Anomalous Role Change of Tertiary Amino and Ester Groups as

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Anomalous role change of tertiary amino and ester groups as hydrogen acceptors in Eudragit® E based solid dispersion depending on the concentration of Naproxen Hiroshi Ueda, Shinobu Wakabayashi, Junko Kikuchi, Yasuo Ida, Kazunori Kadota, and Yuichi Tozuka Mol. Pharmaceutics, Just Accepted Manuscript • DOI: 10.1021/mp5005417 • Publication Date (Web): 05 Feb 2015 Downloaded from http://pubs.acs.org on February 18, 2015

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Molecular Pharmaceutics

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Title page

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Anomalous role change of tertiary amino and ester

3

groups as hydrogen acceptors in Eudragit® E based

4

solid dispersion depending on the concentration of

5

Naproxen

6

Hiroshi Ueda,∗,†,‡, Shinobu Wakabayashi,† Junko Kikuchi,† Yasuo Ida,† Kazunori Kadota,‡ Yuichi

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Tozuka‡

8

† Physicochemical and Preformulation, Applied Chemistry for Drug Discovery, Innovative Drug

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Discovery Research Laboratories, Shionogi & Co., Ltd., 3-1-1, Futaba-cho, Toyonaka-shi,

10 11 12

Osaka, 561-0825, Japan ‡ Laboratory of Formulation Design and Pharmaceutical Technology, Osaka University of Pharmaceutical Sciences, 4-20-1, Nasahara, Takatsuki-shi, Osaka, 569-1094, Japan

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1 Environment ACS Paragon Plus


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Table of Contents (TOC)

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ABSTRACT GRAPHIC

16

ABSTRACT

17

KEYWORDS

18

ABBREVIATIONS

19

TEXT

20

1. INTRODUCTION

21

2. EXPERIMENTAL SECTION

22

3. RESULTS AND DISCUSSION

23

4. CONCLUSION

24

5. ACKNOWLEDMENT

25

6. REFERENCES

26

TABLE

27

FIGURE CAPTIONS

28

FIGURES

29


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ABSTRACT GRAPHIC:

31 32 33

ABSTRACT: Eudragit® E (EGE) is a basic polymer incorporating tertiary amino and ester

34

groups. The role of the functional groups of EGE in the formation of solid dispersion (SD) with

35

Naproxen (NAP) was investigated. The glass transition temperature (Tg) of EGE decreased with

36

the plasticizing effect of NAP up to 20% weight ratio. Addition of NAP at over 30% induced a

37

rise in Tg, with the maximum value being reached at 60% NAP. Further addition of NAP led to a

38

rapid drop of the Tg. A dramatic difference of physical stability between the SDs including 60

39

and 70% NAP was confirmed. The SD including 70% NAP rapidly crystallized at 40°C with

40

75% relative humidity, while the amorphous state could be maintained over 6 months in the SD

41

with 60% NAP. The infrared and 13C-solid state NMR spectra of the SDs suggested a formation

42

of ionic interaction between the carboxylic acid of NAP and the amino group of EGE. The SD

43

with 20% NAP raised the

44

with over 30% NAP. The change in the

45

ester group rose depending on the amount of NAP. From these findings, we concluded that the

46

role as hydrogen acceptor shifted from the amine to the ester group with an increase in amount of

47

NAP. Furthermore, the amino group did not contribute to the interaction of over 70% NAP.

48

These phenomena could be strongly correlated with Tg and stability.

13

C spin-lattice relaxation (T1) of the amino group, but it decreased 13

C-T1 disappeared with 70% NAP. The


13

C-T1 of the


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KEYWORDS: amorphous, solid dispersion, naproxen, Eudragit® E, glass transition temperature,

50

intermolecular interaction, stability, solid-state NMR.

51 52

ABBREVIATIONS

53

NAP,

54

poly(vinylpyrrolidone-co-vinylacetate); IMC, Indomethacin; SD, solid dispersion; Tg, glass

55

transition temperature; XRPD, X-ray powder diffraction; DSC, differential scanning calorimetry,

56

TGA, thermogravimetric analysis; FT-IR, Fourier transform infrared; NMR, nuclear magnetic

57

resonance; CP-MAS, cross-polarization magic angle spinning.; T1, spin-lattice relation time

Naproxen;

EGE,

Eudragit®

E;

PVP,

poly(vinylpyrrolidone);

58


PVPVA,

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TEXT

60

1. INTRODUCTION

61

Amorphization with disruption of the crystal lattice is a promising way to enhance the

62

solubility of a poorly water-soluble drug.1-4 A high-energy amorphous drug is often re-

63

crystallized through a thermodynamically unstable and non-equilibrium state.5 Its re-

64

crystallization in the gastrointestinal tract or during processing/storage causes a drop in solubility

65

and bioavailability. Thus, stabilization of an amorphous drug is an important issue and many

66

efforts have been made to improve the physicochemical properties of amorphous formulations.

67

Stabilization of an amorphous drug via dispersion into hydrophilic polymer at a molecular level

68

is well known. A solid dispersion (SD) formulation stabilizes an amorphous drug by increasing

69

the glass transition temperature (Tg) and causing intermolecular interaction with the dispersed

70

polymer. The physical stability of an amorphous drug generally depends on its storage

71

conditions; the molecular mobility of a drug dramatically increases under high humidity and

72

temperatures above Tg.6-7 The isothermal molecular mobility of an amorphous drug has been

73

evaluated by differential scanning calorimetry (DSC); enthalpy recovery after an aging process

74

was assessed from the endothermic peak at Tg, which reflected enthalpy relaxation.8 In addition

75

to their thermal properties, a formation of intermolecular interaction between drug and carrier

76

was commonly studied and could be correlated with the physical stability of solid dispersion.8-9

77

The specific interactions of amorphous drugs with the hydrophilic polymers such as

78

poly(vinylpyrrolidone) (PVP) or poly(vinylpyrrolidone-co-vinylacetate) (PVPVA) and cellulose

79

derivatives (hydroxypropylmethyl cellulose acetate succinate et al.) were determined by

80

spectroscopic analyses. 9-10 The hygroscopic nature of the polymer had a direct effect on the

81

stability of SD. The sorbed water induced a decrease in Tg and disruption of the drug-polymer



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interaction followed by crystallization.11-14 The phase separation of drug and polymer with

83

disruption of interaction can be detected by the DSC profile and infrared spectra.11-15 Raman

84

mapping directly visualized the drug-polymer miscibility with the distribution image of drug and

85

polymer.11-16 The importance of intermolecular interaction was also confirmed by spectroscopic

86

analysis of a co-amorphous formed from two low molecular weight drugs.17-18 For information

87

on the molecular state of lower weight molecules, solid-state nuclear magnetic resonance (NMR)

88

can be effectively used.19-22 The conversion from crystal to amorphous state, the local molecular

89

motion and the identification of interaction sites were successively evaluated by the solid state-

90

NMR chemical shift, spin-lattice relaxation (1H and 13C et al.) and 2D cross-polarization hetero-

91

nuclear correlation.

92

Selection of a suitable polymer and designing of composition were important for

93

formulation of SD. One of the commonly used polymers for amorphous formulation is Eudragit®

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E (EGE), which is based on dimethyl-amino-ethyl methacrylate, butyl methacrylate and methyl

95

methacrylate, and shows a cationic property through the incorporated tertiary amino group.23 The

96

stability and dissolution rate of the amorphous drugs have been improved by EGE. 24-25 The

97

stabilization effect of EGE on amorphous curcumin was superior to those of PVP and cellulosic

98

polymers. 26 This stability of the SD containing EGE could be correlated with the intermolecular

99

interaction through the tertiary amino group and the increase in the Tg. The formation of ionic

100

interaction between EGE and acidic drug such as Indomethacin (IMC) in the amorphous system

101

has been suggested.27-28 The IMC-EGE SD also gave unusual Tg-proportion profile. The glass

102

transition temperature of SD commonly decreases with increasing in the amount of drug due to

103

its plasticizing effect, while IMC acted as both plasticizer and anti-plasticizer to EGE depending

104

on the drug-polymer ratio. The glass transition temperature of EGE was decreased by IMC with


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the range of 0-20%. The addition of IMC at least 30% showed anti-plasticizing effect on EGE

106

and the Tg value reached the maximum at 70% IMC. Further amount of IMC re-decreased the

107

Tg.27-28 This Tg-proportion profile supported by the rheological experiment as a function of

108

IMC-EGE composition. The interaction between IMC and EGE was analyzed by FT-IR. The

109

infrared spectra showed disappearance of peaks related to the amino group of EGE and a change

110

in the carbonyl peak of IMC, suggesting the formation of IMC-EGE ionic interaction.27 The

111

infrared spectra representing the interaction between IMC and EGE showed a linear dependence

112

on the amount of IMC. This result could not explain the change in the Tg. There were other

113

possible factors, in addition to the ionic interaction, that could have contributed to the Tg-

114

proportion profile in IMC-EGE SD. Further physicochemical investigation for SD including

115

EGE and acidic drug is required, which should contribute to design of optimal formulations.

116

The present study investigated the role of the functional groups of EGE as a function of

117

drug-polymer proportion in SD. Naproxen (NAP) was used as an acidic drug with the potential

118

for rapid crystallization. PVP was selected as a model polymer for comparison with EGE. The

119

Tg with drug-polymer proportion was evaluated by DSC. The relationship between the change in

120

the Tg and physical stability was examined. An intermolecular interaction between NAP and

121

EGE was measured by FT-IR. The role of the functional groups of EGE as hydrogen acceptor in

122

the formation of intermolecular interactions at each proportion was examined based on results of

123

solid state-NMR spectra and spin-lattice relaxation times.

124 125

2. EXPERIMENTAL SECTION



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2.1.1. Materials. Naproxen was purchased from Sigma-Aldrich Japan Co. LLC. (Tokyo, Japan).

127

Eudragit® EPO (EGE: average molecular weight 47000) was a kind gift from Evonik Degussa

128

Japan Co., Ltd (Tokyo, Japan) and Kollidon® 90 (PVP: average molecular weight 125000) from

129

BASF Japan Ltd. (Tokyo, Japan). Methanol was purchased from Kanto Chemical Co., Inc.

130

(Tokyo, Japan).

131

2.2.

132

by the melting-quench cooling method. Crystalline NAP was melted by heating at 165°C and

133

quickly cooled with liquid nitrogen. The amorphization was confirmed by FT-IR and it was

134

carefully and quickly subjected to the measurements because amorphous NAP can undergo very

135

rapid crystallization.

Preparation of amorphous NAP and solid dispersions. Amorphous NAP was prepared

136

The SDs were prepared by spray drying followed by melting-quench cooling processes.

137

The homogeneous mixture was first prepared by spray drying as follows. Portions of 1 g of

138

NAP-PVP or NAP-EGE with 10-90% weight ratios at intervals of 10% were solved in 100 mL

139

of 95/5 (v/v) methanol/water solution. Spray drying of these solutions was performed with a

140

Büchi Mini Spray Dryer B-290 (Nihon Büchi K.K., Tokyo, Japan): inlet temperature 50°C,

141

outlet temperature 30°C, airflow 473 L/hr, aspirator 100% and feed rate 10%. The samples were

142

dried at room temperature under reduced pressure in a vacuum for 1 day. The spray dried

143

samples were placed on an aluminum plate and treated by melting-quench cooling. The

144

amorphization of the samples was confirmed by X-ray powder diffraction. The SDs were

145

abbreviated as follows: the SD which consists of 60% NAP and 40% EGE is given as NAP-EGE

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(60-40) SD.


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2.3.

X-ray powder diffraction (XRPD). The crystallinity of the SD was evaluated with an x-

148

ray diffractometer D8 Discover (Bruker AXS K.K., Kanagawa, Japan); the samples were

149

compressed onto an aluminum plate hole (diameter of 3 mm and depth of 0.2 mm). A Cu Kα

150

radiation point source (λ = 1.5418Å) was operated at 40 kV and 40 mA. The scan was performed

151

from 5 to 25° (2-theta) with oscillation of the sample around a combination of the X and Y axes

152

during data collection and the count time was 120 seconds. The results were analyzed by

153

GADDS for XP/2000 ver. 4. 1. 27 (Bruker AXS K.K., Kanagawa, Japan).

154

2.4.

155

measured with a TG/DTA6300 (SII Nano Technology Inc., Tokyo, Japan). The sample (3-5 mg)

156

was placed in an aluminum pan and heated at 10°C/min to 300°C. The change in gravity as a

157

function of temperature was recorded and analyzed by Muse standard analysis ver. 7.1 (SII Nano

158

Technology Inc., Tokyo, Japan).

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2.5.

160

2.5.1. Evaluation of glass transition temperature. To investigate thermal properties such as

161

Tg and melting temperature, DSC measurement was performed with a TA Q 1000 (TA

162

Instruments Japan, Tokyo, Japan). Indium and sapphire were used to calibrate temperature and

163

enthalpy. Nitrogen was used as the purge gas. The samples (1-2 mg) were weighed into an

164

aluminum pan with sealing. The thermal history of the samples was erased on the first scan:

165

heating from -30 to 170°C at 20°C/min followed by cooling to -30°C at 50°C/min. Subsequently,

166

the sample was re-heated to 170°C at 20°C/min; the glass transition temperature of the sample

167

was used on the second scan. Since amorphous NAP easily crystallizes under this measurement

168

condition, the Tg of NAP was measured as follows. The aluminum pan including NAP was

Thermo gravimetric analysis (TGA). Thermal degradation of NAP, EGE and PVP was

Differential scanning calorimetry (DSC).



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treated by melting-quench cooling and quickly transferred from liquid nitrogen to the DSC

170

chamber followed by heating -30 to 170°C. The results were analyzed using Universal Analysis

171

2000 ver. 4.7A (TA Instruments Japan, Tokyo, Japan). The theoretical Tg of the SD was

172

calculated by the Couchman-Karasz (CK) equation.8

173

Tg = (w1 • Tg1 + K • w2 • Tg2) / (w1 + K • w2)

(1)

174

where w1/ w2 and Tg1/Tg2 are weight fractions and glass transition temperatures (°C) of each

175

component, Tg is the theoretical glass transition temperature (°C), and K is obtained from

176

equation (2).

177

K = ∆Cp2 / ∆Cp1

(2)

178

where ∆Cp1 and ∆Cp2 are the change in the heat capacity (J/g • °C) of each component. The

179

theoretical Tgs were compared with the experimental values.

180

2.5.2. Enthalpy relaxation. Enthalpy relaxation as a molecular mobility index was examined

181

for EGE, NAP-EGE (20-80), (40-60), (60-40) and (70-30) SDs according to a previously

182

described method.8 The thermal history of the samples was erased in the first scan to 170°C

183

followed by rapid cooling to -30°C as mentioned above. The samples were aged at Tg-16.5°C for

184

1, 3, 5, 7 or 10 hours (hr) and re-heated to 170°C; enthalpy recovery was assumed from the

185

endothermic peak area at glass transition. The maximum enthalpy recovery was calculated using

186

equation (3):

187

ΔH∞ = ∆Cp • (Tg – T)

(3)


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where ∆H∞ is the maximum enthalpy recovery (J/g) and ∆Cp and Tg are the change in the heat

189

capacity (J/g • C) with glass transition and the glass transition temperature without aging (°C),

190

respectively. T is the aging temperature (°C). The relaxation fraction at each aging time was

191

calculated using the obtained ΔH∞ with equation (4): φ(t) = 1 – (ΔH/ΔH∞)

192

(4)

193

where ∆H is the observed enthalpy recovery on the DSC profile with the each aging time and

194

φ(t) is the relaxation fraction. The overall average relaxation time was calculated by fitting the

195

relaxation fraction to the Kohlrausch–Williams–Watts (KWW) equation (5): φ(t) = exp ( - (t/τ)β)

196

(5)

197

where t is the aging time (hr), and τ and β are the relaxation time (hr) and relaxation distribution

198

exponent, respectively.

199

2.6.

200

including 20, 40, 60 and 70% NAP were studied. Each sample was compressed on the aluminum

201

plate and stored in a desiccator at 40°C with 75% relative humidity (RH) (sodium chloride

202

saturated solution) condition. Before and after storage, all the samples were measured by XRPD

203

and Raman mapping.

204

2.7.

205

miscibility of the SDs with a Horiba Jobin Yvon LabRAM ARAMIS (Horiba, Ltd., Kyoto,

206

Japan) equipped with a 633 nm He-Ne laser. A SLMPLN20× (Olympus Corporation, Tokyo,

207

Japan) microscope objective lens was used. The Raman scattering was dispersed using a 600

Physical stability. The physical stability of the NAP-PVP and the NAP-EGE SDs

Raman mapping analysis. Raman mapping analysis was performed to evaluate the



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groove/min grating onto a Peltier-cooled changed-coupled device (CCD). Other experimental

209

conditions were as follows: hole 1000 µm, slit 100 µm, exposure time 0.5 second, accumulation

210

2 times and wavenumber range 4000-500 cm-1. The samples of crystalline NAP, EGE, PVP, the

211

NAP-EGE and the NAP-PVP SDs including 20, 40, 60 and 70% of NAP were compressed onto

212

the aluminum plate hole and their Raman spectra were collected. To prevent crystallization,

213

amorphous NAP was carefully treated; amorphous NAP after preparation in liquid nitrogen was

214

quickly set on the stage and measured. The obtained Raman spectra were analyzed by software

215

LabSpec ver. 5. 49. 08 (Horiba, Ltd., Kyoto, Japan). The distribution of NAP and EGE was

216

characterized by the peak intensity ratio of 3070 to 2960 cm-1. Raman images for the NAP-EGE

217

SDs before and after storage were described by mapping analysis for diameter of 1.5 mm at each

218

spot sized 50 × 50 µm.

219

2.8.

220

collected by the attenuated total reflection (ATR) method with a VERTEX 70 (Bruker Optics K.,

221

K., Tokyo, Japan) to evaluate the intermolecular interaction in the SDs. The samples of

222

crystalline NAP, EGE, PVP, NAP-EGE and NAP-PVP SDs at 10% intervals were set on the

223

sample stage and measured: resolution 4 cm-1, scan times 32, wavenumber 4000-500 cm-1. To

224

prevent crystallization, amorphous NAP was carefully and quickly measured: resolution 4 cm-1,

225

scan times 8, wavenumber 4000-500 cm-1. The results were analyzed by OPUS ver. 5. 0. 5.3

226

(Bruker Optics K.K., Tokyo, Japan).

227

2.9.

228

investigation of intermolecular interaction between NAP and EGE. The Varian NMR System

229

(Agilent Technologies, Tokyo, Japan) was used with a magnetic field of 14.09 T operating at 600

230

MHz 1H and the 150 MHz 13C frequency. The pure components and the SDs were placed into the

Fourier-transform infrared spectroscopy (FT-IR). The infrared spectrum was

Solid-state nuclear magnetic resonance. Solid-state NMR was used for the


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231

3.2 mm zirconia rotor before the measurement. The carbon cross-polarization magic angle

232

spinning (13C-CPMAS) spectra were acquired with relaxation delay 5-10 seconds (s), CP contact

233

time 3 ms, MAS speed at 20 kHz and 1H pulse of 2.1 µs. The probe temperature was regulated at

234

0°C. The total number of accumulations was 1500-2500 for each spectrum. All carbon spectra

235

were externally referenced to adamantane by setting the methylene peak to 38.52 ppm. Spin-

236

lattice relaxation time (T1) was evaluated for 1H and

237

recovery (180-τ-90°). 13C-T1 was measured with the reported pulse sequence.20

13

C. 1H-T1 was obtained with inversion

238 239

3. RESULTS AND DISCUSSION

240

3.1.

241

tertiary amino and the ester groups, which is based on dimethyl-amino-ethyl methacrylate, butyl

242

methacrylate and methyl methacrylate at a molar ratio of 2:1:1 (Fig. 1a).23 No evidence was

243

found for the ester groups contributing to intermolecular interaction, although EGE can form an

244

ionic interaction with acidic drug through its cationic property.24-28 Liu et al. studied an

245

interaction mechanism of EGE with acidic drug IMC. The addition of IMC causes broadening of

246

the FT-IR peaks assigned to the amino group of EGE, whereas no change in the peaks

247

corresponding to the ester group was observed.27

Chemical structures. Eudragit® E is widely used as a basic polymer incorporating the

248

Naproxen is a non-steroidal inflammatory drug that is used for pain treatment. The acidic

249

property of NAP is based on the carboxylic acid (Fig. 1b). Amorphous NAP has rapid

250

crystallization potential. The crystallization ability of amorphous drugs was separated into three

251

classes (I, II and III) by DSC analysis.29 The classification of amorphous was based on the

252

presence or absence of crystallization in heating-cooling-reheating cycles. Drugs crystallizing 13 Environment ACS Paragon Plus


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253

during the cooling process after melting were categorized as class I, representing high

254

crystallization ability. Class II drugs represented intermediate crystallization potential, i.e.,

255

crystallizing during the re-heating process but not the cooling process. Highly glass-forming

256

drugs which did not crystallize in any DSC process were defined as class III.29 Löbmann et al.

257

confirmed the high crystallization potential of NAP corresponding to a class I drug.17 In this

258

study, NAP was selected as the model drug for SD formulation with EGE because of its acidic

259

and strong crystallization properties.

260

3.2.

261

3.2.1. Glass transition temperature. Thermogravimetric analysis was performed for NAP,

262

EGE and PVP to confirm the occurrence of thermal degradation during heat treatment. The Tg

263

and melting temperature of the samples were less than 200°C. No drastic weight loss, reflecting

264

thermal degradation, was observed from 30 to 200°C (data not shown).

Thermal properties

265

Glass transition temperature is well-known as a vital index for the preparation conditions

266

and the physical stability of SD.9, 26, 29-31 Solid dispersions have been prepared at several tens of

267

degrees above Tg during heat treatment such as by hot-melt extrusion.30-31 The heating and high-

268

share mixing induced dispersion of the crystalline drug followed by dissolution into the glass

269

rubbery polymer at a molecular level. The physical stability of the amorphous drugs was affected

270

by the storage temperature.6, 26 The molecular mobility of the SD dramatically increased above

271

Tg, which caused drug-polymer phase separation and reduced the induction time of nucleation

272

and crystallization. The amorphous IMC including 5% PVP maintained the amorphous state

273

below Tg for a long period.8 The Tgs of the NAP-PVP and the NAP-EGE SDs as a function of

274

proportion were measured by DSC. Figure 2a shows the Tg plotted against NAP-PVP proportion.


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275

A single Tg reflecting good drug-polymer miscibility was confirmed at all proportions of NAP-

276

PVP. The Tg of PVP decreased depending on the amount of NAP in all concentration ranges.

277

The solid line in Fig 2a represents the theoretical Tg calculated by the CK equation. Although

278

the experimental Tgs exhibit slightly negative deviations from the theoretical Tgs for the whole

279

concentration range, their patterns were closely consistent with each other. Similar results were

280

reported for the other SDs.8, 32 The plot of Tg against the composition of NAP and EGE is given

281

in Fig. 2b; the calculated theoretical value is represented by the solid line. The Tg-proportion

282

profile of NAP-EGE can be divided into three regions. The Tg of EGE decreased up to 20%

283

NAP, where there was small negative deviation from the theoretical Tg like that of the NAP-PVP

284

SD. In contrast, the anti-plasticizing effect of NAP on the Tg was characterized in the SD

285

containing at least 30% NAP. The Tg showed a maximum at 60% NAP and a large positive

286

deviation was observed in the region between 30 and 60% NAP. The dramatic drop in the Tg

287

was induced by further addition of NAP. The single Tg was found for all the NAP-EGE

288

proportions, suggesting that drug-polymer phase separation did not occur. A similar Tg-

289

proportion profile was observed for the IMC-EGE SD.27-28 Indomethacin acted as both

290

plasticizer and anti-plasticizer for EGE in the low and middle concentration regions, respectively.

291

The Tg showed the maximum at 70% IMC.27 The stoichiometries of NAP or IMC to EGE at

292

maximum Tg were compared; the molecular weights of NAP (230.26), IMC (357.79) and

293

monomer unit of EGE were used. The molecular weight of EGE monomer unit was calculated as

294

399.52 based on 1:1:1 molar ratio of dimethyl-amino-methyl methacrylate, butyl methacrylate

295

and methyl methacrylate.33 In the present study; however, the calculation was performed with the

296

molar ratio of 2:1:1 of dimethyl-amino-methyl methacrylate, butyl methacrylate and methyl

297

methacrylate according to the material specification information,23 leading to 556.23 of the



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Page 16 of 50

298

molecular weight towards the EGE monomer unit. The stoichiometries of NAP to EGE with 10-

299

90% of NAP, increasing at 10% intervals, were 0.27, 0.60, 1.04, 1.61, 2.42, 3.62, 5.64, 9.66 and

300

21.74. The 60% weight fraction of NAP corresponded to 3.62 stoichiometry of NAP to EGE.

301

The stoichiometry of IMC to EGE at maximum Tg (70% IMC), interestingly, was 3.63.27 The

302

fact that the stoichiometries of drugs to EGE at maximum Tg were in agreement for the NAP-

303

EGE and the IMC-EGE SDs, suggested that a specific functional group such as the carboxylic

304

acid may be a key factor in the change in the Tg (Fig. 2b). The anti-plasticizing effect of IMC on

305

Tg of polymer was confirmed in the SD with PVA copolymer.34 The Tg of PVA copolymer

306

increased by addition of IMC, where the positive deviation from the theoretical Tg obtained from

307

CK equation was noted over the entire concentration of IMC for 10-90% weight ratios. The

308

increase in the Tg could be correlated with the formation of specific interaction between IMC

309

and PVA copolymer by FT-IR analysis. The peak representing the amide C=O of IMC at 1315

310

cm-1 clearly shifted to a higher wavenumber depending on the weight of PVA copolymer,

311

whereas change in this peak was small in the IMC-PVP and the IMC-PVPVA SDs. This result

312

suggested that the change in the Tg of the NAP-EGE SD with respect to the amount of NAP may

313

have arisen from a change in interaction at each NAP-EGE proportion.

314

3.2.2. Enthalpy relaxation. The non-equilibrium property in amorphous material induces

315

structural relaxation to an equilibrium glassy state with decreasing entropy, energy and free

316

volume.5 Structural relaxation has well been evaluated by DSC measurement.8 The crystalline

317

drug melted on heating and was cooled to below Tg where a sufficient cooling rate caused glass

318

formation without crystallization. The glass material was aged under isothermal temperature for

319

various periods. The amorphous material relaxed with time during the aging process. The

320

material treated with the aging process was subjected to the heating treatment where the


Page 17 of 50

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321

endothermic peak was observed at Tg. This endothermic event reflected the enthalpy recovery

322

from the relaxed state corresponding to the degree of the enthalpy relaxation. Hence, the

323

enthalpy relaxation rate could be estimated from the change in the degree of the enthalpy

324

recovery depending on the aging time. Matsumoto et al. reported the enthalpy relaxation rates of

325

amorphous IMC with or without polymers.8 The enthalpy relaxation rate of amorphous IMC was

326

clearly delayed with addition of polymer, suggesting a decrease in the whole molecular mobility.

327

In order to clarify the molecular mobility, the enthalpy relaxation rates of NAP-EGE SDs of

328

different proportions were evaluated. Figure 3 shows the enthalpy relaxation profiles of EGE and

329

NAP-EGE (20-80), (40-60), (60-40) and (70-30) SDs. The φ(t) of the samples dropped with

330

aging time and a rapid reduction occurred as the NAP concentration rose, implying an increase in

331

the molecular mobility. The enthalpy relaxation parameters were obtained from the fitting of the

332

KWW equation with the experimental values: relaxation time τ and relaxation exponential factor

333

β. The lines fitting the KWW equation for each sample are presented in Fig. 3; the enthalpy

334

relaxation parameters are presented in Table 1. Kawakami and Pikal reported that it was difficult

335

to estimate the enthalpy relaxation rate from τ and β because they were affected by the aging

336

period.35 The τβ was determined as the suitable value representing the enthalpy relaxation rate.

337

The amorphous drug treated with different aging times showed the equal τβ. In this study, τβ was

338

employed as the enthalpy relaxation index. As shown in Table 1, the increase in the weight of

339

NAP induced a decrease of τβ and it mostly reached a plateau at 60% NAP. This result indicated

340

that the whole molecular mobility of the SD including 60% NAP was approximately the same as

341

that of the NAP-EGE (70-30) SD

342

3.3.

Physical stability



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Page 18 of 50

343

3.3.1. Crystallization under humid condition. The physical stability of SD is conventionally

344

predicted from Tg. The crystallization rate of amorphous material was delayed with reduction of

345

the molecular mobility.6, 8, 35 Water sorption is an important factor for prediction of physical

346

stability of SD. Sorbed water in an amorphous formulation can act as a plasticizer exciting the

347

molecular mobility with reduction of Tg. A drug-polymer phase separation following disruption

348

of intermolecular interaction can be caused by sorbed water, which enhances nucleation and

349

crystallization rates of an amorphous drug in SD.11-14 To compare the crystallization rates of SDs

350

of different compositions, the NAP-PVP and the NAP-EGE SDs were stored at 40°C at 75% RH.

351

The XRPD patterns of PVP, NAP-PVP (20-80), (40-60), (60-40) and (70-30) SDs are shown in

352

Fig. 4a. The inhibition effect of PVP on the crystallization of amorphous NAP was confirmed.

353

The NAP-PVP (20-80) SD kept the amorphous state for 30 days. The NAP-PVP (40-60) SD also

354

kept the amorphous state for 3 days, but the sample stored more than 7 days had small X-ray

355

diffraction peaks, which increased with the storage period. More rapid crystallization was

356

induced in the NAP-PVP (60-40) and (70-30) SDs with the higher amounts of NAP. The NAP-

357

PVP SD offered physical stability depending on the concentration of PVP, which was consistent

358

with the change in Tg. On the other hand, the physical stability of the NAP-EGE SDs

359

dramatically changed at above or below 60% NAP. As shown in Fig. 4b, excellent stability was

360

observed for the NAP-EGE SD with between 20 and 60% NAP. The amorphous state was

361

retained for 30 days in these samples. However, the NAP-EGE (70-30) SD quickly crystallized

362

and the crystallinity reached a plateau after 1 day. The drastic decrease in the stability with more

363

than 70% NAP reflected the change in Tg as a function of composition; rapid drop of the

364

maximum Tg at 60% NAP occurred in the NAP-EGE (70-30) SD (Fig. 2b). The Tg of the NAP-

365

EGE (70-30) SD mostly coincided with that of the NAP-EGE (20-80)SD, however, which


Page 19 of 50

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366

showed a difference in their physical stabilities. Although it may be difficult for a Tg value to be

367

directly used as an index for the crystallization, the physical stability was predictable from the

368

change in Tg as a function of the proportion for the NAP-EGE SD. The stabilization effect of

369

EGE on an amorphous acidic drug has been explained by ionic interaction.19,

370

formation throughout the ionic interaction occurs in NAP-EGE SDs with up to 60% NAP where

371

the reduction of the molecular mobility was an ascription of the enhanced stability of the SDs

372

including 20-60% NAP (Fig. 3). We examined whether a stable formation in the NAP-EGE (60-

373

40) SD was retained at 70% NAP. The theoretical Tg between the NAP-EGE (60-40) SD and

374

amorphous NAP was calculated using the CK equation with the following hypothesis: the stable

375

formation composed by NAP-EGE (60:40) was retained in the NAP-EGE (70-30) SD and excess

376

NAP was crystallized. The theoretical Tg is represented as a dashed line in Fig. 2b. The

377

theoretical Tg showed a different pattern against the experimental profile, indicating that the

378

formation of the NAP-EGE (60-40) SD could not be retained in the NAP-EGE (70-30) SD. The

379

difference of stabilities between the NAP-EGE (60-40) and (70-30) SDs is likely to be caused by

380

the change in whole conformation.

381

3.3.2. Phase separation with Raman image. Drug-polymer phase separation is an undesirable

382

phenomenon for maintaining an amorphous state in the SD. An amorphous drug can be

383

stabilized in miscible dispersion into polymer via intermolecular interaction. Disruption of the

384

miscible binary system by physical stresses such as heating and water sorption lead to drug-

385

polymer phase separation followed by nucleation and crystallization.12-16 The miscibility of the

386

SD is usually determined by thermal and spectroscopic analyses; phase separation has been

387

detected from multiple Tg on a DSC profile, change in IR spectrum and inhomogeneous Raman

388

image. Raman mapping is a technique to directly visualize a distribution image of components


27-28

A stable


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Page 20 of 50

389

for phase separation and crystallization in the SD based on local point measurements.15, 36 The

390

Raman spectra of crystalline and amorphous NAP, EGE and the NEP-EGE SDs were first

391

obtained (Fig. 5). The specific peak at 3070 cm-1 appears in both amorphous and crystalline NAP,

392

but not in EGE. This peak decreased with the amount of EGE. The broad peak around 2960-2930

393

cm-1 was noted in the EGE spectrum. Although the peak was observed at 2940 cm-1 in both the

394

crystalline and amorphous NAP spectra, the shoulder peak corresponding to the EGE

395

concentration was found at 2960 cm-1 in the SDs. From these results, the peaks at 3070 and 2960

396

cm-1 were selected as the model peaks. Raman mapping was performed for the NAP-EGE SDs

397

based on the peak intensity ratio of 3070/2960 cm-1. The Raman images of the NAP-EGE (60-

398

40) and (70-30) SDs before and after storage are shown in Fig. 6a and b, respectively. The colors

399

were based on the intensity ratio of 3070/2960 cm-1 as described in Fig. 6. The NAP-EGE (60-

400

40) SD at the initial state exhibited miscible dispersion, which could be maintained after 30 days

401

(Fig. 6a). The miscible images for the NAP-EGE (20-80) and (40-60) SDs were also confirmed

402

before and after storage (data not shown). The Raman image of the NAP-EGE (70-30) SD is

403

shown in Fig. 6b. The miscibility was characterized before storage; the color changed from green

404

to aqua corresponding to the increase in the concentration of NAP compared to the NAP-EGE

405

(60-40) SD. This miscible state, however, could not be kept at 40°C with 75% RH and the

406

immiscible image was observed after 1 day. In addition to this immiscibility, the whole color

407

changed from aqua to red and pink colors. This result showed that the peak ratio of 3070 to 2960

408

cm-1 increased with the storage period. The peak at 3070 cm-1 of crystalline NAP was higher

409

than that of amorphous NAP (Fig. 5), suggesting that the change in the whole color reflected the

410

crystallization following the phase separation. Raman images of the NAP-EGE SDs agreed with


Page 21 of 50

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411

the physical stability (Fig. 4b). Rapid crystallization of the NAP-EGE (70-30) SD was induced

412

by the drug-polymer phase separation during storage.

413

3.4.

414

3.4.1. Fourier-transform

415

amorphous drug and polymer in SD could be determined by FT-IR analysis.9-14, 34 The FT-IR

416

spectra revealed the interaction mechanism on IMC-PVP or IMC–PVPVA SDs.9 The peak

417

corresponding to the carboxylic acid of IMC shifted with the formation of hydrogen bonding

418

with hydrogen acceptor of PVP or PVPVA. FT-IR analysis was used to evaluate the interaction

419

mechanism on NAP-PVP and the NAP-EGE SDs at each proportion. IR spectra of the NAP-PVP

420

SDs are given in Fig. 7a. The peak of amide C=O was observed at 1648 cm-1 in the PVP

421

spectrum. This peak shifted to a higher wavenumber by addition of NAP: 1658 cm-1 for the

422

NAP-PVP (70-30) SD. The peaks assigned to the carboxylic acid appeared in the carbonyl

423

region with amorphous NAP. The two C=O peaks at 1729 and 1699 cm-1 in the amorphous NAP

424

spectrum represented the free and the hydrogen bonded carboxylic acids, respectively. The peak

425

at 1729 cm-1 showed no change in the NAP-PVP SDs whereas that at 1699 cm-1 shifted to a

426

higher wavenumber depending on the amount of PVP; this peak disappeared at the NAP-PVP

427

(70-30) SD. These infrared spectra of the NAP-PVP SD suggested an intermolecular interaction

428

between the carboxylic acid of NAP and amide C=O of PVP. PVP would stabilize amorphous

429

NAP through the anti-plasticizing effect on Tg and the formation of an intermolecular interaction

430

(Fig. 2a and 4a). Liu et al. studied the interaction between IMC and EGE.27 The carboxylic acid

431

played an important role in the formation of the ionic interaction with the tertiary amino group of

432

EGE. The absence of the peak assigned to the carboxylic acid-forming dimer implied the

433

disruption of the carboxylic acid dimer of IMC in the IMC-EGE SD. The NAP-EGE SD showed

Intermolecular interaction depending on NAP-EGE proportion infrared

spectra.

The

intermolecular


interaction

between


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Page 22 of 50

434

a marked change in the carbonyl region; the two carbonyl peaks of amorphous NAP clearly

435

changed in the SD (Fig. 7b). The peak at 1729 cm-1 representing the free carboxylic acid in

436

amorphous NAP showed no change in the NAP-PVP spectra (Fig. 7a), but shifted to a lower

437

wavenumber in the NAP-EGE SD. This peak was located at 1726 cm-1 in the NAP-EGE (70-30)

438

SD and overlapped with the carbonyl peak of EGE at 60% NAP. The peak at 1699 cm-1

439

representing the hydrogen bonded carboxylic acid in amorphous NAP showed a higher shift to

440

1708 cm-1 at 60% NAP and disappeared in the NAP-EGE (50-50) SD. These spectral changes

441

suggested a disruption of the hydrogen bonding in amorphous NAP and a generation of

442

interaction between the carboxylic acid of NAP and a hydrogen acceptor of EGE. The tertiary

443

amino and the ester groups of EGE were focused upon as hydrogen acceptors. The small peaks

444

assigned to the tertiary amino group appeared at 2770 and 2820 cm-1. Their peaks were

445

broadened by addition of 10-40% NAP and disappeared at 50% NAP (data not shown). This

446

result indicated that the amino group of EGE participated in the formation of ionic interaction

447

with amorphous NAP. In addition to the amino group, the possibility of the ester group as a

448

hydrogen acceptor was assessed. The peaks corresponding to the ester group in the EGE

449

spectrum were characterized: C=O at 1722 cm-1 and C-H at 1150, 1190, 1240 and 1270 cm-1.23

450

As shown in Fig. 7b, NAP caused no change in the peaks corresponding to the ester group; thus,

451

a contribution of the ester group of EGE to the intermolecular interaction in the SD could not be

452

determined. Although the possibility of an ionic interaction in the NAP-EGE SD was suggested

453

by the FT-IR spectra, we were not able to differentiate the interaction mechanism between the

454

NAP-EGE SDs of different proportions due to the overlapping of peaks in the carbonyl region

455

and the small broad peaks of the amino group.


Page 23 of 50

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13

456

3.4.2.

C solid state NMR spectra. The FT-IR spectra showed that the carboxylic acid of

457

NAP and the amino group of EGE contributed to the formation of intermolecular interaction in

458

the SD. The role of the hydrogen acceptor of EGE was further investigated by

459

NMR measurement. The solid state-NMR study can give information on molecular state and be

460

applied to multiple component systems such as amorphous materials.19-22 Local interaction has

461

been evaluated by the chemical shift of the solid state-NMR spectra for SD.19, 37 Chauhan et al.

462

studied the inhibition effect of polymer on the precipitation of supersaturated IMC. The rank

463

order of the stabilization effect of polymer on supersaturated IMC was consistent with that of the

464

solid-sate stabilities of the SDs. The stabilization effect of the polymers on the supersaturated

465

drug was explained by the drug-polymer interaction from the FT-IR, Raman and 13C solid state-

466

NMR spectra.37 The 13C solid state-NMR analysis for mefenamic acid-EGE SD characterized the

467

amorphization of mefenamic acid with the peak broadening and the formation of ionic

468

interaction from the peak shifts of N-methyl and N-methylene in the amino groups.19 A similar

469

result was observed in the NAP-EGE SD. Figure 8 shows the

470

crystalline NAP, EGE and the NAP-EGE SDs. No

471

NAP could be detected because of the rapid crystallization feature of NAP during the procedure

472

and/or measurement. The

473

structure.38 The carbon peaks derived from the naphthalene ring appeared around 100-140 ppm.

474

Broadening of these peaks with amorphization was observed for the NAP-EGE SDs, which was

475

independent of the increase in EGE. The peak representing the carboxylic acid appeared around

476

180 ppm in the crystalline NAP spectrum. The peak of the carboxylic acid shifted to 182 ppm

477

with a peak shoulder in the NAP-EGE (70-30) SD. This low level of detection made it difficult

478

to estimate the role of the carboxylic acid in the NAP-EGE SD from the

13

13

13

C solid state-

C solid state-NMR spectra for

13

C solid state-NMR pattern of amorphous

C chemical shift of crystalline NAP was assigned to the chemical


13

C chemical shift.


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Page 24 of 50

479

Some change in the EGE spectrum could be determined in the NAP-EGE SDs. The peak of the

480

ester group was observed at 178 ppm in the EGE spectrum. This peak broadened with increasing

481

NAP concentration, suggesting that the ester group acted as a hydrogen acceptor in the NAP-

482

EGE SD. The peaks around 15-30 ppm in the EGE spectrum were assigned to the main carbon

483

chain. The peak at 20 ppm changed sharply with an increasing amount of NAP. This peak should

484

reflect the C14 peak of amorphous NAP. The N-methyl peak (red circle) was detected at 46 ppm

485

in the EGE spectrum where the shoulder peak appeared at 44 ppm. The disappearance of the

486

shoulder peak was noted in the NAP-EGE SDs. The change in the tertiary amino group of EGE

487

in the SD was observed in N-methylene (red triangle) and O-methyl (black triangle), appearing

488

at 58 and 53 ppm, respectively, in the EGE spectrum. The O-methyl peak showed no change on

489

addition of NAP while the N-methylene peak shifted from 58 to 56 ppm and disappeared at 20

490

and 40 % NAP. Two O-methylene peaks (red and black triangles) were detected at 64 and 65

491

ppm in the EGE spectrum. The increase in the amount of NAP in the SD did not affect the peak

492

at 65 ppm, whereas a reduction of the peak at 64 ppm was observed in the NAP-EGE SD spectra.

493

This result enabled us to assign the peak at 64 ppm to the O-methylene next to the amino group.

494

The findings from the FT-IR and the 13C solid state-NMR measurements strongly indicated that

495

the amino group of EGE played an important role in the formation of the ionic interaction with

496

the carboxylic acid of NAP (Fig. 7b and 8). Moreover, this suggested that the ester group of EGE

497

could act as a hydrogen acceptor.

498

3.4.3. Spin-lattice relaxation time. In order to investigate the whole and local molecular

499

mobilities of the NAP-EGE SD of different proportions, 1H-T1 and

500

carried out. Spin diffusion with neighbor protons is the major pathway for 1H-T1, which reflects

501

average and whole molecular mobility. The 1H-T1 of EGE increased by the formation of the SD


13

C-T1 measurements were

Page 25 of 50

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502

in 20-60% range of NAP (Fig. 9a). The result of the enthalpy relaxation provided information to

503

interpret the 1H-T1 data. The change in the enthalpy relaxation time showed that the whole

504

molecular mobility of the NAP-EGE SDs increased with the amount of NAP (Fig. 3 and Table 1).

505

The increase of the 1H-T1 depending on the NAP concentration should reflect the enhancement

506

of the whole molecular mobility. The 1H-T1 of the NAP-EGE (70-30) was comparable to that of

507

the SD including 60% NAP, which was consistent with the results of the enthalpy relaxation.

508

The physical stability of the NAP-EGE (60-40) SD was not related to the whole molecular

509

mobility (Fig. 3, 4b and 9a). The detection limit of homogeneity of the components was

510

discussed in terms of the DSC profile and the 1H-T1 experiments.39-41 According to these

511

literatures, the single Tg and 1H-T1 for all the NAP-EGE SDs implied good miscibility between

512

NAP and EGE at a several tens of nano-scale.

513

13

C-T1 mainly measures local molecular mobility through spin-spin diffusion of the

514

proton connecting to carbon.19,

42-44

515

mefenamic acid-EGE SD (24-76 weight ratio) has been reported.19 The 13C-T1 values assigned to

516

N-methylene and N-methyl of EGE were higher than that of the main carbon chain. It was

517

assumed that the large

518

motion compared to the main carbon chain in the polymer backbone. The formation of the

519

intermolecular interaction between the carboxylic acid of mefenamic acid and the tertiary amine

520

of EGE led to increases in the

521

mobility. In this study, the local molecular motion of the NAP-EGE SDs with different

522

proportion was measured by the

523

the weight of NAP; the different 13C-T1-proportion profiles could be characterized at each carbon

524

in EGE. The importance of the heterogeneous local motions in a structure was investigated by

A difference of

13

C-T1 values between EGE and the

13

C-T1 of N-methylene and N-methyl was based on high molecular

13

C-T1 assigned to the amino groups via activation of the local

13

C-T1 measurement. Figure 9b shows a plot of 13C-T1 against



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Page 26 of 50

525

Nunes et al.45 The activation energies of the different carbons of Symvastatin were obtained by

526

the spin-lattice relaxation time as a function of temperature, and the difference of these values

527

was discussed with increasing of entropy and physical stability. In the case of the NAP-EGE

528

system, the carbons of N-methylene and ester group showed notable changes depending on the

529

NAP concentration, respectively. The relaxation time of N-methylene increased in the NAP-EGE

530

(20-80) SD as the case of the mefenamic acid-EGE (24-76) SD.19 This result indicated the

531

activation of the amino group via ionic interaction. The

532

dropped at over 20% NAP; it mostly recovered to that of pure EGE at 70% NAP. This profile

533

suggested that the amino group had no interaction with NAP in the NAP-EGE (70-30) SD. It was

534

difficult to discuss the 13C-T1 of N-methyl because the change in the 13C-T1 was smaller than that

535

of N-methylene. In addition to the amino group, the role of the ester group could be

536

characterized by the

537

range of 40-60% NAP. This result indicated that the ester group of EGE can act as a hydrogen

538

acceptor at middle to high concentrations of NAP. The other 13C-T1 values derived from the O-

539

methyl and the main carbon chain showed no change dependent on the proportion. These

540

findings showed that the role of the hydrogen acceptor changed with the proportion; the amino

541

group played an important role in the interaction when the included NAP was relatively low, but

542

this function shifted to the ester group depending on the increase in the amount of NAP. The

543

contribution of the amino group to the intermolecular interaction mostly disappeared in the NAP-

544

EGE (70-30) SD. This phenomenon could cause a rapid drop in the Tg and a dramatic decrease

545

in the physical stability (Fig. 2b and 4b). This speculation is supported by the findings of Claeys

546

et al. who studied the effect of structural modification for EGE on the interaction with ibuprofen

547

(IBP).46 Reduction of the amino group content in EGE from 45% to 28% induced further positive

13

C-T1 value. The

13

13

C-T1 of N-methylene interestingly

C-T1 of the ester group dramatically increased in the


Page 27 of 50

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548

deviation of the Tg from the theoretical value obtained by the Gordon-Taylor equation. However,

549

the phase separation on the DSC profile and the crystallization were led by further reduction of

550

the amino group to 17%. Replacement of the n-butyl neighboring the ester to the t-butyl and the

551

insertion of a bulky isobornyl group did not hinder the ionic interaction between IBP and EGE.

552

The ester next to the n-butyl could not become involved in the interaction with NAP. These

553

findings led to the conclusion presented in the schematic image shown in Fig. 10. The amino

554

group dominantly acted as the hydrogen acceptor against the carboxylic acid of NAP when 80%

555

EGE was present (left image). In the concentration range between 30 to 60% NAP, both the

556

amino and the ester groups contributed to the interaction with NAP (center image). Further

557

increase in the weight of NAP induced a change in the NAP-EGE formation. The ester group

558

played an important role in the intermolecular interaction; the amino group did not act as

559

hydrogen acceptor at over 70% NAP (right image). The ester groups next to the O-methyl and/or

560

the amino group were strongly related to the interaction. The specific weight ratio of NAP-EGE

561

(60:40) corresponding to the 3.62 stoichiometry of NAP to EGE made the most consolidated

562

formation based on the optimal ratio of the carboxylic acid to the amino and the ester groups,

563

offering excellent stability of over 6 months at 40°C with 75% RH (data not shown). This

564

formation was disrupted by over 70% NAP, leading to marked reduction of the Tg and rapid

565

crystallization. The finding that the SDs of NAP-EGE and IMC-EGE showed the similar Tg-

566

proportion profile and the agreement of the molar ratio 3.62 to EGE at maximum Tg suggests

567

that the change in the interaction formation as a function of drug concentration can be based on a

568

specific functional group such as the carboxylic acid. Moreover, a local miscibility in amorphous

569

dispersion was recently investigated in which drug clusters corresponding to several nano-size



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

570

domain was discussed.39-41 A drug clustering at several nano-meter derived from a change in

571

conformation may be caused and lead to the rapid crystallization of the NAP-EGE (70-30) SD.

Page 28 of 50

572 573

4. CONCLUSION

574

We focused on the change in the role of the functional groups of EGE by the formation of

575

intermolecular interaction with NAP according to different proportions. The Tg of EGE

576

decreased with addition of 10-20% NAP. However, the anti-plasticizing effect on the Tg

577

appeared at over 30% NAP; the Tg had a maximum in the NAP-EGE (60-40) SD. The rapid drop

578

in Tg occurred in the range between 70-90% NAP. This Tg-proportion profile reflected the

579

physical stability of the SD; excellent stability was confirmed in the range of 20-60% NAP at

580

40°C with 75% RH, while the NAP-EGE (70-30) SD rapidly crystallized. The results of enthalpy

581

relaxation suggested that the change in the Tg as a function of proportion and the physical

582

stability could not be ascribed to the whole molecular mobility. The contribution of the

583

carboxylic acid of NAP and the amino group of EGE to the interaction was determined from FT-

584

IR and the

585

role of the hydrogen acceptor in EGE changed depending on the NAP concentration. The amino

586

groups played a role in the ionic interaction at 20% NAP. The SD containing the middle

587

concentration of NAP was stabilized by the contribution of both the amino and ester groups to

588

the interaction. The 3.62 stoichiometry of NAP to EGE induced the most consolidated formation

589

corresponding to the maximum Tg. On the other hand, the amount of NAP over 70% made the

590

ester group dominantly act as the hydrogen acceptor where the amino group did not participate in

591

the interaction, leading to the dramatic drop in the Tg and rapid crystallization. We believe that

592

our results are valuable for interpreting the the interaction mechanism for EGE-based SD. These

13

C-solid state NMR measurements. The

13

C-T1 result led to the conclusion that the


Page 29 of 50

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


593

findings should help develop a new SD carrier as well as design a suitable EGE based SD

594

formulation.

595



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

Page 30 of 50

596 597

AUTHOR INFORMATION

598

Corresponding Author

599

* Address: Physicochemical and Preformulation, Applied Chemistry for Drug Discovery,

600

Innovative Drug Discovery Research Laboratories, Shionogi & Co., Ltd., 3-1-1, Futaba-cho,

601

Toyonaka-shi, Osaka, 561-0825, Japan; Tel.: +81-6-6331-5747; Fax: +81-6-6332-6385; E-mail:

602

[email protected]

603 604

ACKNOWLEDGMENT

605

We thank Mr. Kenji Hama (Evonik Degussa Japan Co., Ltd) for the generous gift of Eudragit®

606

EPO and much valuable discussions for this research.

607


Page 31 of 50

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

608 609


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(2)

Sakurai, A.; Sakai, A.; Sako, K.; Maitani, Y. Polymer combination increased both

612

physical stability and oral absorption of solid dispersions containing a low glass

613

transition temperature drug. Chem. Pharm. Bull. 2012, 60, 459–464.

614

(3)

615 616

Chiou, W. L.; Riegelman, S. Pharmaceutical applications of solid dispersion systems. J. Pharm. Sci. 1971, 60, 1281–1302.

(4)

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617

Soluplus® as an effective absorption enhancer of poorly soluble drugs in vitro and in

618

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619

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621

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622

(6)

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amorphous state below and above its glass transition temperature. J. Pharm. Sci. 1994,

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625 626

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629

in relation to indomethacin crystallization. Pharm. Res. 1999, 16, 1722–1728.

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Taylor, LS.; Zografi, G. Spectroscopic characterization of interactions between PVP and indomethacin in amorphous. Pharm. Res. 1997, 14, 1691–1698.

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(10) Al-Obaidi, H; Lawrence, MJ; Al-Saden, N; Ke, P. Investigation of griseofulvin and

633

hydroxypropylmethyl cellulose acetate succinate miscibility in ball milled solid

634

dispersions. Int. J. Pharm. 2013, 443, 95–102.

635 636

(11) Konno, H.; Taylor, LS. Ability of different polymers to inhibit the crystallization of amorphous felodipine in the presence of moisture. Pharm. Res. 2007, 25, 969–978.

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(12) Rumondor, AC.; Taylor, LS. Effect of polymer hygroscopicity on the phase behavior of

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amorphous solid dispersions in the presence of moisture. Mol. Pharm. 2010, 7, 477–

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490.

640

(13) Rumondor, AC.; Wikström, H.; Van, Eerdenbrugh, B.; Taylor, LS. Understanding the

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642

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1209–1219.

644

(14) Marsac, PJ.; Rumondor, AC.; Nivens, DE.; Kestur, US.; Stanciu, L.; Taylor, LS. Effect

645

of temperature and moisture on the miscibility of amorphous dispersions of felodipine

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(15) Qiana, F.; Huanga, J.; Zhub, Q.; Haddadina, R.; Gawela, J.; Garmisea, R.; Hussaina, M.

648

Is a distinctive single Tg a reliable indicator for the homogeneity of amorphous solid

649

dispersion? Int. J. Pharm. 2010, 395, 232-235.

650

(16) Sinclair, W.; Leane, M.; Clarke, G.; Dennis, A.; Tobyn, M.; Timmins, P. Physical

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stability and recrystallization kinetics of amorphous ibipinabant drug product by

652

Fourier transform Raman Spectroscopy. J. Pharm. Sci. 2011, 100, 4687-4699.

653

(17) Löbmann, K.; Laitinen, R.; Grohganz, H.; Gordon, KC.; Strachan, C.; Rades, T.

654

Coamorphous Drug Systems: Enhanced physical stability and dissolution rate of

655

indomethacin and naproxen. Mol. Pharm. 2011, 8, 1919-1928.

656

(18) Löbmann, K.; Laitinen, R.; Grohganz, H.; Strachan, C.; Rades, T.; Gordon, KC. A

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theoretical and spectroscopic study of co-amorphous naproxen and indomethacin. Int. J.

658

Pharm. 2013, 453, 80-87.

659

(19) Kojima, T.; Higashi, K.; Suzuki, T.; Tomono, K.; Moribe, K.; Yamamoto, K.

660

Stabilization of a supersaturated solution of mefenamic acid from a solid dispersion

661

with EUDRAGIT® EPO. Pharm. Res. 2012, 29, 2777-91.

662 663 664

(20) Torchia DA. The measurement of proton-enhanced carbon-13T1 values by a method which suppresses artifacts. J. Magn. Reson. (1969). 1978, 30, 613-616. (21) BVogt, FG; Clawson, JS, Strohmeier, M; Edwards, AJ; Pham, TN; Watson, SA. Solid-

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state NMR analysis of organic cocrystals and complexes. Crystal Growth and Design.

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669

FG. Analysis of amorphous solid dispersions using 2D solid-state NMR and (1)H T(1)

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relaxation measurements. Mol. Pharm. 2010, 7, 1667-1691.

671

(23) Product specifications. EUDRAGIT E100, EUDRAGIT EPO and EDRAGIT E.

672

http://eudragit.evonik.com/product/eudragit/Documents/evonik-specification-eudragit-

673

e-100-e-po-e-12,5.pdf. 2012.

674

(24) Horisawa, E.; Danjo, K.; Haruna, M. Physical properties of solid dispersion of a

675

nonsteroidal anti-inflammatory drug (M-5011) with Eudragit E. Drug Dev. Ind. Pharm.

676

2000, 26, 1271-1278.

677

(25) Valizadeh, H.; Zakeri-Milani, P.; Barzegar-Jalali, M.; Mohammadi, G.; Danesh-

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Bahreini, MA.; Adibkia, K.; Nokhodchi, A. Preparation and characterization of solid

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dispersions of piroxicam with hydrophilic carriers. Drug Dev. Ind. Pharm. 2007, 33,

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45-56.

681

(26) Wegiel, LA.; Zhao, Y.; Mauer, LJ.; Edgar, KJ.; Taylor, LS. Curcumin amorphous solid

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dispersions: the influence of intra and intermolecular bonding on physical stability.

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Pharm. Dev. Technol. 2014, 19, 976-986.

684

(27) Liu, H.; Zhang, X.; Suwardie, H.; Wang, P.; Gogos, CG. Miscibility studies of

685

indomethacin and Eudragit® E PO by thermal, rheological, and spectroscopic analysis.

686

J. Pharm. Sci. 2012, 101, 2204-2212.


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(28) Chokshi, RJ.; Shah, NH.; Sandhu, HK.; Malick, AW.; Zia, H. Stabilization of low glass

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transition temperature indomethacin formulations: impact of polymer-type and its

689

concentration. J. Pharm. Sci. 2008, 98, 2286-2298.

690

(29) Baird, JA; Van Eerdenbrugh, B.; Taylor, LS. A classification system to assess the

691

crystallization tendency of organic molecules from undercooled melts. J. Pharm. Sci.

692

2010, 99, 3787-3806.

693

(30) Nagy, ZK.; Balogh, A.; Vajna, B.; Farkas, A.; Patyi, G.; Kramarics, A.; Marosi G.

694

Comparison of electrospun and extruded Soluplus®-based solid dosage forms of

695

improved dissolution. J. Pharm. Sci. 2012, 101, 322-332.

696

(31) Maniruzzaman, M.; Boateng, JS.; Bonnefille, M.; Aranyos, A.; Mitchell, JC.;

697

Douroumis, D. Taste masking of paracetamol by hot-melt extrusion: an in vitro and in

698

vivo evaluation. Eur. J. Pharm. Biopharm. 2012, 80, 433-442.

699 700

(32) Konno, H.; Taylor, LS. Influence of different polymers on the crystallization tendency of molecularly dispersed amorphous felodipine. J. Pharm. Sci. 2006, 95, 2692-2705.

701

(33) Priemel, PA.;, Laitinen, R.; Grohganz, H.; Rades, T.; Strachan, CJ. In situ

702

amorphisation of indomethacin with Eudragit® E during dissolution. Eur. J. Pharm.

703

Biopharm. 2013, 85, 1259-1265.

704

(34) Ueda, H.; Aikawa, S.; Kashima, Y; Kikuchi, J; Ida, Y; Kadota, K; Tozuka, Y. Anti-

705

plasticizing effect of amorphous indomethacin induced by specific intermolecular

706

interaction with PVA copolymer. J. Pharm. Sci. 2014, in press, DOI: 10.1002/jps.24023.



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707

(35) Kawakami, K.; Pikal, MJ. Calorimetric investigation of the structural relaxation of

708

amorphous materials: evaluating validity of the methodologies. J. Pharm. Sci. 2005, 94,

709

948-965.

710

(36) Ueda, H.; Ida, Y.; Kadota, K.; Tozuka, Y. Raman mapping for kinetic analysis of

711

crystallization of amorphous drug based on distributional images. Int. J. Pharm. 2014,

712

462, 115-122.

713

(37) Chauhan, H.; Kuldipkumar, A.; Barder, T.; Medek, A.; Gu, CH.; Atef, E. Correlation of

714

inhibitory effects of polymers on indomethacin precipitation in solution and amorphous

715

solid crystallization based on molecular interaction. Pharm. Res. 2014, 31, 500-15.

716

(38) Ando, S.; Kikuchi, J.; Fujimura, Y.; Ida, Y.; Higashi, K.; Moribe, K.; Yamamoto, K.

717

Physicochemical characterization and structural evaluation of a specific 2:1 cocrystal of

718

naproxen-nicotinamide. J. Pharm. Sci. 2012, 101, 3214-3221.

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719

(39) Policianova, O; Brus, J; Hruby, M; Urbanova, M; Zhigunov, A; Kredatusova, J; Kobera,

720

L. Structural diversity of solid dispersions of acetylsalicylic acid as seen by solid-state

721

NMR. Mol. Pharm. 2014, 11, 516-530.

722

(40) Yua, X; Sperger, D; Munson, EJ. Investigating miscibility and molecular mobility of

723

nifedipine-PVP amorphous solid dispersions using solid-state NMR spectroscopy. Mol.

724

Pharm. 2014, 11, 329-337.

725

(41) Litvinov, VM;, Guns, S; Adriaensens, P; Scholtens, BJ; Quaedflieg, MP; Carleer, R;

726

Van den Mooter, G. Solid state solubility of miconazole in poly[(ethylene glycol)-g-

727

vinyl alcohol] using hot-melt extrusion. Mol. Pharm. 2012, 9, 2924-2932.


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728 729

(42) Calucci, L.; Galleschi, L.; Geppi, M.; Molliza, G. Structure and dynamics of flour by

730

solid state NMR: effects of hydration and wheat aging. Biomacromol. 2004, 5, 1536-

731

1544.

732 733

(43) Lim, AR.; Kim, JH.; Novak, BM. Solid state 13C nuclear magnetic resonance for polyguanidines. Polymer. 2000, 41, 2431-2438.

734

(44) Luo, H.; Chen, Q.; Yang, G; Xu, D. Phase structure of ethylene-dimethylaminoethyl

735

methacrylate copolymers and its relation to comonomer content as studied by solid-

736

state high-resolution 13C n.m.r. spectroscopy. Polymer. 1998, 39, 943-947.

737

(45) Nunes, TG; Viciosa, MT; Correia, NT; Danède, F; Nunes, RG; Diogo, HP. A stable

738

amorphous statin: solid-state NMR and dielectric studies on dynamic heterogeneity of

739

simvastatin. Mol. Pharm. 2014, 11, 727-737.

740

(46) Claeys, B; De, Coen R; De, Geest BG; de, la Rosa VR; Hoogenboom, R; Carleer, R;

741

Adriaensens, P; Remon, JP; Vervaet, C. Structural modifications of polymethacrylates:

742

impact on thermal behavior and release characteristics of glassy solid solutions. Eur. J.

743

Pharm. Biopharm. 2013, 85, 1206-1214.

744 745



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

746

Page 38 of 50

TABLE

747

Table 1. Enthalpy relaxation parameters τ (hr)

β

τβ (hr)

EGE

67.96

0.49

8.02

NAP-EGE (20-80) SD

104.58

0.28

3.76

NAP-EGE (40-60) SD

13.46

0.30

2.21

NAP-EGE (60-40) SD

7.62

0.28

1.76

NAP-EGE (70-30) SD

4.84

0.30

1.61

748 749


Page 39 of 50

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


750

FIGURE CPATIONS

751

Figure 1. Chemical structures of (a) Eudragit® E (EGE) and (b) Naproxen (NAP).

752

Figure 2. Glass transition temperature as a function of proportion: (a) NAP-PVP and (b) NAP-

753

EGE solid dispersions (SDs). The solid line represents the theoretical Tg in both (a)

754

and (b). The theoretical Tg between the NAP-EGE (60-40) SD and NAP were

755

represented by the dashed line in (b). The error bars were standard deviation of n=3.

756

Figure 3. Enthalpy relaxation data; circle, triangle, square, rhombus and cross symbols are EGE,

757

the NAP-EGE (20-80), (40-60), (60-40) and (70-30) SDs, respectively. The lines

758

represent the best fit to the KWW equation. The solid, dotted, dashed, dash-dotted and

759

chained lines represent EGE, the NAP-EGE (20-80), (40-60), (60-40) and (70-30) SDs,

760

respectively.

761

Figure 4. XRPD patterns of (a) NAP-PVP and (b) NAP-EGE SDs. The data represent initial and

762

1, 3, 7, 15 and 30 days after storage at 40°C with 75% RH from bottom to top,

763

respectively.

764 765

Figure 5. Raman spectra of EGE, the NAP-EGE (20-80), (40-60), (60-40) and (70-30) SDs, amorphous and crystalline NAP, from bottom to top, respectively.

766

Figure 6. Raman images of the NAP-EGE SDs: the NAP-EGE (a) (60-40) and (b) (70-30) SDs

767

before and after storage. The right side bar represents the peak intensity ratio of 3070

768

to 2960 cm-1.



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

769 770 771 772

Figure 7. FT-IR spectra; EGE, the NAP-EGE SDs at 10% interval and amorphous NAP were represented from bottom to top, respectively. Figure 8. 13C solid state NMR spectra of EGE, the NAP-EGE (20-80), (40-60), (60-40) and (7030) SDs, and crystalline NAP, from bottom to top, respectively.

773

Figure 9. (a) 1H-T1 and (b) 13C-T1 values as a function of proportion for the NAP-EGE SD.

774

Figure 10. Schematic image for intermolecular interaction changes with proportion between

775

NAP and EGE.

776 777


Page 40 of 50

Page 41 of 50

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


778

FIGURES

779

Figure 1.

780

(a)

x

y

z

781 782 783

(b)

784 785



786

Figure 2.

787

(a)

180

Tg (°C)

150 120 90 60 30 0 0

20

40

60

80 100

Weight of NAP (%) 788 789 790

(b)

40 30

Tg (°C)

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

20 10 0 0

20

40

60

80 100

Weight of NAP (%) 791


Page 42 of 50

Page 43 of 50

792

Figure 3.

1.0 ● EGE ▲ NAP-EGE (20-80) SD

0.8

φ (t)

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


■ NAP-EGE (40-60) SD ◆ NAP-EGE (60-40) SD ＋ NAP-EGE (70-30) SD

0.6 0.4 0.2 0

2

4 6 Time (hr)

8

10

793 794 795 796



797 798

Figure 4. (a)

NAP-PVP (20-80) SD

NAP-PVP (40-60) SD

NAP-PVP (60-40) SD

NAP-PVP (70-30) SD

Counts

30 days 15 days 7 days 3 days 1 day Initial

5 10 15 20 25

5 10 15 20 25 5 10 15 20 25 2-theta (°)

5 10 15 20 25

799 800 801

(b)

NAP-EGE (20-80) SD

NAP-EGE (40-60) SD

NAP-EGE (60-40) SD

NAP-EGE (70-30) SD

30 days

Counts

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

Page 44 of 50

15 days 7 days 3 days 1 day Initial

5 10 15 20 25

5 10 15 20 25

5 10 15 20 25

2-theta (°) 802 803


5 10 15 20 25

Page 45 of 50

804

Figure 5.

Raman Intensity

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


NAP (crystalline) NAP (amorphous) NAP-EGE NAP-EGE NAP-EGE NAP-EGE EGE

(70-30) SD (60-40) SD (40-60) SD (20-80) SD

3200 3100 3000 2900 2800 Wavenumber (cm-1) 805 806



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

807

Figure 6.

808

(a)

809 810 811

(b)

812 813


Page 46 of 50

Page 47 of 50

Figure 7.

815

(a)

ATR Units

814

NAP (amorphous) NAP-PVP (90-10) SD NAP-PVP (80-20) SD NAP-PVP (70-30) SD NAP-PVP (60-40) SD NAP-PVP (50-50) SD NAP-PVP (40-60) SD NAP-PVP (30-70) SD NAP-PVP (20-80) SD NAP-PVP (10-90) SD PVP

1800 1600 1400 1200 1000 Wavenumber (cm-1) 816 817

(b)

ATR Units

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


NAP (amorphous) NAP-EGE (90-10) NAP-EGE (80-20) NAP-EGE (70-30) NAP-EGE (60-40) NAP-EGE (50-50) NAP-EGE (40-60) NAP-EGE (30-70) NAP-EGE (20-80) NAP-EGE (10-90) EGE

SD SD SD SD SD SD SD SD SD

1800 1600 1400 1200 1000 Wavenumber (cm-1) 818 819



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

820

Page 48 of 50

Figure 8.

C3,4,5,8 C6,9 C15

C1

NAP (crystalline)

C7 C2

C10

C12 C13

14

C14

3 2

12 11

NAP-EGE (60-40) SD NAP-EGE (40-60) SD NAP-EGE (20-80) SD C-CHn

EGE

200

160

120 13C-Chemical

80

40

Shift (ppm)

821 822


0

6 13

4 1

NAP-EGE (70-30) SD

10

16

5

9

7 8

15 17

Page 49 of 50

823

Figure 9.

824

(a)

1.5

1

H-T1 (s)

1.3 1.1 0.9 0.7 0.5 0

20

40

60

80

Weight of NAP (%) 825 826

(b)

20

C-T1 (s)

16

13

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


12 8 4 0 0

20

40

60

80

Weight of NAP (%) 827



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

828

Page 50 of 50

Figure 10 NAP-EGE (20-80)

NAP-EGE (60-40)

NAP-EGE (70-30)

amine

NAP

NAP amine

NAP

amine ester

amine amine

NAP

ester

amine NAP

NAP

ester

NAP

amine ester ester NAP

ester ester NAP

amine

NAP

NAP NAP

NAP

Crystallization

829


Anomalous Role Change of Tertiary Amino and Ester Groups as

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