Temozolomide-Hesperetin Drug-Drug Cocrystal with Optimized Performance in Stability, Dissolution, and Tabletability

Article abstract of DOI:10.1021/acs.cgd.0c01153

A new 1:1 drug-drug cocrystal of temozolomide and hesperetin was successfully prepared by liquid-assisted grinding, slurry conversion crystallization, and evaporation crystallization. The obtained cocrystal was comprehensively characterized by single-crystal and powder X-ray diffraction, differential scanning calorimetry, and thermogravimetric analysis, as well as by Fourier transform infrared and nuclear magnetic resonance spectroscopy. The two drug molecules in the cocrystal are connected via O-H···O hydrogen bonds between the carbonyl oxygen of temozolomide and the phenolic hydroxyl group of hesperetin. The drug-drug cocrystal enhances the hydroscopic stability of hesperetin and the physicochemical stability of temozolomide. In addition, the cocrystal optimizes the dissolution behavior of temozolomide and hesperetin at pH 1.2 and pH 6.8 in comparison to the pristine drugs. Further, a compressibility assessment was also conducted, and the cocrystal exhibits a superior tabletability in comparison with temozolomide. Therefore, the drug-drug cocrystal has the potential to be developed as an efficient oral formulation of a drug combination which will overcome the weaknesses of each parent drug.

Full text of DOI:10.1021/acs.cgd.0c01153

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Article
Temozolomide−Hesperetin Drug−Drug Cocrystal with Optimized
Performance in Stability, Dissolution, and Tabletability
Jie Wang, Xia-Lin Dai,* Tong-Bu Lu, and Jia-Mei Chen*
Cite This: Cryst. Growth Des. 2021, 21, 838−846
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ABSTRACT: A new 1:1 drug−drug cocrystal of temozolomide and hesperetin was successfully prepared by liquid-assisted grinding,
slurry conversion crystallization, and evaporation crystallization. The obtained cocrystal was comprehensively characterized by
single-crystal and powder X-ray diffraction, differential scanning calorimetry, and thermogravimetric analysis, as well as by Fourier
transform infrared and nuclear magnetic resonance spectroscopy. The two drug molecules in the cocrystal are connected via O−H···
O hydrogen bonds between the carbonyl oxygen of temozolomide and the phenolic hydroxyl group of hesperetin. The drug−drug
cocrystal enhances the hydroscopic stability of hesperetin and the physicochemical stability of temozolomide. In addition, the
cocrystal optimizes the dissolution behavior of temozolomide and hesperetin at pH 1.2 and pH 6.8 in comparison to the pristine
drugs. Further, a compressibility assessment was also conducted, and the cocrystal exhibits a superior tabletability in comparison
with temozolomide. Therefore, the drug−drug cocrystal has the potential to be developed as an efficient oral formulation of a drug
combination which will overcome the weaknesses of each parent drug.
intellectual property and enable the life cycle management of
drug products.10 Therefore, drug−drug cocrystals have
captured growing interest in the pharmaceutical industry.
However, this field remains underexplored at present due to
the complexity in the rational design and development.
Temozolomide (TMZ, Scheme 1) is an oral alkylating agent
used to treat malignant gliomas.11,12 TMZ is a prodrug that
spontaneously hydrolyzes into the active compound 5-(3-
monomethyl-1-triazeno)imidazole-4-carboxamide (MTIC)
INTRODUCTION
■
Pharmaceutical cocrystals are defined as homogeneous
crystalline solids composed of an active pharmaceutical
ingredient (API) and pharmaceutically acceptable cocrystal
formers (CCFs), wherein the API and CCFs are combined in
the same crystal lattice via noncovalent interactions in a
stoichiometric ratio.1 The formation of cocrystals offers an
opportunity to ameliorate the physical and chemical properties,
including stability, solubility, dissolution rate, bioavailability,
tabletability, etc., of a given API without changing the covalent
bonding structure.2−7 Drug−drug cocrystals are an emergent
subset of cocrystals, which are composed of two different API
molecules. In comparison to the parent drugs, drug−drug
cocrystals exhibit many advantages, such as the amelioration of
the physicochemical properties of each component and the
opportunity for the development of synergistic therapies.8,9
Moreover, they also provide an attractive avenue to expand the
Received: August 17, 2020
Revised: December 18, 2020
Published: January 2, 2021
https://dx.doi.org/10.1021/acs.cgd.0c01153
© 2021 American Chemical Society
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the present study. The cocrystal was prepared by multiple
methods and characterized comprehensively. The crystal
structure was successfully determined by single-crystal X-ray
diffraction. Furthermore, the pharmaceutical properties,
including physicochemical stability, dissolution characteristics,
and tabletability of the cocrystal, were also investigated to
evaluate the pharmaceutical applicability.
Scheme 1. Chemical Structures of TMZ and HSP
RESULTS AND DISCUSSION
■
Crystal Structure Analysis. Single-crystal X-ray diffraction
(SCXRD) can elucidate the three-dimensional (3D) structure
of cocrystals, including the supramolecular synthons and
crystal-packing details.33 The crystal structure of TMZ-HSP
was determined by SCXRD at 293 K. The crystallographic data
and refinement details are provided in Table 1. The selected
under physiological conditions (Scheme S1 in the Supporting
Information). MTIC further decomposes into 5-amino-
imidazole-4-carboxamide (AIC) and methyldiazonium cation
+
(CH3N2 ), the latter of which is an active alkylated substance
that exerts antitumor efficiency through DNA methylation.13
Currently, TMZ is a first-line chemotherapy drug for the
treatment of malignant glioma.14 However, the efficacy of
TMZ is limited due to its rapid elimination after oral
administration. In addition, TMZ suffers from stability issues,
as it degrades into AIC during storage and processing, which
also reduces the effectiveness of the drug. Some cocrystals of
TMZ with succinic acid, oxalic acid, isonicotinamide,
nicotinamide, pyrazinamide, 4-hydroxybenzamide, etc. have
been studied and have demonstrated improved stability.15−17
Recently, our group reported a drug−drug cocrystal involving
TMZ and baicalein (BAI), which shows optimized stability,
solubility, and pharmacokinetics in comparison to the two
parent drugs.18 This encouraged us to explore more drug−drug
cocrystals of TMZ with other flavonoid active ingredients to
provide more options for potential clinical applications. Hence,
a series of flavonoid compounds with antiglioma activity,
including apigenin, daidzein, hesperetin, morin, naringenin,
puerarin, etc., were selected to cocrystallize with TMZ. Finally,
a drug−drug cocrystal of TMZ with hesperetin (HSP, Scheme
1) was obtained.
HSP is a compound found in citrus fruits which possesses
extensive pharmacological effects, such as antioxidant,
anticarcinogenic, anti-inflammatory, antibacterial, antiallergic,
and antitumor activities.19−22 In contrast to BAI, which
suppresses cell proliferation, promotes apoptosis, and arrests
the cell cycle by reducing the expression of HIF-1α, VEGF,
and VEGFR2 in U87 gliomas,23 HSP induces the apoptosis of
glioma cells by activating p38 MAPK and thereby possesses a
totally different antiglioma mechanism.24 In addition, HSP
does not accumulate in any organs and is safe to be used with
negligible toxicity.25 Therefore, it has the potential to
cooperate with TMZ to exert synergistic effects in the
treatment of malignant glioma with different potential
therapeutic effects and can be applied to different clinic
settings in comparison to TMZ-BAI. However, HSP has the
weakness of poor solubility similar to that of BAI, which
consequently leads to low bioavailability in living organisms
and further limits its potential as an active antitumor drug.26,27
Cocrystal formation of HSP with picolinic acid, nicotinamide,
and caffeine has already been proved to be an effective method
to improve its solubility and oral bioavailability.28
Table 1. Crystallographic Data and Refinement Parameters
for TMZ-HSP
chem formula
formula wt
C22H20N6O8
496.44
temp (K)
293(2)
λ (Å)
0.71073
cryst size (mm3)
0.10 × 0.05 × 0.03
orthorhombic
Pca21
cryst syst
space group
a (Å)
b (Å)
c (Å)
α (deg)
37.3480(4)
7.3427(9)
8.1247(11)
90.00
β (deg)
90.00
γ (deg)
90.00
2228.1(5)
4
V (Å3)
Z
calcd density (g/cm3)
θ range for data collection (deg)
F(000)
1.480
2.734−27.499
1032.0
index ranges
−48 ≤ h ≤ 48
−9 ≤ k ≤ 9
−10 ≤ l ≤ 10
5123
no. of reflns
no. of unique reflns
no. of params
4495
341
0.0951, 0.0879
0.2141, 0.2086
1.061
a
R1all, R1obs
wR2all, wR2obs
b
GOF
CCDC no.
1985464
a
b
2
2
R1 = ∑||Fo| − |Fc||/∑|Fo|. wR2 = [∑[w(Fo − Fc )2]/
2
2
∑w(Fo )2]1/2, w = 1/[σ2(Fo)2 + (aP)2 + bP], where P = [(Fo ) +
2Fc2]/3.
Table 2. Hydrogen-Bonding Distances and Angles for TMZ-
HSP
In the present work, we focused on a drug−drug cocrystal of
TMZ and HSP (TMZ-HSP), aiming to optimize the
properties of both drugs for the synergistic treatment of
glioma. Although TMZ possesses three anhydrous polymorphs
and one monohydrate form29,30 and HSP has one anhydrous
form and one monohydrate form,31,32 no polymorphism
phenomenon was observed during the cocrystallization of
TMZ and HSP and only one cocrystal form was obtained in
H···A
∠D−H···A
hydrogen bond
(Å)
D···A (Å)
(deg)
symmetry code
O3−H3···O2
O4−H4···O2
1.93
1.97
2.627(7)
2.762(7)
143.1
163.9
−x − 3/2, y + 1,
z − 1/2
O5−H5···O7
N6−H6A···O7
1.99
2.09
2.852(8)
2.849(9)
142.0
146.6
−x − 1, −y − 1,
z + 1/2
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Figure 1. (a) Asymmetric unit, (b) cell packing, (c) 2D and (d) 3D hydrogen-bonded frameworks of TMZ-HSP, and (e) 1D hydrogen-bonded
chain of TMZ.
hydrogen-bonding angles and distances are given in Table 2.
TMZ-HSP crystallizes in the orthorhombic space group Pca21,
with one molecule each of TMZ and HSP in the asymmetric
unit (Figure 1a). The C2 atom of the HSP molecule is a chiral
center, which is disordered over two positions with an
occupancy ratio of 0.75:0.25 (for C2A and C2B, respectively).
There are four HSP molecules in the crystal cell, among which
the C2A and C2B atoms of two HSP molecules correspond to
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R and S enantiomers, respectively. For the other two HSP
molecules, the C2A and C2B atoms are representative of S and
R enantiomers, respectively (Figure 1b). Overall, the HSP
molecules in TMZ-HSP are a racemic mixture. There is an
intramolecular O3−H3···O2 hydrogen bond between hydroxyl
and carbonyl groups in each HSP molecule. TMZ and HSP
molecules are connected through an O5−H5···O7 hydrogen
bond to form a dimer (Figure 1a). Two dimers are further
connected via a N6−H6A···O7 hydrogen bond between amide
groups of adjacent TMZ molecules to generate a tetramer. The
tetramers are held together through an O4−H4···O2 hydrogen
bond between hydroxyl and carbonyl groups of neighboring
HSP molecules to generate a one-dimensional (1D) belt
(Figure 1c). The belts are further stacked along the c axis to
form a 3D hydrogen-bonded framework structure (Figure 1d),
within which there also exist 1D hydrogen-bonded chain
structures of TMZ molecules (Figure 1e).
subsequent exothermic peak at 182.3 °C, which could be
attributed to the decomposition of the eutectic (Figure S1 in
the Supporting Information).
1H Nuclear Magnetic Resonance (1H NMR). The
chemical components in the new cocrystalline phase were
1
1
further identified and confirmed by H NMR. The H NMR
spectrum of synthesized TMZ-HSP was the superposition of
the peaks of TMZ and HSP, except for the peaks of active
hydrogen (Figure S2 in the Supporting Information), which
indicates the presence of these two components in the new
phase. The 1H NMR chemical shift assignments are as follows:
peaks of TMZ, δ 8.83 (s, 1H), 7.81 (s, 1H), 7.69 (s, 1H), 3.87
(s, 3H); peaks of HSP, δ 6.91 (dd, J = 25.3, 8.4 Hz, 3H), 5.89
(dd, J = 5.6, 2.1 Hz, 2H), 5.42 (dd, J = 12.3, 3.0 Hz, 1H), 3.78
(s, 3H), 3.17 (dd, J = 17.1, 12.4 Hz, 1H), 2.72 (dd, J = 17.1,
3.1 Hz, 1H). The ratio of TMZ and HSP in the cocrystal was
calculated to be 1:1 by integrating the characteristic proton
signals of each component.
Powder X-ray Diffraction (PXRD) and Thermal
Analyses. PXRD analysis was utilized to identify the
crystalline phase and determine the phase purity of the bulk
sample of TMZ-HSP (Figure 2).34,35 The PXRD pattern of
Fourier Transform Infrared Spectroscopy (FTIR)
Analysis. FTIR spectra can further identify the intermolecular
interactions of functional groups involved by the changes in
their vibrational frequencies. The FTIR spectra for TMZ, HSP,
TMZ-HSP, and the corresponding physical mixture are
presented in Figure 3. HSP shows characteristic peaks at
Figure 2. Comparison of experimental and simulated PXRD patterns
of TMZ-HSP, HSP and TMZ.
Figure 3. FTIR spectra of TMZ, HSP, TMZ-HSP, and a physical
mixture (TMZ + HSP).
synthesized TMZ-HSP is distinguished from those of its
parent materials, suggesting the formation of a new crystalline
phase. Moreover, the experimental PXRD pattern is consistent
with the simulated pattern calculated from single-crystal data,
confirming the crystalline phase purity of the synthesized
cocrystal. The thermodynamic stability of the parent materials
and cocrystal was investigated by means of thermogravimetric
(TG) and differential scanning calorimetry (DSC) analyses.
From TG thermograms it can be seen that TMZ, HSP, and
TMZ-HSP are free from crystalline water or solvents in the
lattice and begin to decompose at approximately 186.8, 276.4,
and 199.8 °C, respectively. The DSC curve of HSP shows an
endothermic peak of melting at 232.4 °C, while those of TMZ
and TMZ-HSP show exothermic peaks at 202.2 and 200.9 °C,
respectively, corresponding to their decomposition processes
(Figure S1 in the Supporting Information). A TG and DSC
analysis of the 1:1 physical mixture of TMZ and HSP has also
been carried out. The DSC curve of the physical mixture
exhibits an endothermic peak at 178.0 °C, which could be
ascribed to the formation of a eutectic of TMZ and HSP, and a
1637 and 3500 cm−1, which are assigned to the carbonyl CO
and O−H stretching vibrations.36 The N−H stretching of
TMZ exhibits characteristic peaks at 3421 and 3388 cm−1, and
the stretching vibrations at 1759 and 1733 cm−1 correspond to
the CO stretching vibrations from the primary and tertiary
amides of TMZ, respectively.37 After the formation of TMZ-
HSP, the CO stretching vibrations were observed at 1635,
1699, and 1743 cm−1 and the O−H and N−H stretchings were
shifted to 3464 and 3301 cm−1, respectively. These spectral
peak shifts reflect that the amide groups of TMZ and the
hydroxyl and carbonyl groups of HSP participate in the change
in hydrogen-bonding modes accompanying cocrystal forma-
tion.
Dynamic Vapor Sorption (DVS) Study. A DVS study
was carried out to compare the hygroscopicity of TMZ-HSP
with those of the parent TMZ and HSP. The resulting vapor
sorption/desorption isotherms are depicted in Figure 4. The
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Figure 4. Water sorption/desorption isotherms for TMZ, HSP, and
TMZ-HSP at 25 °C.
Figure 5. Changes in TMZ assay values during storage under 40 °C/
75% RH for TMZ and TMZ-HSP (n = 3).
possible phase transitions during the DVS experiments were
monitored by PXRD detection. TMZ-HSP absorbs more water
than pure TMZ but absorbs less water than the parent HSP at
all relative humidity (RH) levels. The absorption quantity of
water molecules at 95% RH for TMZ-HSP is 0.18%, which
could be considered as nonhygroscopic.38 As the humidity
drops back to 0% RH, all of the samples lose the absorbed
water reversibly and no hysteresis gap was observed. The
results reveal that there is no phase transition for the three
samples under the experimental conditions. The PXRD
patterns of TMZ, HSP, and TMZ-HSP after DVS experiments
further confirm that all the samples kept their original
crystalline phases (Figure S3 in the Supporting Information).
Accelerated Stability Test. Cocrystal formation can
modulate the physical and chemical stability of the involved
compounds by changing the molecular arrangements and
packing patterns. TMZ suffers from chemical stability issues, as
it tends to degrade to form AIC during storage processing;
thus, chemical stability tests of TMZ and TMZ-HSP were
performed under accelerated ICH conditions (40 °C/75%
RH) with time intervals of 1, 2, and 3 months to better observe
and compare the degradation process of TMZ. The results
show that the parent TMZ powder changed from white to pink
within 1 month and further turned into dark brown after 3
months, confirming that TMZ degraded under 40 °C/75% RH
as previously reported (Figure S4 in the Supporting
Information).39,40 PXRD measurements demonstrate that
TMZ was partially degraded with undesired peaks appearing
at 2θ values of 11.6, 12.9, and 27.3° after 2 months, and some
peaks appeared at 11.2, 12.9, 15.2, 27.0, and 27.8° after 3
months (Figure S5 in the Supporting Information). The
sample of TMZ after 3 months of storage was then studied by
shows a remarkably higher content of TMZ at all sampling
points (Figure 5). The stability test concludes that TMZ-HSP
exhibits significantly improved physical and chemical stability
in comparison with parent TMZ. This could be attributed to
the modulation of crystal structure and intermolecular
interactions after cocrystallization. In the crystal structure of
pure TMZ, the CO group of the tertiary amide forms a
hydrogen bond with the NH2 group, which may promote the
hydrolysis of TMZ. In contrast, the CO group of the tertiary
amide in TMZ-HSP is free from hydrogen-bonding
interactions, which will not advance the hydrolysis of TMZ
and thereby improve its stability. A similar phenomenon has
also been observed in the cocrystal of temozolomide and
baicalein.18
Dissolution Study. The apparent solubility and dissolution
rate of solid-state drugs have an important effect on their in
vivo release and absorption and further affect their effectiveness
and safety.41−43 The powder dissolutions of TMZ, HSP, and
TMZ-HSP were investigated at pH 1.2 and pH 6.8 (Figure 6).
Pure TMZ exhibits a higher solubility with a maximum
apparent solubility (Smax) of 7600 μg/mL (at pH 1.2) and
6424 μg/mL (at pH 6.8) (Table 3). The good aqueous
solubility of TMZ may lead to its rapid absorption and short
retention time in vivo. After the formation of TMZ-HSP, the
Smax of TMZ was effectively reduced to 483.9 and 193.5 μg/
mL at pH 1.2 and pH 6.8, respectively, which is consistent with
the reported solubility decrease of TMZ from TMZ-BAI
(Figure 6a).18 Thus, it can be inferred that the formation of
TMZ-HSP may also help to slow the release and absorption of
TMZ and prolong its retention time in vivo as does TMZ-BAI.
In contrast, pure HSP is insoluble in water and its Smax is only
1.8 μg/mL (at pH 1.2) and 0.8 μg/mL (at pH 6.8) (Table 3).
The limited aqueous solubility of HSP leads to its low oral
bioavailability. For TMZ-HSP, the Smax of HSP was
significantly increased by 17.8 (at pH 1.2) and 26.3 (at pH
6.8) times, which is also similar to the enhanced solubility of
BAI for the reported TMZ-BAI, indicating that the solubility
increase of HSP herein has the potential to transform into the
improvement of its oral bioavailability (Figure 6b). The
modulation of solubility of a multicomponent crystal is relative
to the affinity of each component to the media. The cocrystal
formation between hydrophilic TMZ and hydrophobic HSP
1
a H NMR analysis. The results show that it was a mixture of
TMZ and AIC as well as a small amount of other impurities,
which are consistent with the results of HPLC analysis
(Figures S6 and S7 in the Supporting Information). In
addition, the content of TMZ decreased sharply to 65.43
0.76% and 31.64 0.64% after 2 and 3 months, respectively
(Figure 5). In comparison, the cocrystal demonstrates neither a
color change nor a crystalline phase transformation under the
same conditions until the end of the third month (Figures S4
and S5 in the Supporting Information). Moreover, it also
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The crystalline phases of the remaining solids and the pH
values of the dissolution media were also examined after
powder dissolution experiments. At pH 1.2, TMZ was
transformed into TMZ monohydrate, while the crystal forms
of HSP and TMZ-HSP remained unchanged (Figure S8 in the
Supporting Information). The pH values of the dissolution
media of all samples were changed to 1.3−1.4, which could be
attributed to the weak basicity of TMZ and HSP.44 At pH 6.8,
the PXRD pattern of TMZ after dissolution is similar to that of
TMZ after the accelerated stability test, suggesting that TMZ
was also partially degraded during dissolution (Figure S8 in the
Supporting Information). The sample of TMZ after dissolution
was further proved to be a mixture of TMZ, AIC, and a small
amount of other impurities by 1H NMR analysis (Figure S9 in
the Supporting Information). The crystal form of HSP
remained unchanged, while a small amount of diffraction
peaks of HSP·H2O appeared for the cocrystal phase (Figure S8
in the Supporting Information). The pH values of the
dissolution media for all of the samples remained unchanged.
Compaction Property. Cocrystal formation can modulate
the compaction property and therefore the manufacturability
of solid-state drugs.45,46 Tabletability refers to the ability of the
bulk powders of a drug to be transformed into a tablet with a
specific tensile strength over a certain compaction pres-
sure.47,48 In this study, the tabletabilities of TMZ, HSP, TMZ-
HSP, and a 1:1 physical mixture of TMZ and HSP (TMZ +
HSP) were determined under a compaction pressure from 100
to 400 MPa. TMZ powders cannot form intact tablets under a
compaction pressure up to 400 MPa, and tablet lamination and
capping were observed. In comparison to the poor compaction
property of TMZ powder, HSP, TMZ-HSP, and TMZ + HSP
powders exhibit much better tableting behavior. They can be
made into intact tablets over the entire compaction pressure
range without the need for any excipients. In addition, these
tablets remained intact after 24 h of relaxation without
evidence of delamination or capping. A typical tablet of each
sample compressed at 400 MPa is presented in Figure 7.
The tabletability profiles of the four powdered samples are
shown in Figure 8. The tablet tensile strength of TMZ-HSP is
much higher than that of TMZ but relatively lower than that of
pure HSP under the same compaction pressures. The tablet
Figure 6. Powder dissolution profiles of (a) TMZ and TMZ-HSP and
(b) HSP and TMZ-HSP at 37 °C.
Table 3. Smax Values of TMZ and HSP in HCl Solution (pH
1.2) and PBS Solution (pH 6.8)
Smax (μg/mL)
sample
pH 1.2
pH 6.8
TMZ
TMZ from cocrystal
HSP
7600 (1071)
483.9 (11.1)
1.8 (0.3)
6424 (277)
193.5 (23.9)
0.8 (0.1)
HSP from cocrystal
32 (3)
21 (3)
may reduce the hydrophilicity of TMZ and improve the
hydrophilicity of HSP. This thereby results in the decreased
aqueous solubility of TMZ and the increased aqueous
solubility of HSP at the same time.
In addition, the pure TMZ and HSP demonstrate great
difference in solubility at either pH 1.2 or pH 6.8, which may
lead to compatibility issues when they are given in
combination with the form of a physical mixture. In
comparison, after the formation of TMZ-HSP, the solubility
difference between TMZ and HSP was substantially reduced
(Table 3). This means that the drug−drug cocrystal is a better
alternative for the development of combination preparations of
TMZ and HSP.
Figure 7. (a) TMZ, (b) TMZ-HSP, (c) HSP, and (d) physical
mixture (TMZ + HSP) tablets under a compaction pressure of 400
MPa.
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and Fourier transform infrared and nuclear magnetic resonance
spectroscopy. The two drug molecules in the cocrystal are
connected by O−H···O hydrogen bonds between the carbonyl
oxygen of TMZ and the phenolic hydroxyl group of HSP. The
stability, dissolution, and compaction evaluations highlight that
the formation of TMZ-HSP not only improves the
physicochemical stability and tabletability of TMZ but also
optimizes the dissolution behavior and diminishes the
solubility difference between TMZ and HSP. Therefore,
TMZ-HSP has the potential to be developed as an efficient
oral formulation of a drug combination containing TMZ and
HSP.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.cgd.0c01153.
Experimental details, chemical structures of TMZ,
MTIC, and AIC, DSC and TG thermoanalytical details,
1H NMR spectroscopy, PXRD analysis with regard to
DVS, dissolution and compaction experiments, compar-
ison of color, PXRD patterns and HPLC chromatograms
for stability tests, and a comparison of the crystal
structures of TMZ, HSP, and TMZ-HSP (PDF)
Figure 8. Tabletability profile of TMZ, HSP, TMZ-HSP, and a
physical mixture (TMZ + HSP).
tensile strengths of HSP and TMZ-HSP are increased with an
increase of compaction pressure from 100 to 300 and 350
MPa, respectively. However, a further increase in compaction
pressure results in a decrease in tensile strength. This
phenomenon is known as overcompaction.49,50 The tablet
tensile strength of TMZ + HSP increases with the increase of
compaction pressure over the entire pressure range and is even
better than that of pure HSP above 350 MPa. Although the
tensile strength of TMZ-HSP is below 2 MPa, it is still
significantly improved in comparison to pure TMZ.
The tabletability of crystalline powders is relative to the
molecular arrangements and packing modes of the crystals.
The crystal structure of TMZ is packed in a reticular structure
without potential slip planes (Figure S10a in the Supporting
Information), which makes it difficult to plastically deform and
leads to poor tabletability. The crystal structure of HSP is
packed by 2D layered structures (Figure S10b in the
Supporting Information), which can form slip planes and
thereby shows much better tabletability in comparison to
TMZ. After the formation of TMZ-HSP, the original crystal
structures of TMZ and HSP were broken, and the
reconstructed crystal structure partially retained 2D layered
structures formed by HSP molecules and showed a hydrogen-
bonded network formed by TMZ and HSP at the same time
(Figure S10c in the Supporting Information). Therefore, the
cocrystal demonstrates tabletability intermediate between
those of pure TMZ and HSP.
Accession Codes
CCDC 1985464 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Authors
Xia-Lin Dai − Tianjin Key Laboratory of Drug Targeting and
Bioimaging, School of Chemistry and Chemical Engineering,
Tianjin University of Technology, Tianjin 300384, People’s
Republic of China; Email: 871098922@qq.com
Jia-Mei Chen − Tianjin Key Laboratory of Drug Targeting
and Bioimaging, School of Chemistry and Chemical
Engineering, Tianjin University of Technology, Tianjin
300384, People’s Republic of China; orcid.org/0000-
0002-3959-901X; Email: chenjiamei@email.tjut.edu.cn
Authors
Jie Wang − Institute for New Energy Materials and Low
Carbon Technologies, School of Materials Science and
Engineering, Tianjin University of Technology, Tianjin
300384, People’s Republic of China
Tong-Bu Lu − Institute for New Energy Materials and Low
Carbon Technologies, School of Materials Science and
Engineering, Tianjin University of Technology, Tianjin
300384, People’s Republic of China; orcid.org/0000-
0002-6087-4880
After experiments, the powders of HSP, TMZ-HSP, and
TMZ + HSP were collected and determined by PXRD. The
results reveal that there was no stress-induced polymorphic
transition during the compaction process (Figure S11 in the
Supporting Information).
CONCLUSION
■
In summary, a drug−drug cocrystal composed of TMZ and
HSP (TMZ-HSP) with a 1:1 stoichiometric ratio was
constructed in order to overcome the deficiencies of individual
APIs and realize drug combination at a molecular level. The
cocrystal can be prepared by liquid-assisted grinding, slurry
conversion crystallization, and evaporation crystallization and
was fully characterized by X-ray diffraction, thermal analyses,
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.cgd.0c01153
Notes
The authors declare no competing financial interest.
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Article
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ACKNOWLEDGMENTS
■
This work was financially supported by the National Nature
Science Foundation of China (No. 21571194). We thank Ms.
Cai-Wen Li of Tianjin University of Technology for assistance
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