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Mixing Effect on Stoichiometric Diversity in Benzoic Acid-Sodium Benzoate Co-crystals Tzu-Hsuan Chen, Kuan Lin Yeh, Chih Wei Chen, Hung Lin Lee, Yu Cheng Hsu, and Tu Lee Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.8b01220 • Publication Date (Web): 25 Jan 2019 Downloaded from http://pubs.acs.org on January 27, 2019

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Crystal Growth & Design

1

Mixing Effect on Stoichiometric Diversity in

2

Benzoic Acid-Sodium Benzoate Co-crystals

3 4

Tzu-Hsuan Chen, Kuan Lin Yeh, Chih Wei Chen, Hung Lin Lee, Yu Cheng Hsu and

5

Tu Lee*

6 7

Department of Chemical and Materials Engineering, National Central University

8

300 Zhongda Road, Zhongli District, Taoyuan City 32001, Taiwan R.O.C.

9 10

ABSTRACT

11

The aim of this study was to investigate mixing effect on the stoichiometric

12

diversity of benzoic acid-sodium benzoate (HBz-NaBz) co-crystals.

13

crystallization of HBz-NaBz co-crystals in a 500 mL sized glass vessel was monitored

14

under different agitation speeds and feeding rates of HCl aqueous solution.

15

good micromixing and macromixing, the HBz crystals, 2:1 and 1:1 co-crystals of HBz-

16

NaBz were crystallized out rapidly, and all crystals were transformed to a mixture of

17

2:1 and 1:1 co-crystals of HBz-NaBz in a relatively short time.

*

The

Under

However, the

Corresponding Author : Tel: +886-3-4227151 ext. 34204. Fax: +886-3-4252296,

Email: [email protected] 1 ACS Paragon Plus Environment

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crystallization of 1:1 co-crystals of HBz-NaBz was delayed by poor micro-, meso-, and

19

macromixing simultaneously.

20

different mixing conditions even given with the identical experiment time.

21

feasible to harvest pure 1:1 or pure 2:1 co-crystals of HBz-NaBz by reaction

22

crystallization through the control of the mixing condition, concentration of reactants,

23

and experiment time.

24

water system.

The compositions of the products were altered in It was

The ternary phase diagram was also constructed for HBz-NaBz-

25 26

Keywords: co-crystal; mixing; stoichiometry; process design.

27 28

INTRODUCTION

29

Only very few active pharmaceutical ingredients (APIs), out of thousands of drug

30

candidates in the pharmaceutical industry, can be launched into the marketplace every

31

year.1

32

(bio)pharmaceutical properties, toxicity and lack of efficacy.

33

biopharmaceutical properties, solubility is one of the main factors to determine whether

34

a drug will be developed for medication or not.2

35

APIs have gained increasing attention in the enhancement of the APIs’ solubility,

36

dissolution rate and physical stability.3,4

Most of the drug candidates are ultimately eliminated because of the poor Among those

In the recent years, co-crystals of

Co-crystal is commonly defined as a 2

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Crystal Growth & Design

37

crystalline material consisting of two or more distinct molecules present in a definite

38

stoichiometric ratio in a solid form at an ambient temperature.5

39

methods include liquid-assisted grinding,6 isothermal slurry conversion,7 solution

40

crystallization by evaporation, cooling and/or antisolvent,8-10 and spray drying.11 Co-

41

crystals are usually obtained by crystallization of the API and co-former from a single

42

solvent or a co-solvent.

43

assembling

44

co-crystallization.12,13

45

crystals could also be made via solvent-free processes such as twin-screw extrusion and

46

resonant acoustic mixing.14-16

47

industry because of its readiness to control the attributes of the final crystalline product

48

such as purity, yield, particle size distribution (PSD), crystal habit and polymorphism,

49

and to achieve process and product reproducibility.

several

Co-crystal preparation

Noticeably, we have developed a novel process for

co-crystals

directly

from

chemical

synthesis

to

In addition to these solution-based crystallization methods, co-

However, solution crystallization is still preferred in

50

Mixing is a critical factor in determining how soon the initial segregation of the

51

heat and mass constituents can reach their homogeneity, and the heat and mass of the

52

constituents at any given time can influence the nucleation rate, crystal growth rate,

53

crystal morphology, crystal size distribution and polymorphism.

54

addition rate of antisolvent and agitation speed of impeller play major roles in

55

determining the two polymorphs of carbamazepine-saccharin co-crystal prepared by

For example, the

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Page 4 of 43

56

antisolvent crystallization during a large-scale production.17

57

a periodic mixed suspension mixed product removal (PMSMPR) crystallizer also

58

demonstrated that processing parameters and variables would affect crystal structure of

59

1:1 co-crystals of urea-barbituric acid in both batch and continuous modes.18 However,

60

an in-depth investigation of the mixing effect on co-crystallization is still rare.

61

Another study utilizing

Hydrodynamics in a stirred reactor is quite complex and can vary greatly in space

62

from location to location.

As the reacting fluid travels within a stirred reactor, the

63

interaction of the flow pattern with the chemical reaction occurs at different length

64

scales, ranging from macroscopic to mesoscopic scale, and further down to microscopic

65

sale.

66

referring to an overall mixing performance in a reactor, was based on the concept of a

67

macroscopic lumped population balance.19

68

distributive mixing achieved by bulk motion or convective transport of the fluid at the

69

macroscopic scale, and resulting in a uniform spatial distribution of fluid elements

70

within the whole volume.

71

and Bourne to describe the interaction by mixing between the feed plumes and the

72

bulk.20

73

between macromixing and micromixing.

74

turbulent mixing at the molecular level.

The term of macromixing originally introduced by Danckwerts in 1958,

It is often considered as a kind of

In 1992, the term mesomixing was introduced by Baldyga

Generally speaking, mesomixing is defined as an intermediate mixing level Micromixing is regarded as a kind of It provides viscous-convective deformation 4 ACS Paragon Plus Environment

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Crystal Growth & Design

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of fluid elements, followed by molecular diffusion.

Several studies have reported the

76

effects of different processing parameters or variables, such as impeller type, agitation

77

speed, feed location, mixing intensity at feed point and feeding rate, on PSD of single

78

component product during reaction crystallization in a semi-batch reactor.21

79

Practically, their influences are of considerable importance.

80

that the mean crystal size of the product was initially increased with the rise in a local

81

energy dissipation rate, and finally decreased after reaching a maximum.

One of the findings was

22

82

In general, the local degree of supersaturation at the feed point will be suddenly

83

increased due to a fast reaction rate, and then the degree of supersaturation decays as

84

the solution is conveyed into the bulk.

85

of reactants promoting reaction happening at micro- and meso-scales, and to dilute the

86

local concentration of product in a macroscopic circulation simultaneously.

87

increase in a circulation rate and mixing intensity leads to the formation of larger

88

crystals because of more efficient mass transfer.

89

crystals becomes larger as the feed point is located closer to an impeller.22

90

Mixing is able to agglomerate the molecules

The

Therefore, the size distribution of

Correlations between microm-, meso-, and macromixing should be taken into

91

account.

Rasmuson had presented a concise overview and comparison among micro-,

92

meso-, and macromixing in a single feed U-tube reactor,and evaluated their influence

93

over the PSD of benzoic acid (HBz) crystals which were produced as a sole product by 5 ACS Paragon Plus Environment

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complete neutralization of sodium benzoate (NaBz) and hydrochloric acid (HCl).23

95

Interestingly, HBz-NaBz co-crystals can also exist in two stoichiometric ratios of

96

1:1 and 2:1,24-26 according to the literature, 2:1 co-crystals of HBz-NaBz can have two

97

polymorphs.

98

grinding with methanol and there is no crystal structure available.24

99

crystals of HBz-NaBz were firstly prepared by the liquid-assisted grinding with ethanol,

100

or evaporation in a co-solvent of ethanol/water (4:1 v/v) co-solvent, whereas Form B

101

2:1 co-crystals of HBz-NaBz were made by evaporation in methanol.

102

with one-dimensional tapes of dimers packed in a hexagonal array along the a-axis.25

103

Form B is a metastable form at room temperature, and similarly, it is constructed with

104

rods in a hexagonal array.25

105

different techniques for preparing co-crystal diversity in the stoichiometry.

106

instance, Jones and his co-worker indicated that the mechanochemical grinding method

107

could produce co-crystals having different stoichiometric ratios by adjusting the

108

loading ratio among the initial co-crystal components.27,28

109

applied hot-melt extrusion to control the formation of 1:1 and 2:1 co-crystals of

110

caffeine-maleic acid.29

111

crystals of carbamazepine-4-aminobenzoic acid were made through reaction

112

crystallization by varying the co-former concentration in the solution.30

1:1 co-crystals of HBz-NaBz were only produced by liquid-assisted Form A 2:1 co-

Form A is built

Many research articles have reported the utilization of For

Paradkar and his co-worker

In addition to the above solvent-free methods, 1:1 and 2:1 co-

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Crystal Growth & Design

Consequently, the aim of our study is to investigate the effect of different scales Inspired by the work of Rasmuson,23

114

of mixing mainly on co-crystal’s stoichiometry.

115

the interesting system of HBz is further extended to the co-crystal systems of HBz-

116

NaBz by partial neutralization of NaBz with HCl in a stirred batch reactor.

117

experiments were designed to assemble the co-crystals of HBz-NaBz directly by

118

feeding a HCl aqueous solution into a NaBz aqueous solution in a 500 mL sized glass

119

vessel under various agitation speeds.

120

micromixing was dependent on the local dissipation rate of turbulent energy.

121

mesomixing was mainly related to mixing at the feed point while the macromixing was

122

responsible for conveying heat and constituents to the bulk.23

123

crystal structure and stoichiometric ratio of crystal products were characterized by

124

optical microscopy (OM), powder X-ray diffraction (PXRD) and thermal gravimetric

125

analysis (TGA), respectively, and monitored during each experiment.

Our

During reaction crystallization, the rate of The

The crystal habit,

126 127

EXPERIMENTS

128

Materials.

129

SZBF2470V) and sodium benzoate (NaBz, 99% purity, mp. 410oC, M.W. 144.11 g/mol,

130

Lot: SZBF2150V) were purchased from Sigma-Aldrich (St. Louis, USA).

131

Hydrochloric acid (HCl, M.W. 36.46 g/mol, 37% purity, density 1.19 g/cm3, Lot:

Benzoic acid (HBz, 99.5% purity, mp. 122oC, M.W. 122.12 g/mol, Lot:

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1721545) was obtained from Echo Chemical Co., Ltd (Loughborough, UK).

Water

133

was clarified by reverse osmosis (RO) through a water purification system (model

134

Milli-RO Plus) bought from Millipore (Billerica, MA, USA).

135

without further purification.

136

Instrumentation.

137

Optical Microscopy (OM).

138

microscope (Olympus, Tokyo, Japan) equipped with a digital camera (Moticam 2000)

139

and a cross polarized filter.

140

Plus (Version 2.0) into a digital photograph, and analyzed by Measure Tool (Version

141

4.10).

142

Powder X-ray Diffraction (PXRD).

143

(Bruker, Germany).

144

was operated at 40 kV and 40 mA.

145

of 5o to 35o.

146

Fourier Transform Infrared (FTIR) Spectroscopy.

147

FTIR Spectrum One (Perkin Elmer, Shelton, CT, USA).

148

powder were blended together at a weight ratio of 1 to 99, and pressed into a disk, which

149

was scanned with a scan number of 8 from 400 to 4000 cm-1 and a resolution of 2 cm-

150

1.

All materials were used

Different crystal habits were observed by BX-51 optical

Micrographs were transformed through Motic Images

PXRD patterns were collected by D8 Advance

The source of PXRD was CuKα (1.542 Å), and the diffractometer The scanning rate was set at 0.03o 2θ/sec in a range

FTIR spectra were measured by Solid sample and KBr

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Crystal Growth & Design

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Thermogravimetric Analysis (TGA).

TGA analysis was conducted by Pyris 1 TGA

152

(Perkin Elmer, Norwalk, CT, USA).

153

atmosphere to avoid oxidation.

154

About 5 mg of sample were placed on an open platinum pan suspended in a heating

155

furnace.

156

Methods.

157

1:1 Co-crystal of HBz-NaBz by Reaction Crystallization.

158

5 g (0.0347 mol) of NaBz were dissolved into 10 mL of water (about 3.5 M) in a 20

159

mL scintillation vial at 25oC with a spin bar and an agitation speed of 600 rpm.

160

mL of a 1 M HCl aqueous solution was introduced into the NaBz aqueous solution by

161

a micropipette at an interval of 30 sec.

162

When all of the HCl aqueous solution was added into the NaBz aqueous solution, the

163

resulting solids were isolated immediately by filtration without further rinsing, dried in

164

an oven at 40oC for 24 h, and analyzed by OM, PXRD, FTIR and TGA afterwards.

165

2:1 Co-crystal of HBz-NaBz by Cooling Crystallization

All samples were heated under nitrogen

The heating rate was 10oC /min from 30o to 300oC.

0.1

Total volume of the HCl solution was 2.8 mL.

166

Two different solutions were prepared by dissolving 1.89 g (0.047 mol) of NaOH

167

pellets into 6 mL of ethanol-water co-solvent (2:1 v/v), and by dissolving 7.22 g (0.141

168

mol) of HBz into 50 mL of ethanol-water co-solvent (4:1 v/v) at 25oC.

169

solution of NaOH was added into the other aqueous solution of HBz in a 100 mL round-

The aqueous

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bottom flask with a spin bar at an agitation speed of 175 rpm and 25oC for 1 h.

171

was insoluble in water or in a highly water-containing medium.

172

precipitated out in the beginning of solution mixing.

173

NaOH to form NaBz, which was highly soluble in an aqueous medium.

174

solution became clear eventually.

175

crystals of HBz-NaBz were harvested by filtering the slurry without rinsing, dried in an

176

oven at 40oC for 24 h, and analyzed by OM, PXRD, FTIR and TGA afterwards.

HBz

It was prone to be

Then HBz would react with

It was then cooled to 16oC for 3 h.

The resulting The 2:1 co-

177 178 179

Determination of the Molar Ratio of NaBz to HCl for Reaction Crystallization 5 g (0.0347 mol) of NaBz were dissolved into 10 mL of water (about 3.5 M) in a

180

20 mL scintillation vial at 25oC with a spin bar at 600 rpm.

181

aqueous solution was added dropwise into an aqueous solution of NaBz by a

182

micropipette at an interval of 30 sec.

183

addition volume of a HCl aqueous solution, molar ratio of NaBz to HCl, and experiment

184

time were listed in Table 1 for Experiments No. 1 to No. 6.

185

solution was added into a scintillation vial, the produced solids were immediately

186

isolated from the mother liquor by filtration without rinsing, dried in an oven at 40oC

187

for 8 h, and analyzed by OM, PXRD and TGA afterwards.

0.1 mL of a 1 M HCl

The experimental parameters, including the

While all the HCl aqueous

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Crystal Growth & Design

189

Investigation of the Effects of Different Scales of Mixing on Co-crystal Formation

190

48.1 g (0.334 mol) of NaBz and 192 mL of water were introduced into a 500 mL glass

191

reactor, whose inner diameter and height were 8.0 cm and 17 cm, respectively.

192

reactor was installed with a four-bladed 45o impeller having a diameter of 3.5 cm, and

193

the distance between the bottom and impeller was set to 2 cm.

194

mL of a 3.4 M HCl aqueous solution were fed into the reactor near the impeller through

195

a silicon tube at 25oC using a circulating water bath, and the molar ratio of NaBz to HCl

196

was kept at 12.4:1.

197

agitation speeds were tabulated in Table 2 for Experiments No. 7 to No. 12.

198

feeding rate was controlled by a metering pump.

199

growth, the experiment time for a whole process was fixed to 240 min.

200

solids were withdrawn from the slurry at various sampling times of: 1, 3, 5, 10, 20, 30

201

and 240 min, filtered immediately without rinsing, and dried in an oven at 40oC for 8

202

h.

203

Phase Diagram Establishment

The

For all experiments, 8

The different operating conditions, such as feeding rates and The

To observe the evolution of crystal The produced

The harvested solids were analyzed by OM, PXRD and TGA afterwards.

204

To construct a ternary phase diagram for the HBz-NaBz co-crystal system,

205

approximate solubility values of HBz, NaBz and their co-crystals were measured by

206

the gravimetric method.

207

together according to 22 different predetermined weight percents in a 7 mL vial to

In addition, HBz and NaBz solids, and water were added

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208

prepare the slurries at 25oC.

209

equilibrium, filtered, dried in a 40oC oven, and analyzed by PXRD and TGA for

210

determining the solid phase compositions for all samples.

211

and the phase region that each point was located in the ternary phase diagram were

212

determined

Those slurry samples were shaken for three days to reach

The location of each point

213 214

RESULTS AND DISCUSSION

215

Characterization of HBz-NaBz Co-crystals

216

Three different stoichiometries of HBz-NaBz “complexes” were reported,31

217

however, only the crystal structure of 2 to 1 HBz-NaBz “complex” was determined.

218

Currently, the powder X-ray diffraction pattern and IR spectrum of the 1:1 co-crystals

219

of HBz-NaBz were reported and yet, the stoichiometry was not quantified and

220

compared to the 2:1 co-crystals of HBz-NaBz.24

221

for the compositions of the crystal products were necessary.

Therefore, the quantitative analyses

222

PXRD patterns of NaBz, HBz, 1:1 and 2:1 co-crystals of HBz-NaBz are shown

223

in Figure 1 whose characteristic diffraction peaks are at 2θ = 6.4o, 23.8o, 6o and 7.2o,

224

respectively.25,26,32,33

225

are Form A.25

226

easily be distinguished from the ones of both co-crystals in Figures 1(c) and 1(d).

In our present study, all harvested 2:1 co-crystals of HBz-NaBz

The diffraction patterns of NaBz and HBz in Figures 1(a) and 1(b) can

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Crystal Growth & Design

227

However, 1:1 and 2:1 co-crystals of HBz-NaBz are hardly distinguishable in the PXRD

228

patterns indicating their similar molecular arrangements.

229

FTIR spectra in Figure S1 of Supporting Information reveal the spectra of both

230

kinds of co-crystals were identical, 26,34 which would lead to a serious problem when

231

the composition of harvested crystals is a mixture of co-crystals with different

232

stoichiometric ratios.

233

of HBz crystals, but not the one for NaBz crystals, could reach 100% at 280oC.

234

mass balances of the weight percents of HBz crystals and NaBz crystals were served as

235

a basis to identify the composition of crystals.

236

molecules in 1:1 co-crystals of HBz-NaBz and 2:1 co-crystals of HBz-NaBz was

237

calculated to be 45.7% and 62.9% per mole of co-crystals, respectively, as evidenced

238

in Figure 2.

239

not altered in the HBz-NaBz co-crystals with various stoichiometries.

240

four species of HBz, NaBz, 1:1 and 2:1 co-crystals of HBz-NaBz were almost

241

indistinguishable spectroscopically due to their similar molecular structures and

242

intermolecular interactions, the evolution of the co-crystal system in the stirred reactor

243

could be monitored, and the product mixture could still be qualified with the appropriate

244

use of TGA and mass balance calculations.

According to the TGA scans in Figure 2, only the weight loss The

The theoretical weight percent of HBz

The thermal decomposition behaviors of HBz and NaBz molecules were Although those

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Determination of Molar Ratio of NaBz to HCl for Reaction Crystallization Scheme 1 displayed the synthesis and crystallization of HBz and HBz-NaBz co-

248

crystals with different stoichiometries.

The co-crystals of HBz-NaBz were produced

249

by reacting HCl with NaBz first to precipitate out HBz crystals with the low solubility

250

of only 2.7 mg/mL at 25oC in water, which were then co-crystallized with the pre-

251

existed NaBz free molecules in the aqueous solution.

252

were present in the final product when NaBz free molecules were consumed completely

253

with an excess amount of HCl.

254

significant factor to determine the solid-state structure of the product crystals.

255

results of Experiments No. 1 to No. 6 with various molar ratios of NaBz to HCl of 12.4,

256

10.0, 6.2, 4.1, 3.1, and 2.5 were tabulated in Table 3.

257

crystals of HBz-NaBz, 2:1 co-crystals of of HBz-NaBz, and HBz crystals in all samples

258

were revealed implicitly by TGA scans and PXRD patterns in Supporting Information.

259

The product from Experiment No. 1 contained only 1:1 co-crystals of HBz-NaBz, the

260

products from Experiments No. 2 to No. 4 were the mixtures of 1:1 and 2:1 co-crystals

261

of HBz-NaBz, and the products from Experiment No. 5 and No. 6 were the mixtures of

262

2:1 co-crystals of HBz-NaBz and HBz crystals (Table 3).

263

scans in Figure S2 agreed well with the PXRD patterns in Figure S3.

264

insoluble HBz crystals were likely to precipitate out and remained in a solid state if the

However, only HBz crystals

It implied that the molar ratio of NaBz to HCl was a The

The compositions of 1:1 co-

The results of the TGA The water

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Crystal Growth & Design

molar ratio of NaBz to HCl was very low at values of 2.5 and 3.1. Only Experiment No. 1 with a molar ratio of NaBz to HCl of 12.4 gave less

267

stable 1:1 co-crystals of HBz-NaBz after 4h of aging (Table 3).

All other experiments

268

resulted in a mixture of different crystal types (Table 3).

269

co-crystals of HBz-NaBz, the molar ratio of NaBz to HCl was fixed at 12.4 for the

270

mixing experiments in a stirred reactor.

271

that both 1:1 co-crystals of HBz-NaBz, and 2:1 co-crystals of HBz-NaBz grown from

272

water exhibited needle-like crystal habits.

273

crystals were aggregated together.35

To study the evolution of the

The OM images in Figures 3 (a) to (d) showed

Figures 3(e) to 3(f) displayed that the HBz

274 275 276

Mixing Effect on the HBz-NaBz Co-crystals at Different Scales According to the small scale experiments in the previous section, the molar ratio

277

of NaBz to HCl of 12.4 was chosen for the 500 mL stirred reactor experiments.

To

278

investigate the mixing effect on the stoichiometry of co-crystals, several milliliters of

279

the resulting slurry were withdrawn by a pipette at the sampling times of 1, 3, 5, 10, 20,

280

30 and 240 min.

281

range from 1,531 to 12,250.

282

laminar and turbulent at 75 rpm, and turbulent everywhere at 600 rpm..

283

feeding times at the feeding rates of 3.5 mL/min and 20 mL/min were 2.3 min and 0.4

The Reynolds number of the fluid flow near the impeller was in the Therefore, the flow was in the transition region between The total

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Page 16 of 43

284

min, respectively.

The TGA scans, PXRD patterns and OM images of the crystals at

285

various sampling times in Experiments No. 7 to No. 12 were included in Supporting

286

Information.

The compositions of products were further summarized in Table 4.

287

In Experiment No. 7, under the high agitation speed of impeller at 600 rpm and

288

the low feeding rate of a HCl aqueous solution at 3.5 mL/min, HBz crystal aggregates

289

were formed in the beginning.

290

like co-crystals of HBz-NaBz after only 3 min (Table 4).

291

had enhanced the mixing intensity of both micro- and macromixing, so that the

292

dissolution rate of HBz crystals in a NaBz aqueous solution was significantly increased.

293

The dissolved HBz molecules were constantly consumed by the formation of HBz-

294

NaBz co-crystals whose production rate was also correlated with the mixing intensity.

295

As time went on, the crystals were eventually transformed from a mixture of HBz

296

crystals, 1:1 and 2:1 co-crystals of HBz-NaBz, to a mixture of 1:1 and 2:1 co-crystals

297

of HBz-NaBz after 3 min.

All of the HBz crystals were transformed to the needleThe high agitation speed

298

In Experiment No. 8, with the high agitation speed of impeller at 600 rpm, and

299

high feeding rate of a HCl aqueous solution at 20 mL/min, the aggregated HBz crystals

300

were formed in the beginning.

301

introduced into the reactor faster than the one in Experiment 7, all of the HBz crystals

302

were transformed to needle-like co-crystals of HBz-NaBz after 3 min (Table 4).

Even though 8 mL of a 1 M HCl aqueous solution were

The 16

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Crystal Growth & Design

303

higher agitation speed of impeller led to higher mixing intensity of micro- and

304

macromixing, which increased the dissolution of HBz crystals, and formed the co-

305

crystals of HBz-NaBz rapidly.

306

feeding rate, the evolution of crystal composition in Experiment No. 8 was identical to

307

the one in Experiment No. 7 (Table 4).

308

the crystal composition under the high agitation speed provided with good micromixing

309

and macromixing.

310

Despite of the lower mesomixing by increasing the

The feeding rate did not significantly affect

In Experiment No. 9, the agitation speed of impeller was at 75 rpm and feeding

311

rate of a HCl aqueous solution was at 3.5 mL/min.

The mixing intensity contributed

312

from micro- and macromixing was decreased with the lower agitation speed, it would

313

take a longer time for the system to reach equilibrium.

314

rate of a HCl aqueous solution had led to a better mesomixing.

315

2:1 co-crystals of HBz-NaBz were produced at the experiment time of 1 min (Table 4),

316

then the 1:1 co-crystals of HBz-NaBz were crystallized out following by the dissolution

317

of HBz crystals.

318

poor micro- and macromixing, and good mesomixing, and all of the HBz crystals were

319

transformed to the needle-like co-crystals of HBz-NaBz after 5 min (Table 4).

320

Experiment No. 10, with the agitation speed of impeller at 75 rpm and the feeding rate

321

of a HCl aqueous solution at 20 mL/min, the poor micro-, meso- and macromixing had

However, the lower feeding The HBz crystals and

In addition, 1:1 co-crystals of HBz-NaBz were produced late under

In

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Page 18 of 43

322

led to a local high concentration of HBz at the feed point.

323

zone was dispersed slowly into the whole reactor, which might also slow down the

324

dissolution rate of HBz.

325

Interestingly, the 1:1 co-crystals of HBz-NaBz were not observed in the beginning, and

326

only the 2:1 co-crystals of HBz-NaBz were obtained at 20 min (Table 4).

327

The high concentrate HBz

Therefore, the time for crystal transformation was prolonged.

Micromixing, mesomixing, and macromixing had a profound influence on the

328

stoichiometric ratios of the co-crystals of HBz-NaBz.

The mixing effects on the

329

evolution of HBz crystals and HBz-NaBz co-crystals were summarized in Scheme 2

330

(a).

331

HBz crystals and 2:1 co-crystal of HBz-NaBz were both generated.

332

agitation speed, micro- and macromixing dominated the mixing schemes of the stirred

333

reactor.

334

crystallization of HBz crystals and 2:1 co-crystals of HBz-NaBz, if the system was both

335

good in micro- and macromixing.

336

nucleate HBz-NaBz co-crystals.

337

of 1:1 and 2:1 co-crystals of HBz-NaBz given with long enough time as the system

338

achieved equilibrium.

339

mixing happened at all scales simultaneously.

340

obvious under poor micro- and macromixing.

The HBz molecules were produced by reacting NaBz with HCl at first, and then Under a high

The 1:1 co-crystals of HBz-NaBz were generated, following by the

The HBz crystals could dissolve gradually and

Finally, all crystals were transformed into a mixture

On the other hand, the evolution path was different when poor The effect of mesomixing became Poor mixing slowed down the 18 ACS Paragon Plus Environment

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Crystal Growth & Design

341

formation of 1:1 co-crystals of HBz-NaBz.

As a result, the 2:1 co-crystals were able

342

to appear without the presence of HBz crystals and 1:1 co-crystals of HBz-NaBz during

343

the crystallization event.

344

To further investigate the mixing effects on the stoichiometry of HBz-NaBz co-

345

crystals, Experiments No. 11 and No. 12 were executed with extreme operating

346

parameters.

347

poured into the stirred reactor all at once at an agitation speed of impeller of 75 rpm

348

which led to the poorest micromixing, mesomixing and macromixing situation that was

349

similar to those in Experiment No. 10.

350

20 min.

351

No. 10 (Table 4).

352

crystals and 2:1 co-crystals of HBz-NaBz before 10 min.

353

transformed to co-crystals, and only the 2:1 co-crystals of HBz-NaBz were found at 20

354

min, and eventually became the mixture of 1:1 and 2:1 co-crystals of HBz-NaBz at

355

equilibrium (Table 4).

356

In Experiment No. 11, 8 mL of a 3.4 M HCl aqueous solution were

The feeding time for Experiments No. 12 was

The result of Experiment No. 11 matched well with the ones in Experiment Poor micro-, meso- and macromixing included a plenty of HBz All of the HBz crystals were

Experiment No. 12 was operated by good micro-, meso- and macromixing with

357

the agitation speed of 600 rpm and feeding rate of 0.4 mL/min.

The amount of

358

precipitates was too few to be withdrawn before 10 min.

359

crystals of HBz-NaBz were harvested at 10 min of the experiment time which was

Surprisingly, only 1:1 co-

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Page 20 of 43

360

different from other the experimental results.

A different crystal evolution path as

361

indicated in Scheme 2(b) would be taken when mixing at all scales were extremely

362

strong.

363

in the stirred reactor due to the low feeding rate and high agitation speed.

364

extremely good mixing increased the possibility of the dissolved HBz molecules to

365

meet with the free NaBz molecules in the surroundings, so that HBz and NaBz could

366

satisfy the coordination criterion of 1:1 co-crystals of HBz-NaBz.

367

by, however, the system would eventually reach the same equilibrium state.

In the beginning, a few HBz crystals were precipitated, and circulated rapidly The

As the time went

368

A ternary phase diagram (TPD) for co-crystals could provide important

369

information for designing the operating parameters for manufacturing from the view of

370

thermodynamics.36

371

for NaBz, the TPD of HBz-NaBz-water was an incongruent system.

372

were determined and illustrated in the TPD (Figure 4).

373

area of high concentration of HBz and low concentration of NaBz.

374

molecules could hardly interact to NaBz molecules and formed the two-phase

375

coexistence region for HBz crystal and solution.

376

increased from Region I to Region II, the HBz molecules could interact with more NaBz

377

molecules, and formed the 2:1 co-crystals of HBz-NaBz, therefore the Region II was

378

consisted of HBz crystals, the 2:1 co-crystals of HBz-NaBz and solution.

Since the solubility of HBz in water was much lower than the one Several regions

Region I was located in the The HBz

As the concentration of NaBz

According 20

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Crystal Growth & Design

379

to the Gibbs’ Phase Rule, F = C - P + 2, where F, C and P were number of degrees of

380

freedom, number of components and number of phases, respectively, a four-phase

381

region consisted of HBz, the 2:1 co-crystals of HBz-NaBz, the 1:1 co-crystals of HBz-

382

NaBz and solution could not exist in the TPD for HBz-NaBz-water system.

383

Interestingly, the weight losses of the slurry in region III were higher than 62.9%

384

meaning that HBz crystals did exist in the solid phase.

385

PXRD diffraction peak of the 1:1 HBz-NaBz co-crystals was detected in the solids.

386

As a result, Region III was consisted of the HBz crystals, the 1:1 co-crystals of HBz-

387

NaBz and solution.

388

and III, in the TPD, contain the same constituent of HBz.

389

crystals could exist with the 1:1 co-crystals of HBz-NaBz was still unknown.

390

two-phase coexistence region of the 1:1 co-crystals of HBz-NaBz and the NaBz crystals

391

were observed in Region IV.

392

finally the mixture would be transformed to NaBz crystals as shown in Region V.

393

In addition, the characteristic

It was unusual to observe that these regions, such as Regions I, II The reason why HBz The

If the concentration of NaBz was further increased, and

No pure co-crystal phases were observed in the slurry for the HBz-NaBz-water

394

system in the establishment experiments of TPD.

A reasonable explanation was that

395

the two-phase coexistence region of the 2:1 co-crystals of HBz-NaBz and solution, and

396

the region of the 1:1 co-crystals of HBz-NaBz and solution were too narrow to be

397

observed.

However, it could be anticipated that the two-phase coexistence region for 21 ACS Paragon Plus Environment

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Page 22 of 43

398

the 2:1 co-crystals of HBz-NaBz and solution was located near the boundary between

399

Regions II and III, and the two-phase coexistence region of the 1:1 co-crystals of HBz-

400

NaBz and solution was located near the boundary between Regions III and IV.

401

Nevertheless, it was difficult to accurately prepare the slurry at the composition inside

402

such narrow regions.

403

(Figure 4).

404

crystals of HBz-NaBz were quite narrow in this system, that was why the products of

405

the mixing experiments were easily transformed to a mixture of co-crystals and HBz or

406

NaBz at equilibrium.

407

No. 7 to No. 12 were marked as black solid circle in the TPD.

408

mixing experiments were very close to the boundary between Region II and III

409

indicating that there was a narrow three-phase coexistence region for the 1:1 co-crystals

410

of HBz-NaBz, the 2:1 co-crystal of HBz-NaBz, and solution near the boundary of

411

Regions II and III.

Consequently, the regions were not determined in the TPD

In other words, the operating window for preparing the pure 2:1 or 1:1 co-

Furthermore, the final compositions of the mixing Experiments The location of the

However, it was also difficult to determine its area.

412

Mixing was a critical factor in crystallization process, especially in scale-up.

The

413

contribution of mixing would dominate even more so then the lab-scale in the industrial

414

scale.

415

NaBz co-crystals in this study.

416

components in co-crystals was process dependent!

The significance of mixing effect was demonstrated by the system of HBzIt should be noticed that the stoichiometric ratio of the The stoichiometry of co-crystals 22 ACS Paragon Plus Environment

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Crystal Growth & Design

417

would be altered under different mixing conditions even given with the identical time.

418

This would lead to the challenge of crystal guiding control and reproducibility of co-

419

crystals during mass production due to a more complex mixing pattern in a large scale.

420

As a consequence, a good understanding of the influence of mixing on stoichiometry

421

during co-crystallization in addition to the usual concerns of polymorphism and PSD

422

was necessary for process design, scale-up and product reproducibility.37

423 424 425

CONCLUSIONS The 1:1 and 2:1 co-crystals of HBz-NaBz were directly assembled by reacting

426

NaBz with HCl in an aqueous solution.

The molar ratio of NaBz to HCl, sampling

427

time, feeding rate and agitation speed should be considered for the design of

428

experiments.

429

in the HBz-NaBz co-crystals were controlled by micro-, meso-, and macromixing.

430

Micro- and macromixing were contributed by the agitation speed of the impeller, and

431

mesomixing was by the feeding rate of a HCl aqueous solution: (1) under the high

432

agitation speed, in both good micromixing and macromixing were resulted.

433

products harvested were the mixture of HBz crystals, the 1:1 and 2:1 co-crystals of

434

HBz-NaBz at 1 min, and then the mixture was transformed to the mixture of 1:1 and

435

2:1 co-crystals of HBz-NaBz from 3 to 240 min, (2) if the feeding rate of a HCl aqueous

In the 500 mL stirred reactor, the stoichiometric ratio of HBz to NaBz

The

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Page 24 of 43

436

solution was high coupled with a low agitation speed, the system would end up being

437

poor in micro-, meso- and macromixing.

438

NaBz was delayed and pure 2:1 co-crystals of HBz-NaBz could be observed at a certain

439

experiment time.

440

co-crystals of HBz-NaBz.

441

possible for the evolution crystal formation in the HBZ-NaBz-water system to take

442

another path where the pure 1:1 co-crystals of HBz-NaBz would appear at a certain

443

time point.

444

controlling the mixing condition, concentration of reactants and experiment time.

445

regions were determined for the TPD of HBz-NaBz-water system.

446

coexistence regions for pure co-crystal and solution were too narrow to be determined.

447

Moreover, an unusual region consisting of the 1:1 co-crystals of HBz-NaBz and

448

solution was observed.

449

The formation of 1:1 co-crystals of HBz-

Finally all products were transformed to the mixtures of 1:1 and 2:1 (3) When all mixing scales were extremely strong, it was

It was feasible to harvest the pure 1:1 or 2:1 co-crystals of HBz-NaBz by Six

The two-phase

The scale effect would influence the mixing scheme in a stirred reactor from the

450

lab scale to the industrial scale.

It is a great challenge in manufacturing to control

451

polymorphism, PSD, and the additional component’s stoichiometric ratio for scaling up

452

co-crystals.

453

of the components in co-crystals on crystal quality, reproducibility, and not just merely

454

PSD or polymorphism, is extremely important and should be investigated deeply in the

Applying the correlation between mixing effect and stoichiometric ratio

24 ACS Paragon Plus Environment

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455

Crystal Growth & Design

future.

456 457

ASSOCIATED CONTENT

458

Supporting Information

459

The Supporting Information is available free of charge on the ACS Publications

460

website at DOI:

461

FTIR spectra, TGA scans, PXRD patterns, and optical micrographs

462 463

ACKNOWLEDGEMENT

464

This research was supported by the grant from the Ministry of Science and

465

Technology of Taiwan R.O.C. (MOST 104-2221-E-008-070-MY3 and 107-2221-E-

466

008 -037 -MY3).

467

TGA, and Mr. Chin-Chuan Huang for the assistance in PXRD for the technical support

468

in the Precision Instrument Center at Nation Central University.

We are greatly indebted to Mrs. Li Fan Chen for the assistance in

469

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470

Page 26 of 43

For Table of Contents Use Only

471 472 473

Mixing Effect on Stoichiometric Diversity in Benzoic Acid-Sodium Benzoate Co-crystals

474 475 476

Tzu-Hsuan Chen, Yu Cheng Hsu, Kuan Lin Yeh, Chih Wei Chen, Hung Lin Lee and Tu Lee*

477

478 479 480

Neutralization of sodium benzoate with hydrochloric acid in a semibatch stirred

481

reactor could produce benzoic acid, the 2:1 co-crystal of benzoic acid-sodium benzoate,

482

and the 1:1 co-crystal of benzoic acid-sodium benzoate.

483

products were tuned by modulating the micro-, meso- and macromixing. The mixing

484

effect on the co-crystal should be controlled for process design, scale-up, and product

485

reproducibility.

The compositions of

26 ACS Paragon Plus Environment

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487

Crystal Growth & Design

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Crystal Growth & Design

Stoichiometric Control of Co-crystal Formation by Solvent Free Continuous Cocrystallization (SFCC). Cryst. Growth Des. 2015, 15, 5648-5651. 30

Jayasankar, A.; Reddy, L. S.; Bethune, S. J.; Rodríguez-Hornedo, N. Role of

Cocrystal and Solution Chemistry on the Formation and Stability of Cocrystals with Different Stoichiometry. Cryst. Growth Des. 2009, 9, 889-897. 31

Flammersheim, H. J. Physikalisch‐chemische Untersuchungen am System

Natriumbenzoat/Benzoesäure (I) Infrarotspektropische und röntgenografische Untersuchungen bei Raumtemperatur. Krist. Tech. 1974, 9, 299-311. 32

Khosravan, M.; Shoshtari, A. N.; Hoseinchi, L. Synthesis of Nano Sodium Benzoate

as a Food Preservative and Investigative Its Effect on Food Spoilage Bacteria. Synth. React. Inorg. Met.-Org. Chem. 2016, 46, 51-54. 33

Maruyama, S. A.; Lisboa, F. S.; Ramos, L. P.; Wypych. F.

Alkaline Earth Layered

Benzoates as Reusable Heterogeneous Catalysts for The Methyl Esterification of Benzoic Acid. Quim. Nova. 2012, 35, 1510-1516. 34

Robert, R. M.; Gibert, J. C. Modern Experimental Organic Chemistry, 4th ed.;

Saunders College Publishing: Philadelphia: PA, 1985; pp. 222-223. 35

Villermaux, E.; Duplat, J. Mixing is an aggregation process. Phys. Rev. Lett. 2003,

331, 515-523. 36

Zhang, S.; Rasmuson, Å. C. Thermodynamics and Crystallization of the

Theophylline-Glutaric Acid Cocrystal. Cryst. Growth Des. 2013, 13, 1153-1161. 31 ACS Paragon Plus Environment

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Stelzer, T.; Ulrich, J. No Product Design without Process Design (Control)? Chem.

Eng. Tech. 2010, 33, 723-729.

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Crystal Growth & Design

?



(a) 

(b)



(c)



(d) 5

10

15

20

25

30

35

2θ (degree)

Figure 1. PXRD patterns of (a) NaBz, (b) HBz, and (c) 1:1 and (d) 2:1 co-crystals of HBz-NaBz, whose characteristic peaks were labeled by ♦ 6.4o,  23.8o, ○ 6.0o and ● 7.2o.

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Crystal Growth & Design

100

NaBz

No weight loss

90 80

Weight (%)

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

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70 60

45.7%

1:1 HBz-NaBz

50 62.9%

40 2:1 HBz-NaBz 30 20 10 0

100%

HBz 50

100

150

200

250

300

o

Temperature ( C)

Figure 2. TGA scans of NaBz crystals, HBz crystals, and 1:1 and 2:1 co-crystals of HBz-NaBz.

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Crystal Growth & Design

Figure 3. Optical micrographs of crystals obtained in Experiments: (a) No.1, (b) No. 2, (c) No. 3, (d) No. 4, (e) No. 5, and (f) No. 6 (scale bar = 200 μm).

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Figure 4. Ternary phase diagram for HBz-NaBz-water system at 25oC and 1 atm. The composition was expressed as mass fraction.

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Crystal Growth & Design

Scheme 1. Reaction pathways for NaBz with HCl and optical micrographs of HBz, 2:1 co-crystals of HBz-NaBz and 1:1 co-crystals of HBz-NaBz.

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Scheme 2. Mixing effects on the evolution of HBz crystals, 1:1 and 2:1 co-crystals of HBz-NaBz in (a) Experiments No. 7 to No. 11, and (b) Experiment No. 12.

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Crystal Growth & Design

Table 1. Molar ratio of NaBz to HCl in Experiments No. 1 to No. 6. Experiment No.

1

2

3

4

5

6

Weight of NaBz (g) in 10 mL of water

5

5

5

5

5

5

2.8

3.4

5.6

8.4

11.2

14.0

12.4:1

10.0:1

6.2:1

4.1:1

3.1:1

2.5:1

14

17

28

42

56

70

Added volume of 1M HCl (mL)a Molar ratio of NaBz to HCl Experiment Time (min) a

0.1 mL of a 1M HCl was added into an aqueous solution of NaBz at an interval of 30 sec.

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Table 2. Operating conditions in Experiments No. 7 to No. 12 with the molar ratio of NaBz to HCl of 12.4:1. 7

8

9

10

11

12

Agitation rate (rpm)

600

600

75

75

75

600

Feeding rate (mL/min)

3.5

20

3.5

20

fed instantly

0.4

Experiment No.

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Crystal Growth & Design

Table 3. Compositions of product analysis based on TGA scans in Experiments No. 1 to No. 6. Experiment No.

Molar Ratio of NaBz to HCl

Product Composition

1

12.4

1:1 HBz-NaBz

2

10.0

1:1 HBz-NaBz 2:1 HBz-NaBz

3

6.2

1:1 HBz-NaBz 2:1 HBz-NaBz

4

4.1

1:1 HBz-NaBz 2:1 HBz-NaBz

5

3.1

HBz 2:1 HBz-NaBz

6

2.5

HBz 2:1 HBz-NaBz

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Page 42 of 43

Table 4. Compositions of product analysis versus time in Experiment No.7 to No. 12. 1 min

3 min

5 min

10 min

20 min

30 min

60 min

120 min

240 min

1:1 HBz-NaBz

1:1 HBz-NaBz

1:1 HBz-NaBz

1:1 HBz-NaBz

1:1 HBz-NaBz

1:1 HBz-NaBz

1:1 HBz-NaBz

1:1 HBz-NaBz

2:1 HBz-NaBz

2:1 HBz-NaBz

2:1 HBz-NaBz

2:1 HBz-NaBz

2:1 HBz-NaBz

2:1 HBz-NaBz

2:1 HBz-NaBz

2:1 HBz-NaBz

1:1 HBz-NaBz

1:1 HBz-NaBz

1:1 HBz-NaBz

1:1 HBz-NaBz

1:1 HBz-NaBz

1:1 HBz-NaBz

1:1 HBz-NaBz

1:1 HBz-NaBz

2:1 HBz-NaBz

2:1 HBz-NaBz

2:1 HBz-NaBz

2:1 HBz-NaBz

2:1 HBz-NaBz

2:1 HBz-NaBz

2:1 HBz-NaBz

2:1 HBz-NaBz

HBz

HBz

1:1 HBz-NaBz

1:1 HBz-NaBz

1:1 HBz-NaBz

1:1 HBz-NaBz

1:1 HBz-NaBz

1:1 HBz-NaBz

1:1 HBz-NaBz

1:1 HBz-NaBz

2:1 HBz-NaBz

2:1 HBz-NaBz

2:1 HBz-NaBz

2:1 HBz-NaBz

2:1 HBz-NaBz

2:1 HBz-NaBz

2:1 HBz-NaBz

2:1 HBz-NaBz

HBz

HBz

HBz

HBz

1:1 HBz-NaBz

1:1 HBz-NaBz

1:1 HBz-NaBz

1:1 HBz-NaBz

2:1 HBz-NaBz

2:1 HBz-NaBz

2:1 HBz-NaBz

2:1 HBz-NaBz

2:1 HBz-NaBz

2:1 HBz-NaBz

2:1 HBz-NaBz

2:1 HBz-NaBz

HBz

HBz

HBz

HBz

1:1 HBz-NaBz

1:1 HBz-NaBz

1:1 HBz-NaBz

1:1 HBz-NaBz

2:1 HBz-NaBz

2:1 HBz-NaBz

2:1 HBz-NaBz

2:1 HBz-NaBz

2:1 HBz-NaBz

2:1 HBz-NaBz

2:1 HBz-NaBz

2:1 HBz-NaBz

No solids

No solids

No solids

1:1 HBz-NaBz

1:1 HBz-NaBz

1:1 HBz-NaBz

1:1 HBz-NaBz

1:1 HBz-NaBz

1:1 HBz-NaBz

2:1 HBz-NaBz

2:1 HBz-NaBz

2:1 HBz-NaBz

2:1 HBz-NaBz

2:1 HBz-NaBz

HBz No. 7

1:1 HBz-NaBz 2:1 HBz-NaBz HBz

No. 8

1:1 HBz-NaBz 2:1 HBz-NaBz

No. 9

No. 10

No.11

No. 12

HBz 2:1 HBz-NaBz

2:1 HBz-NaBz

2:1 HBz-NaBz

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Crystal Growth & Design

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