Predicting the nucleation induction time based on preferred

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Predicting the nucleation induction time based on preferred intermolecular interactions Mitulkumar A Patel, Brittany Nguyen, and Keith Chadwick Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.7b00446 • Publication Date (Web): 26 Jul 2017 Downloaded from http://pubs.acs.org on July 30, 2017

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Crystal Growth & Design

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Predicting the nucleation induction time based on

2

preferred intermolecular interactions

3

Mitulkumar A. Patel1*, Brittany Nguyen1, and Keith Chadwick1

4 5

1

Department of Industrial and Physical Pharmacy, College of Pharmacy, Purdue University, West Lafayette, Indiana, United States.

ACS Paragon Plus Environment

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ABSTRACT

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A key challenge in rationally designing heterogeneous surfaces for controlling

8

crystallization is overcoming the lack of understanding the influence of surface properties on

9

nucleation. Previous studies have shown how surface chemistry can be used to control both

10

nucleation rate and polymorphism. However, these approaches are often empirical and lack any

11

predictive capability. Herein, a novel method, PETI (Predicting Efficacy Through Intermolecular

12

Interactions), for predicting the effectiveness of different polymer surfaces in promoting

13

heterogeneous nucleation is described. PETI utilizes the Cambridge Structural Database to

14

determine the likelihood of forming an intermolecular interaction between solute chemical

15

moieties and polymer surfaces. The concept for PETI is the more likely a solute/polymer

16

interaction, the faster the rate of heterogeneous nucleation. PETI was tested by studying the

17

nucleation of model compounds, benzocaine and 1,1'-Bi-2-naphthol, on different polymer

18

surfaces. Results showed that PETIs predictions for the effectiveness of the different polymers at

19

promoting nucleation were in good agreement with experimental observations. This study

20

represents a highly novel approach to predicting the effectiveness of surfaces in promoting

21

crystal nucleation and shows the potential utility of using knowledge of solid state intermolecular

22

interactions as a tool for the rational design of polymer surfaces for controlling heterogeneous

23

nucleation.


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INTRODUCTION

25

Controlling crystallization is crucial for the production of better materials in the field of

26

foods, pharmaceuticals, and electronics.1-5 Crystallization processes can be optimized by

27

controlling nucleation and/or crystal growth.4, 6 Controlling nucleation is of particular interest, as

28

it during this step that the crystal form is determined. Nucleation can occur either

29

homogeneously, or heterogeneously at an interface.7 Both homogeneous and heterogeneous

30

nucleation can be controlled using a variety of approaches. The use of additives, both soluble and

31

insoluble, to control nucleation has received considerable interest.8-17 Soluble additives such as

32

pH modifiers, surfactants, ionic strength modifiers, dissolved polymers and structurally related

33

compounds, have been shown to influence nucleation through direct interaction with a solute in

34

solution.8-12 In contrast, insoluble additives such as polymers, glasses, organic crystals, metal

35

surfaces, and self-assembled monolayers control nucleation by providing a heterogeneous

36

surface (solid-liquid interface) upon which self-assembly can be templated through a variety of

37

epitaxial mechanisms.13-17

38

The chemistry, crystallography, and topography of the surface have all been shown to

39

affect heterogeneous nucleation.18-22 In particular, chemistry has been shown to play a significant

40

role in controlling heterogeneous nucleation.13, 17, 19 Specifically, the intermolecular interactions

41

between the functional groups of the solute and hetero-surface play a key role in directing the

42

epitaxial mechanism.13, 19, 23, 24 Previous studies have shown that modifying the surface chemistry

43

of the hetero-surface can have a significant impact on nucleation rate and polymorphism.20, 25-27

44

However, these approaches are often empirical and lack any predictive capability. To our


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knowledge, no method exists for rationally selecting heterogeneous surfaces or predicting the

46

efficacy of a surface for promoting heterogeneous nucleation.

47

Herein, we discuss a novel method, named PETI (Predicting Efficacy through

48

Intermolecular Interactions) for predicting the relative effectiveness of different polymer surfaces

49

in promoting the heterogeneous nucleation of organic compounds. This is a first attempt

50

developing a predictive method for predicting the nucleation rate. Specifically, the aim of this

51

work is to understand whether knowledge gained from the evaluation of solid state

52

intermolecular

53

crystallographic data sets in CSD could be used to predict (1) heterogeneous nucleation kinetics

54

based on the favorability of an intermolecular interaction between a given functional group

55

present on a molecule of interest and different polymer surfaces and (2) how molecules may

56

orient themselves when adsorbed to a polymer interface. Our hypothesis is that the stronger the

57

interfacial interactions, the faster the rate of nucleation. In addition, heterogeneous nucleation on

58

disordered polymer surfaces is governed by epitaxial mechanisms that orientate the nucleus such

59

that strength of intermolecular interactions between the nucleus and surface are maximized.

interactions

(both

hydrogen

bonding

and

hydrophobic)

from

large

60

The utility of PETI has been tested using two model systems; (1) the nucleation of

61

benzocaine on polyethylene, polypropylene, polyvinylchloride, polyvinyl alcohol, polystyrene,

62

and poly(4-aminostyre) and (2) the nucleation of 1,1'-Bi-2-naphthol on polystyrene and

63

poly(N,N-dimethylacrylamide). We shall discuss how PETI was used to predict the relative

64

effectiveness of each polymer in promoting nucleation. Experimental data will be used to

65

demonstrate that PETI was successful in predicting the most effective polymer surface for

66

promoting the nucleation of both compounds. Finally, we shall describe the limitations of PETI

67

in accurately predicting the order of effectiveness of a library of polymers.


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68 69


EXPERIMENTAL SECTION Materials.

Benzocaine

(BZC),

1,1'-Bi-2-naphthol

(BINOL),

poly(N,N-

70

dimethylacrylamide) (PDMA), polyethylene (PE), polypropylene (PP), polyvinylchloride (PVC),

71

polyvinyl alcohol (PVA), polystyrene (PS), were all purchased from Sigma Aldrich (Saint Louis,

72

MO). Poly(4-aminostyre) (P4AS) was purchased from Polyscience, Inc. (Warrington, PA).

73

Ethanol (200 proof) was purchased from Fisher Scientific Inc.

74

Heterogeneous crystallization of BZC. A stock solution of BZC in ethanol with

75

concentration of 375 mg/mL, 390 mg/mL, and 405 mg/mL were prepared and syringe filtered

76

into scintillation vials (10 mL each) using a 0.2 µm Polytetrafluoroethylene (PTFE) membrane,

77

in order to remove any solid impurities. A pre-weighed amount (200 mg) of the insoluble

78

polymers such as PE, PP, PVC, PVA, PS and P4AS were added into these solutions, the vials

79

were then heated to 45 °C to ensure complete dissolution of the BZC.28-33 Then the vials were

80

quench cooled to 15 °C (supersaturation, σ = (c – csat)/csat = 1.64/1.75/1.85) and held at this

81

temperature until crystallization. Similar experiment was done for different crystallization

82

temperature (keeping the supersaturation = 1.64) BZC solution in ethanol with concentration of

83

425 mg/mL and 475 mg/mL were prepared (at 50 °C) and quench cooled to 18 °C and 21 °C,

84

respectively.

85

Induction time measurements. Nucleation induction time data for BZC with and

86

without different polymer surfaces present were collected using a Crystal16®.20 To observe and

87

compare the differences in acceleration of nucleation kinetics on six hetero-surfaces, the average

88

induction time >100 min and 850,000

152

crystal structures)35,

153

known occurrences (N) there are of an intermolecular interaction between each moiety of the

154

solute and the functional group present on the polymer. It was hypothesized that the greater the

155

value of N, the more favorable the interaction between the moiety and the polymer. Therefore,

156

the moiety with greater value of N is more likely to nucleate on the polymer. Table 1 is an

157

example of a CSD search to determine which BZC moieties (FGs) have the greatest value of N

158

with 6 different polymer surfaces (FGp). Based on these results the PETI predicts that BZC

36

was searched using IsoStar37 (Version 2.2.4) to determine how many


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159

moiety AA is most likely to interact with P4AS, PP, and PVA, while the BZC moieties AAE is

160

most likely to interact with PE, PS, and PVC.

161 162

Table 1: Table showing number of occurrence of intermolecular interactions between FGs

163

with FGp for various polymers (1= most effective and 6 = least effective). Polymer (FGp)

N (AA)

N (AAE)

Predicted interaction

P4AS (uncharged amine)

2924

701

AA

PP (methyl)

1998

1966

AA

PE (methylene)

1703

1987

AAE

PS (phenyl)

1298

1427

AAE

PVA (alcohol OH)

820

490

AA

PVC (terminal chloride)

669

824

AAE

164 165

Predicting the effect of interaction between FGs and FGp on nucleation kinetics. To

166

predict the efficacy of a polymer surface in promoting nucleation, we hypothesized that the more

167

favorable the intermolecular interaction between FGs and FGp the greater the rate of nucleation.

168

To determine the most favorable interaction, we used IsoStar. We propose that the rate of

169

nucleation (J) is directly proportional to the number of occurrences (N) of an intermolecular

170

interaction between FGs and FGp in the database (J ∝ N). Previous research also indicated that

171

the specific complementary/matching molecular functionality between the solute and the hetero-

172

surface influences the rate and the orientation of the nucleating crystal.19,

173

reasonable to hypothesis that the J is directly proportional to N.

25

Therefore, it is

174


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RESULTS AND DISCUSSION

176

Testing the Effectiveness of PETI

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177

To test the ability of PETI to predict the effectiveness of different polymer hetero-

178

surfaces on nucleation rate, BZC and BINOL were selected as the model compounds being

179

crystallized. Compound such as ROY, Carbamazepine, and Acetaminophen are known to

180

undergo polymorphic phase transformation when nucleated on various hetero-surfaces.25, 27, 40, 41

181

In our studies we wanted to study the nucleation kinetics for the same polymorph on different

182

polymeric hetero-surfaces. We found out that both BZC and BINOL do not alter the

183

polymorphic outcome when crystalized with various hetero-surface using different

184

supersaturation. In addition, having no polymorphic variation, BZC and BINOL have amine

185

group and aromatic group(s) which are common to many pharmaceutical compounds. Therefore,

186

BZC and BINOL were selected for this study.

187

First, PETI was used to rank the effectiveness of the polymers in promoting the

188

nucleation of BZC. Six polymer hetero-surfaces with differing chemical functionalities were

189

selected for this test; PE, PP, PVC, PVA, PS, and P4AS (Figure 2). As discussed above, we

190

hypothesized that the nucleation rate, J, is directly proportional to the number of occurrences, N,

191

of an intermolecular interaction between solute moieties (FGs) and FGp in the CSD. The values

192

of N for the interaction between different BZC moieties with FGp are shown in Table 1 and their

193

rankings for promoting nucleation are shown in Table 2. P4AS (N=2924) was predicted to be the

194

most effective polymer for promoting the nucleation of BZC. It was also predicted that BZC

195

would interact with P4AS through the AA moiety. After that, PP showed N=1998 for the BZC

196

AAE moiety, followed by PE which showed a value of N=1987 for BZC AA moiety. Therefore,

197

the PP was ranked second and PE third. PS, PVA, and PVC were ranked fourth, fifth and sixth,


10

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198

respectively. To validate the predictions, the nucleation induction times of BZC in the presence

199

of the different polymer hetero-surfaces were then measured experimentally.

200 201 202 203 204

Table 2: Table showing various polymers with predicted relative order and experimentally

205

observed order for their ability to nucleate BZC. 1 being most favorable to nucleate BZC

206

and 6 being the least favorable to nucleate BZC. Observed Polymer (FGp)

Predicted interaction

Predicted order order

P4AS (uncharged amine)

AA

1

1

PP (methyl)

AA or AAE

2

5

PE (methylene)

AAE

3

3

PS (phenyl)

AAE

4

4

PVA (alcohol OH)

AA

5

2

PVC (terminal chloride)

AAE

6

6

207 208

Experimental measurement of the average nucleation induction times of BZC in the

209

presence of polymer hetero-surfaces

210

Nucleation induction time is defined as the time period between the generation of

211

supersaturation and nucleation, where, nucleation is measured indirectly as the first detectable

212

crystal formation.42, 43 Prior to measuring the heterogeneous nucleation induction times, it was


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213

necessary to verify that (1) all the polymer surfaces were capable of heterogeneously

214

crystallizing the BZC and (2) all polymers surface crystallized the same polymorph of BZC. For

215

confirming the former, cooling crystallizations with the different polymers were carried out and

216

the resulting samples analyzed by SEM. The results showed that all the polymers were capable

217

of heterogeneously crystallizing BZC (Figure 3). To confirm that all the BZC crystallized on all

218

polymers is of same form XRPD analysis was performed. The result of the XRPD analysis

219

showed that in all cases BZC Form I crystallized (Figure S1).

220

Due to the stochastic nature of nucleation, for each polymer 80 induction times were

221

measured (under identical experimental conditions) in order to calculate the average nucleation

222

induction times. In determining nucleation induction times it was assumed that the time required

223

to generate the desired supersaturation was negligible. It was also assumed that the time between

224

primary and secondary nucleation occurring was negligible. Finally, it was also assumed that the

225

growth rate of BZC Form I is sufficiently fast such that the time between nucleation occurring

226

and the crystals becoming experimentally detectable is minimal.19

227

Once the experimental induction time data was collected, the average nucleation

228

induction times for BZC Form I from the ethanol were calculated using equation 2. It was

229

assumed that nucleation is a first order kinetic process and follows a Poisson distribution.19, 44-46

230

(2)

231

Where, P is the probability that crystallization will not be observed during a time interval,

232

t, and τ is average nucleation induction time. The τ was obtained by plotting ln P against t

233

(Figure 4). Using linear regression analysis, the value of τ and its associated error were

234

calculated for BZC with and without the polymers (Table 3). From Table 3 it can be clearly seen

235

that all the polymer hetero-surfaces reduce the average nucleation induction time when compared


12

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to the bulk value. P4AS was found to be the most effective for promoting the nucleation of BZC,

237

while the PVC was found to be the least effective. The experimental ranking of the polymer

238

hetero-surfaces were then compared with the ranking predicted by PETI (Table 2). The result of

239

this study showed that the method was overall successful in predicting the relative nucleation

240

rate of BZC on various polymeric heterogeneous surfaces. However, the order of nucleation of

241

PP and PVA were found to be changed with each other.

242 243

Table 3. Average Induction Times, τ (min), for BZC Form I from Ethanol with or without

244

the presence of various polymeric heterogeneous substrates (R2 for linear regressions were

245

found to be ≥ 0.95 for all conditions)

P4AS

σ = 1.64 at 15 °C 33 ± 1

σ = 1.75 at 15 °C 18 ± 1

σ = 1.85 at 15 °C 13 ± 1

σ = 1.64 at 18 °C 26 ± 2

σ = 1.64 at 21 °C 22 ± 1

PVA

110 ± 2

67 ± 3

38 ± 2

96 ± 3

47 ± 3

PE

126 ± 3

91 ± 2

55 ± 4

124 ± 3

66 ± 2

PS

156 ± 2

98 ± 4

68 ± 3

149 ± 3

76 ± 2

PP

168 ± 3

130 ± 3

77 ± 2

163 ± 4

95 ± 3

PVC

306 ± 3

228 ± 5

106 ± 2

279 ± 3

183 ± 3

none (bulk)

1238 ± 31

608 ± 18

398 ± 12

690 ± 17

424 ± 10

substrate

246 247 248

Effect of supersaturation and temperature of crystallization on BZC induction time

249

To analyze the influence of supersaturation and temperature of crystallization on induction time

250

and nucleating crystal plane, similar experiments were performed with higher supersaturations


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(1.75 and 1.85) and higher crystallization temperatures (18 and 21 °C, keeping supersaturation

252

constant to 1.64). The results indicated that the average induction time decreases as the

253

supersaturation and temperature of crystallization increase (Figure 4 and Table 3). However, the

254

relative order of polymers for their ability to nucleate BZC did not changed. This results suggests

255

that relative order of nucleation of BZC on the polymer surface was not changed over the range

256

of supersaturation and temperature of the crystallization tested in this study.

257

Mechanistic investigation of the BZC nucleation on various polymeric hetero-surfaces

258

As the predicted order of PVA for inducing crystallization of BZC does not match with

259

that of the experimental order further experiments were performed to analyze any effect of

260

slightly dissolved PVA in ethanol. Briefly, the PVA was stirred in the ethanolic solution of BZC

261

at conditions similar to that used for other crystallization experiments, to prepare a suspension.

262

Supernatant from this suspension was syringe filtered in to HPLC vials and analyzed for

263

induction times. The result of the study showed that the average induction times for PVA treated

264

ethanolic solution of BZC was found to be similar to that of the non-treated bulk (Figure S2 and

265

Table S1). This indicates that the slightly soluble PVA does not have any impact on induction

266

time and the observed effect is contribution from the insoluble PVA.

267

To investigate the reason behind the slight perturbation in the predicted and observed

268

nucleation rate of the BZC on the PVA and PP, a mechanistic study of the nucleation of BZC on

269

various polymers was carried out. A preferred orientation study by XRPD was performed to

270

identify the plane of the BZC crystal nucleated on various polymers. The surface chemistry of

271

the nucleated plane provides information regarding the specific polymer-BZC interaction

272

responsible for heterogeneous crystallization of BZC on that polymer. The results of the study

273

indicated that the (004) plane of the BZC Form I crystal nucleated on PVA, PP, PVC, PE, and


14

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274

P4AS films, while the (011) plane of the BZC Form I crystal nucleated on PE films (Figure S3).

275

Furthermore, the molecular chemistry of the (004) plane of the BZC Form I crystal showed the

276

presence of AA moiety (Figure 5A), which is in accordance with our preliminary prediction that

277

the AA moiety of the BZC have higher potential to interact with P4AS and PP.

278

On the other hand, the molecular chemistry of the (011) plane of BZC Form I crystal

279

indicated the presence of mixed aromatic amine and aliphatic-aromatic ester functional moiety

280

(Figure 5B). The PE indicated the presence of the (011) face on its surface, which was consistent

281

with the predictions. Nevertheless, PS and PVC deviate from our predictions and nucleate on the

282

(004) plane, indicating its interaction with AA moiety. A meticulous look at the (004) plane

283

indicates that the Phenyl group of the BZC is always present near the surface. Moreover, PS and

284

PVC form hydrophobic interactions with the aromatic portion (phenyl ring) of the BZC. An

285

IsoStar search for the phenyl group indicated that it has a higher tendency to interact with the

286

aromatic C-H (N=4993), substituted aromatic carbon (N=2496), and any C-Cl (N=4993). Such

287

types of interactions were not taken into consideration while predicting the most favorable

288

interaction between solute and polymer.

289

Similarly, to understand why the PVA was more effective than predicted, we also

290

checked for possible aromatic interactions. An IsoStar search for the phenyl group indicated that

291

it has higher tendency to interact with the alcohol OH (N=3321). In addition, the uncharged

292

aliphatic hydroxyl group was also found to be prone to interact with the substituted aromatic

293

carbon (N=2481) as well as aromatic C-H (N=4961). These results indicate that the interaction

294

between the BZC and the PVA not only involved the AA moiety but also a higher number of

295

nonbonded aromatic interactions. These types of small aromatic moieties (phenyl and aromatic

296

substituted carbon) of BZC were not considered while predicting using PETI. This was the


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297

reason why the PVA showed a higher preference over other polymers for enhancing the

298

nucleation of BZC.

299

The result of the study also indicated that the P4AS (containing 4-aminophenyl) has the

300

greatest effect on enhancing the nucleation rate of the BZC, which was due to their interaction

301

with BZC 4-aminophenyl group. This result was also consistent with the previous study, which

302

indicated that the nucleation rate of the API is enhanced on the substrate with the same

303

chemistry.19 Furthermore, according to these results, the primary amine containing polymer was

304

shown to interact successfully with the amine functional group of the BZC. In addition, the

305

alcohol containing polymer was shown to interact successfully with the amine functional group

306

of the BZC. This result is also consistent with some of the experimental results for the co-crystal

307

in general that showed that the alcohol (hydroxyl group) has a higher tendency to form

308

heterodimer with amine groups, while the primary amine is more prone to form homodimer with

309

amine group.47 This indicates that the information from the CSD regarding solid-state

310

intermolecular interactions can be used to predict the interactions between polymer and solute.

311

Our method was successful for predicting relative nucleation rates as well as the most favorable

312

interactions between a given compound and various polymer surfaces. In this method, while

313

selecting the BZC moieties, the BZC was broken down into only the hydrogen bonding moieties

314

of BZC (AA and AAE) because they are the strongest interactions. However, other weak

315

aromatic interactions that might play a role in influencing the nucleation of BZC were

316

disregarded. To validate this argument that the aromatic carbon plays a significant role in the

317

interactions, we selected a model compound BINOL as it has both aromatic moieties (for

318

nonbonded interactions) as well as hydroxyl moieties (capable of making hydrogen bond).

319

Predicting BINOL nucleation on competing polymer films


16

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320

To further validate the PETI, it was utilized for predicting the nucleation of BINOL, a

321

compound with both hydrogen bonding and nonbonding (aromatic) moieties. Further, to analyze

322

the capability of BINOL to be attract toward the surface containing aromatic FGp (hydrophobic)

323

vs aliphatic FGp (hydrophilic) we have selected PS and PDMA (Figure 6) as polymeric hetero-

324

surface, respectively. The different condition of this test is that the polymers are tested

325

competitively rather than sequentially, i.e. the major goal of this study is to figure out BINOL

326

being a majorly aromatic molecule, what is more important for BINOL crystallization, aromatic

327

surface or aliphatic surface. Therefore, only two polymers, PS and PDMA, were selected.

328

For this study, first, BINOL was categorized as two distinct chemical moieties; (1) all

329

aromatic interactions (aromatic C-H, substituted aromatic carbon, and phenyl) (Figure 6a, dotted-

330

line box) and (2) phenol OH (Figure 6b, solid-line box). The CSD was then searched using

331

IsoStar to determine the value of N for each moiety with the functional groups of PDMA

332

(aliphatic dimethylamino) and PS (phenyl). The search results showed that for the interaction

333

with functional group of PDMA, the N value for (1) all aromatic interactions was found to be

334

6432 and for (2) phenol OH was found to be 70 (Table 4). On other hand, the search results for

335

the interaction with functional group of PS, the N value for (1) all aromatic interactions was

336

found to be 8915 and for (2) phenol OH was found to be 3329 (Table 4). From these results, it

337

was inferred that, for both chemical moieties of BINOL, the N values are greater for PS.

338

Therefore, PETI predicts that the nucleation will be favored on PS. Furthermore, as the N values

339

for aromatic moieties are greater in both PDMA and PS, PETI predicts that a nucleating crystal

340

plane should consist of aromatic rich moieties for both polymers, and lesser chance of expecting

341

OH – surface interactions. To validate our predictions, the nucleation of BINOL was then

342

measured experimentally on both PS and PDMA films.


17


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343 344

Table 4. Table showing number of occurrence of intermolecular interactions between FGs

345

(of BINOL) with FGp for various polymers. Polymer (FGp)

N (all aromatic)

N (phenol OH)

8915 PS (phenyl) (aromatic C-H = 4993, substituted aromatic

3329

carbon = 2496, and phenyl = 1426) 6557 PDMA (aliphatic

(aromatic C-H = 4966, substituted aromatic

dimethylamino)

carbon = 807, and phenyl = 784)

73

346 347

Experimental validation of competitive BINOL crystallization

348

To validate our predictions, crystallizations of BINOL in the presence of both polymers

349

were carried out (supersaturation = 3.16). Visual inspection of the polymer surfaces during

350

crystallization revealed that BINOL first crystallized on the PS film and then the PDMA film

351

(Table 5). In addition, a significantly greater mass of BINOL crystallized on the PS film (Figure

352

7 and Table 5) compared to that on the PDMA film.

353

To analyze the influence of supersaturation and temperature of crystallization on

354

induction time and nucleating crystal plane, similar experiments were performed with higher

355

supersaturations (3.66 and 4.20) and higher crystallization temperatures (7.5 and 10 °C, keeping

356

supersaturation constant to 3.16). The results indicated that the induction time decrease as the

357

supersaturation and temperature of crystallization increase (Table 5). However, in all cases the

358

crystallization on PS was faster and produced more BINOL crystals compared to PDMA. This


18

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359

results suggests that preference of nucleation of BINOL on PS and PDMA surface did not

360

changed over the range of supersaturation and temperature of the crystallization tested in this

361

study.

362

Table 5. Induction time and amount of BINOL crystallized on PS and PDMA film at

363

various supersaturation.

Supersatu ration

Temperature of crystallization (°C)

Induction time on PS (min)

Induction time on PDMA (min)

BINOL on PS (µg/cm2)

BINOL on PDMA (µg/cm2)

4.20

5

7±2

15 ± 4

370 ± 50

50 ± 30

3.66

5

12 ± 3

28 ± 3

328 ± 37

43 ± 19

3.16

5

29 ± 5

74 ± 9

272 ± 21

29 ± 8

3.16

7.5

22 ± 2

62 ± 4

265 ± 17

30 ± 11

3.16

10

15 ± 2

49 ± 3

285 ± 22

35 ± 14

364 365

XRPD was used to identify the nucleating crystal plane(s) of BINOL on PS and PDMA

366

(Figure S4A-E). The result of the study showed that the (200) crystal plane of BINOL nucleated

367

on both surfaces for all different conditions. Analysis of the chemistry of the (200) face showed

368

aromatic rings exposed to the surface, while the OH groups were not present (Figure 8). This is

369

consistent with the PETI predictions that PS would be the most effective polymer for nucleating

370

BINOL and that the nucleating crystal planes for both polymers would be aromatic rich and OH

371

poor. In short, the PETI successfully predicted the effectiveness of polymers for nucleating

372

BINOL. Further, this study also indicates that the aromatic interactions influence the result of the

373

prediction.


19


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CONCLUSIONS

375

In conclusion, this study shows a novel approach to predict the efficiency of

376

heterogeneous nucleation by developing a unique predictive method, PETI. Developing PETI is

377

a first attempt to predict the most effective polymer, from a library of polymers, for promoting

378

heterogeneous nucleation of organic compounds. This method was designed based on the

379

favorability of intermolecular interactions between the functional group of the compound and the

380

surface (according to CSD). PETI utilizes both hydrogen bonding and hydrophobic interactions

381

exist in CSD to predict the relative order of heterogeneous nucleation kinetics and orientation of

382

molecules interacting with the surface. PETI was overall successful in predicting the most

383

effective hetero-surface, which can maximize the nucleation rate of the BZC on the polymer

384

surface. In addition, the PETI was also successful when utilized for predicting the nucleation

385

preference of the BINOL on competing surfaces. In both of these studies the molecules having

386

one or two functional moieties were tested. Furthermore, PETI assumes that there is only one

387

type of interaction involved in nucleation of solute on polymer. In the future, we will try to

388

expand the ability of PETI to make successful predictions using more complex organic

389

molecules containing wider varieties of chemical moieties. PETI could be applied to many

390

different types of industries such as food, electronics, and pharmaceutical for finding the most

391

effective polymer for controlling heterogeneous crystallization as well as the functional group

392

present in nucleating crystal plan. Application of PETI would help in improving the efficiency of

393

the research and development involving crystallization on polymer hetero-surfaces.

394

ASSOCIATED CONTENT

395

Supporting Information


20

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396


It covers materials and methods along with additional data. This material is available free

397

of charge via the Internet at http://pubs.acs.org.

398

AUTHOR INFORMATION

399

Corresponding Author

400

*To whom correspondence should be addressed: Mitulkumar A. Patel, Department of

401

Industrial and Physical Pharmacy, Purdue University, West Lafayette, Indiana-47906, USA.

402

Phone: 765-496-1693, Fax: 765-494-6545. E-mail: [email protected]

403

Author Contributions

404

The manuscript was written through contributions of all authors. All authors have given

405

approval to the final version of the manuscript.

406

ACKNOWLEDGMENT

407

We would like to thank Lilly Endowment, Inc. as this work was supported in part by a

408

grant from the Lilly Endowment, Inc., to the College of Pharmacy, Purdue University, West

409

Lafayette, Indiana-47906, USA.

410

REFERENCES

411 412 413 414 415 416 417 418 419 420 421 422 423 424 425

(1) Ulrich, D. R., Better ceramics through chemistry. In Transformation of Organometallics into Common and Exotic Materials: Design and Activation, Springer: 1988; p 207. (2) Stupp, S. I.; Braun, P. V., Molecular manipulation of microstructures: biomaterials, ceramics, and semiconductors. Science 1997, 277, 1242-1248. (3) Hartel, R. W., Advances in food crystallization. Annu. Rev. Food Sci Technol. 2013, 4, 277-292. (4) Rodríguez‐hornedo, N.; Murphy, D., Significance of controlling crystallization mechanisms and kinetics in pharmaceutical systems. J. Pharm. Sci. 1999, 88, 651-660. (5) Addadi, L.; Weiner, S., Control and design principles in biological mineralization. Angew. Chem. Int. Ed. Engl. 1992, 31, 153-169. (6) Davey, R.; Allen, K.; Blagden, N.; Cross, W.; Lieberman, H.; Quayle, M.; Righini, S.; Seton, L.; Tiddy, G., Crystal engineering-nucleation, the key step. CrystEngComm 2002, 4, 257264. (7) Pino-García, O.; Rasmuson, Å. C., Primary nucleation of vanillin explored by a novel multicell device. Ind. Eng. Chem. Res. 2003, 42, 4899-4909.


21


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

426 427 428 429 430 431 432 433 434 435 436 437 438 439 440 441 442 443 444 445 446 447 448 449 450 451 452 453 454 455 456 457 458 459 460 461 462 463 464 465 466 467 468 469 470

Page 22 of 33

(8) Judge, R. A.; Jacobs, R. S.; Frazier, T.; Snell, E. H.; Pusey, M. L., The effect of temperature and solution pH on the nucleation of tetragonal lysozyme crystals. Biophys. J. 1999, 77, 1585-1593. (9) Canselier, J., The effects of surfactants on crystallization phenomena. J. Dispersion Sci. Technol. 1993, 14, 625-644. (10) Lee, S.; Sanstead, P. J.; Wiener, J. M.; Bebawee, R.; Hilario, A. G., Effect of Specific Anion on Templated Crystal Nucleation at the Liquid−Liquid Interface. Langmuir 2010, 26, 9556-9564. (11) Saleemi, A.; Onyemelukwe, I. I.; Nagy, Z., Effects of a structurally related substance on the crystallization of paracetamol. Front. Chem. Sci. Eng. 2013, 7, 79-87. (12) Ozaki, S.; Kushida, I.; Yamashita, T.; Hasebe, T.; Shirai, O.; Kano, K., Inhibition of crystal nucleation and growth by water-soluble polymers and its impact on the supersaturation profiles of amorphous drugs. J. Pharm. Sci. 2013, 102, 2273-2281. (13) Diao, Y.; Myerson, A. S.; Hatton, T. A.; Trout, B. L., Surface design for controlled crystallization: The role of surface chemistry and nanoscale pores in heterogeneous nucleation. Langmuir 2011, 27, 5324-5334. (14) Tsekova, D. S.; Williams, D. R.; Heng, J. Y., Effect of surface chemistry of novel templates on crystallization of proteins. Chem. Eng. Sci. 2012, 77, 201-206. (15) Kim, K.; Lee, I. s.; Centrone, A.; Hatton, T. A.; Myerson, A. S., Formation of nanosized organic molecular crystals on engineered surfaces. J. Am. Chem. Soc. 2009, 131, 18212-18213. (16) López-Mejías, V.; Kampf, J. W.; Matzger, A. J., Nonamorphism in flufenamic acid and a new record for a polymorphic compound with solved structures. J. Am. Chem. Soc. 2012, 134, 9872-9875. (17) Patel, M. A.; Kaplan, K.; Yuk, S. A.; Saboo, S.; Melkey, K.; Chadwick, K., Utilization of Surface Equilibria for Controlling Heterogeneous Nucleation: Making the “Disappeared” Polymorph of 3-Aminobenzensulfonic Acid “Reappear”. Cryst. Growth Des. 2016, 16, 69336940. (18) Diao, Y.; Helgeson, M. E.; Myerson, A. S.; Hatton, T. A.; Doyle, P. S.; Trout, B. L., Controlled nucleation from solution using polymer microgels. J. Am. Chem. Soc. 2011, 133, 3756-3759. (19) Chadwick, K.; Chen, J.; Myerson, A. S.; Trout, B. L., Toward the rational design of crystalline surfaces for heteroepitaxy: role of molecular functionality. Cryst. Growth Des. 2012, 12, 1159-1166. (20) Quon, J. L.; Chadwick, K.; Wood, G. P.; Sheu, I.; Brettmann, B. K.; Myerson, A. S.; Trout, B. L., Templated nucleation of acetaminophen on spherical excipient agglomerates. Langmuir 2013, 29, 3292-3300. (21) Aizenberg, J.; Black, A. J.; Whitesides, G. M., Control of crystal nucleation by patterned self-assembled monolayers. Nature 1999, 398, 495-498. (22) Diao, Y.; Harada, T.; Myerson, A. S.; Hatton, T. A.; Trout, B. L., The role of nanopore shape in surface-induced crystallization. Nat. Mater. 2011, 10, 867-871. (23) Diao, Y.; Helgeson, M. E.; Siam, Z. A.; Doyle, P. S.; Myerson, A. S.; Hatton, T. A.; Trout, B. L., Nucleation under Soft Confinement: Role of Polymer–Solute Interactions. Cryst. Growth Des. 2011, 12, 508-517. (24) Hillier, A. C.; Ward, M. D., Epitaxial interactions between molecular overlayers and ordered substrates. Phys. Rev. B 1996, 54, 14037.


22

Page 23 of 33

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

471 472 473 474 475 476 477 478 479 480 481 482 483 484 485 486 487 488 489 490 491 492 493 494 495 496 497 498 499 500 501 502 503 504 505 506 507 508 509 510 511 512 513 514 515


(25) Lang, M.; Grzesiak, A. L.; Matzger, A. J., The use of polymer heteronuclei for crystalline polymorph selection. J. Am. Chem. Soc. 2002, 124, 14834-14835. (26) Kavuru, P.; Grebinoski, S. J.; Patel, M. A.; Wojtas, L.; Chadwick, K., Polymorphism of vanillin revisited: the discovery and selective crystallization of a rare crystal structure. CrystEngComm 2016, 18, 1118-1122. (27) Chadwick, K.; Myerson, A.; Trout, B., Polymorphic control by heterogeneous nucleation-A new method for selecting crystalline substrates. CrystEngComm 2011, 13, 66256627. (28) Ober, C. K.; Lok, K. P.; Hair, M. L., Monodispersed, micron‐sized polystyrene particles by dispersion polymerization. Journal of Polymer Science: Polymer Letters Edition 1985, 23, 103-108. (29) Chemical Resistance of PVC Products. http://www.ameriluxinternational.com/SideBarLinks/Technical%20Info/chemical_resistance_pv c.pdf (30) Polypropylene Chemical Resistance Guide. http://www.ineos.com/globalassets/ineosgroup/businesses/ineos-olefins-and-polymers-usa/products/technical-information--patents/ineospp-chemical-resistance-guide.pdf (31) Yang, B.; Liu, R.; Huang, J.; Sun, H., Reverse Dissolution as a Route in the Synthesis of Poly (vinyl butyral) with High Butyral Contents. Ind. Eng. Chem. Res. 2013, 52, 7425-7431. (32) Yuan, Z.; Chen, H.; Tang, J.; Zhao, D., A stable porous superhydrophobic high‐density polyethylene surface prepared by adding ethanol in humid atmosphere. J. Appl. Polym. Sci. 2009, 113, 1626-1632. http://www.polysciences.com/default/catalog(33) Poly(4-aminostyrene) polymer. products/poly4-aminostyrene/ (34) Patel, M. A.; AbouGhaly, M. H. H.; Schryer-Praga, J. V.; Chadwick, K., The effect of ionotropic gelation residence time on alginate cross-linking and properties. Carbohydr. Polym. 2016, 155, 362-371. (35) The Cambridge Crystallographic Data Centre (CCDC). https://www.ccdc.cam.ac.uk/ (36) Groom, C. R.; Bruno, I. J.; Lightfoot, M. P.; Ward, S. C., The Cambridge structural database. Acta Crystallographica Section B: Structural Science, Crystal Engineering and Materials 2016, 72, 171-179. (37) Bruno, I. J.; Cole, J. C.; Lommerse, J. P.; Rowland, R. S.; Taylor, R.; Verdonk, M. L., IsoStar: a library of information about nonbonded interactions. J. Comput. Aided Mol. Des. 1997, 11, 525-537. (38) Chakraborty, S.; Rajput, L.; Desiraju, G. R., Designing ternary co-crystals with stacking interactions and weak hydrogen bonds. 4, 4′-bis-Hydroxyazobenzene. Crystal Growth & Design 2014. (39) Kenneth, D.; AlanáHowie, R., Crystal engineering of hydrogen-bonded co-crystals between cyanuric acid and ‘diamide’molecules. Investigations on the formation and structure of co-crystals containing cyanuric acid and oxalyl dihydrazide. J. Mater. Chem. 1993, 3, 947-952. (40) Parambil, J. V.; Poornachary, S. K.; Tan, R. B.; Heng, J. Y., Template-induced polymorphic selectivity: the effects of surface chemistry and solute concentration on carbamazepine crystallisation. CrystEngComm 2014, 16, 4927-4930. (41) Price, C. P.; Grzesiak, A. L.; Matzger, A. J., Crystalline polymorph selection and discovery with polymer heteronuclei. J. Am. Chem. Soc. 2005, 127, 5512-5517.


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(42) Erdemir, D.; Lee, A. Y.; Myerson, A. S., Nucleation of crystals from solution: classical and two-step models. Acc. Chem. Res. 2009, 42, 621-629. (43) Davey, R.; Garside, J., From molecules to crystallizers: An introduction to crystallization. ed.; Oxford University Press, U. K.: 2000. (44) Laval, P.; Crombez, A.; Salmon, J.-B., Microfluidic droplet method for nucleation kinetics measurements. Langmuir 2008, 25, 1836-1841. (45) Knezic, D.; Zaccaro, J.; Myerson, A. S., Nucleation induction time in levitated droplets. J. Phys. Chem. B 2004, 108, 10672-10677. (46) Barlow, T. W.; Haymet, A., ALTA: An automated lag‐time apparatus for studying the nucleation of supercooled liquids. Rev. Sci. Instrum. 1995, 66, 2996-3007. (47) Wood, P. A.; Feeder, N.; Furlow, M.; Galek, P. T.; Groom, C. R.; Pidcock, E., Knowledge-based approaches to co-crystal design. CrystEngComm 2014, 16, 5839-5848.

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529

“For Table of Contents Use Only”

530

Manuscript title

531

Predicting the nucleation induction time based on preferred intermolecular interactions

532

Author list

533

Mitulkumar A. Patel, Brittany Nguyen, and Keith Chadwick

534

TOC graphic

535 536 537

Synopsis

538

This work describes the development of a novel method PETI – Predicting Efficacy Through

539

Intermolecular Interactions - for predicting the heterogeneous crystallization. PETI was overall

540

successful in predicting the most effective hetero-surface for crystallization of two model organic

541

compounds. Prediction made using PETI would be helpful to improve efficiency of the research

542

and development involving crystallization on polymer hetero-surfaces.


25


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Figure 1. Chemical structure of the BZC. The different functional moieties of benzocaine: (a) aromatic amine (dotted box), (b) aliphatic-aromatic ester (solid box). 103x53mm (300 x 300 DPI)


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Figure 2. Chemical structure various polymer used for prediction and validation of relative nucleation rate. 334x96mm (300 x 300 DPI)



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Figure 3. SEM micrographs of BZC crystallized on the different polymers (A) PE, (B) PVA, (C) PP, (D) PVC, (E) PS, and (F) P4AS. 214x120mm (300 x 300 DPI)


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Figure 4. A plot of ln P (obtained from induction time data) as a function of time for BZC in ethanol. (A) at 15 °C with supersaturation 1.64, (B) at 15 °C with supersaturation 1.75, (C) at 15 °C with supersaturation 1.85, (D) at 18 °C with supersaturation 1.64, and (E) at 21 °C with supersaturation 1.64. By utilizing the equation ln(P) = –t/τ (where P is the probability of not being crystallized with in fixed amount of time, t) the data are presented in the form of linear regression. The negative inverse of the slope (-1/τ) for the lines will give the values of the average induction time, τ. 330x345mm (300 x 300 DPI)



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Figure 5. (A) Molecular structures of the (004) plane of the BZC Form I crystals showing AA (dotted box) and AAE (solid box) groups and at the surface (B) Molecular structures of the (011) plane of the BZC Form I crystal showing presence of both AA (dotted box) and AAE (solid box) groups and at the surface. The solid line indicates the top surface of the corresponding plane. 159x117mm (300 x 300 DPI)


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Figure 6. Chemical structure of the material used for predicting the most favorable interaction between solute and a binary polymeric surface. Model compound 1,1'-Bi-2-naphthol (BINOL) highlighting phenyl (dotted box) and phenol (solid box) functional groups. The binary polymeric surface has two polymers: Polystyrene and Poly(N,N-dimethylacrylamide). 205x89mm (300 x 300 DPI)



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Figure 7. Selective crystallization of BINOL on the binary polymeric surfaces. (A) Photograph of the binary polymeric surface consisting of the PDMA (left) and PS (right) films showing heterogeneous nucleation of the BINOL crystals after cooling crystallization. Optical micrograph of BINOL crystals growing on (B) PDMA and (C) PS surface. 338x102mm (300 x 300 DPI)


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Figure 8. Molecular structures of the (200) plane of BINOL crystal showing the presence of both phenyl (dotted box) and phenolic (solid box) groups. The solid line indicates the top surface of the corresponding plane. 159x65mm (300 x 300 DPI)


Predicting the nucleation induction time based on preferred

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