APPLICATION OF UF TECHNOLOGY TO LARGE-SCALE SYNTHESIS OF GT 267-004, A SEQUESTRANT FOR C. DIFFICILE TOXIN

GT 267-004 is a nonabsorbed, nonantibiotic, high molecular weight anionic polymer that is undergoing clinical evaluation as a Clostridium difficile toxin sequestrant. The API is a mixed salt form that consists of approximately 30 to 50% potassium and 70 to 50% sodium as the counterions on the polymer.

The initial polymerization process results in an aqueous polymer solution with the polymer in the 100% sodium form. It also contains some oligomeric impurities. UF technology was applied in a novel way to convert the single-salt polymer to the mixed salt form and to simultaneously remove the oligomers below the required specification limits in a single-unit operation.

Experiments with a UF lab unit validated the concept of simultaneously performing ion exchange and purification. An appropriate amount of potassium chloride was added to the polymer solution to carry out the ion exchange considering the selectivity of the polymer for the potassium ion over the sodium ion. The resulting mixed salts in solution were removed using ultrafiltration membranes. The process produced the API in excellent purity.

The lab data were used to scale up the process to produce several hundred kg of the API. The engineering analysis of the large-scale UF operation was carried out to run the UF process in the cyclic mode and in the diafiltration mode. The UF operation was optimized with respect to time, water usage, operability, and the concentration of product solution required for the subsequent processing.

The optimized UF process was found to be a very cost-effective and time-efficient route to produce the new API.     

Scale-up of an electrochemical reactor for treatment of industrial wastewater with an electrochemically generated redox mediator

This paper presents the results of a study on the scale-up, from a batch to a continuous flow unit, of an electrochemical reactor applied for the treatment of textile wastewater. Decolourisation of the wastewater bearing a reactive dye Red Procion H-EXGL proceeded via indirect electro-oxidation, mediated by “active chlorine”. The kinetics of decolourisation in a single-cell reactor under different operating conditions were second order, with the highest apparent rate constant (k = 0.523 l mol⁻¹ s⁻¹) achieved at 40 °C. A low Hatta number (Ha = 0.03) indicated that the reaction occurred totally in the bulk solution, hence homogeneous reaction kinetics were used successively to scale-up a continuous flow electrochemical unit: a once-through filter-press reactor. Its hydrodynamic characteristics were defined by the residence time distribution (E(t)) function using a pulse injection method. The decolourisation efficiency experimentally determined in a continuous flow reactor was further compared with that predicted on the basis of the knowledge of the E(t) of the reactor and the homogeneous phase kinetic expression, obtained from the batch study and corrected for the geometric parameters of the reactors. A complete segregation of the fluid inside the flow reactor was assumed. For different applied flow rates, the experimentally defined conversion of the dye was close to the calculated value.     

Model-based scale-up strategy for mycelial fermentation processes

With the aid of a mathematical model describing the interrelationships between mycelial morphology, mycelial growth and product formation, rheology, mass transfer, and environmental conditions, a new scale-up strategy has been developed, simulating the bioreactor performance at different agitation speeds. The simulations have shown that there is an optimum agitation speed, yielding maximum product formation that is different from the conventional scale-up results based on constant P_g/V_T, k_L a and N_I D_I. It has also been shown in the simulations that the product formation scaled up by means of conventional methods is considerably lower than the simulated maximum or is close to the maximum but requiring a higher energy consumption. This indicates that model-based scale-up could be a more accurate and efficient method for scaling up complex systems such as mycelial fermentation processes.     

SCALE-UP OF SPRAY DRYERS

Abstract

Commercial success of a new spray dryer investment depends upon the dryer meeting its specified performance in all respects, and this puts great importance on the scale-up procedures used in the projecting of the new spray dryer. Scale-up still relies heavily on the experience of the designer. However, as the applications and specifications become more and more complex, so does the need for improved test work in pilot plants, and computational fluid dynamics simulations become more important, so that better scale-up tools are available to minimize the possibility for personal errors that may lead to the new dryer investment becoming an unsuccessful commercial venture.     

TURBULENT FLOW IN STIRRED TANKS: SCALE-UP COMPUTATIONS FOR VESSEL HYDRODYNAMICS

A numeric model for turbulent flow was used to compute the flow patterns in Rushton turbine agitated vessels. The cases considered cover two orders of magnitude for the three different scaling criteria of constant impeller Reynolds number, power input per unit mass, and impeller tip speed. The constant power input scale-up criteria maintains the turbulence levels throughout the vessel during scale-up. The circulation times, however, increase with vessel size for this scaling criteria. The other scaling criteria of constant impeller tip speed and impeller Reyonds number lead to decreasing turbulence levels in the tank along with further increases in circulation times.     

Continuous-flow production of a pharmaceutical nanoemulsion by high-amplitude ultrasound: Process scale-up

High-pressure homogenization (HPH, including microfluidization) and high-amplitude ultrasonic processing are currently the leading two methods used to produce nanoemulsions of superior quality. Despite suffering from multiple important drawbacks, HPH is currently the technology of choice for the industrial manufacture of pharmaceutical nanoemulsions. The ultrasonic nanoemulsification technology is free from most of these drawbacks and frequently used in laboratory studies. The challenge for the ultrasonic method, however, has been bridging the gap between laboratory research and its industrial implementation. Due to limitations of conventional ultrasonic technology, scaling up has not been possible without a significant reduction in ultrasonic amplitudes, which compromises product quality. This limitation has been overcome by Barbell Horn Ultrasonic Technology (BHUT), which permits constructing bench and industrial-scale processors capable of operating at high ultrasonic amplitudes. In the present study, a high-quality MF59^®-analog pharmaceutical nanoemulsion has been successfully manufactured using laboratory, bench and industrial-scale high-amplitude ultrasonic processors. The overall laboratory-to-industrial scale-up factor achieved by using BHUT was approximately 55. The ultrasonic amplitude and the resulting product quality were maintained identical at all three scales. To our knowledge, this work is the first reported instance of a successful and systematic industrial scale-up of any high-amplitude ultrasonic process.     

Rational design of the gram-scale synthesis of nearly monodisperse semiconductor nanocrystals

We address two aspects of general interest for the chemical synthesis of colloidal semiconductor nanocrystals: (1) the rational design of the synthesis protocol aiming at the optimization of the reaction parameters in a minimum number of experiments; (2) the transfer of the procedure to the gram scale, while maintaining a low size distribution and maximizing the reaction yield. Concerning the first point, the design-of-experiment (DOE) method has been applied to the synthesis of colloidal CdSe nanocrystals. We demonstrate that 16 experiments, analyzed by means of a Taguchi L₁₆ table, are sufficient to optimize the reaction parameters for controlling the mean size of the nanocrystals in a large range while keeping the size distribution narrow (5-10%). The DOE method strongly reduces the number of experiments necessary for the optimization as compared to trial-and-error approaches. Furthermore, the Taguchi table analysis reveals the degree of influence of each reaction parameter investigated (e.g., the nature and concentration of reagents, the solvent, the reaction temperature) and indicates the interactions between them. On the basis of these results, the synthesis has been scaled up by a factor of 20. Using a 2-L batch reactor combined with a high-throughput peristaltic pump, different-sized samples of CdSe nanocrystals with yields of 2-3 g per synthesis have been produced without sacrificing the narrow size distribution. In a similar setup, the gram-scale synthesis of CdSe/CdS/ZnS core/shell/shell nanocrystals exhibiting a fluorescence quantum yield of 81% and excellent resistance of the photoluminescence in presence of a fluorescent quencher (aromatic thiol) has been achieved.PACS: 81.20.Ka, 81.07.Bc, 78.67.Bf     

Anaerobic treatment of wastewater containing fatty acids in upflow reactors

An extended summary is presented of a Dr.Sc. Thesis in which the results of a study on anaerobic treatment of wastewater containing fatty acids have been reported. This study, concerning the technological features of this process in upflow reactors, was aimed at the following subjects :

• - the dynamics of the fluid flow in the reactor;

• - the dynamic behaviour of the sludge particles in the reactor;

• - the kinetics of the conversion of the fatty acids and of the formation of the products (mainly biogas and anaerobic sludge); and

• - the separation of the gas and the sludge from the treated water.

From the results obtained in experiments on lab-scale and (semi) technical scale, a quantitative model for the operation of the reactor has been derived. This model can be used for scaling-up purposes and for optimisation of the process performance.