Under the Hood: Nucleation

In this installment of "Under the Hood" I will briefly explain nucleation in chemical systems and how that relates to pharmaceutical research.

I find it hard to believe that anyone dislikes the Mentos and Diet Coke experiment.  So, for those of you who are curious about why that works it is because of nucleation.  Now Mythbusters proved that the rough surface of the Mentos leads to nucleation of carbon dioxide.  NOTE: The Mythbusters link is a great explanation of nucleation and may be all you need to understand this concept but I will try to provide a deeper incite into what is nucleation. Essentially, carbon dioxide is dissolved in the liquid of the Diet Coke and is sitting in the meta-stable "zone" of supersaturation.  Above this zone, the carbon dioxide would spontaneously fall out of the liquid phase in create bubbles without any stimulus. Below this zone, nothing occurs as there is not enough carbon dioxide to exhibit any reaction.

Phase Diagram for Crystallization -
[CHE 597 Notes - Purdue University]

So basically the system is unstable and needs some sort of catalyst to create bubbles and allow the carbon dioxide to escape.  Enter the Mentos.  The extremely rough surface of a Mentos creates millions of secondary nucleation sites for the carbon dioxide to react, causing a mass reaction and the explosion of Diet Coke we are accustomed to seeing.

In pharmaceuticals (and most other industrial processes), nucleation refers to the process of creating the initial solid crystals from the liquid phase.  We utilize this process for purification and specific crystal growth patterns, called habits.  Unfortunately, this can be very detrimental if we are trying to keep a drug in the liquid phase, such as the case with any dosage form meant for the blood (~90% of all drugs).  Thus understanding this process is crucial to formulation of medicine.  But, understanding this mechanism is much more difficult than first thought to be.

There are essentially three types of nucleation. The chart below is visual representation and for the sake of time I give a short statement about each.

Nucleation Types - [CHE 597 Notes; Purdue University]

Primary homogeneous nucleation - The most simple type, occurs between only the crystal species in a pure supersaturated solution.  Although the most pure form of nucleation, it is also the least utilized because the energy barrier to produce a new nuclei is the highest.

Primary heterogeneous nucleation - Again, occurs in a supersaturation solution but involves catalytic species that have "preferential sites" for forming a new nuclei.  The Mentos surface is an example of a preferential site for carbon dioxide in Diet Coke.  These sites lower the energy barrier to overcome for nucleation to occur.

Secondary nucleation - Occurs when nuclei or seed crystals of the selected species are introduced to a supersaturated solution, causing nucleation of new new crystals to form on the surface of the seeds.  Again, this lowers the energy barrier to overcome.

So why is this important?  Well, if you remember back to the amorphous post, new novel drugs which are poorly water soluble are forced to obtain higher solubilities because of the meta-stability of the amorphous forms.  This causes supersaturations, which can lead to nucleation (and in the body, heterogeneous nucleation and secondary nucleation dominate making these processes more likely than pure supersaturations).  So, if we can understand how nucleation occurs and can prevent it in the stomach long enough to allow absorption into the blood stream...we have done our job.  If only it were that easy...

Previously, the Classical Nucleation Theory (CNT) dominated the general idea about nucleation.  But over the past 10 years or so, a new two-step theory has begun to emerge, which includes two barriers to overcome (see picture to the right).  There is evidence to support both theories and now the field is at a crossroads as to how to interpret the data and formulate a theory to include all cases.  Obviously it is more complex than we originally thought but there is some truth to the CNT and we cannot discredit all the work that has gone into that theory.

To sum up, understanding nucleation mechanics and kinetics is crucial to the development of novel formulations for new drugs.  Although the science of liquids and solids is well understood, transitions are always tricky and nucleation is no exception.  Hopefully a correlation between all the data and the proposed theories (both classical and two-step) can be determine in the near future.  All and all, part of my graduate work in the future will be dealing with nucleation mechanisms!