The pharmaceutical
industry is undoubtedly facing a series of challenges.
Although many of these challenges are related to the
nature of this industry and current business models,
there is also an urgent need for new science to bring
forward innovative and effective drugs and therapies.
The classic strategies currently being followed are
reaching a saturation point in which it is getting
harder to come up with effective, acceptable new
chemical entities.
Less than a tenth of the
drugs in clinical trials make it to the market, causing
the companies to incur huge losses, and reducing the
availability of efficient pharmaceuticals in the market
for the people who need them. In a scenario in which
the number of new drugs annually approved continues to
decay, the novel active compounds now proposed tend to
have more and more problems in matching all the desired
requirements of solubility, bioavailability, stability,
etc.
A well established,
widely applied approach to overcome such limitations
consists of the development of salts of the targeted
active compounds. But still, old problems remain, such
as the spontaneous polymorphic transformations of
crystalline drug forms, which can be a nightmare for
drug designers, and which can change an effective dose
into a lethal dose by altering the solubility of the
active ingredient. Co-crystals, amorphous forms, and
polymer embedded pharmaceuticals may hold part of the
answer to overcoming some obstacles, but the arrival of
ionic liquids into the pharmaceutical world may offer
even more design options.
Ionic liquids are salts
of low melting point (usually, the arbitrary mark of 100
ºC is considered), but many of them are liquid at room
temperature and below; many with no observable
crystallization at all. The low melting points are
related to the frustration of crystalline network
formation, basically caused by the geometric
characteristics of the constituent ions and their charge
diffuse nature.
One of the major
strengths of ionic liquids resides in their internal
plural nature: since at least one kind of cation and one
kind of anion have to be present, the properties of the
resulting products can be tuned by judicious choice of
cation(s) and anion(s). Any two ionic liquids, even
with one ion in common, can range from hydrophilic to
hydrophobic, or their melting points can differ by over
100 oC. The possible combinations of ions
which could form an ionic liquid are practically
countless, as are the physical, chemical, and biological
property sets that can be obtained by “designer salts”.
About a decade ago,
mainly due to the tunable properties and the extremely
low volatility of many ionic liquids, these substances
started to catch the attention of the academic and
industrial communities as potential alternative solvents
(with some use within the field of the pharmaceutical
industry). Some years later, a notable interest in
materials applications of these liquid salts also arose,
thus focusing attention not only on the physical
properties of the ionic liquids, but on their chemical
properties, as well. But only recently has a major
emphasis been placed on ionic liquids as bearers of
desired biological activity (even though ions known to
be biologically active have been used in ionic liquids
for quite some time).
With this primary focus
on the biological properties, a door is open to the
design of active pharmaceutical ingredients (APIs) in
the form of ionic liquids, with the potential to
overcome many problems currently encountered by APIs, as
well as to offer innovative solutions in new treatment
and delivery options. For example, pairing an API with
known tendencies to undergo undesired polymorphic
transformations, with a counterion with known ability to
produce low melting ionic liquids, one can prepare a
liquid salt of the API which, as a liquid, will not be
susceptible to polymorphism.
One can also envision an
approach where the negative side effects of a given
active compound can be treated by delivering it as an
ionic liquid in which the counterion neutralizes the
unwanted side effects, or where two active ions are
paired for dual treatment therapies with synergistic
rather than additive results. In a recent example, the
local anesthetic lidocaine was proven to have enhanced
and prolonged effect on rats when applied as an ionic
liquid in the form of lidocainium docusate, when
compared to the commonly used solid hydrochloride salt.
The examples cited above
are simply glimpses of the future of ionic liquids as
APIs. It is clear that there will be many challenges
and perhaps regulatory hurdles ahead. Nonetheless, with
some imagination, one can envision a drug discovery
strategy which includes the formation of liquid salts of
active cations or anions, as a major strategy in
Society’s struggle for new pharmaceuticals and new
treatment options.
