Towards Continuous Primary Manufacturing Processes—Particle Design through Combined Crystallization and Particle Isolation

Integrated continuous manufacturing processes of active pharmaceutical ingredients (API) provide key benefits concerning product quality control, scale-up capability, and a reduced time-to-market. Thereby, the crystallization step, which is used in approximately 90% of API productions, mainly defines the final API properties. This study focuses on the design and operation of an integrated small-scale process combining a continuous slug flow crystallizer (SFC) with continuous particle isolation using the modular continuous vacuum screw filter (CVSF). By selective adjustment of supersaturation and undersaturation, the otherwise usual blocking could be successfully avoided in both apparatuses. It was shown that, during crystallization in an SFC, a significant crystal growth of particles (Δd50,3≈ 220 µm) is achieved, and that, during product isolation in the CVSF, the overall particle size distribution (PSD) is maintained. The residual moistures for the integrated process ranged around 2% during all experiments performed, ensuring free-flowing particles at the CVSF outlet. In summary, the integrated setup offers unique features, such as its enhanced product quality control and fast start-up behavior, providing a promising concept for integrated continuous primary manufacturing processes of APIs.

Novel combined crystallization plate for high-throughput crystal screening and in situ data collection at a crystallography beamline

In situ microplates are small in size, crystal cultivation and operation are difficult, and the efficiency of crystal screening is relatively low. To solve this problem, a novel combined crystallization plate was designed for high-throughput crystal cultivation and in situ data collection. A frame was used to hold 48 in situ microplates, and the in situ microplates were sealed on one side with an ultralow background-scattering Kapton film. An automatic liquid handler (Mosquito) was used to add a liquid drop to the in situ microplates in the frame, and CrystalClear HD tape was used to seal the frame. A sealed frame holding 48 microplates was developed as a novel combined crystallization plate and was used for crystal cultivation under different conditions and in situ data collection at the synchrotron beamline. Moreover, individual microplates can be separated from the combined crystal plate and then fixed on a magnetic base or loaded onto a UniPuck for in situ data collection. Automatic grid scanning was used to locate crystals. The efficiency of the combined crystallization plate for crystal screening was verified. This method avoids the manual manipulation of crystals during crystal screening and diffraction data collection; therefore, the combined crystallization plate is suitable for large-scale screening of microcrystals.

Proton-conducting ceramics based on barium hafnate and cerate doped with zirconium, yttrium and ytterbium oxides for fuel cell electrolytes

Nanopowders of the compositions BaHf1 – xYbxO3 – δ (x = 0.04; 0.08; 0.10) and BaCe0.9 – xZrxY0.1O3 – δ (x = 0; 0.5; 0.6; 0.7 and 0.8) were synthesized by the combined crystallization and nitric acid salts using the citrate-nitrate method. Those nanopowders were used to produce ceramic materials with a cubic crystal structure of the perovskite type, with a grain size of ~ 20 – 70 nm. The study of electrophysical properties revealed that they have a proton type of conductivity in the temperature range of 500 – 700 °C; σ = 10–2 – 10–5 Cm/cm. Type and mechanism of electrical conductivity of ceramics of the composition BaHf1 – xYbxO3 – δ (x = 0.04; 0.08; 0.10) have been studied both experimentally and using theoretical calculations-by computer modeling using the electron density functional method; the results are in good agreement. The research shows the prospects of using the obtained ceramic materials as proton-conducting electrolytes of solid-oxide fuel cells.

Combining Surface Templating and Confinement for Controlling Pharmaceutical Crystallization

Poor water solubility is one of the major challenges to the development of oral dosage forms containing active pharmaceutical ingredients (APIs). Polymorphism in APIs leads to crystals with different surface wettabilities and free energies, which can lead to different dissolution properties. Crystal size and habit further contribute to this variability. An important focus in pharmaceutical research has been on controlling the drug form to improve the solubility and thus bioavailability of APIs. In this regard, heterogeneous crystallization on surfaces and crystallization under confinement have become prominent forms of controlling polymorphism and drug crystal size and habits; however there has not been a thorough review into the emerging field of combining these approaches to control crystallization. This tutorial-style review addresses the major advances that have been made in controlling API forms using combined crystallization methods. By designing templates that not only control the surface functionality but also enable confinement of particles within a porous structure, these combined systems have the potential to provide better control over drug polymorph formation and crystal size and habit. This review further provides a perspective on the future of using a combined crystallization approach and suggests that combining surface templating with confinement provides the advantage of both techniques to rationally design systems for API nucleation.

A Method for Calculating a Batch Crystallizer

On the basis of a mathematical model of a combined crystallization process and a chemical reaction, an engineering method for calculating the crystallization process was developed using the example of an aqueous solution of the target substance 4,4'-di-[4"-chlor-6"-(n-sulfoanilino)-symmetric triazine-2"-ylamino]-stilbene-2, 2'-disulfonic acid of tetrasodium salt (sodium salt of Belofor).