If the temperature is above the brittle point preferentially above the T g and the polymer is stretched, the randomly coiled and entangled chains begin to disentangle, unfold, and straighten. This method is called strain-induced crystallization. It occurs when polymers are stretched beyond its yield point. One usually observes a noticeable increase in modulus due to the formation of crystals that act as a physical reinforcements similar to fillers.
Thus when strain induced crystallization occurs, the stress increases as well. The size and structure of the crystals and the degree of crystallinity depend on the type and structure of the polymer, and on the growth conditions. Narrow molecular weight, linear polymer chains, and high molecular weight increase the crystallinity. Crystallinity is also affected by extrinsic factors, like crystallization temperature, cooling rate, and in the case of strain-induced crystallization, by the stretch ratio, strain rate, and by the forming process of the polymer film or fiber.
Nucleating agents such as organic salts, small filler particles and ionomers also affect the crystallization. They act as seeds and can increase the crystallization rate.
The degree of crystallinity also depends on the tacticity of the polymer. The greater the order in a macromolecule the greater the likelihood of the molecule to undergo crystallization. For example, isotactic polypropylene is usually more crystalline than syndiotactic polypropylene, and atactic polypropylene is considered uncrystallizable since the structure of the polymer chain lacks any regularity.
In fact, most atactic polymers do not crystallize. Strong intermolecular forces and a stiff chain backbone favor the formation of crystals because the molecules prefer an ordered arrangement with maximum packing density to maximize the number of secondary bonds. Login processing Previous Video Next Video. Overview Source: Laboratory of Dr. Jimmy Franco - Merrimack College Recrystallization is a technique used to purify solid compounds. Perform all steps in a fume hood to prevent exposure to solvent fumes.
Selecting a Solvent Place 50 mg of the sample N-bromosuccinimide in an Erlenmeyer flask. If the sample dissolves completely, the solubility in the cold solvent is too high to be a good recrystallization solvent. If the sample does not dissolve in the cold solvent, heat the test tube until the solvent boils. If the sample has not completely dissolved at this point, add more boiling solvent drop-wise, until all of the solid dissolves.
If it takes more than 3 mL to dissolve the sample in the hot solvent, the solubility in this solvent is probably too low to make it a good recrystallization solvent.
If the first choice of solvent is not a good recrystallization solvent, try others. If a single solvent that works cannot be found, try a two solvent system. If you cannot find a suitable single solvent system, then a solvent pair may be necessary.
When identifying a solvent pair, there are several key considerations 1 The first solvent should readily dissolve the solid. As a general rule "likes dissolve likes" meaning that polar compounds tend to be soluble in polar solvents and non-polar compounds are often more soluble non-polar compounds.
Also make sure the boiling point of the solvent is lower than the melting point of the compound, so the compound forms as solid crystals rather than as an insoluble oil. Confirm that the impurities are either insoluble in the hot solvent so they can be hot-filtered out, once the compound is dissolved or soluble in the cold solvent so they stay dissolved during the entire process. This is a better choice than a beaker, since the sloping sides help trap solvent vapors and slow the rate of evaporation.
Place the solvent water in a separate Erlenmeyer flask, and add boiling chips or a stir bar to keep it boiling smoothly. Heat it to boiling on a hotplate. Add hot solvent to a flask at room temperature containing the compound in small portions, swirling after each addition, until the compound is completely dissolved. During the dissolution process, keep the solution hot at all times by resting it on the hotplate, too. Do not add more hot solvent than necessary - just enough to dissolve the sample.
If a portion of the solid does not seem to dissolve, even after more hot solvent has been added, it is likely due to the presence of very insoluble impurities. If this happens, stop adding solvent and do a hot filtration before proceeding. To perform a hot filtration, fold a piece of filter paper into a fluted cone shape and place it into a glass stemless funnel. Pour the solution through the paper. If crystals begin to form at any time during the process, add a small portion of warm solvent to dissolve them.
Cooling the Solution Set the flask containing the dissolved compound on a surface that does not conduct the heat away too quickly, such as a paper towel set on a benchtop. Lightly cover the flask as it cools to prevent evaporation and to prevent dust from falling into the solution. Leave the flask undisturbed until it cools to room temperature. Once the crystals have formed, place the solution in an ice bath to ensure that the maximum amount of crystals is obtained. The solutions should be left undisturbed in the ice bath for 30 min to 1 h, or till the compound appears to have completely crystalized out of solution.
If no crystal formation is evident, it can be induced by scratching the inside walls of the flask with a glass rod or by adding a small seed crystal of the same compound. If this still fails to work, then too much solvent was probably used. Reheat the solution, allow some of the solvent to boil off, then cool it. Isolating and Drying the Crystals Set the cold flask containing the newly formed crystals on a benchtop.
Lightly cover the flask to prevent evaporation and to prevent dust from falling into the solution. To dry the crystals, leave them in the filter funnel and draw air through them for several minutes.
Crystals can also be air-dried by allowing them to stand uncovered for several hours or days. More efficient methods include vacuum drying or placing in a desiccator. Common solvent pairs.
Recrystallization is a purification technique for solid compounds. To begin this procedure, place 50 mg of the sample in a glass test tube. Purification by recrystallization is an important tool for chemical synthesis and analysis. Thanks for watching!
Please enter your institutional email to check if you have access to this content. Please create an account to get access. It is only when enough time is allowed for equilibration between the developing solid and the solution that the lowest energy pure solid is formed. The prize rules state that you're only allowed to keep a total of twenty bills. In a similar way, the crystallization process can be though of as the crystal lattice "grabbing" solutes from solution. If the process is hurried, solutes may be "grabbed" indiscriminately, and once embedded in the interior of the solid they become trapped as the equilibrium between solid and solution happens only on the surface.
When the amplitude of the sound wave is sufficiently large cavitation occurs and bubbles form from the release of dissolved gas and evaporated solvent vapor. These bubbles shrink during the compression phase and then they expand again during the subsequent rarefaction phase as the sound wave propagates this repeating oscillation is known as stable cavitation. If the amplitude of the sound wave is large enough bubbles of solvent vapor form during the rarefaction.
These bubbles can coalesce and transient cavitation may occur. This transient cavitation phenomenon is linked with triggering nucleation. Much of the literature relates to aqueous solutions where the range over which transient cavitation is possible is limited to about 15—20 cm from the acoustic source, due to the shielding effect of cavitation bubbles reducing the intensity of insonation further from the acoustic source.
This results in a design constraint for large scale operation. Tubular geometries with multiple acoustic sources are required to insonate large volumes with a maximum duct diameter of around 40 cm. There are a number of reported applications with APIs in organic solvents for example, however the essential physical data required for modelling i.
A consequence of the lack of fundamental measurements linking the underlying physics of ultrasound with measured intensity maps is that the approaches to process development are structured but empirically based. Early pharmaceutical applications of ultrasound in crystallization include Pfizer's patent to reduce the crystal size of procaine penicillin. Wyeth's Hem investigated mechanisms by which ultrasound might be effective in producing small uniform crystals and suggested that the beneficial effects of ultrasound on crystallization are linked to cavitation arising from the passage of ultrasound thorough the solution.
Howard Anderson et al. It relates to evaporative crystallization of adipic acid from aqueous solution and significantly was applied at manufacturing scale. Whilst not typically a continuous process, a particularly attractive application for the pharmaceutical industry is reliably triggering nucleation in a sterile environment. The resulting controlled nucleation was shown to deliver more consistent particles than in the equivalent unseeded process and since conventional seeding is not favored in sterile manufacture, due to the risk of introducing biological contamination, this is clearly beneficial.
Application of continuous wave 42,43 or pulsed lasers 44,45 can dramatically shorten induction times in a wide range of solutions. In principle, this provides an intriguing opportunity for accurate spatial and temporal control of nucleation in both batch and continuous systems.
Furthermore, laser-induced nucleation can lead to different polymorphs being nucleated compared to identical solutions in the absence of lasers. As laser-induced nucleation has been reported for systems which were not significantly absorbing light at the laser wavelengths used, this phenomenon does not necessarily involve photochemical effects. For pulsed lasers, it has been established that a certain threshold laser power is needed to induce nucleation 47,48 and that the probability of nucleation can further increase with increasing laser power.
It has been also observed that the probability distribution of induction time in laser irradiated glycine solutions shows bi-exponential distribution, where a certain fraction of samples undergo fast laser-induced nucleation while the rest undergo much slower spontaneous nucleation. However, the mechanism of laser-induced nucleation in the absence of a photochemical effect is not yet clear. Several mechanisms have been suggested, such as polarization of clusters and cavitation or bubble formation, e.
A theoretical description of the effect of an electric field on the homogeneous nucleation rate preceded experimental work and concluded that depending on the ratio of dielectric constants between solution and solid the nucleation rate will decrease or increase. Electric fields are nowadays known to be able to locally enhance or inhibit nucleation, although the mechanism seems not yet clear. Despite its potential, as far as we know, localized electric field induced nucleation has not yet been applied to continuous crystallization processes.
Secondary nucleation is believed to be the predominant source of nuclei in the vast majority of crystallization processes. The importance of secondary nucleation can be explained with two examples of seeding and particle attrition:. In order to keep the crystal number constant, primary or secondary nucleation needs to be prevented, therefore a zero or negligible rate of secondary nucleation is required.
Typically, this is difficult to achieve in suspension crystallizers because of the preponderance of secondary nucleation. In continuous stirred tank CST crystallization, the secondary nucleation is typically required for steady supply of new crystals, so the rate of secondary nucleation needs to be controlled. This should be the main focus of the process design such that the population density can be maintained at a modest supersaturation consistent with faceted growth, impurity rejection and delaying the onset of encrustation.
The capability to manipulate CST is dominated by the ability to manipulate the secondary nucleation rate and allow the system to readjust to a new steady state through growth. Sucrose represents a special case where the seed crystals are added as very fine particles and because of the high solution viscosity, crystal collisions are relatively rare and sufficiently gentle that very few secondary nuclei form.
Therefore, secondary nucleation of a solid phase of a substance occurs due to presence of particle s of the same substance vs. There are two distinct ways to form new crystals in the presence of pre-existing crystals. In the first one, small abrasion or large pieces fracture can break off from existing crystals and the resulting crystal fragments become new crystals.
It can be argued that this should not be called nucleation at all, as there is no formation of a new solid phase domain, just mechanical division of an existing solid phase domain already present.
This typically happens due to relatively high energy collisions of crystals with impellers, vessel walls, each other, or due to high energy turbulence eddies or cavitation caused by impellers or external fields, such as ultrasound.
Mechanisms of formation of crystal fragments are related to fracture and abrasion mechanics of parent crystals. In the second distinct way to form new crystals in the presence of pre-existing crystals, the existing crystals keep their structural integrity but induce formation of new crystals through contact with the surrounding supersaturated fluid phase, resulting in formation of new solid phase domains within the fluid phase.
This typically happens under conditions of relatively low energy interactions with other solids or fluids, such as gentle tapping, sliding across surfaces or sedimenting. Such mechanisms of secondary nucleation are much less understood. The collision-based processes can be studied separately from crystal growth, i. Small pieces of larger crystals are broken off due to mechanical collisions e.
This effect can be influenced by suitably designing the crystallizer vessel, agitation and suspension density. The collision rate with the stirrer can be increased by, for instance, increasing the stirrer speed or changing the stirrer design.
Another way to increase the collision rate is by increasing the suspension density so that there are more crystals. Also the crystal size plays a role: above a certain size the impulse of the particle originating from the density difference between solution and solid becomes too large for the fluid to drag the particle with it and the probability of collisions drastically increases.
At high stirring speeds, macroabrasion of crystals results in fragments that serve as nucleation sites. As opposed to contact nucleation, which involves microabrasion of the crystals, this phenomenon results in the rounding of edges and corners of crystals. This process is referred to as collision or attrition breeding. Attrition causes small particles of acetaminophen crystals that have already been formed on the surface of the excipient to break and enter the solution, thus causing secondary nucleation acting as seeds.
The effect of mixing on secondary nucleation has been reported in several studies. Three different types of collision can result in attrition: Crystal—crystal impact: a function of both the local micromixing environment and the overall macromixing circulation. Crystal—impeller: a function of the impeller speed, the shape of the blade, and the construction material.
Crystal—wall impact: a function of eddy turbulence, particle velocity and shape, and crystallizer design. The critical mixing factors have been identified as impeller type and speed and their influence on local turbulence and overall circulation.
Particle damage is a function of the shear produced by the agitator, which is nominally proportional to the agitator tip velocity. The attrition and fragmentation can be formed by contact of the crystals with a pump impeller circulation line , the stirrer blade traditional pitch blade impeller , or due to impact of the slurry on vessel walls radial vs. Fluidized bed crystallizers have been used as an alternative approach to provide high mass transfer and mixing will minimize particle—particle and particle—wall attrition.
For instance, classically proportioned stirred vessel with baffles vs. Generally avoid conical base vessels for crystallization; these are encountered in many pilot plants because of the wide dynamic volume range and low minimum stir volume but require very intense agitation to prevent crystals settling in the base of the cone. Ottens et al. Evans et al. Instead of discussing the detailed model, a simpler nucleation rate model is used here: 1.
Then, the overall nucleation rate B is proportional to crystal—impeller collisions, K c—i : 1. A detailed study of the model was performed by van Beusichem. Quantification of secondary nucleation kinetics can be performed at various conditions: 1. Batch seeding with single or multiple crystals by counting numbers of newly formed particles either total or as function of time 2.
Steady state MSMPR experiments by measuring steady state crystal size distribution CSD and analyzing number density data assuming absence of primary nucleation, agglomeration and breakage plus ensuring that the outlet stream is fully representative of the crystallizer contents 3.
A continuous crystallization process will have a clear undersaturated solution as a feed flow and a crystal suspension as an outgoing flow. By decreasing the temperature of a solution generally the solubility of a crystalline solid decreases and if it is changed to below the solution concentration cooling crystallization can take place. A continuous cooling crystallization would have a hot, concentrated but undersaturated feed and a cold suspension as an outflow representative of the crystallizer bulk composition and temperature.
In case of evaporative crystallization the concentration is increased by solvent evaporation. Since solvent evaporation rate is fast at the boiling point of a solution, evaporative crystallization usually takes place close to the three-phase equilibrium point between crystals, solution and solvent vapor.
This point can be shifted for process optimization since the boiling temperature decreases with decreasing pressure.
A continuous evaporative crystallization process would have a hot undersaturated feed, a suspension outflow taken from the base of the crystallizer and an additional evaporated solvent flow. One process challenge is to ensure sufficient height difference between the boiling surface and the outlet to ensure sufficient hydrostatic head to suppress boiling in the outlet stream.
In case of antisolvent crystallization an antisolvent is mixed with the solution. While the addition of antisolvent decreases the overall concentration, the solubility in the mixed solvent is also decreased. If the solubility decrease due to the antisolvent is larger than the concentration decrease due to dilution, supersaturation is created and crystallization can occur.
A continuous antisolvent crystallization would have a solution and an antisolvent feed flow and a suspension outflow. For reactive crystallization two solutions each containing one of the reagents are mixed.
The reagents react to form a solute with a lower solubility so that the solute concentration is higher than the solubility and crystallization occurs. A reactive crystallization could be performed for instance by adding a high pH solution to a low pH solution of a compound: the change in pH upon mixing the solutions reduces the solubility of the compound and crystallization can occur. A continuous reactive crystallization would have two solution feeds and a suspension outflow.
Reactive crystallization is a combination of chemical reaction and crystallization. The reaction rate and solute generation rate reaction product defines the solute concentration, and at the solution temperature, the supersaturation ratio would be determined. Although the reactive crystallization normally runs at steady state, any temperature change or disturbance in any reagent flow concentration could disturb the crystallization phenomena, including the nucleation rate and crystal growth.
Yazdanpanah et al. However, the solubility of the solute increases as the temperature ramps up. Therefore, the supersaturation ratio decreases at higher temperature. The dynamic effect and nonlinearity were modelled in Aspen Plus and bi-direction effects of temperature on crystal size, nucleation rate, and steady-state crystal chord length were demonstrated. The transition time unsteady-state period and amount of residence time required for reaching the steady state, are important aspects in controlling the process and defining control strategies.
Another crucial aspect of the reactive crystallization in a dynamic case is to monitor and model impurity inclusion and the effect of the concentration of unreacted reagents on the crystal's purity, shape, and yield. Further discussion on PAT tools are provided in Chapter 9. Both antisolvent and reactive crystallization use mixing-induced supersaturation to enable crystallization. Under the further assumptions that the crystallizer is perfectly mixed composition, temperature and solids uniformly distributed within the crystallizer volume, the feed stream instantly mixed with the crystallizer volume and the outlet stream identical to the crystallizer contents; i.
Interestingly, for a continuous crystallization process under MSMPR conditions, valuable kinetic data therefore can be extracted from a measured number-based CSD of a product by fitting a straight line to the log-normal CSD plot of ln n against crystal size L.
It is important to note that the nucleation rate determined in this way is an average over the entire crystallizer volume: if the nucleation rate is locally occurring, the volume in which this occurs has to be known in order to determine the true nucleation rate. If, for instance, the secondary nucleation rate due to attrition with the stirrer is the dominant nucleation mechanism, the stirrer speed influences the attrition. After an increase in the stirrer speed for a suspension in a steady state continuous process, the nucleation rate B would increase and with it an increased total crystal surface area would be available for growth.
This would decrease the prevailing average supersaturation in the crystallizer and decrease the growth rate G. Although MSMPR conditions often do not hold, the model is useful and helps understanding of continuous crystallization processes in agitated vessels. All continuous crystallization processes result in a suspension flow with a certain suspension density of the crystalline product having a certain solid form, CSD, shape and purity. These represent the crystalline product quality attributes, which determine performance in downstream processing steps isolation, formulation and of the final product.
Control of crystal nucleation in a continuous crystallization process is crucial to control the final product quality attributes. In continuously seeded crystallization processes for instance, crystal nucleation has to be avoided to allow control over the particle size, however, continuously seeded, continuous crystallizers are quite rare. Moreover, in unseeded continuous crystallization the secondary nucleation process has to continuously produce small crystals with a constant rate to remain in the steady state allowing control over the product size.
The nucleation process thus directly influences the resulting crystal size distribution. It can furthermore cause significant issues with solid form control if nucleation of undesired polymorphs occurs. Fouling and encrustation are other significant issues in the continuous crystallization which are covered in Chapter 3. The kind of nucleation occurring depends strongly on the continuous crystallization process configuration chosen.
A simple continuous crystallization concept is to use a single continuous agitated vessel with a continuous feed solution and suspension outflow, such as a CST, or MSMPR crystallizer. The various crystallization methods can be performed by either maintaining the crystallizer at a lower temperature than the feed solution, evaporating solvent in the crystallizer or adding an additional antisolvent or solution feed to the crystallizer. It is also possible to combine various crystallization methods, for instance, an antisolvent crystallization or a pH shift with a cooling crystallization, if the product still has a substantial solubility at the higher temperature after the antisolvent addition or pH shift, respectively.
Growth is a bulk average driven by bulk composition and temperature , while nucleation is a local phenomenon e. In evaporative crystallization, locally increased concentrations occur in the boiling zone due to the selective evaporation of the solvent. These locations therefore are associated with a high supersaturation at which primary nucleation could occur and be determined. Secondary nucleation can occur for instance due to large crystals colliding with the stirrer so that small crystal fragments secondary nuclei are created.
The encrustation in continuous cooling crystallization MSMPR or oscillatory baffled crystallizer OBC mostly happens at the heat transfer interface that provides a high local supersaturation ratio, which initiates intense and uncontrolled local nucleation. The continuous nucleation on the heat transfer surface is deteriorative to the process stability and longevity of the runs and there have been some control strategies proposed to avoid the rapid nucleation on the surface.
In CST type continuous cooling and evaporative crystallization processes new particles are typically generated through secondary nucleation due to collisions of particles with an agitator. However, there are other types of agitated vessels where secondary nucleation may not be dominant see below. In case of mixing induced crystallization processes such as antisolvent and reactive crystallization, particles often are generated by primary nucleation due to concentration heterogeneities introduced by the mixing process.
Another continuous crystallization concept is a plug flow crystallizer PFC. A PFC is a long tube in which the crystals are allowed to grow along the length of the tube while they are taken along with the solution flowing through the tube.
Use of a PFC allows all crystals to have the same residence time in the tube if the back mixing is sufficiently small. In principle, this allows a tight control over the CSD. In a plug flow type continuous crystallization processes there are 2 routes towards generating particles in the process.
First, primary nucleation can be generated locally at the start of the tube. Second, continuous seeding can be used to prevent the nucleation process altogether. The API-excipient system selection, induction time measurement, and molecular interaction modeling have been studied. Continuous crystallization and process stability, spontaneous nucleation bulk nucleation at high supersaturation ratio, secondary nucleation and mixing, particle—impeller attrition, and heterogeneous nucleation rate are critical aspects to be controlled and monitored.
Understanding the mechanisms driving epitaxy at a molecular level is critical for controlling epitaxial nucleation and growth of crystals. Of particular interest for this concept, the induction time, preferential nucleation rate, and final properties of the composite are highly affected by the mechanisms driving epitaxy and proper API-excipient selection.
Therefore, understanding the mechanisms controlling epitaxial ordering is fundamental for controlling the final properties of the crystalline material. Numerous studies investigated epitaxial ordering on crystalline and other highly ordered surfaces to understand the effect of lattice matching, functional group matching surface functionality , and interaction energy.
Alternately, molecular dynamics modelling could demonstrate that molecular functionality and chain orientation, in such a manner as to utilize as many hydrogen bonding groups as possible to stabilize the prenucleation aggregate of crystalline substrates, are dominant in promoting heterogeneous nucleation of a model API.
The hydrogen bond propensity and bond formation potential between the active groups on the exposed surface of excipient and also chemical bonds at different faces of the solute crystal promote preferential nucleation and crystallization. In this way, the solute molecules prefer to interact and form local nuclei on a certain side of the excipient, in competition with other surfaces i. Therefore, the nucleation and crystal growth on the surface of the excipient benefit from both the heterogenous nucleation and surface Gibbs free energy and also chemical bond formation and surface chemistry.
Heterogeneous nucleation by definition can occur on any foreign particle, such as dust, which is the distinction between homogeneous and heterogeneous nucleation.
The presence of excipient crystals in the crystallization solution enhances the nucleation and yields the epitaxy. As mentioned previously, the difference in excipient selection is based on the matching ranking matrix, which is driven from molecular dynamic modeling and induction time measurement experiments. In a high supersaturation solution, the solute crystals formed on the surface of the D -mannitol excipient, but in the presence of sodium chloride, bulk homogeneous nucleation takes place and the excipient was ineffective.
Population balance modeling can be used to unravel the kinetics of nucleation and growth. In the modeling of the system, the following assumptions could be made. Heterogeneous nucleation is the dominant nucleation event, and primary nucleation is assumed to be absent in the system. The nucleation rate increases with increasing surface area of the excipient, and vice versa.
The active surface of the excipient available for nucleation is assumed to be constant. The growth rate is proportional to the surface area of acetaminophen that is in contact with the solution. Aggregation and breakage of API crystals are absent in the system. The dynamics of the size distribution of crystals of API growing over the excipient surface are described by 1.
The volume growth rate G of any particle is defined as 1. The nucleation rate expression is 1. The mass balance of API particles can be written as 1. To simplify the analysis, the moments of the population density function are solved here.
The j th moment M j of the population density function is defined by 1. The 0th moment M 0 represents the total number of solute crystals present in the system, and M 1 is the total volume of solute crystallized. As is the total surface area of crystals, the rate equation for the concentration of solute can be written as 1.
Multiplying eqn 1. The dynamics of the crystallization process can be obtained by numerical solution of the set of ordinary differential equations:. The shape factor of solute can be obtained from the literature or by image analysis techniques and microscope images.
Seeded batch growth studies help in obtaining the growth rate parameters explicitly. Batch data of heterogeneous nucleation and growth experiments can be used to finally fit the nucleation rate parameters, which is a safe assumption for the continuous crystallization. The previous method was for direct nucleation and crystallization on the surface of the excipient crystalline particles.
The control strategy for tuning the amount of crystal deposition on the surface area has been proposed by controlling the supersaturation ratio of the crystallization solution and also by residence time linear velocity of the film through travels through the pool. In a continuous cooling crystallization for instance the hot solution feed at temperature with concentration and flow rate enters the crystallizer and is mixed up with a suspension which has a specific steady state solution concentration and suspension density of crystals in the solution at temperature.
The outflow with rate contains a suspension having a solution concentration and a suspension density at temperature. The volume change of a solution upon crystallization may be negligible, meaning that for a constant suspension volume in the crystallizer, the feed and outflow rate are equal.
For a continuous cooling crystallization in steady state operation, temperatures, concentrations and suspension densities in crystallizer and outflow are often assumed equal. Then in steady state the CSD and other product quality aspects in the crystallizer suspension and outflow suspension are equal. The crystallizer suspension has a temperature and concentration lower than those of the feed. Crystal growth is an average bulk phenomenon, determined by the average supersaturation S cr in the crystallizer solution through which the crystals travel.
The crystals formed have a chance to end up in the outflow: while some crystals might end up in the outflow right after they formed, some others may take a long time to be removed from the process. The formed crystals thus all experience a different residence time in the crystallizer and therefore a different growth time.
In steady state condition, the CSD in the suspension and in the outflow therefore consist of crystals of various sizes. In a continuous crystallization process the nucleation rate strongly affects final product quality aspects such as the CSD. Since in steady state a suspension of crystals is present there is a high likelihood that one of the secondary nucleation processes is the dominant nucleation mechanism. However, due to their high local supersaturation values upon mixing, in antisolvent and reactive crystallization primary nucleation mechanisms might be dominant in the mixing zones.
Continuous crystallizers can easily be used in a cascade configuration in which the outgoing suspension of one crystallizer is the feed for the subsequent crystallizer. This can increase yield and average product size by for instance decreasing temperature or increasing antisolvent fraction Figure.
Note that for a cascade of well-mixed agitated vessels the overall residence time distribution becomes narrower as the number of vessels increases, ultimately approaching a plug flow process. There are also large, more complex units, which have been routinely used for industrial crystallization of some commodity chemicals see Chapter 6.
There are several approaches available to provide all crystals with the same or very similar residence time which is the hallmark of a plug flow process. In order to achieve turbulent rather than laminar flow conditions in a simple long straight tube, the flow rate would need to be very large, resulting in small residence times. This decoupling of flow rate and turbulence induction can be achieved by using an OBC see Chapter 3.
Since the oscillation cannot achieve perfect plug flow some back-mixing of crystals will occur resulting in a narrow yet substantial residence time distribution of the crystals.
In the case of a PFC in the absence of seeding, primary nucleation is required to generate the initial distribution of crystals that grow out throughout their residence time while travelling through the length of the crystallizer. Details of primary and secondary nucleation, locality and also non-ideal backmixing are discussed in Chapter 3.
It is often taken for granted that primary nucleation processes cannot be well controlled.
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