Process Intensification in Crystallization: Submicron Particle Generation Using Alternative Energy Forms

Abstract

Crystallization is one of the oldest separation and product formation techniques that continues to be in use today. Despite its long history, it only started to develop significantly in the past few decades. In this thesis, the application of Process Intensification in crystallization is investigated. Process Intensification is a set of often radically innovative principles in process and equipment design, which can bring significant benefits in terms of process and chain efficiency, capital and operating expenses, quality, wastes, process safety, etc. Alternative energy forms as basic elements of Process Intensification are investigated by applying electric fields and plasma technology in crystallization processes. Three main topics are discussed in this thesis: a) Submicron-sized and nano-sized particles can have beneficial product properties compared to conventionally sized crystalline products. Electrospray Crystallization, an advanced crystallization technique can serve as a tool to produce such submicron-sized particles. In this thesis, it was investigated whether electrospray crystallization can be used to produce 1. energetic materials with a reduced sensitivity and 2. submicron-sized pharmaceutical compounds for improved dissolution and absorption. Electrospray crystallization of a solution is an integrated process of spraying and crystallization that uses a high voltage to produce a fine aerosol of droplets in the micron-size range. During the process, the emitted solvent droplets evaporate and a droplet disruption process (Coulomb-fission) occurs, which creates even smaller droplets. Due to solvent evaporation, eventually supersaturation is achieved and crystals of submicron particles can commence. Electrospray crystallization is an efficient, cost-effective and simple method for the production of submicron-sized crystals, but it suffers from a low production rate and it could be challenging to scale up. In this thesis, the process parameters for establishing a stable jet for producing submicron-sized particles were determined. The operation window to establish a continuous jet and produce submicron-sized crystals is relatively narrow, but experimentally feasible to maintain. Energetic crystals of RDX and HMX were produced with a mean size of around 500 nm by electrospray crystallization. The produced explosive crystals were tested for impact and friction sensitivity. The samples were remarkably insensitive to friction stimuli, while an insignificant difference for the impact sensitivity was observed. With similar process parameters, submicron-sized crystals of a poorly water-soluble active pharmaceutical ingredient, niflumic acid, were produced. In the absence of excipients, for the case of the submicron-sized niflumic acid, no significant difference was shown in the dissolution profile compared to the conventional one. However, upon mixing the excipients, D-Mannitol and Poloxamer 188, with the submicron-sized niflumic acid, the dissolution rate of the drug was enhanced. Thus, it is possible to increase the bioavailability of drugs by drastically reducing the crystal size, while preventing their aggregation by using the proper excipients. b) Plasma Crystallization is a new crystallization technique, in which an atmospheric pressure cold ionized gas is used to generate submicron-sized crystals. This novel type of plasma, the Surface Dielectric Barrier Discharge (SDBD), is a plasma made by several self-terminating microdischarges on a surface. A nebulizer system sprays the solution aerosol into the plasma with the help of a carrier gas. The plasma charges and heats the droplets. Upon evaporation Coulomb-fission occurs, supersaturation increases, and nucleation and crystal growth take place within the small, confined volume offered by the small droplets. Compared to the electrospray crystallization, much higher production rates can be achieved. The energetic material, RDX, and the active pharmaceutical ingredient, niflumic acid, and its excipient, Poloxamer 188, were produced by plasma crystallization with a significant size reduction compared to the conventional products. While there was no measurable change in the sensitivity of RDX, a substantial increase in the dissolution rate of the submicron niflumic acid crystals was observed in the presence of the plasma-made excipient. c) The effect of a constant high electric field was investigated during the cooling crystallization of isonicotinamide in 1,4-dioxane (Electrostatic Crystallization). Two experimental setups were built in order to examine the electric field effect, with a focus on crystal polymorphism control. An inhomogeneous electric field was generated in a controlled crystallization environment. A Crystalline station with an on-board camera system offered in situ investigation of the experiments. A more homogeneous electric field was generated in a different setup, but without a precise temperature control. Image analysis from the Crystalline station experiments showed that the applied electric field induced fluid motion of the solution due to the Lorentz-force acting on the isonicotinamide molecules in solution. This induced fluid dynamics was further visualized by using a suspension of the isonicotinamide-1,4-dioxane system. Image analysis also showed that the nucleation was localized to the anode, and crystals were formed only on the anode surface. The electric field generated a concentration gradient, with the highest solution concentration around the anode. The crystal growth rate was also measured with the help of the on-board camera system. It was found that in the presence of the electric field, the growth rate of the isonicotinamide crystals formed on the anode is 15 times higher than in the absence of the electric field. From this crystal growth rate increase, the local supersaturation ratio increase was estimated at the anode, and found to be at least 2.5 times higher in the presence of the electric field, than in the absence. In the absence of the electric field, the metastable, chain-like form I isonicotinamide was crystallized in both experimental setups. In the inhomogeneous electric field, both form I and form II of isonicotinamide were crystallized. By applying a more or less homogeneous, constant electric field during the crystallization, only the stable form II was formed. In addition, concerns regarding the reliability of standard small-scale sensitivity tests methods for submicron-sized explosives were discussed in this thesis, since the obtained results for the produced explosive materials are questionable. In order to test the quality of the produced submicron-sized energetic materials, a series of small-scale sensitivity tests were carried out. Impact and friction sensitivity tests and ballistic impact chamber test were performed to determine the product sensitivity. Concerns were found with the standard friction and ballistic impact chamber sensitivity test methods, and suggestions were made to improve these tests. The friction sensitivity for all submicron-sized crystals showed no ignition even at the highest possible load. The ballistic impact chamber tests showed also no or only partial ignition with all the submicron-sized explosives. The submicron-sized crystals were distributed among the grooves of the porcelain plate used in the friction test or among the sand grains of the sandpaper used in the ballistic impact chamber test. There is a need to revisit the ignition mechanism of these sensitivity test methods, and make suggestions for accurate measurement methods for the sensitivity of nano-sized explosives. Recommendations have been suggested to develop new tests that only rely on the interactions between the particles making them applicable to conduct the sensitivity tests for submicron/nano-sized energetic materials. A friction initiation setup as developed at TNO more than 30 years ago, might be a technique that could provide a more reliable measurement of the friction sensitivity of submicron- or nano-sized energetic materials by allowing only the frictional heating between the sample particles and exclude any other sources of frictional heating, allowing more reliable results.