This card is indicated for a crystallization module in a chemical separations course (typically a Junior-level Chemical Engineering class). All of the relevant crystallization theory is summarized as part of this card's materials.

Background

Industrial crystallization is a critical separation process for manufacturing bulk chemicals, fine chemicals, food products, and pharmaceuticals. Despite its widespread use in purification and in the isolation of powders with the right particle attributes, it rarely makes its way into the separations curriculum for Chemical Engineering education. This is often criticized by practitioners, especially in the pharmaceutical sector, as most crystallization scientists end up being self-taught or reliant on external consulting for process design and training.

As an education experience, crystallization englobes most of the core topics in chemical engineering, in a way that few separation processes do: a delicate combination of mass, energy, phase, and population balances, driven by competing kinetic equations that resemble those seen in reactor design, and built into hardware that includes everything from stirred tanks to tubular systems and fluidized beds. However, due to the inherent complexities of the unit operation, combined with a fundamental understanding that is still under development, this topic is difficult to teach in undergraduate courses.

This card describes a crystal growth competition that has been implemented for two consecutive years at Rowan University. The activity is indicated for students in their junior or senior level, taking a chemical separations course as part of the Chemical Engineering core curriculum. Coverage of the relevant theory can be conducted within 4 hours of lecture time, and the activity itself takes 90 min of laboratory time followed by at least 60 min of student presentations. A comprehensive slide deck covering the required theory for the success of the activity is provided in the card’s folder.

Theory and Relevance

Crystallization process design needs to satisfy requirements for both yield and product quality. For batch systems ending at equilibrium, yield is limited by the difference between the total solute concentration and the equilibrium solubility (which can be tuned using temperature or solvent composition). In contrast, crystal quality attributes like size, shape, purity, or structure are closely tied to the kinetics of the process. Three competing kinetic phenomena need to be considered in the design of crystallizers: primary nucleation, secondary nucleation, and crystal growth.

Primary nucleation benefits from high supersaturations and it is typically an unwanted phenomenon. A primary nucleation event can lead to encrustation in the vessel walls, and to the rapid formation of new crystals that will broaden the crystal size distribution. For these reasons, batch crystallizers tend to be operated within a metastable zone – a region of supersaturation where secondary nucleation and growth can occur, but primary nucleation rates are negligible. In a typical cooling crystallization process, an undersaturated feed would be cooled to a supersaturated but metastable state, and then the vessel would be seeded with crystals that contain the desired crystal structure and shape. These seeds then serve as a template for crystal growth (following the desired structure). The seeded crystallizer is slowly cooled following a delicate balance between the cooling rate and the crystallization rate, so that primary nucleation is kept at a negligible level throughout. The limit of supersaturation at which the primary nucleation rate becomes significant is named the metastable limit. It is not a fixed value as it depends on mixing conditions and cooling rate, but it’s a practical, illustrative way to set a limit to the system’s metastability.

Some examples of metastable systems that can be used to illustrate this concept in class include reusable heat packs, hot ice (sodium acetate solutions), or supercooled water. The idea of a seeded, cooling crystallization can also be seen in chocolate manufacturing, where seeds with the right structure are introduced to serve as templates and obtain the chocolate form with the desired attributes (low melting point, or shine, or a pleasant snap).

It is important to note that, if the system is mixed, secondary nucleation will still occur within the metastable zone. This rate will be driven by crystal-crystal and crystal-vessel collisions, as well as fluid shear. However, growth will still dominate as long as the supersaturation level is kept low.

For the success of an industrial crystallizer, especially in the pharmaceutical industry, it is critical to seed at the right temperature: too early, and the seeds will dissolve; too late, and primary nucleation will occur. It is also critical to control the cooling profile so that the metastable limit is never crossed. Slow cooling is beneficial for this, but it also comes at the expense of longer crystallization times.

As it turns out, some crystal growth kits that are sold as toys closely model the typical recipe for operating a batch crystallizer. This is the case for the toy that is used in this activity:

A growth kit provides approximately 100 g of monoammonium phosphate (MAP) powder, a growth container, a hedgehog figure, and a plaster base. That plaster base is filled with seed crystals of MAP, which are further grown with the separate MAP powder during the experiment. In the growth experiment, you first dissolve the powder to generate an undersaturated solution, then the system is cooled to the metastable zone and seeded with the hedgehog. Analogous to the design of batch crystallizers, the final amount of crystals on top of the hedgehog will depend on the total solute concentration, the equilibrium solubility, and the relative rates of nucleation and growth. If nucleation occurs in the vessel, those crystals will form outside the hedgehog (likely at the base of the container) and take up some of the solute mass that would otherwise have helped grow the seeds on the hedgehog. Thus, to maximize the size of the grown hedgehog, one needs to find ways to maximize yield (e.g. solvent evaporation, cooling below room temperature, antisolvent additions…) while also suppressing nucleation, just like it would be done in industrial crystallization.

The critical point here is that this toy is optimized with the goal of getting crystals at home, by kids. It is made to be simple, at the expense of a sub-optimal process. MAP has a solubility of 350 g/kg solution at room temperature, and the recipe calls for preparing solutions with a total concentration of appr. 430 g/kg solution. These conditions are far from desirable in industrial crystallization, not just due to the low attainable yields, but also because the solution that is thrown away is 35% product by mass! There is a lot of room for optimization, and this is what the activity is about.

Activity Description and Implementation

Preparation: Prior to the activity, students are introduced to the basic concepts of crystallization, including solubility, phase balances, supersaturation, nucleation, and crystal growth. It is important to stress the factors that affect nucleation and growth, and to teach them how to calculate crystallization yields using the phase balance. A consolidated slide deck covering the minimum set of relevant topics is provided in this card’s folder.

Students are informed of the activity and rules at least one week before the competition. They will have to form teams of 3-5 people, and they will have 90 min of class time to set up their experiment. Because hedgehogs come in different colors, and some of the darker colors are more difficult to work with (identifying when the powder is fully dissolved, or whether crystals are growing on the hedgehog), groups get to choose their kit in an order assigned by rolling dice.

The instructor then weighs each of the kits, recording the initial mass of the hedgehog as well as the powder mass. This is given to the students so that they can use it in their experimental design, as well as in calculating their yield after the experiment.

Competition Format: Students are made aware that the kit is not optimized, but they are not given information on what to do beyond what is written in the toy’s instructions. To ensure that teams take risks and apply the knowledge from class in the activity, this laboratory is designed as a competition, where the top teams get extra credit for the course. Ranking of teams is done by a panel of 3-4 faculty, and in two different categories: best hedgehog (highest yield, with defined crystal facets and large crystals), and best presentation (quality of the procedure, and scientific background shown in a group presentation). Awards for both categories are separate. Typically, the top three teams get 3, 2, and 1 points extra credit, and all other teams get 0.5 points for participation. Running this activity as a competition makes a significant difference in the level of student engagement, laboratory readiness, and preparation on the class material.  

Prior Student Knowledge: To foster a sense of curiosity, the instructor does not provide any information about the hedgehog kit, other than the instructions provided with the toy. Students are responsible for requesting any information they may need, including the chemical composition of the powder. If they want solubility curves, they need to find them from literature.

Methods: On the day of the experiment, each group gets a hedgehog kit as well as an electric kettle for boiling water, and they are encouraged to request anything that can usually be found in a household or laboratory. By the end of the 90 min period, all students should have reached step 7 in the instructions (hedgehog placed in the supersaturated solution and ready to grow). At this point, they are given one week until the hedgehogs are collected and weighted. During that week, they are welcome to run additional steps, which often include opening the lid to allow solvent evaporation, placing the container in the fridge to drive more yield, or re-crystallizing some of the mother liquor to increase yield. The only rule is that the hedgehogs must remain in the laboratory and cannot be taken home. As an extra credit activity, further engagement is voluntary and we do not use class time for this.

Exactly one week after the experiment, students bring the dry hedgehogs to the instructor, who makes sure that those have been properly dried and then weighs them in front of the team. Students will use that weight to calculate the yield of their process, counting only the material that was recovered on top of the hedgehog. Then, they have a second week to prepare a 10 min presentation covering their procedure, the science behind it, challenges faced, and what would be done differently if they had the chance to re-run the experiment. The panel of 3-4 faculty attend the presentations and have 5 min per group to ask questions to each of the teams. 

Materials Required

The hedgehog kits can be purchased on Amazon (link). Each kit includes 4 hedgehogs, each with their own beaker and spatula. With a recommended group size of 3-5 students per group, one kit would be necessary for every 12-20 students in the class. Access to electric kettles for heating water is especially important due to the short duration of the experiment.

Because of the open nature of the activity, students may request anything that may be reasonably found in a household or chemical laboratory. Thus, it is important to make sure that the laboratory is well-equipped for most common requests. Typical requests include deionized water, materials for insulation (aluminum foil, sponges, paper cups, and paper towels), heating plates, and thermometers. Beyond those, students tend to request additional beakers of sizes ranging from 300 mL to 1000 mL (either as growth containers or to create a cooling jacket), as well as access to a refrigerator. In rare cases, they will also request some organic solvents (usually ethanol) to act as antisolvents for the process, as well as industrial pipe insulation.  

Student Assessment

Beyond the assessment of learning received from the student presentations, students complete a questionnaire that covers their feedback as well as 8 technical questions related to the contents of the experiment. The questionnaire is also provided in this card’s folder.

Some key points from prior assessments (35 responses) include:

• 91% of students agreed or strongly agreed that making this activity a competition motivated them to do more background work than they would have done in a traditional laboratory.

• 86% of students agreed or strongly agreed that they had to apply contents from other courses (primarily heat transfer) in this activity.

• 91% of students agreed or strongly agreed that the competition format made them take more liberties about the experiment, compared to a regular laboratory.

• 100% of the students saw a strong similarity between the experiment and the operation of industrial crystallizers.

Observations / Typical Approaches

This section gives some examples on successful and unsuccessful strategies, to illustrate the learning potential of this activity. It summarizes actual observations from 14 teams.

Common strategies employed by students to maximize yield:

• Insulating the growth vessel to slow down cooling (prevent the system from reaching the metastable limit, and decreasing nucleation induction times):

  

• Sequential crystallization strategies, sometimes with creative setups as the volume of mother liquor keeps decreasing:

  

• Solvent evaporation, either by opening the container lid or by boiling the recovered mother liquor.

• Decreasing the amount of solvent from the recommended amount, using the solubility curve (literature values) to find the new saturation temperature.

• Placing the growth vessel in a refrigerator, to decrease solubility by cooling.

• Seeding in the place where the container will be left, to minimize risk of nucleation from moving the container.

Common mistakes that serve as a learning experience:

• Insulating only the walls of the vessel, or poorly insulating its base and resting the vessel on a cold surface. Most of the heat losses happen by conduction through the base of the vessel. If it’s not insulated properly, crystals will nucleate at the base of the container:

  

• On similar lines, seeding too late (beyond the metastable limit), or not fully dissolving the powder before seeding with the hedgehog:

  

• Understanding the difference between concentrations in g/kg solvent and g/kg solution. Many groups choose to use a different vessel material (aiming to mitigate heterogeneous nucleation surfaces), losing the marks on the container that the manufacturer provides. The recipe calls for adding powder first and then solvent to a total volume of 230 mL (mark on the original container). Students should realize that those 230 mL are powder + solvent, not just solvent. Adding 230 mL of water to appr. 100 g of powder leads to a concentration of appr. 300 g/kg solution, while the recipe is set to obtain an initial concentration of appr. 430 g/kg solution. If they fail to realize that detail, they will dissolve the hedgehog seeds as their solution will be undersaturated, even at room temperature:

  

• Seeding too early, while the solution is still undersaturated, would also lead to the dissolution of the seed crystals.

• Mixing the powder and water before heating, and using a heating plate for the latter. This takes a significant amount of time and often leads to unwanted solvent evaporation and nucleation at the bottom of the vessel.

Connection to Pharmaceutical Crystallization

One of the main applications of this content is in the design of pharmaceutical crystallization processes. Solution crystallization processes play a critical role in the production of pharmaceutical products. Currently, more than 90% of solid-state pharmaceuticals are crystalline materials, and seeded batch crystallization is by far the most popular method for their isolation. The processability and bioavailability of a pharmaceutical powder depend on how it has been crystallized. Different crystal structures present distinct stabilities, solubilities, and dissolution kinetics. Similarly, particle size and shape will affect dissolution rates, as well as batch consistency and processability. Control of solubility and dissolution kinetics is especially important in pharmaceuticals that need to be dissolved in the gastrointestinal tract before they can be absorbed in the bloodstream. If kinetics are too slow, the drug will not build a sufficient blood concentration to have a therapeutic effect; if they are too fast, it can lead to crossing the drug’s toxicity limit and generate adverse health effects. For this reason, pharmaceutical crystallization processes are subject to strict requirements for control of structure, shape, and particle size (at the micrometer scale).

Most batch crystallizers are stirred tanks that receive a liquid mixture containing the synthesized pharmaceutical in dissolved form. To induce crystallization, this mixture is brought to a supersaturated state in one of three ways: cooling, solvent evaporation, or addition of an antisolvent. The rates of cooling, evaporation, or antisolvent addition will thus define how fast supersaturation is generated, and how long the system will remain in a metastable state. Seeding a metastable solution provides a crystal template with the right structure and shape. Similarly, by controlling the mass and size of the seeds, one can control the particle size of the drug. However, this only works if primary nucleation is suppressed in the system. Primary nuclei can form as undesired crystal structures, which often leads to a failed batch and costs upwards of $100M. Even if the nucleated form happens to be the desired one, formation of an uncontrolled number of nuclei will still shift the particle size of the product towards smaller values, thus affecting the powder’s homogeneity, processability, and dissolution kinetics. The key to crystallizer design and operation lies on seeding at the right time and controlling the rate at which supersaturation is generated, so that seeds grow without inducing significant primary nucleation. This is the same objective that the students have in the presented exercise. Throughout the activity, they obtain valuable first-hand experience on the behavior of metastable solutions in crystallization, and they explore creative methods to balance the different risks involved in optimizing a batch crystallization process.