DEVELOPMENT OF A VERSATILE CONTINUOUS-FLOW CRYSTALLIZER

The aim is to develop and test a versatile continuously operated crystallizer system, which is based on the growth of seeds to product particles in a tube. Due to the tubular appearance and the small inner dimensions of the crystallizer in the few millimeter range, it is possible to adjust the temperatures along the tubing according to the needs of the crystallization. Thus, the product can be manipulated under controlled conditions. Furthermore narrow residence time distributions of the crystals in the tube result in narrow crystal size distributions (CSDs) of the product particles. The process should be applicable for fine chemicals, food supplements and especially for manufacturing active pharmaceutical ingredients (APIs). Both, particle shape and size have an influence on the solubility of an API-particle and hence on the bioavailability of the substance. Thus, bulk properties such as the crystal size and shape distribution (CSSD) are important quality attributes of powders. Furthermore, downstream processes (e.g., filtering, washing, drying etc.) and the handling abilities (e.g., flowability, tabletability) of the particles are positively affected by narrow CSDs and favorable crystal shapes. Furthermore the polymorph modification of the crystalline product needs to be controlled tightly since different crystal structures result in different physical properties of the particles and often in different crystal shapes. Again bioavailability and product handling may be compromised. Size, shape as well as the corresponding distributions, and polymorphic modification are important product quality attributes. In order to obtain product crystals with desired features it is important to control numerous critical process parameters (CPP) during a crystallization unit operation. CPP that can be controlled tightly and adjusted individually in order to affect the outcome of the crystallization process in the tube include (i) seed loadings, (ii) temperatures, (iii) cooling gradients, (iv) solution concentrations and the (v) residence time of the crystals in the tubing (i.e.; altering flow rates of the suspension in the tubing or lengths of the tubing respectively). Additionally solvent mixtures or additives to affect solvate formation or shapes of product crystals can be employed. The simple tubular geometry with the small diameter allows for online control of the entire feed- and product stream in respect to the CPP and the quality attributes of the final crystals. Thus, many ideas of the process analytical technology (PAT) and quality by design (QbD) initiatives can be realized in this novel continuous crystallization concept. Moreover this crystallizer system can be, if combined with additional reactor segments, used to develop multi-layer or coated crystals with highly defined properties. The continuous tubular crystallizer will be tested for several substances and the influence of the CPP on the quality attributes of the product particles. Despite the small geometry the system should be able to handle considerable amounts of product in a g/min. scale. Simulations concerning the liquid- (differential mass and heat transfer) and solid phase (population balance equation) will be performed. This will help to design the experiments and to develop and understand a robust continuous crystallization process in the flow through device.

Within the framework of the project Development of a versatile continuous-flow crystallizer at the Institute of Process and Particle Engineering at the TU Graz weve been working on the establishment of a continuous crystallizer for active pharmaceutical ingredients (APIs). More than 90% of all APIs are processed in the crystalline state and therefore the development of a high-throughput facility including tailoring of the compounds particle properties was pursued. Important quality attributes of the final products used in the pharmaceutical industry include the dissolution and disintegration rate, the stability and the flowability as well as the compactibility and tabletability. All of these are closely dependent on crystal properties such as crystal shape, size and size distribution. Using a tubular set-up, primary studies covered the establishment of a robust process for continuous cooling crystallization. During cooling crystallization efficient temperature control was accomplished using simple water baths to remove heat of crystallization for growth of acetylsalicylic acid (ASA) seeds to product crystals within a short residence time. Tests for various flow rates and hence varying residence times confirmed the feasibility of the concept in these proof-of-concept studies. During follow-up studies our group revealed the effect of different seed loadings on the product quality. Several cooling sections to control the temperature profile inside the tubular crystallizer allowed tight regulation of the supersaturation trajectory. Hence, an optimum between sufficiently fast crystal growth, high purity, length of crystallizer and flow rate could be established by adjusting the temperature profile. In this context, tests were performed with decreased flow rates and increased tube lengths of up to 50 m to realize residence times of up to 15 min. Here, limitations of this former set-up became visible, as excessive slow flow rates led to sedimentation of particles in the tube and, ultimately, led to plugging. As a consequence the focus of further development was laid on minimizing the crystals residence time distribution and enhancing particle transport through the tube. Again, our group was among the first to realize gas-liquid segmented flow for tubes in the millimeter range. Due to density differences between solution and solids, crystals tend to settle to the bottom of the tube as they become larger, eventually running the risk of blocking the tube. Introduction of air bubbles proofed to be efficient in transporting particles along the crystallizer, resulting in much smaller crystal size distribution. To proof this concept, proteins, showing an exceptionally slow crystal growth, were chosen as a substrate and constant particle sizes could be achieved despite the low flow rates (< 0.5 mL/min), illustrating the efficient support of particle transport.To account for the topic of automatization a model-free control strategy was developed for seeded crystallization, being able to manipulate product crystal size in intervals of 10m by altering the ratio of feed solution and seed suspension pumped into the crystallizer. By using a device for online continuous crystal size measurements a feedback controller could be developed, facilitating the production of desired product crystals within a size range of 90 140 m.