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!

Under the Hood: Amorphous Solids

Part 1 in my Under the Hood series.


Amorphous solids.  Those of you who may be frequent readers of my blog in the future, this may be the single most important scientific post to understanding what my graduate research is all about.  Entire journals and books can be written about the amorphous state, but I will do my best to summarize and generalize as best I can.

Amorphous Solids lack the long range order of Crystalline solids,
which leads to greater molecular mobility.
(Taken from IPPH 587 notes)

This free energy diagram shows how the phases change with
respect to theromdynamics of the system.
Tm is the melting point, and Tg is the
glass transition temperature of the amorphous solid.
(Taken from IPPH 587 notes)

So, what is an amorphous solid?  I like to tell people it is the state between solid and liquid, however that is not exactly true.  It is between these two in the classical sense.  In grade school, a solid is anything that has long range order and a melting point (some even define a solid as anything that doesn’t take the shape of the container it is in).  Well, this is the definition of a crystalline solid.  The majority of “solids” are crystalline solids including metals, alloys, salts, etc.  Then there are amorphous solids.  These are essentially solids that lack the long range order of crystalline solids, but also lack the mobility of liquids.  For simplicity I will refer to all amorphous solids as the same thing but there are really two types of amorphous solids; those being glasses and super-cooled liquids. The diagram to the right shows a thermodynamic view of these states.  Overall, these are meta-stable states and need some kind of thermodynamic event or action to occur.  Nature prefers crystalline solids and liquids over amorphous forms.

BCS drug classifcation system.  Here, BCS is not some
money hungry way to exploit football, but actually a way
to classify drugs and allow biowaivers to expedite the drug
development process.

And why do we care about amorphous solids?  Let’s begin with drug development/discovery.  Here in the western hemisphere (and increasingly in the entire world) we prefer solid dosage forms compared to liquids or parenterals (injections).  They are more patient compliant and easier to market not to mention it is much easier to ask someone to take a pill twice a day rather than give them a shot or make them drink really, really nasty tasting liquids.  So we want pills, tablets, capsules, something solid to swallow.  There are many other reasons why these are preferred but this will have to suffice for this explanation. Now, the stomach and intestine need to be able to dissolve the drug and as you probably learned in 4^th grade, we are roughly 60% water.  Thus new drugs need to be water soluble.  Unfortunately new molecules which show some biological activity are not water soluble.  Depending on who you ask 60-80% of new drug molecules fall into this not water soluble category (Class II/IV drugs, see BCS chart).  Thus, we must come up with strategies to obtain higher solubility.  Here is where amorphous solids come in.  Since these solids have less order and are more unstable than their crystalline counterparts, they can obtain higher solubilities.  Sometimes 10-50 fold higher.  Thus we can use drugs in their amorphous form to utilize drug molecules that otherwise we have rendered useless.  Not to mention we can lower doses, lower prices, and increase efficacy on drugs already on the market.  I think everyone can agree those are all worthwhile. 

Studying the crystal growth rates from the amorphous
state is very critical to our research.  This is a crystal
growing from the amorphous state under cross-
polarizing light to determine crystallinity.

And where does my research fit in?  Well, these amorphous forms are unstable and want to convert to their non-soluble crystalline forms.  The research I am working on deals with understanding the kinetics and mechanisms behind stabilization of amorphous drugs.  Even though we can observe what happens, we want to be able to explain and even predict what will happen to drugs in the amorphous form.

I will leave you with an example and an explanation of one more common term.  First, most glass is amorphous.  If glass had a crystal lattice structure, light would refract through it like a prism and we couldn’t see through it clearly.  So the next time you are in a really old building or barn, check out the windows.  They may appear to be “collecting” at the bottom like they are liquids.  And finally, if you ever see the term amorphous solid dispersion (or ASD), it is when a drug or compound is “dispersed” with a polymer to create an amorphous state.  The polymer, which is inherently amorphous because of the repeating nature and large molecular size, acts to inhibit crystallization of the drug.  Using these ASD’s are common place in both research and pharmaceuticals and are the basis for most of the research on our lab. 

Well, there is a quick overview of amorphous solids.  If you have any questions just leave a comment or shoot me an email and I can try to answer, or point you toward a source that can hopefully explain in better.

Under the Hood

Well, for those of you curious about what exactly I do...my "Under the Hood" series of posts will hopefully help to explain it.  I chose to name it Under the Hood for two reasons;  one, it's kinda catchy and relates to a fume hood in a laboratory. Two, so I can keep all of these related posts organized and can easily find them.  

First up...amorphous solids!

2011 Camaro Engine

Not as elegant as the Camaro hood
(and note this is not a
 Purdue fume hood).