Solubility Advantage of Amorphous Drugs and Pharmaceutical Cocrystals

Hi everyone, I thought I might begin this week talking about crystallizations.  One of the most popular postings I had on my website was one on polymorphs.   Although this week’s pick or review is not on polymorphs, it is a burgeoning area of study in the crystallization field.  I am talking about the use of co-crystals in active pharmaceutical ingredient crystallizations.  This is definitely something I don’t know too much about, but feel that is of great importance.  I have done a few crystallizations and wanted to steer clear of amorphous drugs.  In fact, a few of the projects that I have worked on, the product was not crystalline.  One of them had to spray-dried as a mesylate salt.  Adding another compound into the mix didn’t seem like a solution at the time, but who am I to know ?  Would you have considered it ?

So I was intrigued when I came across the following article, “Solubility Advantage of Amorphous Drugs and Pharmaceutical Co-crystals”, by N. Jagadeesh Babu and Ashwini Nangia, Crystal Growth & Design,2011, 11, 2662–2679. I found out that over 40 % of marketed drugs today have low solubility and in the R & D pipeline, 80 – 90 % of drug candidates could fail because of solubility issues.  The reason given for coming up with a lot of these low solubility materials was the use of DMSO and PEG as solvents in rapid screening panels for biological activities.  They mislead one into thinking that a certain drug target will have no solubility issues, the so-called “brick dust” or “chalk-powder” compounds.

This last statement led to an epiphany, that indeed this was a good description of some of the compounds that I had been working on ages ago.  If I can see a glimpse in truth of what the author is saying, I am sure you can too.  The statement that a drug’s behaviour depends on more than its molecular structure.  So does that mean in the past, that although certain compounds destined to become drug targets might have passed a biological screening but were doomed to fail due to solubility issues.  That’s pretty heavy stuff, I think.   And that isn’t the bulk of what this paper is about.  I veered off-topic.

Anyhow, let’s get back to what the paper is about.  I guess before I get into this topic of co-crystals, we should talk about what the co-crystal is, are there only certain types of co-crystals, etc.  A co-crystal is a compound selected from a benign group of chemicals that are considered safe by the FDA or GRAS, that crystallizes with your product.  So, you can’t pick any crystal, it has to be considered “safe”.  The use of a co-crystal can affect the dissolution rate of your drug product.  Why is this important ?  Because in order for the drug to be effective, it must be absorbed quickly in the stomach and GI tract ( I forgot to include any oral drug, in tablet form).

One of the classic ways to accomplish drug solubility was to form salts.  I have made them and I am sure you have too.   That’s makes sense.  If it is insoluble, we could make the base of the free-acid or acid of the free-base.  Plenty of mineral acids, organic acids and the like to use for this.  To increase solubility, we could have our drug undergo amorphization (cool word) to have amorphous material.  Micronizing crystallline material is one way of doing this and it is understandable.  However, in the instance where you have the following, you might consider co-crystals.


1.  Drug molecules which lack easily ionizable functional groups (such as those containing     carboxamide,phenol, weakly basic N-heterocycles, etc.) can be intermolecularly manipulated via cocrystals to tune their physicochemical properties.2.  If the compound has particular sensitive groups to treatment of acid and base, it is nice to know that you could tweak your physicochemical properties with a co-crystal.

3. There is a larger number of neutral GRAS compounds to make co-crystals than there are counterions to make pharmaceutical salts.

There are quite a few example in this paper where co-crystals have been beneficial but I think I will only present one, you can pick up the paper if you are interested.

One of the examples in this paper is celecoxib (otherwise know as Celebrex, an anti-inflammatory drug).  Here is the gratuitous structure that has been missing in this post.


Celecoxib exists in 4 polymorphic forms, of which Cel-III is the marketed form of the drug, but it has low solubility (< 1 mg/L).  Cel-IV dissolves twice as fast, has twice the bioavailability and is shelf-stable for up to a year.  Attempts to improve the bioavailability of this drug through salts gave low oral drug delivery.    From another researcher, celecoxib-nicotinamide co-crystal was discovered.  80 % of the drug was dissolved in 30 minutes at a concentration of 400 mg/L, where Cel-III was only dissolved in 50 % of this claim.  So there was a quite a substantial improvement in the dissolution of this drug with nicotinamide as a co-crystal.

I know that this all well and good, that this improves the bioavailability of the drug.  But what is beneficial about using co-crystals to the process chemist ??  Fun, you should ask.  In most cases, everyone is under tight deadlines to deliver material and if the product is amorphous, the process chemist has to slug through it and if filtering the product takes hours to do, one must do it.   Co-crystals can help with filterability though.  I never thought of co-crystallizing a compound to improve its filterability.  This would require co-operation with ARD and your formulation group to see if you want to develop your product as a co-crystal.  It is intriguing, nonetheless.  It can also improving compaction for the formulating into tablets.

I hope you found this post interesting.


 This is an old post from PHARMNBIOFUEL.COM, originally posted on 2012-02-27.


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