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Transformations between co-amorphous and co-crystal systems and their influence on the formation and physical stability of co-amorphous systems Wenqi Wu, Yixuan Wang, Korbinian Loebmann, Holger Grohganz, and Thomas Rades Mol. Pharmaceutics, Just Accepted Manuscript • DOI: 10.1021/ acs.molpharmaceut.8b01229 • Publication Date (Web): 09 Jan 2019 Downloaded from http://pubs.acs.org on January 9, 2019
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Molecular Pharmaceutics
1
Transformations
between
co-amorphous
and
co-crystal
2
systems and their influence on the formation and physical
3
stability of co-amorphous systems
4
Wenqi Wu1, Yixuan Wang1,2, Korbinian Löbmann1, Holger Grohganz1, and Thomas Rades1,3*
5
1 Department
6
2
7
110016, China
8
3
9
Finland
of Pharmacy, University of Copenhagen, Copenhagen, Denmark
School of Functional Food and Wine, Shenyang Pharmaceutical University, Wenhua Rd. 103, Shenyang Pharmaceutical Sciences Laboratory, Faculty of Science and Engineering, Åbo Akademi University, Turku,
10 11
Key words: co-amorphous systems, co-crystal systems, transformation, recrystallization, physical
12
stability
13 14
Abbreviations: CBZ, carbamazepine; BA, benzoic acid; MEA, maleic acid; SUC, succinic acid;
15
TAR, tartaric acid; SAC, saccharin; NIC, nicotinamide; MIX, mixture; PM, physical mixture; BM,
16
ball milling; CC, co-crystal; XRPD, X-ray powder diffraction; DSC, differential scanning
17
calorimetry; Tg, glass transition temperature.
18 19
Abstract
20
The formation of co-amorphous and co-crystal systems are attractive formulation strategies for
21
poorly water-soluble drugs. Intermolecular interactions between the drug and the co-former(s) play
22
an important role in the formation of both systems, making the investigation of transformations
23
between the two systems specifically interesting. The aim of this study thus was to investigate the
24
transformation between the two systems and its influence on the formation and physical stability of
25
co-amorphous systems. Carbamazepine (CBZ), together with benzoic acid, maleic acid, succinic
26
acid, tartaric acid, saccharin, and nicotinamide were used as materials. First, CBZ-co-former co-
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crystals were prepared. Then the co-crystals, and CBZ-co-former physical mixtures, were ball
28
milled to investigate the possible co-amorphization process. The XRPD and DSC results showed
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that CBZ and co-formers tended to maintain (co-crystals as the starting material) or form co-crystals
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(physical mixtures as the starting material), rather than to form co-amorphous systems. Next, co-
31
amorphization from CBZ-co-former physical mixtures via quench cooling was studied. Whilst co-
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amorphous systems were obtained, the physical stability of these was very low, and the samples
33
recrystallized to either co-crystal forms, or the individual components. In conclusion, a possible
34
transformation between the two systems was confirmed, but the resulting co-amorphous systems
35
were highly unstable.
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1. Introduction
38
An estimated 90% of drug candidates under development and nearly 40% of marketed drugs are
39
poorly water-soluble.1, 2 Poor water solubility often results in low and variable bioavailability and
40
therefore suboptimal therapeutic efficacy.3,
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poorly water-soluble drugs is therefore one of the main challenges in pharmaceutical drug
42
development.
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Compared to crystalline drugs, their amorphous counterparts show a higher dissolution rate and
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apparent solubility.5, 6 However, most amorphous drugs have low physical stability and revert back
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to their respective crystalline form.7 Besides the formulation of amorphous solid dispersions with
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polymers, preparation of co-amorphous systems constitutes a useful method to stabilize amorphous
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drugs.8-10 These systems are attracting increasing attention in recent years.11,
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systems consist of the drug and one or more low molecular weight co-formers. The co-formers can
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be other drugs, such as in indomethacin-naproxen13 and simvastatin-glipizide14 co-amorphous
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systems, or other low molecular weight excipients, such as amino acids,8, 15 organic acids,16, 17 and
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aspartame.18 The use of co-formers can improve the physical stability as well as the dissolution rate
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of the co-amorphous drugs, compared to the neat amorphous drug.19-21
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The use of co-crystals is another strategy to improve the solubility of poorly water-soluble drugs.22,
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23
55
solubility, and bioavailability, compared to the respective neat crystalline drug.24-26 Similar to co-
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amorphous systems, co-crystals also contain two or more components (with one of them being the
4
Improving water solubility and dissolution rate of
12
Co-amorphous
Previous studies have demonstrated the potential of co-crystals to improve dissolution rate, water
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Molecular Pharmaceutics
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drug) present in definite stoichiometric ratios and are structurally homogenous materials. In contrast
58
to co-amorphous systems, however, co-crystals are crystalline materials.27
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A common property of co-amorphous and co-crystal systems is that in both systems intermolecular
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interactions between the drug and the co-former(s), such as hydrogen bonding, π-π stacking or van
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der Waals interactions, play a key role in the formation of practically stable co-amorphous and
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thermodynamically stable co-crystal systems,28-30 indicating the possibility of transformations
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between the two systems. However, to the knowledge of the authors, it has never been shown in the
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published literature that a co-amorphous system recrystallized into a co-crystal upon storage.
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Theoretically, as crystalline materials, co-crystals can be thermodynamically stable compared to the
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high-energy co-amorphous systems. The aim of the current study therefore was not to produce
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stable co-amorphous systems or to find new preparation techniques but to investigate the
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transformations between the two systems, i.e., whether co-crystals can be transformed into “stable”
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co-amorphous systems or if such co-amorphous systems recrystallize quickly to their respective co-
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crystal forms, and more important, to investigate the influence of the transformations on the
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formation and physical stability of co-amorphous systems. It would reduce the necessary screening
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options when developing co-amorphous systems if a clear trend can be concluded from this study.
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In this study, carbamazepine (CBZ, a BCS II drug with low water solubility31) was chosen as a
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model drug, since it has been shown to form co-crystals with a range of co-formers. Also co-
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amorphous systems have previously been produced from CBZ to improve its water solubility and
76
dissolution rate, albeit with co-formers that did not allow the formation of a co-crystal.8 Benzoic
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acid, maleic acid, succinic acid, tartaric acid, saccharin, and nicotinamide were used as co-crystal
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co-formers.24,
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Then the formation of co-amorphous systems was investigated following both, a mechanical and a
80
thermal pathway. The possible co-amorphization from co-crystals, as well as CBZ-co-former
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physical mixtures, was studied by ball milling. Quench cooling was used to investigate the
82
formation of co-amorphous systems from CBZ-co-former physical mixtures. X-ray powder
83
diffraction (XRPD) and differential scanning calorimetry (DSC) were used to identify and
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characterize co-crystal and co-amorphous systems. Subsequently, a physical stability study of co-
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amorphous systems prepared from quench cooling was performed, followed by a FTIR study for
86
investigations of molecular interaction between CBZ and the co-formers. Finally, intrinsic
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dissolution study was conducted to evaluate the dissolution profiles of pure CBZ and co-crystals.
32
In this study, CBZ-co-former co-crystals were prepared and characterized first.
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2. Materials and Methods
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2.1. Materials
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Carbamazepine (CBZ, MW = 295.29 g/mol) was purchased from Hawkins Pharmaceutical Group
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(Minnesota, USA). Benzoic acid (BA, MW = 122.12 g/mol), succinic acid (SUC, MW = 118.09
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g/mol), tartaric acid (TAR, MW = 150.09 g/mol), and saccharin (SAC, MW = 183.19 g/mol) were
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obtained from Sigma-Aldrich (St. Louis, USA). Maleic acid (MEA, MW = 116.07 g/mol) and
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nicotinamide (NIC, MW = 122.13 g/mol) were purchased from Merck KGaA (Darmstadt,
96
Germany). Chloroform, ethyl acetate and ethanol were obtained from Sigma-Aldrich Chemie
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GmbH (Steinheim, Germany). Acetonitrile and methanol were purchased from VWR International
98
Ltd (Leicestershire, UK) and Th. Geyer GmbH & Co. KG (Regensburg, Germany), respectively.
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All materials were used as received. The chemical structures of CBZ and the co-formers are shown
100
in Figure 1.
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Molecular Pharmaceutics
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Figure 1. Chemical structures of CBZ and six co-formers used in this study.
103 104
2.2. Preparation of co-crystals
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CBZ co-crystals were prepared based on previous studies: CBZ-organic acid co-crystals,32 CBZ-
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SAC co-crystal33 and CBZ-NIC co-crystal.34 The preparation methods are briefly described below.
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CBZ-BA co-crystal (molar ratio 1:1)
108
CBZ (945.8 mg) and BA (489.0 mg) was dissolved in 12 mL chloroform under stirring (IKA RH
109
digital, Werke GmbH & Co. KG, Staufen, Germany) at 300 rpm for 5 min. The solvent was then
110
allowed to evaporate. After 24 h, the powder was collected and dried in a vacuum oven (APT.
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lineTM VD, Tuttlingen, Germany) at 50 °C for 3 h.
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CBZ-MEA co-crystal (molar ratio 2:1)
113
MEA (463.7 mg) was dissolved into 40 mL acetonitrile at 50 °C, followed by the addition of 1887.6
114
mg of CBZ into the acetonitrile under stirring at 600 rpm until CBZ was completely dissolved. The
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solution was sealed and kept at room temperature for 24 h. The precipitated solid was isolated and
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dried in a vacuum oven at 50 °C for 3 h.
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CBZ-SUC co-crystal (molar ratio 2:1)
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SUC (472.2 mg) was dissolved in a mixture of ethanol (60 mL) and ethyl acetate (30 mL) and
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sonicated (Branson 5510, Marshall Scientific, Hampton, US). CBZ (1896.2 mg) was then added to
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the SUC solution under heating at 50 °C and stirring at 500 rpm. The resulting clear solution was
121
filtered through a 0.2 µm nylon filter and the solvent mixture was allowed to evaporate overnight at
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room temperature. The precipitated powder was collected and dried in a vacuum oven at 50 °C for
123
3 h.
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CBZ-TAR co-crystal (molar ratio 1:1)
125
TAR (4502.5 mg) was added to 150 mL acetonitrile and stirred for 24 h at room temperature to
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prepare a saturated TAR solution (indicated by excess TAR powder in the solution). CBZ (1417.6
127
mg) was added into a vial containing 30 mL of the saturated TAR solution and stirred at 500 rpm
128
for 6 h. The molar ratio of CBZ and TAR in the solution was 1:1. Then the vial was sealed and
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placed on a rotating wheel for 48 h and the precipitated solid was washed with cold acetonitrile and
130
dried in a vacuum oven at 50 °C for 3 h.
131
CBZ-SAC co-crystal (molar ratio 1:1)
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CBZ (1417.8 mg) and SAC (1099.0 mg) was dissolved under stirring at 500 rpm in 100 mL
133
methanol at room temperature. The solvent (under stirring) was then allowed to evaporate slowly
134
for 24 h. The final product was dried in a vacuum oven at 50 °C for 3 h.
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CBZ-NIC co-crystal (molar ratio 1:1)
136
CBZ (1181.5 mg) and NIC (610.7 mg) was dissolved in 25 mL ethanol under stirring at 300 rpm for
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30 min at 80 °C. The solvent was then allowed to evaporate at room temperature for 72 h. The
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precipitated powder was dried in a vacuum oven at 50 °C for 3 h.
139 140
2.3. Characterization of co-crystals
141
2.3.1 X-ray powder diffraction (XRPD)
142
XRPD was used to identify whether the co-crystals had been prepared successfully. The
143
measurements were performed with an X’Pert PANalytical X’Pert PRO X-ray diffractometer
144
(PANalytical, Almelo, The Netherlands) using Cu Kα radiation (λ = 1.54187 Å). The current and
145
acceleration voltage were 40 mA and 45 kV, respectively. Reflection mode was used, and the
146
samples were scanned from 5˚ to 30˚ 2θ, with a step size of 0.026˚ 2θ at a rate of 0.067˚ 2θ/s. The
147
data was collected using X'Pert Data Collector software (PANalytical, Almelo, The Netherlands).
148
2.3.2 Differential scanning calorimetry (DSC)
149
The melting points (Tms) of co-crystals and physical mixtures were determined using a Discovery
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DSC (TA Instruments, New Castle, USA). An indium standard was used for the routine calibration
151
of the instrument. Nitrogen gas flow was set to 50 mL/min. Approximately 4 mg (2 - 6 mg) of
152
powder was added into the Tzero pans. A steel stainless cylinder was used to smooth the sample to
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ensure good contact with the Tzero pans. The samples were sealed with hermetic lids with a pinhole,
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and measured using a standard DSC method: samples were heated from room temperature to 180 °C
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at a rate of 10 °C/min. The heat flow signal was collected and analyzed using TA instruments Trios
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software (version 4.3.1).
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2.4. Co-amorphization from co-crystals and CBZ-co-former physical mixtures by ball milling
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Vibrational ball milling (BM) was used to investigate a possible co-amorphization from co-crystals
160
and CBZ-co-former physical mixtures (at the same molar ratios than for the respective co-crystals).
161
Ball milling was performed in an oscillatory ball mill (Mixer Mill MM400, Retsch GmbH & Co.,
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Haan, Germany) placed in a cold room (5 °C). A mass of 500 mg of CBZ-co-former physical
163
mixtures or the co-crystals was added into a 25 mL jar with two 12 mm stainless steel balls. The
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ball milling jars were sealed with parafilm to avoid possible moisture absorption. The samples were
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ball milled at 30 Hz. After milling for 30, 60, 90, 180 min, the samples were withdrawn and
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characterized by XRPD and DSC, to identify whether the samples became co-amorphous or
167
remained crystalline. Amorphized samples were collected and stored in the desiccator over P2O5 at -
168
20 °C for further studies.
169 170
2.5. Preparation of co-amorphous samples by quench cooling
171
Quench cooling was used to prepare co-amorphous samples from the various physical mixtures.
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The physical mixtures of CBZ and co-formers were prepared by manual mixing: a total mass of 2 g
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of CBZ and co-former was weighed into a mortar. The molar ratios of CBZ to co-former were the
174
same as for the respective co-crystals: CBZ-BA 1:1, CBZ-MEA 2:1, CBZ-SUC 2:1, CBZ-TAR 1:1,
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CBZ-SAC 1:1 and CBZ-NIC 1:1. After mixing with a spatula, the powders were gently ground with
176
a pestle for 60 s. Then the powders were placed on aluminum foil and heated until complete melting.
177
For the cooling process, several cooling conditions were used: after maintaining the samples at the
178
molten state for 2 min, the samples were allowed to cool at room temperature, at 4 °C and at -20 °C.
179
CBZ-SUC and CBZ-NIC immediately recrystallized when cooled at room temperature and 4 °C,
180
and these samples could only be converted to an amorphous form at high cooling rates. Thus, a -
181
20 °C freezer was used for the quench cooling of all investigated samples (samples were stored in
182
the freezer for 10 min). The quench cooled samples were then collected and brought back to room
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temperature for further study.
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2.6. Characterization of co-amorphous samples
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2.6.1. XRPD
187
The quench cooled samples were immediately characterized by XRPD measurements to determine
188
whether an amorphous form was obtained. The measurement method was the same as described in
189
section 2.3.1. A halo in the diffractogram indicted amorphization.
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2.6.2. DSC
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The thermal properties of the co-amorphous samples were investigated by DSC. The same
192
instrument and settings were used as described in section 2.3.2. Approximately 4 mg of CBZ-co-
193
former physical mixtures were filled into Tzero pans and smoothed by using a steel stainless
194
cylinder, and sealed with a hermetic lid with a pinhole. The samples were heated up to
195
predetermined temperatures (2 to 3 °C higher than the respective melting points of CBZ or the pure
196
co-formers) and maintained isothermally for 3 min, followed by quench cooling at a rate of
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50 °C/min to -50 °C. The samples were held for 3 min at this temperature before reheating up to
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80 °C at a rate of 10 °C/min. The midpoint of the glass transition was recorded as the glass transition
199
temperature (Tg). Each sample was measured in independent triplicates, and the Tg is reported as
200
mean ± standard deviation. TA instruments Trios software (version 4.3.1) was used to collect and
201
analyze the data.
202 203
2.7. Physical stability of co-amorphous systems
204
Amorphous CBZ and CBZ-co-former co-amorphous samples were stored in desiccators over P2O5
205
at 40 °C. At predetermined time points (3 h, 6 h, 1 d, 7 d, 1 month and 2 months), samples were
206
analyzed by XRPD to detect if the amorphous form was maintained and to investigate the
207
occurrence of a transformation from co-amorphous to co-crystal systems.
208 209
2.8. Attenuated total reflectance Fourier-transform infrared spectroscopy (ATR-FTIR)
210
FTIR was used to investigate possible molecular interactions between CBZ and the co-formers. The
211
measurements were performed using an MB300 FTIR spectrometer (ABB Ltd, Zurich, Switzerland)
212
combined with an attenuated total reflectance accessory (MIRacle™ Single Reflection ATR, PIKE
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Technologies, Fitchburg, US). Samples were scanned from 4000-500 cm-1 (64 scans) at a resolution
214
of 4 cm-1. The spectra were collected with Horizon MB 300 software. Origin 2016 (OriginLab
215
Corporation, Northampton, MA, USA) was used to analyze the data.
216 217
2.9. Intrinsic dissolution study
218
2.9.1 Dissolution tests
219
An intrinsic dissolution study was performed to investigate the intrinsic dissolution rate (IDR) of
220
crystalline CBZ and co-crystal systems. Co-amorphous systems were excluded due to their fast
221
recrystallization and therefore low practical pharmaceutical relevance. A mass of 150 mg of
222
powders was compressed into stainless steel cylinders with a diameter of 1 cm under a pressure of
223
127.3 MPa and a dwell time of 40 s. The intrinsic dissolution study was conducted using an
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ERWEKA DT70 dissolution tester (Heusenstamm, Germany) equipped with a custom-made
225
downscaled dissolution set-up described earlier.35 The miniaturized set-up shows essentially similar
226
hydrodynamics to the standard USP apparatus 2. A volume of 250 mL of pH 6.8 phosphate buffer
227
(0.1 M) at 37.0 ± 0.5 °C was used as the dissolution medium, and the rotation speed was set to 50
228
rpm. At predetermined time points (3, 5, 10, 20 and 30 min), 1 mL sample was withdrawn and
229
replaced with pre-warmed fresh medium. After dilution with methanol at a 1:1 volume ratio,
230
samples were analyzed by HPLC to quantify the concentration of dissolved CBZ. The HPLC
231
method is described below (section 2.9.2). The IDR test for each sample system was performed in
232
triplicate. The IDR was calculated according to the accessible surface area of CBZ in the tablet; the
233
detailed calculation method was described in an earlier study.8
234
2.9.2. HPLC method
235
A Dionex HPLC system (Germering, Germany) equipped with an UltiMate 3000 auto-sampler, an
236
UltiMate 3000 pump, an UltiMate 3000 diode array detector and a C18 column (Phenomenex,
237
100×4.6 mm) was used. The wavelength for detection was set to 285 nm. The mobile phase
238
consisted of 50% water, 40% methanol and 10% acetonitrile (v/v). The flow rate and injection
239
volume were set to 1 mL/min and 20 μL/min, respectively. The injection volume was 20 μL and the
240
retention time was approximately 3.8 min.
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241 242
3. Results and discussion
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3.1. Co-crystal samples preparation and characterization
244
XRPD was used to confirm the successful preparation of the co-crystals. The diffractograms of the
245
CBZ-co-former physical mixtures and the co-crystal samples are shown in Figure 2(a) and Figure
246
2(b), respectively.
247
248 249
Figure 2. XRPD diffractograms of (a) pure CBZ and CBZ-co-former physical mixture samples and
250
(b) co-crystal samples.
251 252
As shown in Figure 2, the XRPD diffractograms of the co-crystal samples were different from those
253
of the respective CBZ-co-formers physical mixtures, indicating the formation of a new crystal
254
structure. As the preparation methods for the co-crystals were based on the literature (CBZ-organic
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acid co-crystals,32 CBZ-SAC co-crystal33 and CBZ-NIC co-crystal34), the success of co-crystals
256
preparation was confirmed by comparison with the published XRPD diffractograms of these co-
257
crystals.
258
As discussed above, co-crystals are homogenous crystalline materials composed of two or more
259
different molecules in the same crystal lattice, which means they only show one single melting
260
point upon heating,23 whereas two melting events can be observed in the respective physical
261
mixtures. The experimental and reported Tms of the co-crystal samples are summarized in Table 1.
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One homogenous crystal lattice was formed in the co-crystal samples, indicated by one single
263
melting peak, while two or more melting peaks can be seen in the DSC thermograms of the physical
264
mixture samples (Supporting information Figure S1). The Tm results confirmed that the desired co-
265
crystals were prepared successfully and could thus be used for further studies below.
266
Table 1. Experimental and reported Tms of co-crystal samples.
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Sample content
Experimental Tm of co-crystal
Reported Tm of co-crystal
± standard deviation (°C) CBZ-BA
113.1 ± 0.6
112.5 32
CBZ-MEA
161.3 ± 0.7
157.6 32
CBZ-SUC
190.3 ± 0.4
188.6 32
CBZ-TAR
162.7 ± 0.1
159.7 32
CBZ-SAC
174.7 ± 1.0
175-177 33
CBZ-NIC
160.1 ± 0.1
160.1 34
268 269
3.2. Co-amorphization from co-crystal systems and CBZ-co-former physical mixtures by ball
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milling
271 272
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Figure 3. XRPD diffractograms of the starting and ball milled co-crystals and CBZ-co-former
276
physical mixtures after different milling times. (a) (b) CBZ-BA systems, (c) (d) CBZ-MEA systems,
277
(e) (f) CBZ-TAR systems, (g) (h) CBZ-SAC systems. BM: ball milling.
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Table 2. Tgs of ball milled CBZ-co-former samples.
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Sample content
Tg ± standard deviation (°C)
CBZ-MEA MIX (milling 30 min)
30.4 ± 0.8
CBZ-TAR CC (milling 30 min)
41.3 ± 0.7
CBZ-TAR MIX (milling 60 min)
40.1 ± 0.2
CBZ-SAC MIX (milling 30 min)
31.0 ± 2.5
280 281
Figure 3 shows the XRPD diffractograms of the co-crystals and physical mixtures after different
282
ball milling times with BA, MEA, TAR and SAC as co-formers (SUC and NIC as co-formers and
283
pure CBZ are shown in the supporting information Figure S2). The XRPD diffractograms of freshly
284
prepared co-crystal samples are also shown for comparison. The majority of samples were and
285
remained crystalline forms and only few of them became amorphous. The amorphized samples
286
were further investigated by DSC to identify whether they became single-phase co-amorphous
287
systems. The Tg results are shown in Table 2 (the corresponding thermograms are shown in the
288
supporting information Figure S3). Some observations can be made from the results. Firstly, of all
289
co-crystal systems, only CBZ-TAR formed a co-amorphous system successfully, while the other
290
CBZ co-crystal systems maintained their crystalline forms during the whole milling process.
291
Secondly, of all physical mixtures, only CBZ-MEA, CBZ-TAR, and CBZ-SAC formed amorphous
292
systems during milling, but the co-amorphous forms were maintained only for short times since
293
recrystallization was observed after longer milling times. It should be noted that the co-amorphized
294
CBZ-co-former physical mixture samples recrystallized to their respective co-crystal forms. The
295
XRPD diffractograms of CBZ-BA, CBZ-SUC and CBZ-NIC physical mixture samples after milling
296
for 30 min were similar to the respective co-crystal forms and maintained the co-crystal forms upon
297
continued milling.
298
Finally, if the CBZ-co-former physical mixture could not be converted to an amorphous form, the
299
corresponding CBZ-co-former co-crystals also could not be converted to an amorphous form. These
300
observations indicate that physical mixtures may be better starting materials than co-crystals to
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prepare co-amorphous samples, since CBZ-co-former physical mixtures showed a higher tendency
302
to obtain co-amorphous systems, at least in the cases of MEA and SAC as co-formers.
303
Pure crystalline CBZ remained crystalline upon milling, even when milling was performed for 180
304
min. Previous studies have shown that it is a challenge to prepare amorphous CBZ (as also shown
305
in this study),36 as well as stable co-amorphous forms of CBZ.37 From this study, it can be
306
concluded that CBZ and co-formers showed a trend to form or maintain co-crystal forms during
307
milling with the only exception of CBZ-TAR. The CBZ-TAR co-crystal formed and maintained a
308
co-amorphous form during the milling process, and the CBZ-TAR physical mixture formed co-
309
amorphous sample after milling for 60 min and maintained the co-amorphous form until 90 min of
310
milling, but then recrystallized to the co-crystal form after 180 min of milling. CBZ-MEA and
311
CBZ-SAC physical mixtures formed co-amorphous systems initially followed by recrystallization
312
to their respective co-crystal forms.
313
In general, co-crystals tended to maintain co-crystal forms upon milling, with the exception of
314
CBZ-TAR. This might due to the relatively higher Tg (41.3 °C) compared to other co-amorphous
315
systems (Table 2). Similarly, CBZ-co-former physical mixtures showed a clear trend to form co-
316
crystals, rather co-amorphous systems upon ball milling. Though some co-amorphous systems
317
(CBZ-MEA, CBZ-TAR and CBZ-SAC) were obtained initially during the milling process, they
318
recrystallized to respective co-crystals after longer milling time. It is assumed that the
319
intermolecular interactions between CBZ and co-formers were strong and thus lead to co-crystal
320
maintenance or formation, which remains to be further studied.
321 322
3.3. Characterization of co-amorphous samples prepared via quench cooling
323 324
Figure 4. XRPD diffractograms of quench cooled CBZ-co-former samples.
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325 326
Table 3. Tgs of quench cooled CBZ-co-former samples and pure CBZ. Sample content
Tg ± standard deviation (°C)
CBZ-BA
12.4 ± 0.4
CBZ-MEA
30.6 ± 0.1
CBZ-SUC
13.4 ± 1.3
CBZ-TAR
44.8 ± 0.5
CBZ-SAC
28.6 ± 0.7
CBZ-NIC
22.6 ± 0.2
CBZ
51.1 ± 0.5
327 328
All physical mixture samples became optically transparent after quench cooling. As shown in
329
Figure 4, all samples, including pure CBZ, can be made amorphous by quench cooling. The Tg
330
information of the quench cooled CBZ-co-former and pure CBZ are summarized in Table 3, and the
331
corresponding thermograms are shown in the supporting information Figure S4. Co-amorphous
332
samples for the DSC measurements were prepared by quench cooling in the DSC instrument to
333
determine accurate dry Tgs because possible moisture absorption was avoided. The presence of only
334
one single Tg indicates that the amorphized CBZ-co-former samples formed single-phase
335
homogeneous co-amorphous phases. It should be noted that the Tgs of the co-amorphous systems
336
were lower than that of pure amorphous CBZ, which is likely to be due to the low Tgs of the co-
337
formers (for example, the Tg of BA is -29.5 °C16). This study proved that CBZ and co-formers could
338
be converted to co-amorphous form via the quench cooling, which confirmed that the preparation of
339
co-amorphous CBZ-co-former was possible even though there are thermodynamically more stable
340
co-crystal forms.
341 342
3.4. Physical stability of co-amorphous systems prepared via quench cooling
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The difficulties in the preparation of the co-amorphous samples by ball milling (section 2.5)
344
indicated that the co-amorphous systems, once prepared, are likely to have low physical stability.
345
The transformation from co-amorphous systems to co-crystal systems were hence investigated in a
346
physical stability study. For this purpose, the co-amorphous systems prepared by quench cooling
347
were evaluated. The results are shown in Figure 5 (results for pure amorphous CBZ are shown in
348
the supporting information Figure S5).
349
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350
Figure 5. XRPD diffractograms of co-amorphous CBZ-co-former samples (a) CBZ-BA, (b) CBZ-
351
MEA, (c) CBZ-SUC, (d) CBZ-TAR, (e) CBZ-SAC and (f) CBZ-NIC, after storage at 40 °C under
352
dry condition.
353 354
A low physical stability of all CBZ co-amorphous systems, as well as pure amorphous CBZ, was
355
observed. All co-amorphous systems recrystallized within 1 d whilst the pure amorphous CBZ
356
recrystallized within 3 h. It is worthy to point out that CBZ-BA, CBZ-MEA and CBZ-NIC
357
recrystallized to their respective co-crystal form. The other co-amorphous systems recrystallized to
358
pure CBZ (form I) and its respective co-formers. There is a clear trend that co-formers with a low
359
Tm were more likely to recrystallize with CBZ together and form co-crystals. The Tms of BA
360
(122 °C), MEA (137 °C) and NIC (128.1 °C) are much lower than those of SUC (187 °C), SAC
361
(224 °C) and TAR (169 °C).32-34 Correspondingly, the transformations from co-amorphous CBZ-
362
BA, CBZ-MEA and CBZ-NIC to their respective co-crystals were observed during the storage.
363
Intermolecular interactions between the drug and the co-former(s) play an important role in the
364
formation of stable co-amorphous systems, but low physical stability of co-amorphous systems can
365
be expected if the same interactions are also the basis of a co-crystal system, as there is a crystal
366
structure the co-amorphous systems can crystallize to. The low physical stability of CBZ-co-former
367
co-amorphous systems most likely resulted from the fact that CBZ and the co-formers can form co-
368
crystals, at least for the cases of CBZ-BA, CBZ-MEA and CBZ-NIC. However, the low Tgs of these
369
amorphous systems may only play a minor role in the low physical stability of CBZ-co-former co-
370
amorphous systems, since the Tg of pure amorphous CBZ was the highest among all samples, but
371
pure amorphous CBZ showed lower stability than the CBZ-MEA, CBZ-TAR and CBZ-SAC co-
372
amorphous systems. A similar phenomenon has also been shown in previous studies: a low Tg does
373
not necessarily lead to low physical stability.18, 38
374
It is worthy to mention that Pan et al. reported that azelnidipine-oxalic acid could form co-crystal at
375
a specific molar ratio by specific solvent-assisted grinding, while in most cases azelnidipine-oxalic
376
acid co-amorphous systems were obtained.39 This finding indicates that the molar ratios of the drug
377
and the co-former might also play an important role in the formation of co-crystals and co-
378
amorphous systems. Thus, it is worthy to investigate the effect of the molar ratio of CBZ and the
379
co-former on the formation and physical stability of co-amorphous systems in the future.
380
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3.5. Molecular interactions between CBZ and co-formers in co-amorphous and co-crystal systems
382
To confirm whether there were molecular interactions between CBZ and the co-formers in co-
383
amorphous and co-crystals systems, an FTIR study was conducted and the results are shown in
384
Figure 6 (including CBZ-BA, CBZ-MEA, CBZ-TAR and CBZ-SAC systems). The spectra of CBZ-
385
SUC and CBZ-NIC systems can be found in the Supporting information, Figure S6.
386 387
Figure 6. FTIR spectra of (a) CBZ-BA systems, (b) CBZ-MEA systems, (c) CBZ-TAR systems and
388
(d) CBZ-SAC systems. The peak shifts are indicated by arrows.
389
As shown in Figure 6(a), significant changes can be seen from 1200 cm-1 to 1800 cm-1 between the
390
different CBZ-BA systems. The peak at 1384 cm-1 for the CBZ-BA physical mixture, which is
391
believed to be representing the –NH2 rocking from CBZ, involved in dimer hydrogen bonding
392
between two carboxamide groups,40 disappeared for both, the co-amorphous and co-crystal sample,
393
indicating that the –NH2 of CBZ might in fact interact with the –C=O group of BA in the co-
394
amorphous and co-crystal samples. In addition, the intensity of the shoulder peak at 1640 cm-1 for
395
CBZ-BA physical mixture is increased in both, co-amorphous and co-crystal samples. As reported
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396
earlier, the peak at 1640 cm-1 can be attributed to the -C=O stretching vibration (amide I band).41
397
The increased intensity of this peak in both, co-amorphous and co-crystal samples, indicates
398
hydrogen bonding between CBZ and BA.
399
For CBZ-MEA systems (Figure 6(b)), the main spectral differences were observed for the peak at
400
3645 cm-1, which is corresponding to the stretching vibration mode of the N-H group, involved in
401
hydrogen bonding of the CBZ molecular dimer.40 The intensity of this peak for co-amorphous and
402
co-crystal samples was significantly decreased compared to the physical mixture. Moreover, it
403
should be noted that the peak at 1382 cm-1 (–NH2 rocking) found in the physical mixture shifted to
404
1397 cm-1 for the co-amorphous system and 1413 cm-1 for the co-crystal system, respectively.
405
These two changes indicate a disruption of CBZ dimers and the formation of hydrogen bonding of
406
CBZ with MEA for both co-amorphous and co-crystal systems. A similar phenomenon can also be
407
seen in CBZ-TAR systems (as shown in Figure 6(c)): a significant intensity decrease of the peak
408
around 3645 cm-1 can be observed for the co-amorphous and co-crystal sample when compared to
409
the physical mixture sample, again indicating the formation of hydrogen bonding between CBZ and
410
TAR for the co-amorphous and co-crystal samples.
411
The CBZ-SAC co-amorphous systems, as the systems described above, again showed a similar
412
spectrum to the CBZ-SAC co-crystal, and both spectra were different from that of the physical
413
mixture. Briefly, the peak at 1384 cm-1 for the physical mixture shifted to 1422 cm-1 (in the co-
414
amorphous sample and 1423 cm-1 (in the co-crystal sample), similar to the shifts observed for the
415
CBZ-MEA systems. Shifts of 1601 cm-1 (corresponding to the –C=O vibration of CBZ) to 1644 cm-
416
1
417
amorphous and co-crystal samples were also confirmed.42,
418
hydrogen bonding between CBZ and SAC.6
419
The spectra of the CBZ-SUC and CBZ-NIC systems can be found in the Supporting information
420
(Figure S6). For CBZ-SUC co-crystal, hydrogen bonding was indicated by the vibrations at 1430,
421
1534, 3471 cm-1 in the co-amorphous and co-crystal samples, which were shifted from 1385, 1594
422
and 3465 cm-1 found in the CBZ-SUC physical mixture, respectively. These results are similar to a
423
previous study on CBZ-SUC co-crystal.44 The results for the CBZ-NIC co-crystal were also similar
424
to an earlier study: hydrogen bonding between CBZ and NIC can be confirmed by the fact that the
425
peaks at 1655 and 3386 cm-1 were shifted to 1675 and 3345 cm-1, respectively.45 It should be noted
and of 3466 cm-1 (corresponding to the −NH stretching vibration of CBZ) to 3496 cm-1 in the co-
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43
All of these changes indicated
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426
that no molecular interactions in CBZ-SUC and CBZ-NIC co-amorphous systems could be
427
detected, indicated by their similar spectra to that of the corresponding physical mixtures.
428
In summary, hydrogen bonding between CBZ and co-formers was confirmed in all co-amorphous
429
and co-crystal samples, with the exceptions of CBZ-SUC and CBZ-NIC co-amorphous samples.
430
Considering that all the obtained co-amorphous systems were not stable, it can be concluded that
431
molecular interactions (hydrogen bonding) between CBZ and the co-former did not play a key role
432
in the physical stability of co-amorphous systems investigated in this study.
433 434
3.6. Intrinsic dissolution study
435
An intrinsic dissolution study was performed to evaluate the dissolution performance of pure CBZ
436
and CBZ-co-former co-crystals. The results are summarized and shown in Table 4.
437
Table 4. IDR of crystalline CBZ and CBZ-co-former co-crystals and comparison of the IDR of the
438
different systems with that of pure crystalline CBZ. Sample content
Linear equation for the IDR
R2
IDR enhancement compared to pure CBZ (%)
Crystalline CBZ
y = 13.572x + 25.522
0.9995
N/A
CBZ-BA CC
y = 16.897x + 56.288
0.9976
24.5
CBZ-MEA CC
y = 12.047x + 24.226
0.9967
-11.2
CBZ-SUC CC
y = 9.5762x + 16.963
0.9988
-29.4
CBZ-TAR CC
y = 14.251x + 43.111
0.9949
5.0
CBZ-SAC CC
y = 20.603x + 62.381
0.9992
51.8
CBZ-NIC CC
y = 17.879x + 49.582
0.9989
31.7
439
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440
As can be seen in Table 4, CBZ-BA, CBZ-SAC and CBZ-NIC co-crystals showed significant
441
dissolution rate enhancement (from 24.5 % to 51.8 %) compared to pure CBZ, while the IDR of the
442
CBZ-TAR co-crystal was similar to that of pure CBZ. However, decreased IDRs were observed for
443
the other two co-crystal systems, CBZ-MEA and CBZ-SUC, which can possibly be attributed to
444
these two samples becoming sticky when exposed to the dissolution medium. In conclusion, co-
445
crystals can in principle be used as a strategy to improve the dissolution rate of CBZ, but suitable
446
co-formers are necessary to obtain satisfying degrees of dissolution rate improvement.
447 448
4. Conclusion
449
In this study, CBZ was used as a model drug, together with six co-formers, and various co-crystal
450
and co-amorphous systems were prepared. The transformations between co-amorphous and co-
451
crystal systems were confirmed. Considering whether the existence of a co-crystal would be
452
beneficial for the formation of a co-amorphous system, it could be shown that for a given co-former,
453
the presence of a CBZ-co-former co-crystal is a negative indicator for a stable co-amorphous
454
sample preparation. This was confirmed by the fact that the physical mixtures of CBZ and co-
455
formers tend to form co-crystals, or form co-amorphous systems initially and then recrystallize after
456
a short time. It will thus be challenging to prepare stable co-amorphous systems if co-crystals
457
between a drug and a co-former exist. In other words, a co-former can be excluded for a given drug
458
as soon as a co-crystal pair is reported, which actually reduces the necessary screening options quite
459
a lot in the development of co-amorphous systems.
460 461
Acknowledgment
462
Wenqi Wu acknowledges the China Scholarship Council (201508510083) for financial support.
463 464
Supporting information
465
Figure S1: thermograms of (a) physical mixture samples and (b) co-crystals;
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466
Figure S2: XRPD diffractograms of the starting and ball milled co-crystals, CBZ-co-former
467
physical mixtures, and crystalline CBZ after different milling times. (a) (b) CBZ-SUC systems, (c)
468
(d) CBZ-NIC systems, and (e) pure CBZ;
469
Figure S3: DSC thermograms of ball milled CBZ-co-former samples;
470 471
Figure S4: thermograms of quench cooled CBZ-co-former samples;
472 473
Figure S5: XRPD diffractograms of amorphous CBZ after storage at 40 °C under dry condition.
474
Figure S6: FTIR spectra of (a) CBZ-SUC systems and (b) CBZ-NIC systems.
475 476
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30. Pindelska, E.; Sokal, A.; Kolodziejski, W. Pharmaceutical cocrystals, salts and polymorphs: Advanced characterization techniques. Advanced Drug Delivery Reviews 2017, 117, 111-146. 31. Kasim, N. A.; Whitehouse, M.; Ramachandran, C.; Bermejo, M.; Lennernäs, H.; Hussain, A. S.; Junginger, H. E.; Stavchansky, S. A.; Midha, K. K.; Shah, V. P. Molecular properties of WHO essential drugs and provisional biopharmaceutical classification. Molecular Pharmaceutics 2004, 1, (1), 85-96. 32. Childs, S. L.; Rodríguez-Hornedo, N.; Reddy, L. S.; Jayasankar, A.; Maheshwari, C.; McCausland, L.; Shipplett, R.; Stahly, B. C. Screening strategies based on solubility and solution composition generate pharmaceutically acceptable cocrystals of carbamazepine. CrystEngComm 2008, 10, (7), 856-864. 33. Wang, I.-C.; Lee, M.-J.; Sim, S.-J.; Kim, W.-S.; Chun, N.-H.; Choi, G. J. Anti-solvent co-crystallization of carbamazepine and saccharin. International Journal of Pharmaceutics 2013, 450, (1-2), 311-322. 34. Shayanfar, A.; Velaga, S.; Jouyban, A. Solubility of carbamazepine, nicotinamide and carbamazepine– nicotinamide cocrystal in ethanol–water mixtures. Fluid Phase Equilibria 2014, 363, 97-105. 35. Klein, S.; Shah, V. P. A standardized mini paddle apparatus as an alternative to the standard paddle. AAPS Pharmscitech 2008, 9, (4), 1179-1184. 36. Patterson, J. E.; James, M. B.; Forster, A. H.; Lancaster, R. W.; Butler, J. M.; Rades, T. The influence of thermal and mechanical preparative techniques on the amorphous state of four poorly soluble compounds. Journal of Pharmaceutical Sciences 2005, 94, (9), 1998-2012. 37. Kasten, G.; Grohganz, H.; Rades, T.; Löbmann, K. Development of a screening method for coamorphous formulations of drugs and amino acids. European Journal of Pharmaceutical Sciences 2016, 95, 28-35. 38. Mahlin, D.; Bergström, C. A. Early drug development predictions of glass-forming ability and physical stability of drugs. European Journal of Pharmaceutical Sciences 2013, 49, (2), 323-332. 39. Pan, Y.; Pang, W.; Lv, J.; Wang, J.; Yang, C.; Guo, W. Solid state characterization of azelnidipine–oxalic acid co-crystal and co-amorphous complexes: The effect of different azelnidipine polymorphs. Journal of Pharmaceutical and Biomedical Analysis 2017, 138, 302-315. 40. Czernicki, W.; Baranska, M. Carbamazepine polymorphs: Theoretical and experimental vibrational spectroscopy studies. Vibrational Spectroscopy 2013, 65, 12-23. 41. Zhou, X.; Zhang, P.; Jiang, X.; Rao, G. Influence of maleic anhydride grafted polypropylene on the miscibility of polypropylene/polyamide-6 blends using ATR-FTIR mapping. Vibrational Spectroscopy 2009, 49, (1), 17-21. 42. Rahman, Z.; Samy, R.; Sayeed, V. A.; Khan, M. A. Physicochemical and mechanical properties of carbamazepine cocrystals with saccharin. Pharmaceutical Development and Technology 2012, 17, (4), 457465. 43. Jayasankar, A.; Somwangthanaroj, A.; Shao, Z. J.; Rodríguez-Hornedo, N. Cocrystal formation during cogrinding and storage is mediated by amorphous phase. Pharmaceutical Research 2006, 23, (10), 23812392. 44. Fuliaş, A.; Vlase, G.; Vlase, T.; Şuta, L.-M.; Şoica, C.; Ledeţi, I. Screening and characterization of cocrystal formation between carbamazepine and succinic acid. Journal of Thermal Analysis and Calorimetry 2015, 121, (3), 1081-1086. 45. Rahman, Z.; Agarabi, C.; Zidan, A. S.; Khan, S. R.; Khan, M. A. Physico-mechanical and stability evaluation of carbamazepine cocrystal with nicotinamide. AAPS Pharmscitech 2011, 12, (2), 693-704.
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