Transformations between co-amorphous and co-crystal systems and

Subscriber access provided by UNIV OF NEW ENGLAND ARMIDALE

Article

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

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 26 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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-

27

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

ACS Paragon Plus Environment

Molecular Pharmaceutics 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 2 of 26

29

that CBZ and co-formers tended to maintain (co-crystals as the starting material) or form co-crystals

30

(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-

32

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.

36 37

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,

41

poorly water-soluble drugs is therefore one of the main challenges in pharmaceutical drug

42

development.

43

Compared to crystalline drugs, their amorphous counterparts show a higher dissolution rate and

44

apparent solubility.5, 6 However, most amorphous drugs have low physical stability and revert back

45

to their respective crystalline form.7 Besides the formulation of amorphous solid dispersions with

46

polymers, preparation of co-amorphous systems constitutes a useful method to stabilize amorphous

47

drugs.8-10 These systems are attracting increasing attention in recent years.11,

48

systems consist of the drug and one or more low molecular weight co-formers. The co-formers can

49

be other drugs, such as in indomethacin-naproxen13 and simvastatin-glipizide14 co-amorphous

50

systems, or other low molecular weight excipients, such as amino acids,8, 15 organic acids,16, 17 and

51

aspartame.18 The use of co-formers can improve the physical stability as well as the dissolution rate

52

of the co-amorphous drugs, compared to the neat amorphous drug.19-21

53

The use of co-crystals is another strategy to improve the solubility of poorly water-soluble drugs.22,

54

23

55

solubility, and bioavailability, compared to the respective neat crystalline drug.24-26 Similar to co-

56

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


Page 3 of 26 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


57

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

59

A common property of co-amorphous and co-crystal systems is that in both systems intermolecular

60

interactions between the drug and the co-former(s), such as hydrogen bonding, π-π stacking or van

61

der Waals interactions, play a key role in the formation of practically stable co-amorphous and

62

thermodynamically stable co-crystal systems,28-30 indicating the possibility of transformations

63

between the two systems. However, to the knowledge of the authors, it has never been shown in the

64

published literature that a co-amorphous system recrystallized into a co-crystal upon storage.

65

Theoretically, as crystalline materials, co-crystals can be thermodynamically stable compared to the

66

high-energy co-amorphous systems. The aim of the current study therefore was not to produce

67

stable co-amorphous systems or to find new preparation techniques but to investigate the

68

transformations between the two systems, i.e., whether co-crystals can be transformed into “stable”

69

co-amorphous systems or if such co-amorphous systems recrystallize quickly to their respective co-

70

crystal forms, and more important, to investigate the influence of the transformations on the

71

formation and physical stability of co-amorphous systems. It would reduce the necessary screening

72

options when developing co-amorphous systems if a clear trend can be concluded from this study.

73

In this study, carbamazepine (CBZ, a BCS II drug with low water solubility31) was chosen as a

74

model drug, since it has been shown to form co-crystals with a range of co-formers. Also co-

75

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

77

acid, maleic acid, succinic acid, tartaric acid, saccharin, and nicotinamide were used as co-crystal

78

co-formers.24,

79

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

81

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

84

characterize co-crystal and co-amorphous systems. Subsequently, a physical stability study of co-

85

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

87

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.



Page 4 of 26

88 89

2. Materials and Methods

90

2.1. Materials

91

Carbamazepine (CBZ, MW = 295.29 g/mol) was purchased from Hawkins Pharmaceutical Group

92

(Minnesota, USA). Benzoic acid (BA, MW = 122.12 g/mol), succinic acid (SUC, MW = 118.09

93

g/mol), tartaric acid (TAR, MW = 150.09 g/mol), and saccharin (SAC, MW = 183.19 g/mol) were

94

obtained from Sigma-Aldrich (St. Louis, USA). Maleic acid (MEA, MW = 116.07 g/mol) and

95

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

97

GmbH (Steinheim, Germany). Acetonitrile and methanol were purchased from VWR International

98

Ltd (Leicestershire, UK) and Th. Geyer GmbH & Co. KG (Regensburg, Germany), respectively.

99

All materials were used as received. The chemical structures of CBZ and the co-formers are shown

100

in Figure 1.


Page 5 of 26 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


101 102

Figure 1. Chemical structures of CBZ and six co-formers used in this study.

103 104

2.2. Preparation of co-crystals



Page 6 of 26

105

CBZ co-crystals were prepared based on previous studies: CBZ-organic acid co-crystals,32 CBZ-

106

SAC co-crystal33 and CBZ-NIC co-crystal.34 The preparation methods are briefly described below.

107

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.

111

lineTM VD, Tuttlingen, Germany) at 50 °C for 3 h.

112

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

115

solution was sealed and kept at room temperature for 24 h. The precipitated solid was isolated and

116

dried in a vacuum oven at 50 °C for 3 h.

117

CBZ-SUC co-crystal (molar ratio 2:1)

118

SUC (472.2 mg) was dissolved in a mixture of ethanol (60 mL) and ethyl acetate (30 mL) and

119

sonicated (Branson 5510, Marshall Scientific, Hampton, US). CBZ (1896.2 mg) was then added to

120

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

122

room temperature. The precipitated powder was collected and dried in a vacuum oven at 50 °C for

123

3 h.

124

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

126

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

129

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)


Page 7 of 26 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


132

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.

135

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

137

30 min at 80 °C. The solvent was then allowed to evaporate at room temperature for 72 h. The

138

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

150

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

153

ensure good contact with the Tzero pans. The samples were sealed with hermetic lids with a pinhole,

154

and measured using a standard DSC method: samples were heated from room temperature to 180 °C

155

at a rate of 10 °C/min. The heat flow signal was collected and analyzed using TA instruments Trios

156

software (version 4.3.1).

157



Page 8 of 26

158

2.4. Co-amorphization from co-crystals and CBZ-co-former physical mixtures by ball milling

159

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.,

162

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

164

ball milling jars were sealed with parafilm to avoid possible moisture absorption. The samples were

165

ball milled at 30 Hz. After milling for 30, 60, 90, 180 min, the samples were withdrawn and

166

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.

172

The physical mixtures of CBZ and co-formers were prepared by manual mixing: a total mass of 2 g

173

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,

175

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

183

temperature for further study.

184 185

2.6. Characterization of co-amorphous samples


Page 9 of 26 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


186

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.

190

2.6.2. DSC

191

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

197

50 °C/min to -50 °C. The samples were held for 3 min at this temperature before reheating up to

198

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



Page 10 of 26

213

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

224

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.


Page 11 of 26 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


241 242

3. Results and discussion

243

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



Page 12 of 26

255

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.

262

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.

267

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

270

milling

271 272


Page 13 of 26


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 273 60



Page 14 of 26

274 275

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.

278

Table 2. Tgs of ball milled CBZ-co-former samples.

279

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


Page 15 of 26 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


301

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.



Page 16 of 26

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


Page 17 of 26 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


343

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



Page 18 of 26

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


Page 19 of 26 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


381

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



Page 20 of 26

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-


43

All of these changes indicated

Page 21 of 26 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


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



Page 22 of 26

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;


Page 23 of 26 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


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

References

477 478 479 480 481 482 483 484 485 486 487 488 489 490 491 492 493 494 495 496 497 498 499 500 501 502 503 504 505

1. Loftsson, T.; Brewster, M. E. Pharmaceutical applications of cyclodextrins: basic science and product development. Journal of Pharmacy and Pharmacology 2010, 62, (11), 1607-1621. 2. Takagi, T.; Ramachandran, C.; Bermejo, M.; Yamashita, S.; Yu, L. X.; Amidon, G. L. A provisional biopharmaceutical classification of the top 200 oral drug products in the United States, Great Britain, Spain, and Japan. Molecular Pharmaceutics 2006, 3, (6), 631-643. 3. Babu, N. J.; Nangia, A. Solubility advantage of amorphous drugs and pharmaceutical cocrystals. Crystal Growth & Design 2011, 11, (7), 2662-2679. 4. Hauss, D. J. Oral lipid-based formulations. Advanced drug delivery reviews 2007, 59, (7), 667-676. 5. Hancock, B. C.; Zografi, G. Characteristics and significance of the amorphous state in pharmaceutical systems. Journal of Pharmaceutical Sciences 1997, 86, (1), 1-12. 6. Brough, C.; Williams Iii, R. Amorphous solid dispersions and nano-crystal technologies for poorly watersoluble drug delivery. International Journal of Pharmaceutics 2013, 453, (1), 157-166. 7. Wu, W.; Löbmann, K.; Rades, T.; Grohganz, H. On the role of salt formation and structural similarity of co-formers in co-amorphous drug delivery systems. International Journal of Pharmaceutics 2018, 535, (1-2), 86-94. 8. Löbmann, K.; Grohganz, H.; Laitinen, R.; Strachan, C.; Rades, T. Amino acids as co-amorphous stabilizers for poorly water soluble drugs–Part 1: Preparation, stability and dissolution enhancement. European Journal of Pharmaceutics and Biopharmaceutics 2013, 85, (3), 873-881. 9. Laitinen, R.; Löbmann, K.; Grohganz, H.; Strachan, C.; Rades, T. Amino acids as co-amorphous excipients for simvastatin and glibenclamide: physical properties and stability. Molecular Pharmaceutics 2014, 11, (7), 2381-2389. 10. Lim, A. W.; Löbmann, K.; Grohganz, H.; Rades, T.; Chieng, N. Investigation of physical properties and stability of indomethacin–cimetidine and naproxen–cimetidine co‐amorphous systems prepared by quench cooling, coprecipitation and ball milling. Journal of Pharmacy and Pharmacology 2016, 68, (1), 3645. 11. Laitinen, R.; Löbmann, K.; Strachan, C. J.; Grohganz, H.; Rades, T. Emerging trends in the stabilization of amorphous drugs. International Journal of Pharmaceutics 2013, 453, (1), 65-79. 12. Dengale, S. J.; Grohganz, H.; Rades, T.; Löbmann, K. Recent advances in co-amorphous drug formulations. Advanced Drug Delivery Reviews 2016, 100, 116-125.



506 507 508 509 510 511 512 513 514 515 516 517 518 519 520 521 522 523 524 525 526 527 528 529 530 531 532 533 534 535 536 537 538 539 540 541 542 543 544 545 546 547 548 549 550 551 552 553

Page 24 of 26

13. Löbmann, K.; Laitinen, R.; Grohganz, H.; Gordon, K. C.; Strachan, C.; Rades, T. Coamorphous drug systems: enhanced physical stability and dissolution rate of indomethacin and naproxen. Molecular Pharmaceutics 2011, 8, (5), 1919-1928. 14. Löbmann, K.; Strachan, C.; Grohganz, H.; Rades, T.; Korhonen, O.; Laitinen, R. Co-amorphous simvastatin and glipizide combinations show improved physical stability without evidence of intermolecular interactions. European Journal of Pharmaceutics and Biopharmaceutics 2012, 81, (1), 159-169. 15. Jensen, K. T.; Blaabjerg, L. I.; Lenz, E.; Bohr, A.; Grohganz, H.; Kleinebudde, P.; Rades, T.; Löbmann, K. Preparation and characterization of spray‐dried co‐amorphous drug–amino acid salts. Journal of Pharmacy and Pharmacology 2016, 68, (5), 615-624. 16. Wu, W.; Ueda, H.; Löbmann, K.; Rades, T.; Grohganz, H. Organic acids as co-formers for co-amorphous systems–Influence of variation in molar ratio on the physicochemical properties of the co-amorphous systems. European Journal of Pharmaceutics and Biopharmaceutics 2018, 131, 25-32. 17. Fung, M.; Be̅rziņš, K. r.; Suryanarayanan, R. Physical Stability and Dissolution Behavior of Ketoconazole– Organic Acid Coamorphous Systems. Molecular Pharmaceutics 2018, 15, (5), 1862-1869. 18. Wu, W.; Löbmann, K.; Schnitzkewitz, J.; Knuhtsen, A.; Pedersen, D. S.; Grohganz, H.; Rades, T. Aspartame as a co-former in co-amorphous systems. International Journal of Pharmaceutics 2018, 549, (12), 380-387. 19. Heikkinen, A.; DeClerck, L.; Löbmann, K.; Grohganz, H.; Rades, T.; Laitinen, R. Dissolution properties of co-amorphous drug-amino acid formulations in buffer and biorelevant media. Die Pharmazie-An International Journal of Pharmaceutical Sciences 2015, 70, (7), 452-457. 20. Jensen, K. T.; Löbmann, K.; Rades, T.; Grohganz, H. Improving co-amorphous drug formulations by the addition of the highly water soluble amino acid, proline. Pharmaceutics 2014, 6, (3), 416-435. 21. Ueda, H.; Wu, W.; Löbmann, K.; Grohganz, H.; Müllertz, A.; Rades, T. Application of a Salt Coformer in a Co-Amorphous Drug System Dramatically Enhances the Glass Transition Temperature: A Case Study of the Ternary System Carbamazepine, Citric Acid, and l-Arginine. Molecular Pharmaceutics 2018, 15, (5), 20362044. 22. Blagden, N.; de Matas, M.; Gavan, P. T.; York, P. Crystal engineering of active pharmaceutical ingredients to improve solubility and dissolution rates. Advanced Drug Delivery Reviews 2007, 59, (7), 617630. 23. Qiao, N.; Li, M.; Schlindwein, W.; Malek, N.; Davies, A.; Trappitt, G. Pharmaceutical cocrystals: an overview. International Journal of Pharmaceutics 2011, 419, (1-2), 1-11. 24. Hickey, M. B.; Peterson, M. L.; Scoppettuolo, L. A.; Morrisette, S. L.; Vetter, A.; Guzmán, H.; Remenar, J. F.; Zhang, Z.; Tawa, M. D.; Haley, S. Performance comparison of a co-crystal of carbamazepine with marketed product. European Journal of Pharmaceutics and Biopharmaceutics 2007, 67, (1), 112-119. 25. Almarsson, Ö.; Zaworotko, M. J. Crystal engineering of the composition of pharmaceutical phases. Do pharmaceutical co-crystals represent a new path to improved medicines? Chemical Communications 2004, (17), 1889-1896. 26. Vangala, V. R.; Chow, P. S.; Tan, R. B. Characterization, physicochemical and photo-stability of a cocrystal involving an antibiotic drug, nitrofurantoin, and 4-hydroxybenzoic acid. CrystEngComm 2011, 13, (3), 759-762. 27. Vishweshwar, P., McMahon, J. A., Bis, J. A., & Zaworotko, M. J. Pharmaceutical co-crystals. Journal of Pharmaceutical Sciences 2006, 95(3), 499-516. 28. Löbmann, K.; Laitinen, R.; Grohganz, H.; Strachan, C.; Rades, T.; Gordon, K. C. A theoretical and spectroscopic study of co-amorphous naproxen and indomethacin. International Journal of Pharmaceutics 2013, 453, (1), 80-87. 29. Löbmann, K.; Laitinen, R.; Strachan, C.; Rades, T.; Grohganz, H. Amino acids as co-amorphous stabilizers for poorly water-soluble drugs–Part 2: Molecular interactions. European Journal of Pharmaceutics and Biopharmaceutics 2013, 85, (3), 882-888.


Page 25 of 26 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

554 555 556 557 558 559 560 561 562 563 564 565 566 567 568 569 570 571 572 573 574 575 576 577 578 579 580 581 582 583 584 585 586 587 588 589 590 591 592 593 594


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.

595 596



85x35mm (600 x 600 DPI)


Page 26 of 26

Transformations between co-amorphous and co-crystal systems and

Recommend Documents