What do co-crystals and chirality have to do with each other ?

Before I begin this post, I want to thank everyone for dropping by.  I have been blogging for a few years off and on and I am always learning.  I think every blogger wants to get an audience and have people pay attention to what they have written.  I try to spice up the title of the post to peak your curiosities.  The posts I get excited about aren’t the ones you particularly like.   We both take what we can get out of the post, hopefully, you find out some information you didn’t have.  I try to remain current with current chemical literature.  Win-win, I say.

I admit that the use of co-crystals has me interested.  I have blogged about them before.

If you can’t remember them from previous posts, check out:

https://developingtheprocess.wordpress.com/2014/07/09/solubility-advantage-of-amorphous-drugs-and-pharmaceutical-cocrystals/

https://developingtheprocess.wordpress.com/2014/05/23/this-shouldnt-be-a-bitter-pill-to-swallow/

Okay, well, there is at least two of them.

I picked up a paper recently and it dealt with co-crystals and chirality.  (I didn’t believe it when I saw it either). Co-crystals ??  Chirality ??  I remember reading that co-crystals could be used to change the bioavailability of your API, filterability and a few other uses.

Have you ever worked on a synthetic route that produced racemic material and you needed to separate the enantiomers at the end ?  In the middle ?  (I am sure there is a few hands out there).  Let’s face it, there are still synthetic routes producing racemic material.  You have a few options for separating them.  I can think of a chiral resolution.  Or use chromatography (SMB) for example.

What I didn’t realize and I hope you haven’t either is that, with the appropriate (one that is chiral) coformer, one of the enantiomers may crystallize as a co-crystal.  A co-crystal is defined as a a crystalline solid composed of two or more molecular or ionic compounds, that are solids at ambient temperatures.  In the event that your molecule doesn’t have an ionizable functional group like a carboxylic acid or an amine, this is another strategy you can use to resolve your racemic material.  I thought it sounded important ( I had never heard of this approach before, I have a quick poll at the end of the post to make sure I am not the only one that missed this concept (just for my own info)).

The first paper I looked at was the following, “Does Chirality Influence the Tendency toward Cocrystal Formation?” by Fanny George, Nikolay Tumanov, Bernadette Norberg, Koen Robeyns, Yaroslav Filinchuk, Johan Wouters, and Tom Leyssens*, Cryst. Growth Des. 2014, 14, 2880−2892. doi: 10.1021/cg500181t.

 

etiracetam

 

The author of the above-mentioned paper used Etiracetam and Levetiracetam (the racemic and chiral drug product for their study), which is an anti-convulsant for epilepsy.  I thought it was interesting that crystallizations of  cocrystals are enantiospecific when a chiral coformer is used with a racemate whereas using a chiral acid/base with racemic material (assuming the racemate has appropriate functional groups to form a salt) is diastereomeric.  The coformers form hydrogen-bonding interactions ( as well as other interactions, such as π-π stacking) with the API and one of the enantiomers can crystallize out with the coformer as a cocrystal.  The coformer should have similiar structural features as the API and functional groups.  The paper describes the screening of Etiracetam and Levetiracetam with achiral coformers.

I may be quite wrong about this, but when a chiral drug is selected for development, a racemic synthetic route to produce material is designed to satisfy the need for clinical material while an asymmetric synthesis is undertaken.  Sometimes, this occurs concurrently.

Racemic material then becomes much more readily available and your chiral API’s value increases to the value of gold.  You don’t want to spend it on the screening if you don’t have to.

What the authors established was that by screening Etriacetam (the racemate) with 152 possible coformers, they were able to get quite a few new co-crystals.  Comparing that to the chiral drug Levetiracetam, there was overlap of the coformers used .  When screening Levetiracetam by itself with 152 coformers, they had a success rate of about 10 %.  They were able to increase the efficiency of their screen from 10 to up to 73 % by first performing a screen of the racemic drug with possible coformers and then screening the chiral drug.  Otherwise, I am sure it is close to “a shot in the dark” by using available coformers on a screen of your chiral material (something that is potential very precious).  In fact, if you use the strategy in the paper by screening the racemic API with a cocrystal screen, you will save 90 % of your chiral API when you reduce the number of possible coformers to the hits attained in the racemic API.

 

 

co-crystals

Figure 1. A few of the coformers used to form a co-crystal with Etiracetam and Levetriacetam

 

I was going to review the second paper but realized it has been a while since I posted.  I am not sure how interested my readers will be in this topic.   I find it fascinating.  I always thought that chromatography, and chiral resolution was all that could be used to separate enantiomers.

I realized at the end of this paper that I was more interested in using a chiral coformer as opposed to an achiral one.  I want to separate the chiral drug product from the racemate.  You still may want an achiral coformer if you  wanted to increase bioavailability or filterability.

I found also that the FDA considers a co-crystal as an intermediate.  If you want to try and submit for approval an API that is a co-crystal, they offer some guidance and that can be found in the following document.

 http://www.fda.gov/downloads/Drugs/Guidances/UCM281764.pdf (as of April 2013).

I would welcome any comments on this post and hope to get a discussion, maybe even on my site.  I value what you might have to say.  If you had a comment and  wanted anonymity, you could send me an e-mail to developtheprocess@gmail.com.

Have a great week !!

 

 

 

 

 

 

 

 

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