Cavity-containing supramolecular gels as a crystallization tool for hydrophobic pharmaceuticals

Article abstract of DOI:10.1039/c6cc04037c

We present two approaches to low-molecular-weight supramolecular gels bearing hydrophobic cavities based on calixarene-containing building blocks. Gels are formed by a calixarene based tetrahydrazide gelator or a co-gel of a calixarene diammonium salt and

Full text of DOI:10.1039/c6cc04037c

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Cavity-containing supramolecular gels as a
crystallization tool for hydrophobic
Cite this:DOI: 10.1039/c6cc04037c
pharmaceuticals†
Received 13th May 2016,
Accepted 29th June 2016
Lena Kaufmann,a Stuart R. Kennedy,b Christopher D. Jonesb and
Jonathan W. Steed*b
DOI: 10.1039/c6cc04037c
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We present two approaches to low-molecular-weight supramolecular In these systems small covalent building blocks with a defined
gels bearing hydrophobic cavities based on calixarene-containing chemical structure self-assemble through non-covalent, weak and
building blocks. Gels are formed by a calixarene based tetrahydrazide reversible interactions like hydrogen bonding or p–p-stacking
gelator or a co-gel of a calixarene diammonium salt and a bis-crown into one-dimensional fibres. By interconnection of these fibres
ether. The calixarene hydrophobic cavity enables the complexation a self-supporting three-dimensional network is formed and solvent
of hydrophobic drug molecules in a generic fashion thus providing molecules can be trapped within it by surface tension.13
an anchor site on the surface of the gel fibre to initiate drug crystal
One emerging potential application of such reversible and
nucleation and growth. This technique potentially represents a route synthetically versatile gels is in the area of pharmaceutical
to growth of hard-to-nucleate polymorphic modifications. The co-gel crystallization.21–25 Control of polymorphic or solvate form is of
comprising two components holding together by non-covalent key industrial importance.26–29 Gels based on LMWGs represent a
ammonium-crown ether interaction can be easily switched back highly tuneable medium adaptable to a range of solvents including
to the sol state by adding competitive binding cations.
those commonly used in pharmaceutical manufacture and they
offer the possibility of specific gelator–solute interactions which
Gels are a class of dynamic soft materials that are becoming may influence the solid form outcome and hence make LMWGs a
increasingly important as they might open the way to completely useful part of a pharmaceutical solid form screening strategy.30,31
new functional systems.1,2 The gel state is defined as ‘‘a two- A supersaturated mixture of LMWG and solute represents a non-
component, colloidal dispersion with a continuous structure with equilibrium, weakly coupled orthogonal self-assembling system
macroscopic dimensions that is permanent on the time scale of in which gel and crystal assembly occurs in a self-sorting fashion
the experiment and is solid-like in its rheological behaviour’’.3,4 but with the possibility of mutual influence on the emergent
Compared with for example ceramics, metals or plastic, gels are properties of the whole.22,32 Specifically binding of drug molecules
not as long-lasting and stable, but instead provide interesting to the locally ordered gel fibre surface offers a novel heteroge-
properties, e.g. the ability to be switched between gel and sol neous nucleation pathway in which the local periodicity of the gel
states by external stimuli and free fluid-like diffusion within their may be imparted to the growing crystal nucleus, hence potentially
structure.5 Traditionally, cross-linked covalent polymers have subverting the normal polymorphic outcome of the crystallization
been used as gelators.6–10 These polymers are notable for their process. In this work we report two approaches to the design of
ability to swell up by taking in solvent molecules, in amounts that broadly applicable gels capable of binding, in a generic way, the
can considerably outweigh their own mass.11 In the last two decades hydrophobic residues of small molecule pharmaceuticals with
supramolecular gelation systems based on low-molecular-weight this application in mind. Modern drugs are increasingly
gelators (LMWGs) have received substantial attention owing to hydrophobic.33 By incorporating a series of hydrophobic cavities
their straightforward preparation, interesting self-assembly proper- into the gel fibre18 it should be possible to bind a locally ordered
ties and the reversibility of the inter-component interactions.12–20 layer of drug molecules to the gel fibres and, under super-
saturation conditions, use these sites as the starting point for
a
¨
Freie Universitat Berlin, Takustr. 3, 14195 Berlin, Germany
the crystallization of drug solid forms.
b Durham University, South Road, DH1 3LE, UK. E-mail: jon.steed@durham.ac.uk
† Electronic supplementary information (ESI) available: Synthesis of new com-
pounds, experimental details for crystallization and gelation studies. CCDC
1478493. Underlying research data for this paper is available in accordance with
EPSRC open data policy from DOI: 10.15128/37720c73c. For ESI and crystal-
lographic data in CIF or other electronic format see DOI: 10.1039/c6cc04037c
The basic structural element of the target gels incorporates a
calix[4]arenes whose bowl shaped molecular structure offers a
hydrophobic cavity suitable for the inclusion of hydrophobic
residues of a range of potential solutes.34–36 These gelation
systems should be widely applicable for all kind of drug
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Scheme 1 Structure of gelator 1 and schematic representation.
molecules with a residue that can fit into the calixarene cavity.
Calixarenes can be easily modified at either the upper and/or
lower rims of the molecular skeleton.37,38 For calixarene incor-
poration into a gel we report two different concepts:
(1) A one-component approach, in which the calixarene mono-
mers are functionalised with directional hydrogen bonding groups
to enable them to act as LMWG.
(2) A two-component approach in which a supramolecular
co-gelator is formed from the non-covalent interaction of two
components that are non-gelators individually.
Fig. 1 (a) Schematic of the proposed self-assembly of 1 to produce a gel
fibre (b) vial inversion test of the 1,2-dibromoethane gel of 1 (2% w/v) (c) SEM
images of the xerogel.
A single component gelator. Compound 1 (Scheme 1) was
designed to produce gel fibres by mutual association of the
hydrazide groups leaving the calixarene cavity exposed on the
gel fibre surface. Compound 1 was prepared in moderate yield
by functionalization of calix[4]arene with ethyl bromoacetate39
followed by reaction with hydrazine hydrate.40 The resulting
hydrazide was then coupled with benzoylhydrazinyl oxobutanoic
acid,41 leading to the desired product 1 with two diformylhydra-
zine groups (see ESI,† for details). The gelation ability of 1 was
screened in a wide variety of organic solvents but proved to form
strong reproducible gels only in 1,2-dibromoethane with a critical
gelation concentration of 1% w/v as evidenced by the vial inversion
test (Fig. 1b). The resulting gel was analysed by stress sweep
rheometry (Fig. 2) which revealed a strong gel with a plateau G0
value of approximately 10 000 Pa, around an order of magni-
tude higher than G00 confirming the solid-like nature of the
material.42,43 SEM images of the dried xerogel (Fig. 1c) revealed
a fibrous structure typical of self-assembled fibrillar networks
involving hydrogen bonded chains of gelators.42 We postulate
that gelation occurs by the aggregation mode depicted in Fig. 1a.
Placing 1 in a concentration of 2% w/v in a non-polar solvent
like 1,2-dibromoethane leads to gel formation through multiple
CQOꢀ ꢀ ꢀHN hydrogen bonding of the diformylhydrazine
groups.19,44
Fig. 2 Stress sweep rheometry for a 2% w/v gel of 1 in 1,2-dibromoethane.
with crown ethers46,47 and we reasoned that a one dimensional
hydrogen bonded polymer with potential gelation properties
would result from the combination of 2 with bis(crown ether) 3
(Scheme 2).48 The proposed assembly mode is shown schemati-
cally in Fig. 3b. Synthetic details are given in the ESI.† The
formation of compound 2b was also confirmed by single crystal
X-ray crystallography as a chloroform solvate. The X-ray data is
of poor quality and does not permit any quantitative description
(see ESI†) but reveals the key gross structural details of the cone
conformation and 1,3-disubstituted nature of the compound
with the two ammonium groups situated on the same side of
the calixarene cavity, Fig. 4, supporting the assembly mode
proposed in Fig. 3b.
A two-component co-gel. While suitable for proof of principle,
compound 1 is not particularly versatile in its gelation properties
and requires a number of steps to prepare. As a result we also
investigated the preparation of multicomponent co-gels from
simpler components. A bis(3-aminopropyl) calixarene is readily
synthesised following the procedure reported by Durmaz45 which
yields the tosylate salt 2 (as either the t-butyl form 2a or unsub-
stituted derivative 2b) on protonation with p-toluenesulfonic acid.
Ammonium groups are well known to form host–guest complexes
Neither 2 nor 3 alone are gelators individually, however, after
screening 1 : 1 mixtures of the compounds in a variety of solvents
we established that a 1 : 1 mixture of either 2a or 2b with 3 in 1,2,4-
trichlorobenzene at 6% w/v results in gel formation (Fig. 3a).
Gel formation was recognised by a simple vial inversion test
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Scheme 2 Structures of gelators 2 and 3 and schematic representations.
Fig. 5 Schematic representation of the collapse of gel 2ꢀ3 and photo-
graphs of the gel samples upon addition of upon addition of KPF6 in
acetonitrile solution.
value of G0 compared to G00 (see ESI,† Fig. S1) while the SEM
images confirm the fibrillar nature of the xerogel. Interestingly
the 2ꢀ3 co-gel formed only with tosylate counter ions. The analogous
hexafluorophosphate or trifluoromethanesulfonate salts preci-
pitated instead of forming gels in 1,2,4-trichlorobenzene. This
anion dependence suggests that the gelation properties may be
anion controlled allowing selective gel turn-off, for example to
recover gel grown crystals.21 In addition, even the tosylate salt
of the gel can be ‘switched off’ in the presence of potassium ions.
An aliquot of 10 ml of a saturated solution of KPF6 in acetonitrile
was carefully layered onto the gel. After 3 hours the whole gel
collapsed and did not re-form on heating and cooling (Fig. 5).
The gel was unaffected by acetonitrile alone. This experiment
suggests that K+ can competitively bind with the crown ether
and break up the hydrogen bonded polymer structure, with the
strong binding of K+ displacing the ammonium ions.49
Fig. 3 (a) Vial inversion test of the 2aꢀ3 co-gel (2% w/v in 1,2,4-trichlo-
robenzene) (b) schematic view of the interaction of the proposed self-
assembly mode. (c) SEM images of the xerogel.
Crystallization experiments. Preliminary crystallization experi-
ments with model drug substances were carried out in order to
demonstrate the utility of the new calixarene-containing gels in
a pharmaceutical crystallization context. Compounds tested were
Fig. 4 X-ray crystal structure of the ammonium terminated calixarene 2b
showing hydrogen bonding to the tosylate counter ions.
and confirmed by stress sweep rheology and SEM. The solid like paracetamol, the NSAID fenbufen (4-(4-biphenyl)-4-oxobutyric
nature of the gel was confirmed by the much greater plateau acid), the depigmentation drug monobenzone (4-(benzyloxy)phenol)
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