bs_bs_banner
Review
Journal of Pharmacy
And Pharmacology
New forms of old drugs: improving without changing
Sofia Domingosa, Vânia Andréa,b, Sílvia Quaresmaa, Inês C. B. Martinsa, M. Fátima Minas da Piedadea,c
and Maria Teresa Duartea
a
Centro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa, cDepartamento de Química e Bioquímica, Faculdade de Ciências
da Universidade de Lisboa (FCUL), Lisbon and bCentre for research in ceramics and composite materials (CICECO), Department of Chemistry,
Universidade de Aveiro, Aveiro, Portugal
Keywords
API metal coordination; drug performance;
multicomponent crystals; solid forms;
structure–property relationship
Correspondence
Maria Teresa Duarte, Centro de Química
Estrutural, Department of Chemical
Engineering, Instituto Superior Técnico,
Universidade de Lisboa, Av. Rovisco Pais, 1,
1049-001 Lisbon, Portugal.
E-mail: teresa.duarte@tecnico.ulisboa.pt
Vânia André, Centro de Química Estrutural,
Department of Chemical Engineering, Instituto
Superior Técnico, Universidade de Lisboa, Av.
Rovisco Pais, 1, 1049-001 Lisbon, Portugal.
E-mail: vaniandre@tecnico.ulisboa.pt
Received October 10, 2014
Accepted December 21, 2014
doi: 10.1111/jphp.12384
Abstract
Objectives In a short approach, we want to present the improvements that have
recently been done in the world of new solid forms of known active pharmaceutical ingredients (APIs). The different strategies will be addressed, and successful
examples will be given.
Key findings This overview presents a possible step to overcome the 10–15 years
of hard work involved in launching a new drug in the market: the use of new
forms of well-known APIs, and improve their efficiency by enhancing their
bioavailability and pharmacokinetics. It discusses some of the latest progresses.
Summary We want to present, in a brief overview, what recently has been done to
improve the discovery of innovative methods of using well-known APIs, and
improve their efficiency. Multicomponent crystal forms have shown to be the
most promising achievements to accomplish these aims, by altering API physicochemical properties, such as solubility, thermal stability, shelf life, dissolution rate
and compressibility. API-ionic liquids (ILs) and their advantages will be briefly
referred. An outline of what has recently been achieved in metal drug coordination and in drug storage and delivery using bio-inspired metal-organic frameworks (BioMOFs) will also be addressed.
Preamble
In the last decade, several approaches to attain
multicomponent pharmaceutical forms have been used and
different kinds have been obtained. The most notorious
cases are undoubtedly co-crystals and molecular salts[1] and
their design, using crystal engineering principles, strategic
and synthetic approaches have been the subject of different
reviews.[2–5] Also, their characterization and implications for
regulatory control and intellectual property protection have
been presented and discussed. Here, we go one step forward
and taking into account the recent definition of pharmaceutical co-crystal; from the published outcome of the
Indo-US bilateral meeting in 2012[6] and the FDA guidance
draft for co-crystals,[7] which classifies co-crystals as
‘dissociable API-excipient molecular complexes’ where the
co-former is the excipient, we call pharmaceutical companies’ attention to the fact that following FDA rules,
co-crystals can be treated as drug product intermediate,
offering the potential of abbreviated new drug application
rather than the full new drug application. This can be
looked upon as not only a prompt process involving fewer
830
risks, but also a less cost-effective process. Different steps
have also been given to enhance drug properties through
API metal coordination, generating metallodrugs and
metallopharmaceuticals and more recently bio-inspired
metal-organic frameworks (BioMOFs) for drug storage and
controlled delivery. Here, we briefly present and discuss
some of the recent published work, giving examples where
the proposed routes proved to be beneficial.
Introduction
It is well known that launching a new drug in the market is
a cost-intensive process that takes more than 10–15 years of
hard work, from synthesis and characterization passing to
the different phase trials. Although time and costs on drug
research and development increase annually, very few of
the evaluated drugs in clinical tests actually make it to the
market, decreasing the accessibility of more efficient
therapies.[8] There is an urgent need to have new reliable
product development programmes to obtain more effective
© 2015 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, 67, pp. 830–846
Sofia Domingos et al.
active Pharmaceutical Ingredients (API) with limited cost
and time range.
Pharmaceutical industry is indeed facing a series of challenges, and the development and fabrication of new formulations and new forms of well-known drugs might bring a
unique opportunity. Concurrently, 9 out of 10 marketed
drugs are available in their solid form, and preferably delivered in crystalline forms, primarily because of their purity,
thermal stability and easy manufacture. Therefore, the
design and synthesis of new crystal forms offer a new
way of improving their efficiency by enhancing its solubility, dissolution, thermal stability, bioavailability and/or
pharmacokinetics.[1,3,9–13] The combination of crystal engineering and supramolecular chemistry principles is an
excellent tool to achieve this goal.[5]
Crystal engineering, the rational design of functional
molecular solids,[4,14] was defined in 1989 by Desiraju as ‘the
understanding of intermolecular interactions in the context
of crystal packing and the utilization of such interactions in
the design of new solids with the desired physical and
chemical properties’.[15] In practice, it is the combination of
three related stages: (1) the study of intermolecular interactions (geometries and energies), most commonly by crystallographic or theoretical approaches; (2) the use of these
interactions in the synthesis of crystals by developing
strategies for the construction of a particular crystal architecture; and (3) the structural characterization and its correlation with the properties of crystalline materials to
optimize specific properties that depend on the structure.
These three stages represent the ‘what’, ‘how’ and ‘why’ of
crystal engineering.[14,16]
For molecular crystals, crystal engineering may be
regarded as a solid-state branch of supramolecular chemistry,[5,15,17] an area of chemistry that became well known after
the award of the Nobel Prize to Donald J. Cram and JeanMarie Lehn in 1987. Lehn defined supramolecular chemistry as ‘chemistry beyond the molecule’, that is, the chemistry
of molecular aggregates assembled via noncovalent interactions.[18] From Lehn’s argument that a supermolecule is
to the molecule as an intermolecular interaction is to the
covalent bond,[19,20] Dunitz stated that the crystal is a
supermolecule par excellence, and the knowledge and
control of intermolecular interactions is as vital to crystal
synthesis as control of the covalent bond is to molecular
synthesis.[21]
Combining these two principles, besides the long-known
cases of polymorphs,[22–26] hydrates, solvates[27–29] and
salts,[30–37] co-crystals also[1,38–54] emerged in the last few
decades offering a great potential to design new forms
towards improved specific properties. More recently, ionic
co-crystals (ICCs)[7,55–59] appeared as a way to outstandingly
increase the number of available crystal forms of drugs, also
envisaging the optimization of their performance.
New forms of old drugs
Nevertheless, the use of metals in pharmaceuticals has
been widely explored. Particular emphasis has been given to
metallodrugs[60] and metallopharmaceuticals,[61] in which
the metal can be the active site or display synergetic effects,
respectively. A new approach that has been explored consists on developing BioMOFs for controlled drug delivery
and storage.[62–69]
Indeed the challenge to optimize the properties of old
drugs has led to an expanding world of crystal forms, and
many successful examples have already been reported. This
is not intended to be an exhaustive review, but just present a
brief overview of what has been done and mention a few
examples of the many that are reported.
Polymorphs and multicomponent
crystal forms
Design, synthesis and characterization
The design and preparation of pharmaceutical multicomponent solid forms is a comprehensive and multistage
process, well-illustrated in Figure 1.[70–72]
The first step is the choice of the API, which should be
chosen bearing in mind the resolution of a specific
problem. A key concept in the design is a systematic
analysis,[70–72] recurring to the Cambridge Structural Database (CDS),[73] to identify the most reliable supramolecular
synthons,[74] noncovalent bonding patterns or motifs that
encode the molecular recognition information during the
crystallization process.[8,75,76] This is fundamental for the
selection of co-formers for co-crystals, or counter-ions for
salts and API-ILs, not disregarding that this choice should
be restricted to compounds included in the Everything
Added to Food in the US or Generally Regarded as Safe
(GRAS) lists.[77]
API polymorphic screening is usually the first step in the
supramolecular synthesis, aiming to identify and characterize new possible polymorphic forms as well as to disclose
possible hydrates or solvates of the API molecule under
study.
Multicomponent solid forms are traditionally obtained
by solution techniques, based on three main synthetic strategies: (1) crystallization by conventional evaporation,[72] (2)
reaction crystallization method[78] and (3) cooling crystallization.[72] However, mechanochemistry has recently demonstrated to be an efficient technique in multicomponent
solid form synthesis, and it includes three major methods:
(1) neat/dry grinding,[79] which involves mixing the two
components in stoichiometric ratios and grinding them,
and (2) liquid-assisted grinding (LAG), also known as
solvent drop,[80] which consists on the addition of
catalytic amounts of solvent to promote the reaction;[81,82]
(3) ion- and liquid-assisted grinding (ILAG), in which catalytic amounts of inorganic salts and solvent are added also
© 2015 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, 67, pp. 830–846
831
New forms of old drugs
Sofia Domingos et al.
DESIGN
Selection of API
SYNTHESIS
Selection of
co-former
or counter-ion
CHARACTERIZATION
Multicomponent crystal
forms screening
(CC, Salts, ICC, API-IL)
Structural
characterization
Hydrates, Solvates
Physicochemical
properties
determination
Polymorphic screening
Performance
evaluation
Figure 1 Schematic representation of the design, synthesis and characterization processes in the development and screening of active pharmaceutical ingredients polymorphs and multicomponent crystal forms.
to facilitate the reaction.[83,84] These techniques proved to be
particularly useful for polymorph control and selective
polymorph conversion, avoiding excessive use of solvent
and hence they can be regarded as ‘green processes’.[28,80,85]
Recently, supercritical fluids, ultrasound and microwave
technology have also been used in synthesis of crystalline
solid forms.[72]
In the specific case of API-ILs, there are three basic
methods: (1) direct neutralization of the acid with base, (2)
solution metathesis in a suitable solvent and (3) solvent free
metathesis via grinding or melting.[86–88]
The final step of this process involves the characterization of the solid forms, including the structural characterization based on powder and single-crystal X-ray diffraction,
solid-state Nuclear Magnetic Resonance (NMR) and vibrational spectroscopy (FT-IR and FT-Raman), the determination of physicochemical properties, the assessment of the
thermal behaviour by Differential Scanning Calorimetry
(DSC), thermogravimetic analysis (TGA) hot-stage microscopy and ultimately the evaluation of the performance of
the new form.
Polymorphs, hydrates and solvates: a
multiplicity of novel forms
In 1968, McCrone defined polymorph (from the Greek
poly = many and morph = form) as ‘a solid crystalline phase
of a given compound resulting from the possibility of at
least two crystalline arrangements of the molecules of that
832
compound in the solid state’. Even though some debate
about polymorphism’s definition still goes on, it is nowadays reasonable to consider polymorphism as the ability of
a compound to crystallize in two or more crystalline phases
with different arrangements and/or conformations of the
molecules in the crystal lattice.[89] Hence, polymorphs are
different crystalline forms of the same pure chemical compound, as schematically represented in Figure 2.[90]
The different arrangement and/or conformation of
polymorphs often result in critical differences in the
physico-chemical properties such as stability, solubility and
dissolution rate, from one polymorph to another. Therefore, inducing and controlling a specific polymorphic form
is of great importance, not only in the chemistry of pharmaceuticals, but also in chemistry in general.[91]
Over the last decade, different methods such as solution (from single or mixed solvents) and supercritical
crystallization,[92–94] seeding strategies,[95,96] heteronucleation
on substrates[97] and laser-induced nucleation[97] have been
developed to help in controlling APIs polymorphism. A new
approach using ILs[97] has also been reported as a way to
design and control the crystallization of polymorphs. For
example, in the case of adefovir dipivoxil, a reverse
transcriptase inhibitor for hepatitis B treatment, drowningout and solvent–antisolvent crystallization using ILs were
successfully used.[97,98]
Polymorphism, a solid-state phenomenon,[99] tends to be
more prominent in molecules that contain multiple functional groups, promoting hydrogen bonding and thereby
© 2015 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, 67, pp. 830–846
Sofia Domingos et al.
New forms of old drugs
Polymorphs
- API
- Solvent
Solvates / Hydrates
Figure 2 Schematic representation of polymorphs, solvates and
hydrates.
forming multiple supramolecular synthons.[91] Solvation
and hydration products, illustrated in Figure 2, are often
involved in polymorphism discussions and sometimes
called pseudo-polymorphs.[90,91,100]
In the pharmaceutical industry, a metastable form is
sometimes desirable on account of its singular properties,
such as higher bioavailability, better behaviour during
grinding and compression or lower hygroscopicity.
However, a metastable form has a thermodynamic tendency
to reduce its free energy by transforming into the stable
form. Such transition is often detrimental to the efficacy of
the formulation. Furthermore, manufacturing processes
and pharmaceutical processing can also result in polymorphic transitions.[89,101]
The best known and most polemic case of polymorphism
is ritonavir, an antiretroviral drug used in HIV and AIDS
treatment. In the summer of 1998, several problems with
semisolid capsules of the marketed drug Norvir® (AbbVie,
North Chicago, Illinois, United States) were reported,
because the wrong polymorph was crystallized. Besides the
bad and bitter taste, the undesired polymorph was much
less soluble and until the problem was solved, only the
liquid formulations were allowed.[102]
Another case of a polymorphic API is risperidone, an
antipsychotic drug used in schizophrenia, which has three
well-known forms. Studies revealed that the active form can
be safely used in pharmaceutical formulations because no
transformation takes place during the manufacturing or
during the storage period of 2 years.[100]
Another meaningful example of polymorphism in pharmaceuticals is carbamazepine, an important drug in the
treatment of epilepsy and trigeminal neuralgia.
Carbamazepine has a lower solubility and a limited
bioavailability, facts that inspired an active search for new
crystalline forms to improve its performance. Until now,
four polymorphs are reported as well as several solvates.[103]
Carbamazepine is an excellent example of crystal polymorphism in which conformation and a strong intermolecular
hydrogen-bonding pattern remain constant throughout all
of its polymorphic forms.[104]
Nabumetone, an anti-inflammatory, analgesic and antipyretic agent, has shown to have two polymorphs with different crystals’ morphology, represented in Figure 3, and
physicochemical properties.[105,106]
In addition, temozolomide, an antitumor prodrug
against malignant melanoma, is reported to exist in nine
polymorphs.[107] A new polymorphic form of adefovir
dipivoxil association, used in the treatment of hepatitis C and
herpes simplex virus infection, was recently disclosed.[108]
Nalidixic acid is one of the earliest fluoroquinolone antibiotics used in the treatment of urinary tract infections, but only
in 2012, a systematic search for new solid-state forms was
conducted to expose two new polymorphs (Forms II and
III).[109] A recent study reported the appearance and characterization of three new polymorphic forms of indomethacin,
in addition to the four previously reported.[110]
These are just some examples that illustrate the importance of polymorphic screening and the need to control and
avoid polymorphism, a prevailing and always modern
dilemma in pharmaceutical industry.
Co-crystals, salts and API-ILs: improving and
reviving old drugs
The design of new forms of old drugs has been receiving an
increasing attention over the last decade, and the role of
novel multicomponent crystal forms in the development of
pharmaceuticals has become extremely important.[111,112]
Co-crystals and salts, not disregarding solvates and
hydrates, are among the most commonly studied systems.
Co-crystals, salts and API-ILs can be defined as multiple
component systems, as they contain more than one entity.
But while in co-crystals all the components must be solid
under ambient conditions and only neutral entities are
involved, in salts and API-ILs there are charged-assisted
interactions among the ionic constituents.[49,87]
Figure 4 represents an illustrative scheme of these
multicomponent forms. Co-crystals are obtained via
supramolecular synthesis through the establishment of
strong hydrogen bonds and/or other noncovalent bonds
such as π···π interactions and halogen bonds. As previously
referred, their design is based on the supramolecular
© 2015 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, 67, pp. 830–846
833
New forms of old drugs
Sofia Domingos et al.
Nabumetone crystal morphology and crystal packing of forms I (top) and II (bottom) – Copyright.[105]
Figure 3
- Neutral API
- Anionic/cationis API
- Neutral coformer
- Anionic/cationic coformer
Co-crystals
Figure 4
Schematic representation of co-crystals, molecular salts and active pharmaceutical ingredient-ionic liquids.
OH
O
O
HO
2
Acid dimer R2(8)
Figure 5
Molecular salts / API-ILs
NH
O
O
O
H
OH
HN
OH
N
O
2
Amide dimer R2(8)
HN
Acid amide
heterosynthon R22(8)
Representation of the most common hydrogen-bonding supramolecular synthons along with their graph-set notations.
synthon approach, wherein the hydrogen bonding and/or
the predisposition for the establishment of other
noncovalent bonds between the molecule in study and the
potential co-crystal former are taken into consideration.
Two important aspects need to be considered in this
process: the possible hydrogen-bonded synthons and the
robustness of those synthons,[91,113] both assessed by data
mining. Represented in Figure 5 are the most common
hydrogen-bonding supramolecular synthons.[114] Molecular
salts are enrolled in a similar process, but usually, some of
hydrogen bonds are charge-assisted due to their intrinsic
nature.
834
Acid pyridine
2
heterosynthon R2(7)
O
Many examples of molecular salts have been reported.
As an example, a series of novel crystalline forms of
blonanserin, an antipsychotic drug having poor aqueous
solubility, was disclosed. The four salts and the salt hydrate
synthesized showed high improvements in stability, solubility and dissolution rate as represented in Figure 6.[115]
Over the last years, many co-crystals of API have been
reported. A few cases will be mentioned here as examples,
emphasizing those that have proven to be of benefit.
As previously said, carbamazepine presents several challenges regarding solubility and bioavailability aspects. As an
attempt to solve these problems, a series of co-crystals of
© 2015 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, 67, pp. 830–846
Sofia Domingos et al.
New forms of old drugs
BLONANSERIN
TsOH
BLNH+–TsO–
(1:1)
NIA
SA
SB
M
BLN–SBA (1:0.5)
+
–
BLNH –NIA (1:1)
BLNH+–MSA– (1:1)
BLNH+–MSA––H2O (1:1:1)
BLN comm
BLNH+–SUC–
BLN–SBA
BLNH+–NIA–
BLNH+–TsO–
BLNH+–MSA–
BLNH+–MSA––H2O
Amount dissolved (mg/cm2)
SUC
A
BLNH+–SUC–
(1:1)
1100
1000
900
800
700
600
500
400
300
200
100
0
–100
HIGH SOLUBILITY AND GOOD STABILITY
0
10
20
30
Time (mins)
40
50
(a)
(b)
Plasma concentration (ng/mL)
Figure 6 Novel crystalline forms of blonanserin with succinic acid, suberic acid, nicotinic acid, methanesulfonic acid and toluenesulfonic acid and
there dissolution profile. Copyright.[115]
3000
Co-crystal 1
Tegretol(R)
2000
1000
0
0
2
4
6
8
t (hours)
10
12
(c)
Figure 7 Comparison of absorption profile in dog’s plasma between the marketed form of carbamazepine – Tegretol (a) and carbamazepine : saccharin co-crystal (b). Copyright.[117]
carbamazepine were synthesized.[116] From the several
co-crystals disclosed so far, it is worth mentioning the
studies comparing carbamazepine : saccharin co-crystal
with the marketed form of the compound, both represented
in Figure 7, which evaluated the propensity for crystal polymorphism, physical stability, in-vitro dissolution, oral
bioavailability and suitability for multigram scale up.[117]
Results proved that co-crystal is a viable alternative to the
anhydrous polymorph present in solid oral formulations,
showing several advantages like the relative lack of polymorphism and equivalent chemical stability; favourable
dissolution properties and suspension stability; and comparable oral absorption profile in dogs, illustrated in
Figure 7.[117] Therefore, this study is one of the first to illustrate the utility of a co-crystal as a type of material that is
suitable for drug development.
Co-crystals of nicotinamide with two different antiinflammatory drugs, ibuprofen and flurbiprofen, had also
shown great improvements in the aqueous solubility and
physicochemical properties like moisture sorption and
mechanical properties.[118]
Co-crystals could also be helpful to solve manufacturing
process problems. For example, co-crystals of paracetamol,
whose polymorph form I presents tableting problems, were
developed in an attempt to overcome the issue.[119,120] Some
of them are shown to mimic the tableting behaviour of the
metastable paracetamol polymorph form II, which displays
an adequate tableting behaviour. Also, it was reported that
paracetamol : theophylline co-crystal had a faster dissolution rate when compared with its pure components and
physical mixtures.[121]
Co-crystals and molecular salts of gabapentin and
gabapentin-lactam, highly soluble drug and prodrug, have
also been disclosed, clearly affecting the solubility.[44,113,122,123]
Mathematical models with gabapentin-lactam were developed to accurately predict the solubility of the co-crystals
© 2015 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, 67, pp. 830–846
835
New forms of old drugs
Sofia Domingos et al.
0.25
O
0.20
O
N
H
H
N
O
H
Solubility (m)
H
cocrystal solubility
0.15
GBPL solubility
coformer solubility
0.10
0.05
O
0.00
0
1
2
3
4
5
6
7
pH
Figure 8 Overall crystal packing of gabapentin-lactam:4-hydroxybenzoic acid co-crystal, schematic representation of its strongest synthons, and
solubility profiles for the novel form vs the starting reagents (from left to right).[123]
based on the pka of the drug and the co-former. An
example of this study is illustrated in Figure 8.[123]
Cheney et al. used the supramolecular synthon approach
to prepare 19 novel pharmaceutical co-crystals enclosing
carboxylic acids and meloxicam, a nonsteroidal antiinflammatory drug (NSAID) with low aqueous solubility
and high permeability.[124] The majority of meloxicam
co-crystals was found to achieve higher meloxicam concentrations in dissolution media and improved oral
absorption compared with that of pure meloxicam.[125] The
problems presented by meloxicam were also solved by its
co-crystallization with aspirin, an analgesic API that acts as
a co-former. This is a successful case where a combination
of two APIs in the same crystalline form can be advantageous for an application in a drug with multiple/synergetic
effects.[126]
Also, the 1 : 1 co-crystal of the anti-HIV drugs
lamivudine and zidovudine was found to have better flow
properties and optimum bulk density compared with a
physical mixture of lamivudine and zidovudine.[127,128]
Another successful example of co-crystal reported is the
celecoxib : nicotinamide co-crystal (Cel : Nic). Celecoxib, a
non-steroidal anti-inflammatory drug, is used in the
treatment of osteoarthritis, rheumatoid arthritis and acute
pain, among others. This drug is reported to exist in four
polymorphic modifications with the stable form, Cel-III,
exhibiting poor water solubility. The Cel : Nic co-crystal
presented an opportunity to highlight the importance of
formulation strategies as part of evaluating the potential
utility of a co-crystal. Cel : Nic’s performance was tested
with different excipients to establish a comparison with the
marketed celecoxib form. In the absence of excipients,
Cel : Nic is rapidly converted into another polymorphic
form. Although, different results are obtained in the pres836
ence of excipients, with the co-crystal revealing in this case
some benefits over the used form, such as a higher solubility
in water. The main conclusions of this study is that careful
selection of crystal form of a low solubility compound,
coupled with critical analysis of dissolution conditions
and the dynamics of form conversion during contact
with various simulated fluids, is an essential part of
driving success in the complex process of pharmaceutical
form selection.[129] Also, celecoxib : venlafaxine[130] and
celecoxib : tramadol[131] co-crystals were reported for the
treatment of pain, showing an improved bioavailability and
a clear synergism if compared with the compounds alone.
Amoxicillin-clavulanate is an antibiotic combination
with broad spectrum activity used worldwide. Co-crystal
prepared with these two compounds showed improvements
in its antibiotic activity against nonbeta lactamase bacterial,
Sarcina lutea sp.[132]
In 2011, pyrazinamide, an antituberculosis drug, was
co-crystallized with diflusinal, a nonsteroidal antiinflammatory compound. The co-crystal synthesized
showed a decrease in the side effects of pyrazinamide
and was proven to improve the diflusinal’s aqueous
solubility.[133]
Even though co-crystals were initially considered as a way
to control polymorphism in API, the phenomenon of polymorphism revealed to be a notable obstacle in the path of
rational co-crystal design. Polymorphic co-crystals are not
uncommon and a few systems have already been reported
to date.[80] Examples of polymorphic co-crystals only
recently have been reported, and it opened a new field in
API screening: efforts on solving a problem can bring new
ones. Once more, using carbamazepine, co-crystals of
carbamazepine with nicotinamide and saccharin have
shown to be polymorphic.[116] Also, polymorphic co-crystals
© 2015 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, 67, pp. 830–846
Sofia Domingos et al.
New forms of old drugs
of temozolomide and 4,4′-bipyridine-N,N-dioxide have
been reported.[107]
Considering the problems related to polymorphism, and
the fact that co-crystals do not seem to be always a possible
alternative, the so-called third generation of pharmaceuticals brought a new class of compounds – API-ILs, which are
a combination of the active cation/anion and an inert
anion/cation.[86,134] The first API-IL synthesized was
ranitidine docusate, well known for its polymorphic conversion.[86] Other examples have then been reported with lidocaine,[134,135] sulfacetamide,[134,135] ibuprofen,[134,135] cinnamic
acid,[135] piperacillin,[135] penicillin G,[135] docusate,[134,135] and
ampicillin.[86,136,137]
ICCs: an emerging contribution for diversity
ICCs are an emerging class of multicomponent pharmaceutical materials that are formed from a salt and a molecular
or ionic compound. ICCs can be represented by the general
formula [A+B−N], where A+ is a cation, B− is an anion and N
is neutral molecule or another salt, as represented in
Figure 9.[7]
Considering that at least one of its components a pharmaceutical compound (either the salt, e.g. fluoxetine
HCl,[138] or the neutral compound, e.g. barbituric acid[59]), it
is possible to adjust the physicochemical and biological efficacy of the drug. In these three-component systems, usually
two of them can be switched to optimize the desired properties, without changing the structure of the pharmaceutical
compound.
This approach represents an outstanding way to exponentially increase the number of available API solid forms,
greatly contributing also for the development of intellectual
property.
Although the first ICC was reported at least as far back as
1843 (NaCl with glucose), they remain underexplored. It is
important to notice that some ICCs have been reported
prior to this nomenclature was first introduced, and so they
were disclosed under other designation. For example, the
reported fluoxetine (Prozac®, Eli Lilly, Indianapolis,
Indiana, United States), co-crystals with benzoic, succinic
and fumaric acids, which targets changes in solubility, are
indeed ICCs.[138]
Braga et al. reported ICCs of barbituric acid with alkali
bromides and cesium iodide, which revealed to affect the
dissolution properties of barbituric acid in water.[59] Also, a
series of organic molecules, including piracetam, formed
ICCs with metal halides.[139]
Furthermore, synergetic effects between salt and API can
be explored, for example using Li salts with antidepressants.
ICCs of racetams (brivaracetam, seletracetam) with different salts (Mg2+, Ca2+ and Li+) were explored.[55,57] These
studies could lead to a pharmacologically relevant association and the development of an original drug substance.
Also, piracetam and lithium salts ICCs could be explored as
potential co-drugs.[58]
Smith et al. also reported ICCs (Figure 10) that shown to
improve lithium therapeutics.[7] These studies were the first
to assess the biological efficacy of the ICCs, finding that
the speciation did not affect negatively the established
bioactivity of lithium.[7]
There are several other examples that have been reported
with lithium. ICCs of homochiral and achiral amino acid
zwitterions (sarcosine, N,Ndimethylglycine, betaine and
L-proline) with Li salts, have shown to be stable up to 200°C
and readily soluble in water.[140]
Metallopharmaceuticals,
metallodrugs and BioMOFs
Metallopharmaceuticals and
metallodrugs: exploring metals for
pharmacological applications
Coordination complexes and networks of pharmacological
active molecules are a much less explored class of new solid
forms of known APIs. Among these metallodrugs, in which
the metal ion is the biologically active component, and
metallopharmaceuticals, where the metal ion plays the role
of a carrier for the API molecule, similar to the counterion
in a pharmaceutical salt or the co-former in a pharmaceutical co-crystal, have been successfully prepared.[141]
Metallopharmaceuticals and metallodrugs are represented
in Figure 11.
Ma and Moulton proposed the potential design of
metallopharmaceuticals, exploring the copper(II) carboxy-
- Neutral API
- Anionic/cationic API
- Neutral coformer
- Anionic/cationic coformer
Ionic Co-crystals
Figure 9
- Anionic/cationic coformer
Schematic representation of ionic co-crystals.
© 2015 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, 67, pp. 830–846
837
New forms of old drugs
Sofia Domingos et al.
(a)
L-proline
(amino acid coformer)
Lithium salicylate
(salt)
Ionic cocrystal (LISPRO)
(b)
Lithium hydroxide
Nicotinic acid
L-proline
(base)
(organic counterion) (amino acid coformer)
Ionic cocrystal (LNAPRO)
Figure 10 Reaction diagrams for (a) Lithium salycilate:L-proline ionic co-crystal (LISPRO) and (b) Lithium nicotinate:L-proline ionic co-crystal
(LNAPRO). Copyright.[7]
- API
Metallopharmaceutical
- GRAS ligand
- Safe metal
Metallodrug
- Metal with
pharmacological activity
Figure 11 Schematic representation of metallopharmaceutical and
metallodrugs.
late paddlewheel motif to enhance the lipophilicity of
carboxylate APIs.[142] In 2008, two derivatives of the
neuroleptic drug gabapentin with zinc and copper(II) were
the first API metal complexes prepared by mechanochemistry,[143] and since then, several other similar systems
have been reported, such as the coordination networks
obtained with gabapentin and several lanthanides (LnCl3),
Y(III) and Mn(II).[60,84,144–149] Worth mentioning are the
silver nitrate and nickel chloride metal-organic derivatives
with the antibiotic 4-aminosalicylic acid (4ASA) and the
nootropic piracetam prepared by Braga et al.[150] Complexes
of silver nitrate and 4ASA are particularly interesting in
terms of a possible pharmaceutical application due to the
synergetic effect that can result from the combination of an
antibiotic with a known antimicrobial agent (Ag+), demonstrating the potential of coordination chemistry in generating new solid forms of APIs.
API coordination complexes involving biologically
benevolent magnesium ions directly from magnesium
838
oxide[149] have been studied, and several derivatives
of the NSAIDs S- and RS-ibuprofen (RS-Hibu),[149] salicylic
acid (Hsal)[149] (Figure 12) and S-naproxen were
reported.[141,149,151] Due to the formation of a metal-organic
material, represented in exhibiting a higher solubility than
the neutral NSAID, the activity of ibuprofen was enhanced
when formulated with MgO.[141,149] The variation of water
activity in mechanochemical reactions of MgO and
naproxen lead to the formation of three complexes with different hydration contents.[151]
Widely known examples of metallodrugs are platinum
complexes used in cancer treatment, such as cisplatin,
carboplatin or oxaliplatin,[152] and bismuth subsalicylate
marketed as Pepto-Bismol.[153]
In 2011, the rapid, efficient and selective synthesis by
ILAG[83] of bismuth subsalicylate, as well as two other
bismuth salicylates, directly from Bi2O3 was reported by
André et al.,[61] revealing the first crystal structure of a
bismuth salicylate without auxiliary ligands. All of these
forms are depicted in Figure 13. This structure was a particularly relevant addition to the understanding of the
chemistry of bismuth salicylates as it: (1) complements the
existing model compounds based on discrete oligonuclear
clusters involving auxiliary organic ligands; (2) confirms the
propensity of bismuth salicylate to adopt extended structures in the absence of organic auxiliaries; and (3) demonstrates the absence of basic hydroxide or oxide species in
bismuth disalicylate. In this work, mechanochemistry
revealed to be an excellent alternative to the synthesis of
bismuth salicylates from solution, which requires harsh
conditions to which the product is sensitive[154] and is
© 2015 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, 67, pp. 830–846
Sofia Domingos et al.
New forms of old drugs
LAG
30 min
(a)
MgO + 2 R-COOH
Mg(RCOO)2 + H2O
COOH
O
OH
(b)
H3C
CH3
CH3
O
O
COOH
RS-Hibu
Hsal
(c)
O
O
15c5
Intensity
simulated, 180 K
simulated, 295 K
LAG reaction
neat grinding
RS-Hibu
MgO
10
20
30
40
50
2θ/°
(d)
O
Mg
Figure 12 (a) Expected reaction of MgO and carboxylic acid-based
drugs; (b) ligands studied herein; (c) powder X-ray diffraction (PXRD)
patterns (for bottom to top): MgO; RS-Hibu; neat grinding of RS-Hibu
and MgO; liquid-assisted grinding of MgO and RS-Hibu; simulated for
Mg(H2O)6(Ibu)2·2H2O at room temperature and at 180 K; (d) fragment
of crystal structure of Mg(H2O)6(Ibu)2·2H2O. Copyright.[149]
limited by issues of environmental nature and reactant
toxicity.
BioMOFs: a new approach for controlled
drug storage and delivery
Nanoporous materials attracted the interest of both academia and industry in several areas, the most known being
gas storage and separation, and shape/size selective catalysis.[66,155,156] Within these compounds, major attention has
been given to extended metal-ligand networks with metal
nodes and bridging organic ligands such as coordination
networks, porous coordination networks (PCNs), porous
coordination polymers (PCPs) and metal-organic frameworks (MOFs).[64,155–158] Recently, they became of relevant
use in the medicinal and pharmacological fields for drug
storage, delivery and controlled release, in addition to applications in imaging and sensing for therapeutic and diagnostic applications.[63,64,66,67,69,155,157,159,160]
MOFs, a unique class of crystalline nanoporous
materials, are defined as hybrid self-assemblies of metal ions
or metal clusters (coordination centres) and organic fragments (linkers).[155,157,161] They exhibit some of the highest
porosities known[66] and versatile architectures,[162] turning
them into the ideal materials for drug carrier and
deliver,[63,69,163,164] and more recently, as contrast agents for
magnetic resonance imaging[159] and other biomedical
applications.[69]
Up to now, drug delivery from porous solids has been
achieved by encapsulation in mesopororous silicas or zeolites, which is strongly dependent on the pore size and on
the host–guest interactions. Both hypotheses suffer from
important drawbacks: low drug-storage capacity, too rapid
delivery and solid degradation that brings toxicity concerns.[64,66,69,160,165] The use of BioMOFs (Figure 14) as new
drug carriers has been proposed as a way to tackle these
problems, requiring a biologically friendly composition,
making compulsory the use of safe metals and linkers
(mainly GRAS) with acceptable toxicity. Compared with
other nanocarriers, MOFs are excellent candidates to extensive applications because they combine high pore volume
with a regular porosity, and the presence of tunable organic
groups allows an easy modulation of the framework as well
as of the pore size.[63,64,66,155,157]
The first families of MOFs considered as potential drug
delivery systems are: CPO-27(Mg) (CPO for Coordination
Polymer from Oslo),[166] built up from magnesium coordination polymers and the MIL (Materials of Institute
Lavoisier) family.[63] Horcajada et al.,[63,69] prepared MIL100
(with trimesic acid) and MIL101 (with terephthalic acid)
for the delivery of ibuprofen; both exhibit a high drugstorage capacity up to an unprecedented 1.4 g of drug per
gram of porous solid, and a complete drug-controlled
release under physiological conditions from 3 to 6 days, as
presented in Figure 15.[63,69] Less toxic systems, using iron
and more flexible MILs are under study,[157] and the first
biodegradable therapeutic MOF was recently synthesized,
BioMIL-1, illustrated in Figure 16.[67]
When building BioMOFs, the decision to exclude one
linker and/or metal depends on several parameters: application, balance between risk and benefit, degradation kinetics,
biodistribution, accumulation in tissues and organs as well
as body excretion.[64,66,69,157,159,167,168] Until now, exogeneous
(not intervening in the body cycles) and endogeneous (constitutive part of body composition) linkers have been used
in MOF synthesis for drug delivery, the first with a higher
prevalence.[64,66,67,157,159–161] Therefore, the best approach to
use these porous solids in biomedical applications, such as
drug delivery, consists of introducing the therapeutic molecule directly as a linker to avoid unwanted effects, such
as low drug-storage capacity, too rapid delivery and solid
degradation.[66,165]
© 2015 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, 67, pp. 830–846
839
New forms of old drugs
Sofia Domingos et al.
O
1:2 (a)
OH
Bi
O
O
OH +
ILAG
O
Bi2O3
Catalytic
salt
OH
(d)
1:4 (b)
Bi.2SA
(e)
a
20
40
2-θ / °
60
1:6 (c)
Bi.3SA
b
c
80
Figure 13 Representation of the ion- and liquid-assisted grinding synthesis of bismuth subsalicylate (a), as well as two other bismuth salicylates (b
and c), directly from Bi2O3; (d) first crystal structure of a bismuth salicylate without auxiliary ligands; (e) crystal structure of a Bi38 core structure resulting from DMF recrystallization.
- API as linker
- API as guest
- GRAS linker
- Safe metal
BioMOF: API as linker
Figure 14
BioMOF: API as guest
Schematic representation of bio-inspired metal-organic frameworks.
MOFs are still widely synthesized using solvo/
hydrothermal techniques, the most common methods to
obtain coordination networks.[64,157,159,160] Nevertheless, interesting alternatives are being used based on environmentalfriendly synthetic routes: microwave and sonochemical
synthesis,[64,157,159] and mechanosynthesis.[169,170]
Declarations
Final remarks
Although in Japan co-crystals are already marketed, we are
still far from seeing co-crystal forms in the market in
Europe and USA. Undoubtedly, there is a growing awareness that they present a real and viable option for drug
development, involving fewer risks and being a less costeffective process. The same might apply in the future to
other multicomponent solid forms, such as ICCs and
molecular salts that present promising enhancements in
APIs performance.
840
Metal coordination networks, metallodrugs and
mettalopharmaceuticals seem also to have an auspicious
future easily allowing synergetic effects. BioMOFs, still in
their early steps, might in the near future present some
viable alternatives for drug storage and delivery, avoiding
some of the side effects of the carriers in use nowadays.
Conflict of interest
The Author(s) declare(s) that they have no conflicts of
interest to disclose.
Funding
Authors acknowledge Fundação para a Ciência e a
Tecnologia for funding (PTDC/CTM-BPC/122447/2010,
PEST-OE/QUI/UI0100/2013, RECI/QEQ-QIN70189/2012,
SFRH/BPD/78854/2011 and SFRH/BD/93140/2013).
© 2015 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, 67, pp. 830–846
Sofia Domingos et al.
New forms of old drugs
MIL-101
1.4
.
13.04 A
.
7.85 A
g drug/g solid
1.2
.
11.34 A
1.0
0.8
MIL53-np
Ibuprofen
MIL53-Ibu
MCM-41
0.4
(b)
MIL53-Ip
0.6
MIL-100
MCM-41Pr-NH2
0.2
.
29-34 A
MIL-53
.
25-29 A
0
0
2
(a)
4
6
Time (days)
8 14
16
20
(c)
MIL100/101
Figure 15 (a) Kinetics of delivery of ibuprofen from several porous metal-organic frameworks carriers (Simulated Body Fluid (SBF), 37°C) (left); (b)
pore openings of the solid Materials of Institute Lavoisier-53: water (left), ibuprofen (centre) and open form (right); (c) schematic view of the larger
cage (left) and the smaller cage (right) of Materials of Institute Lavoisier-100. Metal octahedral, oxygen and carbon atoms are represented in orange,
red and black, respectively. Copyright.[64]
Bioactive MOF
BioMOF
Bio-friendly
Building unit
Biomolecule
Body fluid
37°C
Release of the
drug
Figure 16 Schematic view of the formation of the bio-inspired metal-organic frameworks Bio-Materials of Institute Lavoisier-1 built up from a
bioactive linker – nicotinic acid – and its delivery into simulated body fluid over a few hours. Copyright.[66]
References
1. Elder DP et al. Use of pharmaceutical
salts and cocrystals to address the
issue of poor solubility. Int J Pharm
2013; 453: 88–100.
2. Biradha K et al. Recent developments
in crystal engineering. Cryst Growth
Des 2011; 11: 875–886.
3. Braga D et al. The growing world of
crystal forms. Chem Commun 2010;
46: 6232–6242.
4. Desiraju GR. Crystal engineering:
a brief overview. J Chem Sci 2010;
122: 667–675.
5. Nangia A. Supramolecular chemistry
and crystal engineering. J Chem Sci
2010; 122: 295–310.
6. Aitipamula S et al. Polymorphs, salts,
and cocrystals: what’s in a name?
Cryst Growth Des 2012; 12: 2147–
2152.
7. Smith AJ et al. Improving lithium
therapeutics by crystal engineering of
© 2015 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, 67, pp. 830–846
novel ionic cocrystals. Mol Pharm
2013; 10: 4728–4738.
8. Shan N, Zaworotko MJ. The role of
cocrystals in pharmaceutical science.
Drug Discov Today 2008; 13: 440–
446.
9. Almarsson O, Zaworotko MJ. Crystal
engineering of the composition of
pharmaceutical phases. Do pharmaceutical co-crystals represent a new
path to improved medicines? Chem
Commun 2004; 17: 1889–1896.
841
New forms of old drugs
10. Tomaszewska I et al. Pharmaceutical
characterisation and evaluation of
cocrystals: Importance of in vitro
dissolution conditions and type of
coformer. Int J Pharm 2013; 453:
380–388.
11. Lahiani-Skiba M et al. Improvement
in the water solubility and stability of
4ASA by the use of cyclodextrins.
J Inclusion Phenom Macrocyclic Chem
2011; 69: 327–331.
12. Chency ML et al. Effects of crystal
form on solubility and pharmacokinetics: a crystal engineering case
study of lamotrigine. Cryst Growth
Des 2010; 10: 394–405.
13. Braga D et al. Making crystals from
crystals: a solid-state route to the
engineering of crystalline materials,
polymorphs, solvates and co-crystals;
considerations on the future of
crystal engineering. Eng Crystalline
Mater Properties 2008; NATO Science
for Peace and Security Series B:
Physics and Biophysics: 131–156.
14. Desiraju GR. Crystal engineering:
a holistic view. Angewandte ChemieInt Ed 2007; 46: 8342–8356.
15. Desiraju GR. Crystal Engineering: The
Design of Organic Solids. Amsterdam:
Elsevier, 1989.
16. Desiraju GR. Crystal engineering:
structure, design and function. Curr
Opin Solid State Mater Sci 2009; 13:
35.
17. Schmidt GMJ. Photo dimerization in
the solid state. Pure Appl Chem 1971;
27: 647–678.
18. Lehn JM. Cryptates – inclusion complexes of macropolycyclic receptor
molecules. Pure Appl Chem 1978; 50:
871–892.
19. Lehn JM, Rigault A. Helicates –
tetranuclear
and
pentanuclear
double helix complexes of CU-I
and
poly(bipyridine)
strands.
Angewandte Chemie-Int Ed Eng 1988;
27: 1095–1097.
20. Lehn JM. Supramolecular chemistry
– scope and perspectives molecules,
supermolecules, and
molecular
devices. Angewandte Chemie-Int Ed
Eng 1988; 27: 89–112.
21. Dunitz JD. Phase-transitions in
molecular-crystals from a chemical
842
Sofia Domingos et al.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
viewpoint. Pure Appl Chem 1991; 63:
177–185.
Bernstein J. Polymorphism – a perspective. Cryst Growth Des 2011; 11:
632–650.
Jie L et al. Polymorphism of pharmaceutical molecules: perspectives on
nucleation. Front Chem Eng China
2010; 4: 37–44.
Braga D et al. Crystal polymorphism
and multiple crystal forms. Mol Netw
2009; 132: 25–50.
Bond AD et al. On the polymorphism of aspirin. Angewandte
Chemie-Int Ed 2007; 46: 615–617.
Karpinski PH. Polymorphism of
active pharmaceutical ingredients.
Chem Eng Technol 2006; 29: 233–237.
Dematos LL et al. Solvent influences
on metastable polymorph lifetimes:
Real-time interconversions using
energy dispersive X-ray diffractometry. J Pharm Sci 2007; 96: 1069–
1078.
Karki S et al. Screening for pharmaceutical cocrystal hydrates via neat
and liquid-assisted grinding. Mol
Pharm 2007; 4: 347–354.
Pudipeddi M, Serajuddin ATM.
Trends in solubility of polymorphs.
J Pharm Sci 2005; 94: 929–939.
Andre V et al. Transforming aspirin
into novel molecular salts of salicylic
acid. Struct Chem 2014; 25: 707–714.
Braga D et al. Molecular salts of
anesthetic lidocaine with dicarboxylic acids: solid-state properties
and a combined structural and spectroscopic study. Cryst Growth Des
2013; 13: 2564–2572.
Kumar A et al. (2008) New
perindopril salts e.g. perindopril
phthalic acid salt, perindopril tartaric
acid salt, perindopril phosphate
and perindopril camphor sulfonate,
useful in therapies of arterial hypertension and cardiac insufficiency.
Ipca Lab Ltd.
Serajuddin ATM. Salt formation to
improve drug solubility. Adv Drug
Deliv Rev 2007; 59: 603–616.
Black SN et al. Structure, solubility,
screening, and synthesis of molecular
salts. J Pharm Sci 2007; 96: 1053–
1068.
35. Childs SL et al. The salt-cocrystal
continuum: the influence of crystal
structure on ionization state. Mol
Pharm 2007; 4: 323–338.
36. Trask AV et al. Screening for crystalline salts via mechanochemistry.
Chem Commun 2006; 1: 51–53.
37. Giron D. Characterisation of salts of
drug substances. J Therm Anal Calorimetry 2003; 73: 441–457.
38. Perman JA et al. Cocrystal controlled
solid-state synthesis of a rigid
tetracarboxylate ligand that pillars
both square grid and Kagome lattice
layers. Crystengcomm 2011; 13: 3130–
3133.
39. Elbagerma MA et al. Characterization of new cocrystals by Raman
spectroscopy, powder X-ray diffraction, differential scanning calorimetry, and transmission Raman
spectroscopy. Cryst Growth Des 2010;
10: 2360–2371.
40. Bethune SJ et al. Understanding and
predicting the effect of cocrystal
components and pH on cocrystal
solubility. Cryst Growth Des 2009; 9:
3976–3988.
41. Friscic T, MacGillivray LR. Engineering cocrystal and polymorph architecture via pseudoseeding. Chem
Commun 2009; 7: 773–775.
42. Friscic T, Jones W. Recent advances
in understanding the mechanism of
cocrystal formation via grinding.
Cryst Growth Des 2009; 9: 1621–
1637.
43. Good DJ, Rodriguez-Hornedo N.
Solubility advantage of pharmaceutical cocrystals. Cryst Growth Des 2009;
9: 2252–2264.
44. Reddy LS et al. Cocrystals and salts of
gabapentin: pH dependent cocrystal
stability and solubility. Cryst Growth
Des 2009; 9: 378–385.
45. Schartman RR. On the thermodynamics of cocrystal formation. Int J
Pharm 2009; 365: 77–80.
46. Connelly PR et al. (2008) Co-crystal,
useful e.g. for treating hepatitis C
virus infection and molecular modeling to identify other possible
co-crystal forms, comprises vertex
hepatitis C virus protease inhibitor,
salicylic acid, aminosalicylic acid or
© 2015 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, 67, pp. 830–846
Sofia Domingos et al.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
oxalic acid. Vertex Pharm Inc;
Connelly P R.
He GW et al. Screening for
cocrystallization tendency: the role of
intermolecular interactions. J Phys
Chemistry B 2008; 112: 9890–9895.
Takata N et al. Cocrystal screening of
stanolone and mestanolone using
slurry crystallization. Cryst Growth
Des 2008; 8: 3032–3037.
Aakeroy CB et al. Cocrystal or salt:
does it really matter? Mol Pharm
2007; 4: 317–322.
Friscic T, Jones W. Cocrystal architecture and properties: design and
building of chiral and racemic
structures by solid-solid reactions.
Faraday Discuss 2007; 136: 167–178.
Wenger M, Bernstein J. Cocrystal
design gone awry? A new dimorphic
hydrate of oxalic acid. Mol Pharm
2007; 4: 355–359.
Friscic T et al. Exploring cocrystal –
cocrystal reactivity via liquid-assisted
grinding: the assembling of racemic
and dismantling of enantiomeric
cocrystals. Chem Commun 2006; 48:
5009–5011.
Jones W et al. Pharmaceutical
cocrystals: an emerging approach to
physical property enhancement. MRS
Bull 2006; 31: 875–879.
Trask AV et al. Pharmaceutical
cocrystallization:
engineering
a
remedy for caffeine hydration. Cryst
Growth Des 2005; 5: 1013–1021.
Grepioni F et al. Ionic co-crystals
of racetams: solid-state properties
enhancement of neutral active pharmaceutical ingredients via addition
of Mg2+ and Ca2+ chlorides.
Crystengcomm 2014; 16: 5887–5896.
Martinez-Alejo JM et al. A twist in
cocrystals of salts: changes in packing
and chloride coordination lead to
opposite trends in the biopharmaceutical performance of
fluoroquinolone
hydrochloride
cocrystals. Cryst Growth Des 2014;
14: 3078–3095.
Wouters J et al. Novel pharmaceutical compositions through cocrystallization of racetams and Li+
salts. Crystengcomm 2013; 15: 8898–
8902.
New forms of old drugs
58. Braga D et al. Combining piracetam
and lithium salts: ionic co-crystals
and co-drugs? Chem Commun 2012;
48: 8219–8221.
59. Braga D et al. From unexpected reactions to a new family of ionic
co-crystals: the case of barbituric
acid with alkali bromides and
caesium iodide. Chem Commun
2010; 46: 7715–7717.
60. Quaresma S et al. Gabapentin coordination
networks:
mechanochemical synthesis and behavior
under shelf conditions. Cryst Growth
Des 2013; 13: 5007–5017.
61. André V et al. Mechanosynthesis of
the metallodrug bismuth subsalicylate from Bi(2)O(3) and structure of
bismuth salicylate without auxiliary
organic ligands. Angewandte ChemieInt Ed 2011; 50: 7858–7861.
62. An JY et al. Cation-triggered drug
release from a porous zinc-adeninate
metal-organic framework. J Am
Chem Soc 2009; 131: 8376–8377.
63. Horcajada P et al. Flexible porous
metal-organic frameworks for a controlled drug delivery. J Am Chem Soc
2008; 130: 6774–6780.
64. Horcajada P et al. Metal-organic
frameworks in biomedicine. Chem
Rev 2012; 112: 1232–1268.
65. Horcajada P et al. Porous metalorganic-framework nanoscale carriers as a potential platform for drug
delivery and imaging. Nat Mater
2010; 9: 172–178.
66. McKinlay AC et al. BioMOFs:
metal-organic frameworks for biological and medical applications.
Angewandte Chemie-Int Ed 2010; 49:
6260–6266.
67. Miller SR et al. Biodegradable therapeutic MOFs for the delivery of
bioactive molecules. Chem Commun
2010; 46: 4526–4528.
68. Llewellyn PL et al. Prediction of the
conditions for breathing of metal
organic framework materials using
a combination of X-ray powder
diffraction, microcalorimetry, and
molecular simulation. J Am Chem
Soc 2008; 130: 12808–12814.
69. Horcajada P et al. Metal-organic
frameworks as efficient materials for
© 2015 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, 67, pp. 830–846
70.
71.
72.
73.
74.
75.
76.
77.
78.
79.
80.
81.
82.
83.
84.
drug delivery. Angewandte ChemieInt Ed 2006; 45: 5974–5978.
Miroshnyk I et al. Pharmaceutical
co-crystals-an opportunity for drug
product enhancement. Expert Opin
Drug Deliv 2009; 6: 333–341.
Qiao N et al. Pharmaceutical cocrystals: an overview. Int J Pharm 2011;
419: 1–11.
Asija R et al. Pharmaceutical cocrystals: an overview. J Drug Discov Ther
2013; 1: 10–14.
Allen FH. The Cambridge Structural
Database: a quarter of a million
crystal structures and rising. Acta
Crystallogr B 2002; 58: 380–388.
Desiraju GR. Supramolecular synthons in crystal engineering – a
new organic-synthesis. Angewandte
Chemie-Int Ed Eng 1995; 34: 2311–
2327.
Vishweshwar P et al. Pharmaceutical
co-crystal. J Pharm Sci 2006; 95: 499–
516.
Wood PA et al. Knowledge-based
approaches to co-crystal design.
Crystengcomm 2014; 16: 5839–5848.
Blagden N et al. Pharmaceutical
co-crystals – are we there yet? Cryst
EngComm 2014; 16: 5753–5761.
Jayasankar A et al. Mechanisms by
which moisture generates cocrystals.
Mol Pharm 2007; 4: 360–372.
Tanaka K, Toda F. Solvent-free
organic synthesis. Chem Rev 2000;
100: 1025–1074.
Trask AV et al. Solvent-drop grinding: green polymorph control of
cocrystallisation. Chem Commun
2004; 7: 890–891.
Braga D et al. Mechanochemical
preparation of co-crystals. Chem Soc
Rev 2013; 42: 7638–7648.
James SL et al. Mechanochemistry:
opportunities for new and cleaner
synthesis. Chem Soc Rev 2012; 41:
413–447.
Friscic T et al. Ion- and liquid-assisted
grinding: improved mechanochemical
synthesis of metal-organic frameworks
reveals salt inclusion and anion
templating. Angewandte Chemie-Int
Ed 2010; 49: 712–715.
Friscic T. New opportunities for
materials synthesis using mechano843
New forms of old drugs
85.
86.
87.
88.
89.
90.
91.
92.
93.
94.
95.
96.
97.
844
chemistry. J Mater Chem 2010; 20:
7599–7605.
Friscic T et al. Screening for inclusion compounds and systematic
construction of three-component
solids by liquid-assisted grinding.
Angewandte Chemie-Int Ed 2006; 45:
7546–7550.
Shamshina JL et al. Ionic liquids in
drug delivery. Expert Opin Drug
Deliv 2013; 10: 1–15.
Marrucho IM et al. Ionic liquids in
pharmaceutical applications. Ann Rev
Chem Biomol Eng 2014; 5: 527–546.
Ferraz R et al. Development of novel
ionic liquids based on ampicillin.
Medchemcomm 2012; 3: 494–497.
Bernstein J. Polymorphism in Molecular Crystals. Oxford: Clarendon Press,
2002.
Threlfall TL. Analysis of organic
polymorphs – a review. Analyst 1995;
120: 2435–2460.
Bis JA et al. Concomitant and conformational polymorphism, conformational isomorphism, and phase
relationships in 4-cyanopyridine center dot 4,4 ‘-biphenol cocrystals. Cryst
Growth Des 2006; 6: 1048–1053.
Teychene S et al. Crystallization of
eflucimibe drug in a solvent mixture:
effects of process conditions on polymorphism. Cryst Growth Des 2004; 4:
971–977.
Alleso M et al. Solvent diversity in
polymorph screening. J Pharm Sci
2008; 97: 2145–2159.
Moribe K et al. Supercritical carbon
dioxide processing of active pharmaceutical ingredients for polymorphic
control and for complex formation.
Adv Drug Deliv Rev 2008; 60: 328–
338.
Beckmann W. Seeding the desired
polymorph: background, possibilities, limitations, and case studies.
Org Process Res Dev 2000; 4: 372–383.
Muller M et al. Process development
strategy to ascertain reproducible
API polymorph manufacture. Cryst
Growth Des 2006; 6: 946–954.
An J-H, Kim W-S. Antisolvent crystallization using ionic liquids as
solvent and antisolvent for polymorphic design of active pharmaceutical
Sofia Domingos et al.
98.
99.
100.
101.
102.
103.
104.
105.
106.
107.
108.
109.
110.
111.
ingredient. Cryst Growth Des 2013;
13: 31–39.
An J-H et al. Application of ionic
liquid to polymorphic design of
pharmaceutical ingredients. Cryst
Growth Des 2010; 10: 3044–3050.
Stahly GP. Diversity in single- and
multiple-component crystals. The
search for and prevalence of
polymorphs and cocrystals. Cryst
Growth Des 2007; 7: 1007–1026.
Karabas I et al. Analysis and stability
of polymorphs in tablets: the case of
Risperidone. Talanta 2007; 71: 1382–
1386.
Brittain HG. Polymorphism in Pharmaceutical Solids. New York: Taylor &
Francis, 1999.
Bauer J et al. Ritonavir: an extraordinary example of conformational
polymorphism. Pharm Res 2001; 18:
859–866.
Fleischman SG et al. Crystal engineering of the composition of
pharmaceutical phases: multiplecomponent crystalline solids involving carbamazepine. Cryst Growth Des
2003; 3: 909–919.
Grzesiak AL et al. Comparison of
the four anhydrous polymorphs of
carbamazepine and the crystal structure of form I. J Pharm Sci 2003; 92:
2260–2271.
Price CP et al. Polymorphism of
nabumetone. Cryst Growth Des 2002;
2: 501–503.
Prabhakar C et al. Process research
and structural studies on nabumetone. Org Process Res Dev 1999; 3:
121–125.
Babu NJ et al. Polymorphs and polymorphic cocrystals of temozolomide.
Chem Asian J 2008; 3: 1122–1133.
Lee MK et al. Novel polymorphic
form of adefovir dipivoxil derived
from polymer-directed crystallization. Pharmazie 2011; 66: 766–770.
Gangavaram S et al. Polymorphs and
cocrystals of nalidixic acid. Cryst
Growth Des 2012; 12: 4963–4971.
Surwase SA et al. Indomethacin: new
polymorphs of an old drug. Mol
Pharm 2013; 10: 4472–4480.
Najar AA, Azim Y. Pharmaceutical
co-crystals: a new paradigm of
112.
113.
114.
115.
116.
117.
118.
119.
120.
121.
122.
123.
crystal engineering. J Indian Ins Sci
2014; 94: 45–67.
Steed JW. The role of co-crystals
in pharmaceutical design. Trends
Pharmacol Sci 2013; 34: 185–193.
Wenger M, Bernstein J. An alternate
crystal
form
of
gabapentin:
a cocrystal with oxalic acid. Cryst
Growth Des 2008; 8: 1595–1598.
Thakuria R et al. Pharmaceutical
cocrystals and poorly soluble drugs.
Int J Pharm 2013; 453: 101–125.
Maddileti D et al. High solubility
crystalline pharmaceutical Forms of
blonanserin. Cryst Growth Des 2014;
14: 2557–2570.
Porter WW et al. Polymorphism in
carbamazepine cocrystals. Cryst
Growth Des 2008; 8: 14–16.
Hickey MB et al. Performance comparison of a co-crystal of carbamazepine with marketed product. Eur
J Pharm Biopharm 2007; 67: 112–
119.
Chow SF et al. Simultaneously
improving the mechanical properties, dissolution performance, and
hygroscopicity of ibuprofen and
flurbiprofen by cocrystallization with
nicotinamide. Pharm Res 2012; 29:
1854–1865.
Karki S et al. Improving mechanical
properties of crystalline solids by
cocrystal formation: new compressible forms of paracetamol. Adv Mater
2009; 21: 3905–3909.
Andre V et al. Revisiting paracetamol
in a quest for new co-crystals.
Crystengcomm 2012; 14: 5005–5014.
Lee HG et al. Cocrystal intrinsic dissolution behavior using a rotating
disk. J Pharm Sci 2011; 100: 1736–
1744.
Andre V et al. On the track of new
multicomponent gabapentin crystal
forms: synthon competition and pH
stability. Cryst Growth Des 2011; 11:
2325–2334.
Maheshwari C et al. Tailoring
aqueous solubility of a highly soluble
compound via cocrystallization:
effect of coformer ionization,
pHmax, and solute-solvent interactions. Cryst Eng Comm 2012; 14:
4801–4811. accepted.
© 2015 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, 67, pp. 830–846
Sofia Domingos et al.
124. Cheney ML et al. Supramolecular
architectures of meloxicam carboxylic acid cocrystals, a crystal engineering case study. Cryst Growth Des
2010; 10: 4401–4413.
125. Weyna DR et al. Improving solubility
and pharmacokinetics of meloxicam
via multiple-component crystal formation. Mol Pharm 2012; 9: 2094–
2102.
126. Cheney ML et al. Coformer selection
in pharmaceutical cocrystal development: a case study of a meloxicam
aspirin cocrystal that exhibits
enhanced solubility and pharmacokinetics. J Pharm Sci 2011; 100:
2172–2181.
127. Bhatt PM et al. 2009. New co-crystal
of lamivudine with zidovudine comprising one molecule each of
lamivudine, zidovudine and water,
useful in the treatment of HIV infections in humans. Lupin Ltd.
128. Bhatt PM et al. Co-crystals of the
anti-HIV drugs lamivudine and
zidovudine. Cryst Growth Des 2009;
9: 951–957.
129. Remenar JF et al. Celecoxib: nicotinamide dissociation: using excipients to capture the cocrystal’s
potential. Mol Pharm 2007; 4: 386–
400.
130. Planta Salaman CR et al. 2011. New
co-crystal comprising venlafaxine
(either as free base/its salt) and
celecoxib, useful to treat e.g. chronic
pain and depression in patients with
chronic musculo-skeletal inflammatory illness (osteoarthritis/rheumatoid arthritis). Lab Del Esteve Sa.
131. Soler Ranzani L et al. 2011. Composition, useful for treating e.g. pain,
preferably acute pain, chronic
pain, neuropathic pain, nociceptive
pain, and hyperalgesia, comprises co-crystal of (rac)-tramadol
hydrochloride-celecoxib, and solubility enhancer polymer. Lab Del Esteve
Sa.
132. Nugrahani I et al. The antibiotic
potency of amoxicillin-clavulanate
co-crystal. Int J Pharmacol 2007; 3:
475–481.
133. Evora AOL et al. Pyrazinamidediflunisal: a new dual–drug co-
New forms of old drugs
134.
135.
136.
137.
138.
139.
140.
141.
142.
143.
crystal. Cryst Growth Des 2011; 11:
4780–4788.
Hough WL et al. The third evolution
of ionic liquids: active pharmaceutical ingredients. New J Chem 2007; 31:
1429–1436.
Rogers RD et al. (2012) Multifunctional ionic liquid compositions
for overcoming polymorphism and
imparting improved properties for
active pharmaceutical, biological,
nutritional, and energetic ingredients. (Vol. US 8,232,265 B2).
Ferraz R et al. Development of novel
IL-APIs based on ampicillin derivatives. Med Chem Commun 2012; 3:
494–497.
Florindo C et al. Evaluation of solubility and partition properties of
ampicillin-based ILs. Int J Pharm
2013; 456: 553–559.
Childs SL et al. Crystal engineering
approach to forming cocrystals of
amine hydrochlorides with organic
acids. Molecular complexes of
fluoxetine hydrochloride with benzoic, succinic, and fumaric acids.
J Am Chem Soc 2004; 126: 13335–
13342.
Braga D et al. Ionic co-crystals of
organic molecules with metal
halides: a new prospect in the solid
formulation of active pharmaceutical
ingredients. Cryst Growth Des 2011;
11: 5621–5627.
Ong TT et al. 2:1 cocrystals of
homochiral and achiral amino acid
zwitterions with Li+ salts: waterstable zeolitic and diamondoid
metal-organic materials. J Am Chem
Soc 2011; 133: 9224–9227.
Delori A et al. The role of
mechanochemistry and supramolecular design in the development of
pharmaceutical materials. Crystengcomm 2012; 14: 2350–2362.
Ma Z, Moulton B. Supramolecular
medicinal chemistry: mixed-ligand
coordination complexes. Mol Pharm
2007; 4: 373–385.
Braga D et al. Simple and quantitative mechanochemical preparation of
the first zinc and copper complexes
of the neuroleptic drug gabapentin.
Crystengcomm 2008; 10: 469–471.
© 2015 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, 67, pp. 830–846
144. Braga D et al. Simple and quantitative mechanochemical preparation of
a porous crystalline material based
on a 1D coordination network
for uptake of small molecules.
Angewandte Chemie-Int Ed 2006; 45:
142–146.
145. Yuan W et al. High reactivity of
metal-organic frameworks under
grinding conditions: parallels with
organic
molecular
materials.
Angewandte Chemie-Int Ed 2010; 49:
3916–3919.
146. Bowmaker GA et al. The role of
short-range diffusion in solventassisted mechanochemical synthesis
of metal complexes. Dalton Trans
2008; 39: 5290–5292.
147. Belcher WJ et al. Channel-containing
1D coordination polymers based on
a linear dimetallic spacer. Chem
Commun 2002; 15: 1602–1603.
148. Braga D, Grepioni F. Reactions
between or within molecular crystals.
Angewandte Chemie-Int Ed 2004; 43:
4002–4011.
149. Chow EHH et al. Mechanochemistry
of magnesium oxide revisited: facile
derivatisation of pharmaceuticals
using coordination and supramolecular chemistry. Chem Commun
2010; 46: 6368–6370.
150. Braga D et al. Drug-containing
coordination and hydrogen bonding
networks obtained mechanochemically. Crystengcomm 2009; 11: 2618–
2621.
151. Friscic T et al. A rational approach
to screen for hydrated forms of the
pharmaceutical derivative magnesium naproxen using liquid-assisted
grinding. Crystengcomm 2011; 13:
3125–3129.
152. Guo ZJ, Sadler PJ. Metals in medicine. Angewandte Chemie-Int Ed
1999; 38: 1513–1531.
153. Ge R, Sun H. Bioinorganic chemistry
of bismuth and antimony: target sites
of metallodrugs. Acc Chem Res 2007;
40: 267–274.
154. Andrews PC et al. Towards a structural understanding of the anti-ulcer
and anti-gastritis drug bismuth
subsalicylate. Angewandte Chemie-Int
Ed 2006; 45: 5638–5642.
845
New forms of old drugs
155. Janiak C, Vieth JK. MOFs, MILs and
more: concepts, properties and applications for porous coordination networks (PCNs). New J Chem 2010; 34:
2366–2388.
156. Notash B et al. Anion-controlled
structural motif in one-dimensional
coordination networks via cooperative weak noncovalent interactions. Crystengcomm 2012; 14:
6788–6796.
157. Keskin S, Kizilel S. Biomedical applications of metal organic frameworks.
Ind Eng Chem Res 2011; 50: 1799–
1812.
158. Ferey G, Serre C. Large breathing
effects in three-dimensional porous
hybrid matter: facts, analyses, rules
and consequences. Chem Soc Rev
2009; 38: 1380–1399.
159. Della Rocca J et al. Nanoscale metalorganic frameworks for biomedical
imaging and drug delivery. Acc Chem
Res 2011; 44: 957–968.
846
Sofia Domingos et al.
160. Sun C-Y et al. Metal-organic frameworks as potential drug delivery
systems. Expert Opin Drug Deliv
2013; 10: 89–101.
161. Imaz I et al. Metal-biomolecule
frameworks
(MBioFs).
Chem
Commun 2011; 47: 7287–7302.
162. O’Keeffe M. Design of MOFs and
intellectual content in reticular
chemistry: a personal view. Chem Soc
Rev 2009; 38: 1215–1217.
163. Ferey G. Hybrid porous solids: past,
present, future. Chem Soc Rev 2008;
37: 191–214.
164. Millange F et al. Effect of the nature
of the metal on the breathing steps in
MOFs with dynamic frameworks.
Chem Commun 2008; 39: 4732–
4734.
165. Kuroda R et al. Varied chargetransfer complex crystals formed
between diols and benzoquinone
in the solid and solution states.
Crystengcomm 2008; 10: 1881–1890.
166. Dietzel PDC et al. Base-induced formation of two magnesium metalorganic framework compounds with
a bifunctional tetratopic ligand. Eur J
Inorg Chem 2008; 23: 3624–3632.
167. An J et al. Cation-triggered drug
release from a porous zinc-adeninate
metal-organic framework. J Am
Chem Soc 2009; 131: 8376–8377.
168. Babarao R, Jiang J. Unraveling the
energetics and dynamics of ibuprofen in mesoporous metal-organic
frameworks. J Phys Chem C 2009;
113: 18287–18291.
169. Pichon A et al. Solvent-free synthesis
of a microporous metal-organic
framework. Crystengcomm 2006; 8:
211–214.
170. Perman JA et al. Cocrystal controlled
solid-state synthesis of a thermally
stable nicotinate analogue that sustains an isostructural series of porous metal-organic materials. Cryst
Growth Des 2009; 9: 5021–5023.
© 2015 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, 67, pp. 830–846