M. Schoenitz

Controlled polymorphic transformation of continuously crystallized solid lipid nanoparticles in a microstructured device: A feasibility study

The contribution describes the transfer from a batch to a micro-continuous process for the production of stable solid lipid nanoparticles as drug carrier systems. Solid lipid nanoparticles are commonly prepared batch-wise often resulting in poorly defined product qualities with regard to the polymorphic state of their lipid matrix. In order to obtain solid lipid nanoparticle dispersions that meet the requirements for an acceptable pharmaceutical product, the manufacture of reproducible product qualities preferably containing the stable crystal form of the respective matrix lipid is necessary. These requests are addressed by the continuous preparation process of solid lipid nanoparticles. A four step feasibility study for the standardized evaluation whether or not a colloidal lipid dispersion is suitable for continuous crystallization of the particles resulting in stable crystal forms is presented. The process is based on the continuous crystallization and subsequent thermal treatment of differently stabilized, tripalmitin-based nanoparticle formulations in microstructured devices. The successful production of the stable crystal form by means of a continuous process chain is shown for a dispersion stabilized with a blend of hydrogenated soybean lecithin and sodium glycocholate.

Evaluation of a Cleaning Procedure for Micro-Structured Devices by Optical Inspection

Fouling and cleaning evaluations are commonly performed integrally, for instance, via pressure drop measurements of selected devices. For micro-structured devices, local fouling and cleaning behavior is of great interest due to the reduced dimensions and characteristic lengths of some hundred micrometers, which can lead to totally blocked microchannels. In this work, a method for local visual cleaning evaluations in microchannels was investigated. It is based on a visually accessible micro heat exchanger with a digital microscope that can be moved to different observation points within one experiment. Captured images are converted via a MATLAB® (The MathWorks, Natick, Massachusetts, USA) algorithm into black-and-white images containing only one descriptor for each pixel: soiled (black) or clean (white). The soil coverage is then calculated through the ratio of black pixels to the number of all pixels in the regarded images. It is shown that the method is suitable for on-line monitoring of cleaning progress in microchannels. Different developments in the calculated soil coverage are discussed. Decreasing soil coverage is found for successful cleaning methods; increasing soil coverage is found for blocked sections, which act like a filter for upstream detached particles or agglomerates; and constant soil coverage is found for sections with no change in soiled surface area. Gas bubble growth at attached particles for nucleation are found in sudden and short increases of the soil coverage.

Fouling in a Micro Heat Exchanger During Continuous Crystallization of Solid Lipid Nanoparticles

During the continuous crystallization of various solid lipid nanoparticle (LNP) formulations, certain formulations lead to fouling and blocking of small passages in the applied micro heat exchanger. In order to investigate the fouling behavior of different LNP formulations in detail, integral fouling evaluations by pressure drop measurements were performed. Results show more fluctuations compared to particle fouling experiments in macro devices. These variations result from detached agglomerates from compounds formed in micro devices in the inlet header regions, breaking off randomly due to shear stress. This results in downstream microchannel blockage, in the transfer tubings or in subsequent unit operations. During corresponding cleaning experiments different observations compared to macro dimensions were made: Based on significant lower ratios of characteristic dimension of the microchannel to particle or agglomerate diameter, agglomerates remain in the microchannels, preventing smaller particles from being washed off (i.e., capturing effect). Furthermore, low Reynolds numbers, high surface-to-volume ratios, and small characteristic dimensions may result in a total blockage of microchannels.

Early process development of API applied to poorly water-soluble TBID

Graphical abstract Figure. No Caption available. ABSTRACT Finding and optimising of synthesis processes for active pharmaceutical ingredients (API) is time consuming. In the finding phase, established methods for synthesis, purification and formulation are used to achieve a high purity API for biological studies. For promising API candidates, this is followed by pre‐clinical and clinical studies requiring sufficient quantities of the active component. Ideally, these should be produced with a process representative for a later production process and suitable for scaling to production capacity. This work presents an overview of different approaches for process synthesis based on an existing lab protocol. This is demonstrated for the production of the model drug 4,5,6,7‐tetrabromo‐2‐(1H‐imidazol‐2‐yl) isoindolin‐1,3‐dione (TBID). Early batch synthesis and purification procedures typically suffer from low and fluctuating yields and purities due to poor process control. In a first step the literature synthesis and purification procedure was modified and optimized using solubility measurements, targeting easier and safer processing for consecutive studies.

In-Process Cleaning of a Micro Heat Exchanger With Ultrasound During the Continuous Crystallization of Solid Lipid Nanoparticles

Process intensification by the application of microscale process engineering in reaction and heat transfer processes provides the opportunity of moving from batch to continuous manufacturing, mainly due to enhanced heat and mass transfer. These effects are primarily caused by the very high surface to volume ratio in microstructured devices. Further advantages, particularly suitable for sensitive products, are the low shear stress in the typically occurring laminar regime and the short residence time. The crystallization of drug carrying lipid nanoparticles (LNP) is a typical batch process for pharmaceutical products and is used here to demonstrate benefits, challenges and application possibilities of the conversion into a continuous microscale process. During the continuous crystallization of various LNP formulations in a micro-crystallizer, designed as a micro heat exchanger with square channels, several formulations led to fouling and blocking of small passages in the micro heat exchanger. To investigate the fouling behavior of different LNP formulations in detail, integral pressure drop measurements over the micro heat exchanger were performed. This contribution addresses the in-process cleaning of a micro heat exchanger for the continuous crystallization using ultrasound. Different ultrasound amplitudes and operation procedures were investigated. During processing the overall pressure drop was decreased significantly by induced ultrasound pulses. The investigations showed that in-process cleaning of a micro heat exchanger with ultrasound is possible for screening as well as for long term production of LNP. Also the product quality, given by the particle size and particle size distribution, is not affected by the ultrasound input.Copyright