Coformer Selection in Pharmaceutical Cocrystal Development:
a Case Study of a Meloxicam Aspirin Cocrystal That Exhibits
Enhanced Solubility and Pharmacokinetics
MIRANDA L. CHENEY,1,2 DAVID R. WEYNA,1,2 NING SHAN,1 MAZEN HANNA,1 LUKASZ WOJTAS,2
MICHAEL J. ZAWOROTKO2
1
Thar Pharmaceuticals Inc., Tampa, Florida 33612
2
Department of Chemistry, University of South Florida, Tampa, Florida 33620
Received 14 September 2010; revised 3 November 2010; accepted 16 November 2010
Published online 22 December 2010 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/jps.22434
ABSTRACT: Meloxicam is a nonsteroidal anti-inflammatory drug with low aqueous solubility
and high permeability. Because of its low solubility under acidic conditions (e.g., pH 1–5), it can
take more than 2 h for meloxicam to reach its therapeutic concentration in humans. Although
the slow onset of meloxicam does not necessarily impact the current label indications, the slow
onset does prevent meloxicam from its potential application for the relief of mild-to-mediumlevel acute pain. Pharmaceutical cocrystallization of meloxicam, which represents a promising
approach to generate diverse novel crystal forms, could be used to improve the aqueous solubility and accelerate the onset of action. In this contribution, we describe how a novel method can
be used for coformer selection to enable the efficient and effective development of a pharmaceutical cocrystal with desired physicochemical and pharmacokinetic properties. Aspirin was
selected as the coformer for meloxicam based upon this alternative route, which combines the
supramolecular synthon approach with findings in the previous pharmacological and toxicological studies of meloxicam. The resulting cocrystal of meloxicam and aspirin exhibited superior
kinetic solubility and possessed the potential to significantly decrease the time required to
reach the human therapeutic concentration compared with the parent drug, meloxicam. © 2010
Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 100:2172–2181, 2011
Keywords: cocrystal; solubility; pharmacokinetics
INTRODUCTION
Crystalline forms are preferred for oral delivery of active pharmaceutical ingredients (APIs) because crystallization tends to afford highly pure products with
superior reproducibility and scalability.1 Typically in
drug development, novel API crystal forms, particularly pharmaceutical polymorphs and salts that exhibit diverse physicochemical properties, are identified through screening processes.2,3 More recently,
significant efforts have been made in the exploration
of pharmaceutical cocrystals as a result of their ability
to enhance the physicochemical properties of APIs.4–9
Pharmaceutical cocrystals have been defined as mulCorrespondence to: Ning Shan (Telephone: +1-813-9783980;
E-mail: nshan@tharpharma.com), Michael J. Zaworotko (Telephone: +1-813-9743451; E-mail: xtal@usf.edu)
Journal of Pharmaceutical Sciences, Vol. 100, 2172–2181 (2011)
© 2010 Wiley-Liss, Inc. and the American Pharmacists Association
2172
tiple component crystals in which at least one component is molecular and a solid at room temperature
(coformer) and forms a supramolecular synthon with
a molecular or ionic API.10 A given API may form
cocrystals with a variety of pharmaceutically acceptable and/or approved coformers and such cocrystals
can exhibit enhanced solubility,11,12 compressibility,13
stability,14 or bioavailability.15 To date, at least 90
APIs have been targeted for pharmaceutical cocrystallization due, in part, to their undesirable solubility and/or stability and their inherent hydrogen
bonding capability.16 For example, lamotrigine, a lowsolubility anticonvulsant drug, was recently targeted
for crystal form development in an attempt to enhance the physicochemical and pharmacokinetic (PK)
properties.17 In this study, efforts to generate novel
materials afforded a variety of crystalline forms including cocrystals, salts, solvates, and hydrates. It
was observed that the aqueous solubilities of the
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 100, NO. 6, MAY 2011
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lamotrigine cocrystals were similar to lamotrigine,
whereas the salt of lamotrigine and saccharin showed
a substantially higher solubility. In contrast, under
acidic conditions designed to mimic the stomach under fasted conditions (pH 1, 37◦ C), the cocrystals exhibited higher solubility compared with the parent
lamotrigine, whereas the saccharin salt was the least
soluble crystal form. This study exemplifies the ability of different crystal forms to diversify the physicochemical properties of an API. Pharmaceutical cocrystals are also capable of modifying PK properties. As
reported in another study, a novel cocrystal of glutaric
acid and a sodium channel blocker with low solubility was prepared.15 The cocrystal was evaluated with
respect to its stability, particle size, intrinsic dissolution rate, and PK properties. The intrinsic dissolution measurements showed that the cocrystal was 18
times more soluble than the API in water at 37◦ C.
Additionally, when the cocrystal was administered to
dogs in a single oral dose of 50 mg/kg, the area under the curve (AUC) of the resulting PK profile increased approximately three-fold in comparison with
the same dose of pure API. A recent review of the scientific and patent literature indicated that there have
been at least 10 pharmaceutical cocrystal case studies with PK details reported to date, many of which
support that pharmaceutical cocrystals are a viable
option to enhance the clinical performance of a poorly
soluble API.17,18 Clearly, pharmaceutical cocrystals
represent an opportunity to diversify the number of
crystal forms of a given API and in turn fine tune or
even customize its physicochemical and PK properties
without the formation/breakage of covalent bonds.
One of the main challenges in pharmaceutical
cocrystal development is the selection of coformers
that are compatible with a particular API. A general approach to coformer selection is by “tactless”
cocrystal screening, whereby a predetermined library
of pharmaceutically acceptable/approved compounds
is used to attempt cocrystallization. The lead cocrystal
candidate with superior physicochemical and pharmacological properties can then be developed into
a dosage form. It has been found recently that the
exploitation of supramolecular synthons,19 to a certain extent, can facilitate the cocrystal screening
process. Specifically, the “supramolecular synthon
approach”10,17 uses crystal engineering20 to analyze
the supramolecular arrangements that an API might
exhibit. The supramolecular synthon approach is a
statistical analysis that utilizes the Cambridge Structural Database (CSD)21 to effectively prioritize coformers for crystal form screening if an appropriate supramolecular heterosynthon can be identified.
Supramolecular heterosynthons, typically involving
hydrogen bonds between different but complementary groups, are exemplified by carboxylic acid/amide
and carboxylic acid/aromatic nitrogen supramolecuDOI 10.1002/jps
2173
lar heterosynthons.10 This approach offers little predictability concerning whether there will be property
improvement in the resulting cocrystals, thus recent
efforts have been directed to correlating the physicochemical properties of coformers to those of the resulting cocrystals.22 However, to the best of our knowledge, very limited progress has been achieved in this
context. As part of our continuous exploration of pharmaceutical cocrystals, we herein report an even more
refined approach in the identification of a coformer
to generate a pharmaceutical cocrystal with superior
physicochemical and pharmacological properties.
R
Meloxicam (Mobic , Boehringer Ingelheim, Ridgefield, CT, USA) is a nonsteroidal anti-inflammatory
drug (NSAID) indicated for the relief of the signs
and symptoms of osteoarthritis and rheumatoid
arthritis.23 The solubility of meloxicam varies depending upon pH and solvent polarity due to interconversion between ionization states.24 Meloxicam was
found to be practically insoluble in water25 and is
considered a Class II drug (i.e., low solubility and
high permeability) by the Biopharmaceutics Classification System.26 Because of its low solubility under
acidic conditions, orally delivered meloxicam exhibits
a Tmax (time to reach maximum concentration) of
4–6h in humans,23 and requires approximately 2–3h
to reach the therapeutic concentration that enables
the onset of action.27 Such a slow onset limits meloxicam from its full potential for the application of mildto-medium-level acute pain relief, which by estimation requires the attainment of the therapeutic concentration within approximately 30 min after dosing.
It is noted that an accurate prediction for the time
required to reach the therapeutic concentration for
acute pain relief is difficult for meloxicam. This estimation was determined based on an evaluation of
other NSAIDs for the indication of acute pain relief.
To decrease the time to reach the therapeutic concentration and accelerate the onset of action, numerous
meloxicam-based formulations have been prepared
and evaluated with respect to aqueous solubility.28–31
In spite of all the efforts that were taken, a faster
onset oral dosage form of meloxicam remains absent
to date. Given the fact that pharmaceutical cocrystals can influence the physicochemical properties of
APIs including solubility, a study was designed and
performed to explore their effect on improving the solubility and subsequently the onset of action of meloxicam.
MATERIALS AND METHODS
Materials
Meloxicam was purchased from Jai Radhe Sales
(Ahmedabad, Gujarat, India) with a purity of 99.64%
and was used without further purification. All other
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CHENEY ET AL.
chemicals were supplied by Sigma–Aldrich (St Louis,
MO, USA) and used without further purification.
Synthesis of Meloxicam Aspirin Cocrystal
Cocrystals of meloxicam and aspirin (1) were successfully prepared by solution,32 slurry,17 and solventdrop grinding33 methods.
Solution—23.2 mg (0.0660 mmol) of meloxicam and
11.0 mg (0.611 mmol) of aspirin were dissolved in
8 mL of ethyl acetate at room temperature and left to
slowly evaporate. Cocrystals of 1 were obtained (ca.
35% yield) concomitantly with crystals of meloxicam
form I and aspirin.
Slurry—0.905 g (2.56 mmol) of meloxicam and
0.452 g (2.51 mmol) of aspirin were slurried in 3 mL of
tetrahydrofuran (THF) overnight sealed under ambient conditions at approximately 250 rpm. The resulting solid was filtered and washed with THF. 1 was
isolated in 96% yield.
Solvent-drop grinding—0.182 g (0.517 mmol) of
meloxicam was ball-milled (SPEX Mixer/Mill 8000M,
Spex Sample Prep, Metuchen, NJ, USA) with 0.0966 g
(0.536 mmol) of aspirin and 40 :L of chloroform for
30 min to obtain 1 in approximately 100% conversion,
as evidenced by the powder X-ray diffraction (PXRD)
and differential scanning calorimetry (DSC) analyses.
Crystal Form Characterization
Single-Crystal X-Ray Diffraction
Single-crystal analysis for 1 was performed on
a Bruker-AXS SMART APEX CCD diffractometer
(Bruker, Madison, WI, USA) using Cu K" radiation (λ = 1.54178 Å). Data for 1 were collected at
293 K. Lattice parameters were determined from
least-squares analysis, and reflection data were integrated using SAINT (Bruker, Madison, WI, USA).34
Structures were solved by direct methods and refined
by full matrix least squares based on F2 using the
SHELXTL package (Gottingen, Germany).35 All nonhydrogen atoms were refined with anisotropic displacement parameters. All hydrogen atoms bonded
to carbon, nitrogen, and oxygen atoms were placed
geometrically and refined with an isotropic displacement parameter fixed at 1.2 times Uq of the atoms to
which they were attached. Hydrogen atoms bonded to
methyl groups were placed geometrically and refined
with an isotropic displacement parameter fixed at 1.5
times Uq of the carbon atoms.
Powder X-ray Diffraction
1 was characterized using a D-8 Bruker X-ray Powder
Diffractometer (Bruker, Madison, WI, USA) using Cu
K" radiation (λ = 1.54178 Å), 40 kV, 40 mA. Data were
collected at room temperature over an angular range
of 3◦ to 40◦ 2θ value in continuous scan mode using a
step size of 0.05◦ 2θ value and a scan rate of 5◦ /min.
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 100, NO. 6, MAY 2011
Calculated PXRD
A calculated PXRD diffractogram was generated
from the single-crystal structure of 1 using Mercury
2.2 (Cambridge Crystallographic Data Centre, Cambridge, UK) and compared with the pattern obtained
for the bulk sample.
Differential Scanning Calorimetry
Differential Scanning Calorimetry was performed
on a PerkinElmer Diamond differential scanning
calorimeter (PerkinElmer, Waltham, MA, USA) with
a scan range of 25◦ C–280◦ C, scan rate of 10◦ C/min,
and nitrogen purge of approximately 30 psi.
Fourier-Transform Infrared Spectroscopy
Fourier-transform infrared spectroscopy (FTIR) analysis was performed at room temperature on a
PerkinElmer Spectrum 100 FTIR spectrometer
(PerkinElmer, Waltham, MA, USA) equipped with a
solid-state attenuated total reflectance (ATR) accessory.
Solubility Study
Kinetic solubility was measured for meloxicam and 1
in deionized water at 25◦ C to enable an initial solubility comparison between the API and cocrystal. Subsequently, an additional solubility evaluation of meloxicam and 1 was performed in the pH 7.4 phosphate
buffer at 37◦ C to facilitate a fair comparison between
the resulting solubility data and the following animal PK study. Before the solubility study, meloxicam
and 1 were sieved to achieve a particle size between
53 and 75 :m. The solubility study was conducted by
adding increments of a specified amount of solvent
to a preweighed amount of meloxicam and 1. Solubility was determined by adding water or pH 7.4 phosphate buffer in 10 mL increments approximately every 10 min with constant agitation until complete dissolution was observed. The experiment was repeated
twice to allow for statistical analysis.
Animal PK Study
Pharmacokinetic studies were conducted using a
single-dose oral administration of meloxicam and
1. An intravenous (IV) dose of pure meloxicam
(1 mg/kg) was also administered to enable calculation of bioavailability. Five male Sprague–Dawley
rats (250–300 g) with preimplanted indwelling jugular vein catheters were used for each crystal form.
Meloxicam and 1 were administered at a dosage of
1 mg/kg meloxicam or its equivalent. For oral administrations, a mixture of 5% polyethylene glycol 400
(PEG 400) and 95% methyl cellulose aqueous solutions were used as the vehicle to facilitate oral gavage. Meloxicam and 1 were observed as insoluble in
the vehicle. For the IV administration, meloxicam was
DOI 10.1002/jps
COFORMER SELECTION IN PHARMACEUTICAL COCRYSTAL DEVELOPMENT
dosed as a PEG 400/dimethyl sulfoxide solution. After
dosing, 0.2 mL of blood was withdrawn at 5, 15, 30,
45, 60, 120, 240, 480, 720, and 1440 min. The blood
samples were immediately clotted and centrifuged at
room temperature to obtain the rat serum samples,
which were subsequently processed and analyzed by
liquid chromatography/mass spectrometry according
to the literature.36 The PK data were processed by
the WinNonlin Professional version 4.0.1 (Pharsight
Corporation, West Chester, PA, USA).
RESULTS AND DISCUSSION
Coformer Selection for Meloxicam
The selection of appropriate coformers for pharmaceutical cocrystallization of meloxicam was initialized
via the supramolecular synthon approach. Analysis
of form I37 of meloxicam (Refcode: SEDZOQ) from
a supramolecular synthon approach indicates that
meloxicam molecules form supramolecular chains
that are sustained by sulfonyl-amide and sulfathiazole–alcohol supramolecular heterosynthons (Fig. 1).
The chains are held together by various weak interactions, stacking along the a-axis in a slipped fashion. Thus, for meloxicam cocrystallization, one or
all of these supramolecular synthon motifs must be
interrupted.38 The CSD analysis examined the reliability of supramolecular heterosynthon versus homosynthon formation between a simple azole (fivemembered ring containing one nitrogen atom and
at least one additional heteroatom) and a carboxylic
acid, a primary amide, or an alcohol. Only hydrogen
bonding interactions were considered for heterosynthon and homosynthon formation.39
A search of the CSD40 for entries that contain both
an azole and a carboxylic acid moiety resulted in 450
hits. A closer look at the 450 entries revealed that the
carboxylic acid dimer or catemer occurred in 39 entries, or 9% of the time. However, when the 450 entries
2175
were investigated for the presence of the azole–carboxylic acid supramolecular heterosynthon, 102 entries (23%) were identified. Thus, when an azole and
carboxylic acid are present in the same crystal structure, the supramolecular heterosynthon is more likely
to occur. Because of the potential for meloxicam to
generate salts or neutral complexes depending upon
the acidity of the complexing moiety, carboxylate–azole interactions were also searched in the CSD. The
search result suggested that the carboxylate–azole
supramolecular heterosynthon could also be a potential target supramolecular heterosynthon. Interestingly, a search of the CSD indicated that a cocrystal
of meloxicam with a coformer containing a primary
amide moiety is less likely to occur due to the greater
percentage of occurrence of the amide supramolecular homosynthon versus the heterosynthon. In addition, complexation of alcohols with azoles was also
studied in the CSD. Collectively comparing the occurrence of the supramolecular homosynthon with the
heterosynthon, heterosynthon formation dominates
in all cases except for primary amides. The analysis
revealed that the azole–carboxylic acid and azole–alcohol supramolecular heterosynthons are persistent.
The results of these searches are listed in Table 1.
Simultaneously, special attention was drawn to the
US Food and Drug Administration Summary Basis of
R
Approval (SBA) document for Mobic . It was observed
that the oral coadministration of meloxicam and aspirin (1000 mg three times a day) to healthy humans
would lead to an unexplained increase of AUC and
Cmax (maximum plasma concentration) of meloxicam.
Therefore, the concomitant administration of meloxicam and aspirin was “not generally recommended,”
although no significant adverse effect was reported
as a consequence of this coadministration. Realizing that aspirin is an aromatic carboxylic acid, coupled with the CSD analytical results, we speculated
that meloxicam and aspirin would form a cocrystal
Figure 1. Meloxicam molecules oriented in a chain motif (CSD Ref. code: SEDZOQ).
DOI 10.1002/jps
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CHENEY ET AL.
Table 1.
Summary of the CSD Analysis of the Azole Moiety and its Interaction with an Additional Complementary Functional Group
Complementary
No. of Entries Containing
Functional Group
Both Moieties
Carboxylic acid
Carboxylate
Alcohol
Primary amide
a
b
450
1708
722
115
Entries that Contain the
Supramolecular Heterosynthona
Entries that Contain the
Supramolecular Homosynthonb Distance Range (Å)
102 (23%)
123 (7%)
296 (41%)
24 (21%)
39 (9%)
NA
184 (25%)
64 (56%)
2.50–2.80
2.59–2.90
2.60–3.10
2.80–3.20
The supramolecular heterosynthon is typically an azole hydrogen bonded to a complementary functional group.
The supramolecular homosynthon represents the complementary functional group only (i.e., carboxylic acid dimer).
using the conventional cocrystallization techniques
and that it could increase the in vivo absorption of
meloxicam.41 Such an AUC improvement could potentially reduce the time to reach the therapeutic concentration and result in a faster onset. With this in mind,
aspirin was selected as the coformer in the study of
meloxicam cocrystallization.
the C C aromatic region. After cocrystallization, the
carbonyl peak of aspirin shifted from its original position of 1751 to 1756 cm−1 . The FTIR peaks associated
with the C C stretch on the aromatic ring systems
shifted from 1455 cm−1 for aspirin and 1457 cm−1 for
meloxicam to 1447 cm−1 in 1.
Solid-State Characterization
To confirm that 1 is a cocrystal and identify the proton location, three factors were taken into consideration: pKa value [i.e., pKa(base) − pKa(acid) ], C O
bond lengths of aspirin, and the C N C angle of the
meloxicam sulfathioazole ring. The difference in pKa
values between the base and the acid is widely used
as a guide for determining whether an experiment
will result in the formation of a salt or cocrystal.42–45
It is generally accepted that if pKa < 0, a cocrystal will almost always result, and if the pKa > 3,
the result will most likely be a salt. When the pKa
falls in between (i.e., 0 < pKa < 3), the product can
Cocrystals of meloxicam and aspirin (1) were obtained from grinding, solution, and slurry. Solid-state
physical characterizations including X-ray diffraction, DSC, and FTIR were performed on 1. Singlecrystal X-ray diffraction showed that 1 crystallizes
in the space group P21 /c. The asymmetric unit of
1 contains one meloxicam molecule and one aspirin
molecule. The meloxicam dimer is observed in 1
with the planar meloxicam molecules held into the
dimer conformation by
OH···S interactions. The
supramolecular heterosynthon that sustains the 1:1
complex of meloxicam and aspirin is a two-point
recognition OH···N (O···N 2.665(3) Å) and NH···O
(N···O 2.856(3) Å) hydrogen-bonded dimer (Scheme
1). As the meloxicam aspirin units extend along the
a-axis, corrugated sheets are formed and propagated
with a dihedral angle of 73.69◦ (Fig. 2). The corrugated sheets stack with a separation distance of
approximately 3.87 Å, producing a herringbone motif. The crystallographic details of 1 are listed in
Table 2. To confirm the homogeneity of the powder obtained from grinding, the experimental PXRD profile
has been compared with the profile calculated from
the single-crystal X-ray diffraction data. As shown in
Figure 3, the single-crystal structure represents the
solid-state form of the powder from grinding.
Additional characterization results of 1 including
DSC and FTIR are shown in Figures 4 and 5, respectively. As shown in the DSC curve, 1 exhibited
a melting point of 166◦ C, which is between the melting points of aspirin (140◦ C) and meloxicam (254◦ C).
No thermal event of dehydration or desolvation was
observed throughout the characterization. It was observed that the cocrystal decomposed after heating to
a temperature higher than the melting point of 1. A
comparison of the FTIR spectra of 1 to meloxicam and
aspirin showed distinct shifts in both the carbonyl and
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 100, NO. 6, MAY 2011
Salt or Cocrystal?
Table 2.
Crystallographic Data of 1
Empirical formula
Formula weight
C23 H21 N3 O8 S2
531.55
Temperature
Wavelength
Crystal system, space group
Unit cell dimensions
293(2) K
1.54178 Å
Monoclinic, P21 /c
a = 6.8026(4) Å; α = 90◦
b = 19.158(1) Å; β = 94.914(4)◦
c = 18.758(1) Å; γ = 90◦
2435.6(2) A3
4, 1.450 Mg/m3
2.459 mm−1
1104
0.40 × 0.30 × 0.18 mm3
3.30–67.21◦
−8 ≤ h ≤ 8, −22 ≤ k ≤ 22, −22 ≤
l ≤ 21
15496/4238 [R(int) = 0.0502]
67.24◦ ; 97.3%
Semiempirical from equivalents
0.6655 and 0.4392
Volume
Z, Calculated density
Absorption coefficient
F(000)
Crystal size
Theta range for data collection
Limiting indices
Reflections collected/unique
Completeness to theta
Absorption correction
Maximum and minimum
transmission
Refinement method
Data/restraints/parameters
Goodness-of-fit on F2
Final R indices [I > 2sigma(I)]
R indices (all data)
Largest diff. peak and hole
Full-matrix least-squares on F2
4238/0/330
1.020
R1 = 0.0419, wR2 = 0.1043
R1 = 0.0593, wR2 = 0.1143
0.200 and −0.280 eÅ−3
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2177
Figure 2. Primary supramolecular units of meloxicam and aspirin translating along the 21
screw axis.
be either species or present partial proton transfer.46
The pKa value of 0.68 for 1 implies cocrystal formation but is not definitive. In addition, the C O bond
lengths were measured and found to be 1.311 and
1.212 Å, indicating aspirin is present as the neutral
species. The C N C angle of the sulfathiazole ring
is also a valuable indicator of protonation where a
protonated species will maintain a larger angle (ca.
113◦ )24 in comparison with the neutral species (ca.
109◦ ).37,47 The C N C angle in 1 was 110.20◦ , suggesting that meloxicam is also present as the neutral
species. Therefore, it is confirmed from all three considerations that 1 is indeed a cocrystal.
Solubility Study
A kinetic solubility study of meloxicam and 1 was
performed as a preliminary solubility comparison
DOI 10.1002/jps
between the original API and the resulting cocrystal. It showed that the aqueous solubility of
meloxicam at room temperature was approximately
0.001 mg/mL, whereas that of 1 was comparable at
ca. 0.0013 mg/mL.48 However, a much more significant solubility difference was observed in conditions
designed to mimic a part of the mammalian gastrointestinal tract. In a pH 7.4 phosphate buffer
solution at 37◦ C, the solubility of meloxicam was
found to be approximately 0.005 mg/mL, whereas
that of 1 was found to be approximately 0.22 mg/
mL. It is noted that this solubility study did
not use the standard United States Pharmacopeia
(USP) apparatus due to the limitations of our inhouse facility. Nevertheless, it is believed that our
solubility study produced reasonably comparable
results.
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CHENEY ET AL.
Figure 3. Profiles of (a) experimental PXRD of 1 and
(b) calculated PXRD of 1 based on the single-crystal X-ray
diffraction data.
PK Study
Inspired by these promising solubility study results,
an animal PK study was conducted. Meloxicam and 1
were each administered as a single-dose suspension
in PEG 400 to male Sprague–Dawley rats (n = 5) via
oral gavage at an equivalent dose of 1 mg/kg. The PK
profiles of meloxicam and 1 are presented in Figure
6. Significant improvement of meloxicam absorption
was observed after oral administration of 1, which exhibited an oral bioavailability of 69% compared with
16% for meloxicam. In addition, the plasma concentration correlating to the time to reach the human
therapeutic concentration of meloxicam (i.e., 2 h) was
found to be 0.51 :g/mL. It was noted that the Cmax
of 1 is over four times greater than that of meloxicam, although the Tmax of both 1 and meloxicam is
Figure 4. DSC profile of 1. The cocrystal melts at approximately 166◦ C and decomposes at higher temperatures.
Thermal events of cocrystal decomposition were omitted for
clarity.
4 h. As a result, the concentration of 0.51 :g/mL was
achieved only approximately 10 min after oral administration of an equivalent dose of 1. Given that the
efficacy of meloxicam is directly associated with its
plasma concentration, the onset of action should be
much faster for 1 compared with that of meloxicam
with the same dose. The PK study result illustrated
that 1 is a promising candidate for the development
of a meloxicam oral dosage form indicated for rapid
mild-to-medium acute pain relief. A summary of the
PK parameters are included in Table 3.
In light of the precaution outlined in the SBA associated with concomitant administration of meloxicam
and aspirin, there is a potential for adverse effects
after oral administration of 1. However, no significant adverse effects were observed during our rat PK
study. Furthermore, only 7.7 mg of aspirin (i.e., 2% of
the regular human adult dose)49 is present in 1 when
the largest approved human dose of meloxicam (i.e.,
15 mg) is used. 1 was also well tolerated when a single dose with a 10-fold dosage increase (i.e., 10 mg/
kg meloxicam equivalent, equivalent to a 333 mg
Table 3. Pharmacokinetic Parameters for 1 and Meloxicam from
a Single-Dose Oral Gavage Administration of 1 mg/kg Meloxicam
or its Equivalent of 1
Scheme 1. Molecular structure of meloxicam and aspirin.
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Cmax (:g/mL)
Time to reach therapeutic
concentration (min)
Tmax (h)
Mean residence time (h)
AUC0–24h (:g·h/mL)
Mean absorption time (h)
Bioavailability
1
Meloxicam
2.70
10.6
0.59
120
4.00
24.56
44.14
9.86
69(7)%
4.00
21.80
10.0
7.10
16(4)%
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2179
Figure 5. FTIR spectrum of (a) 1, (b) aspirin, and (c) meloxicam. The carbonyl shift is highlighted by a dashed blue line and the C C aromatic shift is highlighted by a dashed orange
line.
Figure 6. Plasma PK profiles over 24 h for 1 and meloxicam from a 1 mg/kg dose of meloxicam or its equivalent
of 1.
human dose50 ) was administered in an additional rat
PK study, as no significant adverse effect was found
in the clinical observations.
CONCLUSIONS
In summary, we have targeted and prepared a cocrystal of meloxicam and aspirin, 1, which enabled an approximately 12-fold decrease in the time required to
reach a concentration of 0.51 :g/mL in rats compared
with pure meloxicam at an equivalent dose. Such an
improvement could also translate to a faster onset of
pain relief in humans.51 For the first time, the selection of a coformer was guided by the combination of
the supramolecular synthon approach and findings
in the pharmacological and toxicological studies of
the parent API, while the intensive cocrystal form
DOI 10.1002/jps
screening was avoided. Considering that pharmaceutical cocrystallization is frequently used to improve
the properties of existing APIs, the selection of coformers could be facilitated by the available pharmacological and toxicological information of the parent
APIs. In many cases, drug interactions as well as
drug–excipient interactions have been well studied
and reported for the parent APIs. Such information
could be incorporated in pharmaceutical cocrystal design targeting a specific physicochemical and/or pharmacological property. As demonstrated herein, pharmaceutical cocrystal development becomes more efficient and effective with the strategy of combining the
supramolecular synthon approach and the available
preclinical/clinical information. Further pharmaceutical cocrystal development is underway with this approach.
Crystallographic data of 1 have been deposited with the Cambridge Crystallographic Data
Centre (CCDC) as a supplementary publication number CCDC 801314. Copies of the data can be obtained free of charge on application to CCDC via
www.ccdc.cam.ac.uk/data request/cif.
ACKNOWLEDGMENTS
We thank Mr. Raymond Houck for stimulating discussions and valuable input to the project and Dr.
William Weiss for his assistances in the PK testing.
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