Gel networks in pharmaceuticals Max Flint
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Gel networks and their influence on the crystallisation
of pharmaceutical ingredients
Max Flint
Department of Chemistry, University of Sheffield, Sheffield S3 7HF, UK.
Abstract. Gels have been utilised for crystal growth for decades now due to their myriad
properties which make them an ideal medium for crystallisation. The need for gel networks
in the discipline of crystallography has been apparent for many years in light of the need
for large, high quality samples often only accessible via the use of gels. There has been a
recent surge of research interest in the field of Low Molecular Weight Gelators (LMWGs),
molecules which reversibly form a supramolecular network and can be used to grow
crystals of hitherto inaccessible forms. Particular topics explored include the effect of using
gel networks to affect crystal habit, polymorphism and optical isomerism, with focus on how
these properties are relevant when considering the manipulation of organic crystal
structures such as Active Pharmaceutical Ingredients (APIs). This article will begin with a
brief assessment of crystal growth in gels and go on to consider how these gels can be
implemented, to great effect, in the pharmaceutical industry.
Introduction
Growing crystals in gels has been practised for around 120 years,1 beginning with
Liesegang in 1896 and his formation of the famous ‘Liesegang rings’.2 What followed was a
great deal of attention from notable scientists such as Ostwald and Rayleigh, and then by
geologists who saw the research as a way of explaining certain crystal formations found in
rock formations. Later research (throughout the early-mid 20th century) served to further
illustrate the usefulness of gel media for the growth of high quality crystal structures. We
can see examples of this kind of growth in many forms in nature and perhaps most
beautiful is the formation of the mollusc shell, whereby the crystallisation of calcium
carbonate occurs in an organic medium comprising of glycoproteins and polysaccharides
(Figure 1).3 It is clear from many instances, both natural and anthropomorphic, that the
control of crystal growth to favour a particular kind (morphology, polymorph, habit etc.)
over others is immensely important and the current academic interest in the field is
reflective of this.
Figure 1. A Giant Clam. The formation
of a mollusc shell can be thought of as
the crystallisation of CaCO3 in an
organic gel network.
A gel can be described as a semi-solid system in which a liquid is responsible for the
majority of the weight, while the remaining weight (~1%) is accounted for by a 3D network
of fibres formed by a certain type of molecule known as a gelator.4,5 A hydrogel is a gel in
which the liquid phase is water, while an organogel describes one in which the liquid phase
is an organic solvent, such as toluene. Their solid-like rheology, occurring due to the liquid
being immobilised in the fibrous network (Figure 2) by surface tension, prevents convection
and reduces the number of nucleation sites. This greatly slows down diffusion and,
therefore, the rate at which the crystals grow.6 These features of the gel allow the crystal to
grow uniformly in all directions, effectively serving to produce much higher quality crystals,
with far fewer defects than if the process were undertaken in a non-gel aqueous medium.
Gel networks in pharmaceuticals Max Flint
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Figure 2. Left: A basic scheme of the structure of a gel. Right: In the case of LMWGs (here ‘LMOG’ describes a
‘Low Molecular Weight Organogelator’), as will be explored in this article, small molecules such as (bis)urea self-
assemble reversibly to form supramolecular networks.
Polymeric gelators e.g. gelatin and silica, are used in many different aqueous and non-
aqueous environments. LMWGs are an alternative class of gelators that have only recently
been explored and they are able to self-assemble away from equilibrium, also in a diverse
variety of solvents. These supramolecular gels can be distinguished from polymeric gels in
that they form Self-Assembled Fibrillar Networks (SAFINs) via various non-covalent
interactions.7 This makes their formation thermally reversible and they can be easily
transformed back into a fluid. The reasons why these types of gelators have caught so much
attention in recent years are numerous and range (in the context of pharmaceuticals) from
the improved synthesis of certain ingredients to the ways in which drugs are delivered.
Seeing as the reason why many treatments have, in the past, been unsuccessful due to
their inability to effectively deal with issues such as tumour targeting and problems
associated with intravenous chemotherapy treatments,8 further research into the
mechanism of crystal growth seems necessary.
LMWGs are remarkable in that they are formed through self-assembly via intermolecular
forces such as hydrogen bonding, aromatic stacking and the hydrophobic effect. What
makes them so useful in terms of pharmaceuticals, both for their delivery and their
synthesis, is that they can be tailored to undergo the sol-gel transition as a response to a
wide range of stimuli, such as pH triggers, temperature change or a trigger in the form of
anion-tuning. In most cases, the gel simply acts as an inert medium in which the crystal is
free to form. However, recent developments have demonstrated that their potential reaches
further: they can in fact influence the ways in which the crystals form, including
enantiomorphism, polymorphism and habit.9 The ability to control these features has long
been sought after, as many organic compounds are found to exist in multiple solid forms on
a frequent basis.10 Thus far, work on LMWGs has been dominated by biomineralisation
studies on the formation of CaCO3 crystals. However, this article will focus primarily on the
plethora of applications to improve the availability of high-quality pharmaceutical
ingredients.
Discussion
Crystal Growth in Gels – Habit Modification
Gels are often described as an ideal medium in which to grow crystals. This is attributed to
the suppression of convection currents in the bulk liquid, rendering diffusion the controlling
factor in crystal growth. The dramatic reduction in the number of nucleation sites is
brought about by the increased viscosity of the gel. This reduces the number of random
collisions between molecules and therefore the number of nucleation sites.11 Put simply, if
the crystals are only able to grow slowly and from very few sites, then large, microscopically
ordered crystals with few defects can be obtained. The crystals grown often display novel
morphologies, which is a particularly exciting phenomenon for the field of pharmaceuticals
due to the enormous potential for drugs with new properties.
Crystal habit is the characteristic external shape of a crystal. One early study into the
manipulation of crystal habits dates back to 1979 following the earlier work of Henisch.
Barium molybdate crystals were grown under various conditions and in-depth
investigations were carried out into the morphology and sizes of their samples. Although
the temperature at which they were grown had no effect on the crystals, they did manage to
generate crystals of different habits by modifying both pH and concentration.12 A more
recent example of influence over crystal habit using gels is the use of hydrogel media to
modify the habit of Aspargine monohydrate crystals. Aspargine, first isolated by Pierre
Jean Robiquet in 1806,13 is an amino acid, one of the fundamental building blocks of
proteins and is essential for the development of the human brain.14 Swift and co-workers
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used a range of hydrogels to synthesise Aspargine monohydrate (Asn.H2O) crystals and the
morphologies of these crystals were compared against those grown in alternative aqueous
media. They were able to ascertain that the use of gels as media for crystal growth is a
viable pathway to obtaining new morphologies for crystals.15 This research serves as an
important indicator that gels have the potential to be used to great effect in the
pharmaceutical industry.
Table 1. Summary of different media used by Swift and
co-workers11 to obtain novel morphologies for Asn.H2O
crystals with the Miller indices indicated. Since this
study, much more work has gone into understanding the
mechanism of crystal growth in gel media in the hope
that the properties of the gel can be tailored to favour a
desired product.
Using Gels to Aid Polymorphism Screening
Polymorphism describes the phenomenon of crystallisation into two or more structurally
distinct compounds which share identical chemical composition. The importance of
polymorphism in the pharmaceutical industry was recognised first in 1969 by McCrone and
Haleblian.16 They recognised that if polymorphism in pharmaceutical ingredients goes
unmonitored and uncontrolled then dangerous variations in drug availability to the patient
will be prevalent. This issue is seen as so important that the common practice now
(enforced in the US by the Food and Drug Administration) is to identify and analyse the
known polymorphic forms of an active pharmaceutical ingredient (API) at all stages of drug
development - a long and arduous process known as polymorphism screening.10 It is
necessary because polymorphic forms of APIs are considered to be different chemical
entities by drug regulators due to their different physio-chemical properties in solution.
This is an area where gel networks are starting to be used. For example, interesting
research has been undertaken by Steed and co-workers looking into growing organic
crystals (in this case, pharmaceuticals) using anion-tuned gel phase materials (Figure 3)
i.e. using LMWGs to generate a responsive gel material, one in which triggered gelation can
occur. They have concluded that bis(urea) organogels can be used to access different
polymorphs of pharmaceutical ingredients, such as carbamazepine. This efficient way of
accessing different polymorphs of a crystal can provide a powerful tool for the process of
pharmaceutical polymorph screening.17
Figure 3. A single crystal of carbamazepine is recovered via acetate-anion-dissolution of a gel. Note the large size
of the crystal, suitable for single crystal X-ray crystallography, and the ease with which it was recovered.
One of the first examples of successful growth of an API in gels was of (±)-modafinil in
tetramethoxysilane (TMOS) gels by Coquerel and co-workers,18 with the focus prior to this
being on inorganic crystals. Up until 2006, organic crystals of the metastable racemic
polymorphic form III of (±)-modafinil (Figure 4) had not been grown of a sufficient size to be
studied properly by X-ray diffraction. Crystallisation in TMOS gels was found to be an
effective technique for the growth of this form, where crystallisation in solution had
previously failed. The presence of, and accessibility to, different polymorphs of the same
API is significant in the context of pharmaceuticals. Papers like those published by
Coquerel et al show that gels could be used not only to develop previously inaccessible
polymorphs of APIs with possibly useful properties, but also to exclude those which are
inactive, or even harmful.
Gel networks in pharmaceuticals Max Flint
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Figure 4. (±)-modafinil in TMOS gels. The number of crystals then decreases with the degree of supersaturation
involved (from left to right the water/methanol ratio decreases). Crystals grown in the centre tube were mainly of
form III, a form which has proved elusive in other aqueous media.
However, as recently as 2015 it has been acknowledged that there is still a need for novel,
modern polymorph screening technologies due to the regulatory necessity of being aware of
all possible forms of a new drug substance. Steed and co-workers expanded upon their work
undertaken in 2010 using LMWGs to a more pharmaceutically relevant approach by
tailoring the structure of the gelator itself to mimic that of the drug substance, in this case
the anti-cancer drug cisplatin.19 Cisplatin displays only limited polymorphism due to its
simple structure and labile chloro ligands and thus presented an interesting challenge.
However, it was determined that the structural similarities between the cisplatin-mimetic
gelator and cisplatin together with the relatively ordered assembly of the gel enhanced the
influence of the ‘C3’ gels (Figure 5) on cisplatin crystallization. This work represents a new
and advanced pharmaceutical crystallisation strategy for the discovery of novel
polymorphs.
Figure 5. A scheme showing the formation of cisplatin-mimetic gelators and the structure of Cisplatin. The C3 gel
was found to be the most versatile and effective gelator, and in the presence of C3 consistently high-quality
crystals formed.
Using Gels to Influence Chirality in APIs
The importance of chirality in the pharmaceutical industry is something of immense
significance. The most well-publicised and far-reaching consequence of this phenomenon
came to light in the late 1950s in West Germany when a company called Chemie
Grünenthal developed and sold Thalidomide under the trade name ‘Contergan’. One
enantiomer of the drug, (R)-thalidomide, was an effective cure for morning sickness in
pregnant women while the other, (S)-thalidomide, had horrific effects on the foetus.
Although purifying and administering only (R)-thalidomide is futile20 (Figure 6),
acknowledging this case study is a useful exercise in demonstrating the need for
enantiomerically pure APIs. Gels can be used not only for growing only one enantiomer of
an API (chiral gel networks) but also for the separation of enantiomers in capillary
electrophoresis, a method for separation and analysis of macromolecules and their
fragments using a polymeric gel as a medium, based on their size and charge.21
Figure 6. The two enantiomers of thalidomide. The acidic hydrogen indicated above means that the compound will
rapidly racemise at physiological pH, so even if an enantiomerically pure drug were administered, it would still be
potentially very harmful to a foetus. The case study nevertheless serves to highlight the importance of chirality in
the pharmaceutical industry.
The advantages of providing a drug in its pure enantiomeric form are summarised
succinctly by Professor Gohel of L. M. College of Pharmacy,22 the most important one being
Gel networks in pharmaceuticals Max Flint
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the reduced likelihood of side-effects. There is a need to identify and isolate the
enantiomers of racemates which are useful, not harmful and the pharmacodynamic effects
of which are known.23 Supramolecular gel networks clearly represent a potential solution
where this is concerned.
A study undertook in 2000 involved using proteins as chiral selectors to separate
enantiomers of drugs. A silica gel was immobilised by a 3D protein network and
enantioseparation occurs by each enantiomer interacting differently with an immobilized or
adsorbed protein selector.24 More recently, studies have shown that gels made from chiral
building blocks can be used to amplify both chirality and crystal growth in crystals. That is
to say, enantiomeric excesses are able to convert racemic mixtures into enantiomerically
enriched mixtures. Petrova and Swift were able to use agarose gel (a naturally occurring
chiral polysaccharide) as an effective medium for the growth of large enantiomeric excesses
of either d- or l-NaClO3, where using pure aqueous solutions yielded a racemate. The
growth of d-NaClO3 crystals was favoured when the aqueous gel was imparted with 48%
weight NaClO3 at 279K, with enantiomeric excess reaching as high as 22% (Figure 7).25
Figure 7. Enantiomeric excess gained from crystallisation in gel rather than aqueous media.
Sánchez et al used organogelators 1 and 2 (Figure 8) to investigate the enantiomeric and
polymorphic outcome of the crystallisation of various APIs (Aspirin, Caffeine,
Carbamazepine and Indomethacin) in gel media using toluene as the solvent. The crystals
can be easily recovered from the gel by washing and shaking the samples in toluene. This is
advantageous as it is a simple procedure which does nothing to alter the crystalline
product. Non-covalent interactions (i.e. those utilised by LMWGs) play a significant part in
the amplification of chirality in biological systems,26 and this realisation was explored and
extended to investigate the manipulation of the aforementioned APIs.
Figure 8. Structure of organogelators 1 and 2 used by
Suarez et al to investigate the influence of chirality in
gel network structure on the growth of some APIs.
Conclusions – Looking Forward
The ability to grow organic, pharmaceutical crystals in gel media has been demonstrated
along with the ability to easily recover these crystals without altering or harming them. It
has also been shown that gel networks, specifically those formulated using LMWGs, can be
an extremely useful and versatile tool in helping to solve the issue of limited access to
crystal forms of APIs which have previously been difficult to grow and recover. The
potential of these media for influencing the properties of APIs represents a significant
milestone on the road to easier and cheaper polymorphism screening and habit
modification. Overall, this new tool in the field of crystallisation is something which could
revolutionise the discipline, as it could shed light on the growth and nucleation processes,
both of which are relatively poorly understood, especially when considering crystal habit
modification. There is now a diverse and substantial library of different supramolecular
gels which will allow us to choose the correct gelator to suit the crystallisation conditions.
This class of gelator opens up huge opportunities for fine-tuning the interactions we
observe between the gel and the solute, allowing us to hope for much greater control over
the crystallisation of APIs (and other products of interest) in the not-too-distant future.
As our understanding of this new frontier in soft materials science grows, so will the scope
for applying gel networks to challenges other than those presented by API growth. For
example, we have seen that gel-phase crystallisations can offer high-quality single crystals
Gel networks in pharmaceuticals Max Flint
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and this can be of particular use in macromolecular crystallography, where the crystal
quality of small samples is very important. The developments in the field of metallogels
such as the cisplatin-mimetic gel mentioned earlier (Figure 5) are of immense significance
for future studies. As recently as January 2016, a paper has reported the discovery of “A
novel low molecular weight supergelator showing an excellent gas adsorption, dye
adsorption, self-sustaining and chemosensing properties in the gel state”.27 LMWGs clearly
have enormous potential in industry and medicine, and represent a new and exciting
branch of chemistry, the versatility of which will surely be instrumental in allaying a wide
range of future and current issues.
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