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CHAPTER 1
Nucleation and Crystal Growth in Continuous Crystallizationā
John McGinty a , Nima Yazdanpanah*b , Chris Price a , Joop H. ter Horst a and Jan Sefcik a
a EPSRC Centre for Innovative Manufacturing in Continuous Manufacturing and Crystallisation, University of Strathclyde, Glasgow, UK
b Department of Chemical Engineering, Massachusetts Institute of Technology, USA,
*E-mail:
[email protected] This chapter discusses the fundamental aspects of nucleation and particle formation in the continuous crystallization context, with a main focus on nucleation and crystal growth. The classic crystallization phenomena, fundamental, thermodynamic or kinetic driven, will not be covered here. The primary and secondary nucleation, and some methods of nuclei generation in continuous crystallization are discussed in this chapter. The performance of continuous crystallization processes and challenges with process kinetics and control (such as seeding, mixing, and process dynamics) are also addressed in this chapter.
1.1 Introduction
Continuous crystallization has been a common process in the fine chemicals and petrochemical industries for decades. The advantage of continuous crystallization led other industries to employ the technology on the manufacturing scale. Continuous crystallization processes need smaller process equipment leading to substantial reduction in capital and operating costs. While batch processes can demonstrate significant batch-to-batch variability in product quality, continuous crystallization processes tend to give the continuously created crystals the same process experience, irrespective of their time in production, and therefore are potentially more consistent. Additionally, using a recycle, it is feasible to achieve higher yields in continuous processes. Continuous crystallization also tends to yield lower impurity inclusion in the products due to lower accumulation of impurity in the mother liquor by continuous fresh feed addition.
The pharmaceutical industry is beginning to adopt continuous manufacturing. 1 Although crystallization has been identified as one of the bottlenecks for full adoption of continuous manufacturing as it is considerably slower than the upstream continuous synthesis, 2,4 a number of principal drivers for switching from batch to continuous crystallization have been identified. 5
Continuous crystallization is a collection of sub-processes such as solution feeding, supersaturation generation, heat transfer, evaporation, primary nucleation, secondary nucleation, crystal growth, agglomeration and particle suspension. While it sets the rate of formation of new crystalline particles over which the crystallizing mass is distributed in a continuous crystallization process, the sub-process of crystal nucleation is poorly understood and controlled. 6 Once a supersaturation is created crystallization can commence. Crystallization is a collection of the subprocesses of crystal primary nucleation, crystal growth, secondary nucleation and agglomeration, which are all governed by the prevailing supersaturation as well as other parameters. The rates of these subprocesses determine the crystalline product quality.
In order to achieve enhanced control over the crystal nucleation and growth in a continuous crystallization processes, a higher level of nucleation understanding and control is needed. Nucleation can be circumvented by seeding which is especially useful during start-up to minimize the peak of supersaturation associated with conventional unseeded crystallization and along with this reduce the risk of encrustation forming, as once formed this ultimately limits the duration of a continuous crystallization process. Seed suspension can also be continuously fed into a crystallizer operating at a steady state as an additional input. Continuous nucleators also have been proposed as a workaround technique, as well as in situ milling, or the inherent in situ secondary nucleation in mixed suspension mixed product removal (MSMPR) due to particleāparticle or particleāimpeller attrition.
1.2 Crystal Nucleation
Industrial crystallization involves the formation of a particulate crystalline phase from a thermodynamically metastable solution. 7,8 A continuous crystallization process will have a clear (particle free) undersaturated solution as an input and a slightly supersaturated suspension as an output. The product crystals will need to be generated in the crystallizer by creating the supersaturation driving force for crystallization using an external action.
One of the ways to define the driving force for crystallization is by the
supersaturation ratio
S:
1.1 S = C/C*
The supersaturation ratio S is defined by the concentration C and solubility C* at the current value of the parameters being adjusted to generate supersaturation (temperature, solvent mixture composition, pH etc). [Note: concentration can have various units (e.g., mole fraction or mg per mL solvent), which will result in different values for S and therefore it is important that it is clearly specified which units are used]. The supersaturation can be increased by, for instance, a concentration increase through solvent evaporation or a solubility decrease by decreasing the temperature. Crystal growth would reduce the solution concentration and thus the supersaturation.
If the concentration exceeds the solubility, the supersaturation ratio S > 1, the solution is supersaturated and any crystals present can grow. If the concentration is lower than the solubility (S < 1) the solution is undersaturated and any crystals present will tend to dissolve. At thermodynamic equilibrium the solution is saturated, concentration and solubility are equal (S = 1), any crystals present will be maintained in equilibrium with the flux of molecules arriving and leaving the collective crystal surface being in balance. Since the supersaturation ratio drives the crystallization process, the solubility of a compound is a crucial parameter in the crystallization process design. For instance, a strongly increasing solubility with temperature and a sufficiently small solubility at a low temperature direct the preferred supersaturation generation method towards cooling. In addition, the difference between the inlet concentration and the end point solubility is strongly associated with the yield and productivity of a crystallization process.
Within an industrial crystallization process, crystals can be formed from an initially clear solution (primary nucleation) or due to the presence of parent crystals (secondary nucleation). In turn, primary nucleation generally is divided into homogeneous and heterogeneous nucleation. In a supersaturated solution new crystals can be formed in the absence of crystalline solids of the same substance, which is termed primary nucleation, or in the presence of crystalline solids of the same substance, which is termed secondary nucleation. Primary and secondary nucleation will be discussed in respectively Sections 1.2.1 and 1.2.2. Both primary and secondary nucleation as well as crystal growth kinetics vary widely under thermodynamically metastable conditions. However, the nucleation rate varies over many orders of magnitude while growth rate has more gentle increase with increasing supersaturation. During heterogeneous primary nucleation, the crystals form at surfaces such as dust particles, crystallizer wall, airāsolution interface or deliberately added template particles. Homogeneous primary nucleation takes place in the absence of heterogeneous particles in a clear solution. It is important to note that in the laboratory and more so in large-scale processes on an industrial scale, the presence of many different heterogeneous particles or surfaces is impossible to avoid. Despite their importance, usually no information is available on the amount and kind of heterogeneous particles that are finally responsible for the occurrence of heterogeneous nucleation.
Thus, while an unseeded batch cooling crystallization process usually relies on primary nucleation to provide the crystals, during a continuous crystallization process the omnipresent crystals continuously generate more crystals through secondary nucleation. Only in extreme cases are there indications that homogeneous nucleation is the dominant nucleation mechanism. Introduction of crystals into a crystallization process is based on either nucleation or seeding. Seeding relies on addition of previously formed crystals while nucleation implies birth of new crystals. The nucleation rate expresses the number of new crystals that are generated per unit of time per unit solution volume at a given composition and temperature. Nucleation events could be evenly distributed across the bulk fluid volume. However, it may more often be the case that locally extreme conditions (supersaturation, fluid dynamics, mixing points) lead to local nucleation events. While the resulting suspension is distributed over the entire crystallizer, the generation of crystals through nucleation can be highly localized.
1.2.1 Primary Nucleation
In supersaturated solutions, the nucleation rate varies highly non-linearly with supersaturation. Classical Nucleation Theory describes the supersaturation dependent nucleation rate
J as a function of a supersaturation dependent nucleation barrier
B/ln
2 S:
9,10 1.2 J...
