surface with a Gaussian correlator is used, is much more accurate in determining the elastic and storage moduli as losses from the uneven interface are considered. A further step considers that the film is in fact a composite consisting of hard spherical particles of siderite with water in the vacant spaces. This is treated by considering the individual contributions of the phases to the losses measured, thereby further improving the accuracy of the description of the film and the QCMD data. Collectively, this work presents a new framework for the use of QCMD, paired with traditional approaches, to enhance the understanding of crystal deposition and film formation as well as quantify the often evolving mechanical properties.

Controlling simonkolleite crystallisation via metallic Zn oxidation in a betaine hydrochloride solution.

Zinc oxide nanoparticles, with a hexagonal flake structure, are of significant interest across a range of applications including photocatalysis and biomedicine. Simonkolleite (Zn5(OH)8Cl2·H2O), a layered double hydroxide, is a precursor for ZnO. Most simonkolleite synthesis routes require precise pH adjustment of Zn-containing salts in alkaline solution, and still produce some undesired morphologies along with the hexagonal one. Additionally, liquid-phase synthesis routes, based on conventional solvents, are environmentally burdensome. Herein aqueous ionic liquid, betaine hydrochloride (betaine·HCl), solutions are used to directly oxidise metallic Zn, producing pure simonkolleite nano/microcrystals (X-ray diffraction analysis, thermogravimetric analysis). Imaging (scanning electron microscopy) showed regular and uniform hexagonal simonkolleite flakes. Morphological control, as a function of reaction conditions (betaine·HCl concentration, reaction time, and reaction temperature), was achieved. Different growth mechanisms were observed as a function of the concentration of betaine·HCl solution, both traditional classical growth of individual crystals and non-traditional growth patterns; the latter included examples of Ostwald ripening and oriented attachment. After calcination, simonkolleite's transformation into ZnO retains its hexagonal skeleton; this produces a nano/micro-ZnO with a relatively uniform shape and size through a convenient reaction route.

Needles to Spheres: Evaluation of inkjet printing as a particle shape enhancement tool.

Active pharmaceutical ingredients (APIs) often reveal shapes challenging to process, e.g. acicular structures, and exhibit reduced bioavailability induced by slow dissolution rate. Leveraging the API particles' surface and bulk properties offers an attractive pathway to circumvent these challenges. Inkjet printing is an attractive processing technique able to tackle these limitations already in initial stages when little material is available, while particle properties are maintained over the entire production scale. Additionally, it is applicable to a wide range of formulations and offers the possibility of co-processing with a variety of excipients to improve the API's bioavailability. This study addresses the optimization of particle shapes for processability enhancement and demonstrates the successful application of inkjet printing to engineer spherical lacosamide particles, which are usually highly acicular. By optimizing the ink formulation, adapting the substrate-liquid interface and tailoring the heat transfer to the particle, spherical particles in the vicinity of 100 µm, with improved flow properties compared to the bulk material, were produced. Furthermore, the particle size was tailored reproducibly by adjusting the deposited ink volume per cycle and the number of printing cycles. Therefore, the present study shows a novel, reliable, scalable and economical strategy to overcome challenging particle morphologies by co-processing an API with suitable excipients.

Development of a Workflow to Engineer Tailored Microparticles Via Inkjet Printing.

PURPOSE: New drug development and delivery approaches result in an ever-increasing demand for tailored microparticles with defined sizes and structures. Inkjet printing technologies could be promising new processes to engineer particles with defined characteristics, as they are created to precisely deliver liquid droplets with high uniformity. METHODS: D-mannitol was used as a model compound alone or co-processed with the pore former agent ammonium bicarbonate, and the polymer polyethylene glycol 200. Firstly, a drop shape analyzer was used to characterize and understand ink/substrate interactions, evaporation, and solidification kinetics. Consequently, the process was transferred to a laboratory-scale inkjet printer and the resulting particles collected, characterized and compared to others obtained via an industrial standard technique. RESULTS: The droplet shape analysis allowed to understand how 3D structures are formed and helped define the formulation and process parameters for inkjet printing. By adjusting the drop number and process waveform, spherical particles with a mean size of approximately 100 µm were obtained. The addition of pore former and polymer allowed to tailor the crystallization kinetics, resulting in particles with a different surface (i.e., spike-like surface) and bulk (e.g. porous and non-porous) structure. CONCLUSION: The workflow described enabled the production of 3D structures via inkjet printing, demonstrating that this technique can be a promising approach to engineer microparticles.

Exploring the role of crystal habit in the Ostwald rule of stages.

The crystallization of calcium carbonate is shown to be dictated by the Ostwald rule of stages (ORS), for high relative initial supersaturations ( S CaCO 3 = [ C a 2 + ] [ CO 3 2 - ] / K SP, Calcite > 2500 ), under sweet (carbon dioxide saturated) and anoxic (oxygen depleted) solution conditions. Rhombohedral calcite crystals emerge after the sequential crystallization and dissolution of the metastable polymorphs: vaterite (snowflake-shaped) and aragonite (needle-shaped). However, the presence of certain cations, which can form trigonal carbonates (e.g. Fe2+ and Ni2+), in concentrations as low as 1.5 mM, triggers the emergence of calcite crystals, with a star-shaped crystal habit, first. These star-shaped crystals dissolve to yield needle-shaped aragonite crystals, which in turn dissolve to give the rhombohedral calcite crystals. The star-shaped crystals, formed at high SCaCO3 , possess higher surface free energy (therefore higher apparent solubility) than their rhombohedral counterparts. This sequence of dissolution and recrystallization demonstrates that the ORS does not only drive the crystal towards its thermodynamically most stable polymorph but also towards its most stable crystal habit.

Τhe role of surface energy in the apparent solubility of two different calcite crystal habits.

The interplay between polymorphism and facet-specific surface energy on the dissolution of crystals is examined in this work. It is shown that, using cationic additives, it is possible to produce star-shaped calcite crystals at very high supersaturations. In crystallization processes following the Ostwald rule of stages these star-shaped crystals appear to have higher solubility than both their rhombohedral counterparts and needle-shaped aragonite crystals. The vapour pressures of vaterite, aragonite, star-shaped calcite and rhombohedral calcite crystals are measured using thermogravimetric analysis and the corresponding enthalpies of melting are obtained. Using inverse gas chromatography, the surface energy of the aforementioned crystals is measured as well and the surface energy of the main crystal facets is calculated. Combining the effect of facet-specific surface energies and the enthalpies of melting on a modified version of the classical solubility equation for regular solutions, it is proved that the star-shaped calcite crystals can indeed have higher apparent solubility than aragonitecrystals.

Influences of Crystal Anisotropy in Pharmaceutical Process Development.

Crystalline materials are of crucial importance to the pharmaceutical industry, as a large number of APIs are formulated in crystalline form, occasionally in the presence of crystalline excipients. Owing to their multifaceted character, crystals were found to have strongly anisotropic properties. In fact, anisotropic properties were found to be quite important for a number of processes including milling, granulation and tableting. An understanding of crystal anisotropy and an ability to control and predict crystal anisotropy are mostly subjects of interest for researchers. A number of studies dealing with the aforementioned phenomena are grounded on over-simplistic assumptions, neglecting key attributes of crystalline materials, most importantly the anisotropic nature of a number of their properties. Moreover, concepts such as the influence of interfacial phenomena in the behaviour of crystalline materials during their growth and in vivo, are still poorly understood. The review aims to address concepts from a molecular perspective, focusing on crystal growth and dissolution. It begins with a brief outline of fundamental concepts of intermolecular and interfacial phenomena. The second part discusses their relevance to the field of pharmaceutical crystal growth and dissolution. Particular emphasis is given to works dealing with mechanistic understandings of the influence of solvents and additives on crystal habit. Furthermore, comments and perspectives, highlighting future directions for the implementation of fundamental concepts of interfacial phenomena in the rational understanding of crystal growth and dissolution processes, have been provided.