Insight > Raw materials & formulation

The
co-crystal
classification
conundrum
Draft guidance relating to the classification of co-crystals,
recently issued by the FDA, has left many puzzling over its
definitions and distinctions. Abi Millar asks Gino Martini
of Kings College London; Patrick Crowley, formerly
of GlaxoSmithKline; and Brian Carlin of IPEC USA
for their interpretations of the new guidelines.

I
n December 2011, the Food and Drug
Administration (FDA) in the US issued
draft guidance on the Regulatory
Classification of Pharmaceutical Co-Crystals.
The guidance appeared to take the industry a
little by surprise and, judging by some of the
responses from major players, there appear to be some
potentially important
shortcomings in the
draft guidance as it
stands, issues that may,
unintentionally, have a negative
impact on the development of
pharmaceutical co-crystals.
So what exactly are
co-crystals?
A pharmaceutical
co-crystal is a single crystalline
solid that incorporates two or
more molecules in the same crystal
lattice; one being the active
drug, and the other the
co-former, being either an
excipient or even another drug,
says Gino Martini, professor of
pharmaceutical innovation at Kings College
London. This could include a salt, where

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 Insight > Raw materials & formulation
there is an acid-base reaction, but the FDA guidance appears to
exclude salts, focusing on the components in the crystal lattice
that are in a neutral or non-ionic state.
Co-crystals are used to enhance novel or existing material so
that it is more useful as a drug. Effectively, it is just another way
of providing a form of a drug with different physicochemical
properties, making up for deficiencies such as poor solubility or
processing properties.
You could have a novel drug that is perfect for interacting at a
particular receptor site, but you may find that it has a deficiency
stopping it from being absorbed and getting to that receptor,
preventing it being used in the body, says Patrick Crowley,
former VP of pharmaceutical development at GlaxoSmithKline,
and founder of pharmaceutical consultants Callum Consultancy.
A co-crystal of the drug with another material could have
other enhanced properties, he continues. These might include
stability the drug being less susceptible to degradation. Or, for
tablet processing, it might have better compressibility or flow
better. So, like a lot of excipients, it is compensating for a
deficiency in the drug that might prevent its optimum use. But in
the case of co-crystals, the association is at the molecular level.
The recent regulatory focus on co-crystals reflects their growing
pharmaceutical use, says Brian Carlin, who is chair of the QbD and
Excipient Composition Committees for IPEC USA, and director of
open innovation at FMC BioPolymer, a leading excipient supplier.
Co-crystals, salt selection and
co-processing with excipients are all
multiple ways of addressing the
shortcomings of pure crystals, designed
without regard for fitness for purpose.
The traditional model was that you isolate a pure crystalline
form of drug, separately from processing to a pharmaceutical
product, Carlin says. As an industry, we spend our time
developing exquisitely pure designer crystals, the properties
of which may not be optimal for production of pharmaceutical
dose forms.
Uncooperative crystal forms, such as needles, will not flow,
you cannot compact them to tablets, and they may be practically
insoluble. To add insult to injury, it is a major process control
hazard, because generally, the purer the crystal, the more unstable
the control of the crystallisation becomes.
Most modern drugs designed to target receptors have many
hydrophobic groups to ensure potency and high receptor
selectivity (at least in isolated tissue or enzyme systems), but
consequently many were poorly soluble, so they would not be
absorbed when you took them orally, for example.
The industry used to like pure crystalline solids for the drug
development programme, adds Martini. In the 1980s and 1990s,
when mass screening and high throughput became the norm
we ended up producing a large amount of poorly soluble, poorly
bio-available candidate drugs. Amorphous non-crystalline forms,
with better solubility were sometimes seen as a remedy and
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amorphous forms gained some currency as a way to overcome
solubility problems. I think co-crystallisation is just another
variation of that evolution.
So co-crystals, salt selection and co-processing with excipients
are all multiple ways of addressing the shortcomings of pure
crystals, designed without regard for fitness for purpose.
Draft guidance
In December 2011, the US FDA published draft guidance for API-
excipient co-crystals, stating that, ...an API that has been
processed with a co-crystallising excipient to generate an API-
excipient co-crystal should be treated as a drug product
intermediate... Co-crystal-containing drug products will not be
considered to contain new APIs, but rather to contain a specifically
designed formulation component called a co-crystal drug product
intermediate. Presumably, the FDA is referring to drugs already in
use, as a co-crystallised new API would still be a new API.
It is not immediately apparent why the FDA decided to issue
classification guidance on co-crystals. Although, as Crowley and
Carlin speculate, there are a number of possible reasons.
Crowley connects it to the evolution in compendia like
pharmacopoeias, with monographs specifying the standards for
purity, residue, impurities and so on for a particular drug. If a firm
wants to state on its label that its medicine contains
pharmacopoeial quality material, it has to take the drug and test it
against the pharmacopoeial monograph, he says.
You cannot really do that if you have already mixed it up
with an excipient, and never isolated it as a pure crystal. So that
has driven the need to make the crystalline drug first, test it, and
then take that and make the pharmaceutical product.
But the co-crystal approach means crystallising the drug
with another material at the same time, and never isolating the
pure API. I sense that the agencies may have identified some
problems with that.
Alternatively, says Carlin, the combination of excipients and API
is occurring at a much earlier stage, in what we call primary [API]
manufacture, as opposed to the traditional secondary manufacture
[usually at a different site from the API synthesis], combining the
active ingredient with the excipients to make products. Perhaps
the FDA regards this earlier introduction of excipients as secondary
manufacture, as opposed to primary manufacture.
Consequences and confusion
There are, however, as Carlin, Crowley and Martini all agree,
some powerful arguments against the approach adopted by the
FDA in its guidance.
For one, the definition is too broad, argues Carlin. If co-crystals
are solids that are crystalline materials composed of two or more
molecules in the same crystal lattice, the proposed definition
would cover existing commercially produced API forms such as
hydrates and salts.
The classification as a drug intermediate is also problematic. As
the biopharmaceutical giant Amgen pointed out in its written
response to the guidance, the draft guidance considers API-
excipients drug intermediates because of their neutral guest
component at a molecular level. But hydrates or solvates also
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 Insight > Raw materials & formulation
have a neutral guest component, and are not generally considered
drug product intermediates.
If I am making a citrate salt of a drug, and taking my citric acid
excipient into a primary site, that is perfectly acceptable as long as
it is a salt. But combining the same drug with a so-called neutral
guest molecule, all of a sudden is considered to be in a different
category. Theres no scientific basis for the distinction, says Carlin.
If they need to control drug-excipient combinations on a primary
manufacturing site and want to provide guidance that is fine. But
dont try and use the status neutral versus ionic, co-crystal versus
salt as the basis of distinction because the two are not parallel.
Perhaps the FDA regards this
earlier introduction of excipients as
secondary manufacture, as opposed
to primary manufacture.
It is not as if the level of association between API and
excipients at molecular level is new, either. The prior act of
mixing drug and excipient together at the site of primary
manufacture is happening already, says Crowley, and has been for
some 20 years without any regulation. It has been happening for
safety reasons, with biopharmaceuticals where the biological
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The draft guidance also appears to extend the regulations
applicable to API manufacturing facilities. Co-crystals are often
produced in late-stage API synthesis. If they are classified as a
drug product intermediate, how should API production
facilities be regulated?
The implications could be onerous. When companies are
working with a drug product, they are expected to follow current
good manufacturing practices (cGMP).
These are enshrined in federal law in the US, with equivalent
rules in most jurisdictions worldwide. The standards to be
followed are very stringent, far more so than a typical chemical
site where an API would be manufactured, although there is an
expectation that as you get closer to the finished API crystal,
there will be a degree of GMP.
It is not like a pharmaceutical plant with full cGMP, says
Carlin. Because precursors and intermediates undergo
subsequent purification steps, many areas and operations on an
API site do not require the rigour of secondary cGMP. The
problem is, if the FDA starts to label excipient-API combinations
on a primary API site as drug product, then it could change the
legal basis of site approval, and the degree of GMP compliance
required, a not insignificant consideration.
If that is the case, and it is followed to its logical conclusion, it
suggests a number of sites may close, if firms are not able, or
cannot afford, to upgrade their facilities. This would have the
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 Insight > Raw materials & formulation

shortages, inflating costs and so on without any discernible

enhancements of quality. Equally, for defensive regulatory reasons
and cost avoidance, co-crystal development will not be practised,
inhibiting innovation in API quality by design.

Unnecessary change?
Perhaps understandably there has not been a rush of support from
the industry for this draft guidance. The FDA has brought in new
guidelines on co-crystals, and what the industry is saying is that
such forms can be covered within existing regulatory
requirements, says Martini.
That is the crux of it from an industry perspective. I think the
theme from industry is not to introduce more regulation,
bureaucracy and red tape, as it makes life very difficult.
Overzealous regulation will kill innovation.

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