Don’t let phase changes faze you

Phase changes in the downstream processing or handling of solids cause many process problems that have inexpensive solutions.

By Tom Blackwood, Healthsite Associates LLC

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Impact of polymorphs
A very similar crystallization situation occurred at another plant. There, a large variation in filtration rate occurred, but it was never repeatable. Occasionally, the plant would get a “super” batch that filtered in half the normal time. This was a very desirable, but seemingly random outcome. That batch had a slightly larger and narrower PSD.

Examination of the particles under a microscope revealed that the habit was different. No polymorphs or solvates were known for this material — however, an evaluation of the chemical structure suggested at least four polymorphs and two solvates.

This led to a closer look at process conditions. The standard operating procedure called for cooling of the under-saturated solution until a heat flux was observed in the jacket of the vessel. The difference between the inlet temperature and the outlet temperature was used to mark this heat flux. The temperature was held constant for a fixed period of time and then the batch cooled to the final temperature at a constant rate. In the super batch case, this step-change in heat flux was not observed; cooling occurred below the normal holding temperature at which the heat flux usually was seen. There was no holding period and cooling continued to the final temperature.

What was really happening in the process got lost in translating the research work to the process development and operation. This material exhibited classic enantiotropic behavior: a transition temperature between two polymorphs (alpha and gamma) as shown in Figure 1. The gamma form is unstable and has lower solubility above the transition temperature while the alpha form has the lower solubility below the transition temperature.

Figure 1

The under-saturated solution at the starting temperature has a solute concentration below the solubility of gamma and alpha. As the temperature decreases, the gamma form comes out of solution and crosses the transition temperature. More crystallization occurs until the concentration is outside of the meta-stable limit for the alpha form. Rapid nucleation (the heat flux) of alpha begins and the gamma form begins to dissolve. At that point the rate of cooling is slowed but the damage has been done. The excessive amount of nuclei hinders growth and results in a wider and smaller PSD.

The simple solution to this problem is to dilute the solution to below the concentration that corresponds to the transition temperature. If the volume of solvent that results is too large for the solid/liquid separation, consider other methods for controlling the initial nucleation. Possible remedies are: seeding, cooling below the transition temperature and then heating slightly or installing a “nucleation detector.” In this case, seeding was chosen because it produced a faster overall crystallization time. A cooling crystallizer was not the best choice for this process but it would not be cost effective to replace it.

Don’t be fazed
In both of these cases, a key indicator of a phase change issue was the dramatic shift in the ease of filtration. It is important to identify polymorphs and solvates for a product and to determine any critical temperature early in process development and design (see sidebar). Also, watch out for minor changes in the processing layout. Understand what you are measuring and why. In these examples finding the potential cause of the problem was a fairly short and easy process once the fundamentals were examined. Verifying it was much more difficult. However, in most production environments we don’t need a definitive study but can alter the processing conditions to test the causes. Then a more cost-effective solution often can be developed and implemented.


Guide to evaluating crystal phase

1. Vital experiments to conduct for scale-up and design
• Establish basic process route and evaluate alternatives
• Define required product properties such as PSD and solubility
• Identify polymorphs and solvates (look very hard)
• Find temperature sensitivity (any heat flux is a concern)
• Obtain basic filtration and drying data on single particles

2. Tools and data to use to evaluate phase or solvate change
• Molecular modeling
• X-Ray diffraction
• Differential scanning calorimetry
• Raman spectroscopy
• Infrared spectra
• Microscopy (optical, SEM and TEM)
• Water vapor sorption
• Other physical properties (density, color, etc.)
• Drying rate or critical moisture

3. Ways to minimize production problems
• Identify the ground state of the chemical
• Avoid excess energy inputs
• Draw the structure at the first sign of a problem
• Watch out for “minor” changes in processing steps
• Ensure that solvents have been removed
• If all else fails, go back to the lab!

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