Characterization and performance assessment of solid dispersions prepared by hot melt extrusion and spray drying process

Accepted Manuscript Title: Characterization and performance assessment of solid dispersions prepared by hot melt extrusion and spray drying process Author: Anjali M. Agrawal Mayur S. Dudhedia Ashwinkumar D. Patel Michelle S. Raikes PII: DOI: Reference:

S0378-5173(13)00815-6 http://dx.doi.org/doi:10.1016/j.ijpharm.2013.08.081 IJP 13614

To appear in:

International Journal of Pharmaceutics

Received date: Revised date: Accepted date:

16-2-2013 8-8-2013 28-8-2013

Please cite this article as: Agrawal, A.M., Dudhedia„ Mayur S., Patel, A.D., Raikes, M.S., Characterization and performance assessment of solid dispersions prepared by hot melt extrusion and spray drying process, International Journal of Pharmaceutics (2013), http://dx.doi.org/10.1016/j.ijpharm.2013.08.081 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Characterization and performance assessment of solid

2

dispersions prepared by hot melt extrusion and spray drying

3

process

ip t

1

4

Anjali M. Agrawal1, Mayur S. Dudhedia1, Ashwinkumar D. Patel2, Michelle S. Raikes1

us

6

cr

5

7

9

an

8 1

Boehringer Ingelheim Pharmaceuticals Inc., 900 Ridgebury Road, Ridgefield, CT

06877, United States

11

2

12

Brooklyn, NY 11201, United States

M

10

ed

Department of Pharmaceutical Science, Long Island University, 1 University Plaza,

pt

13

Correspondence Author: Anjali Agrawal (Telephone: 203-791-5215; Fax: 203-791-

15

6197; E-mail: [email protected])

16

Ac ce

14

17

KEY WORDS:

18

Solid dispersions, hot melt extrusion, spray drying, amorphous, dissolution,

19

compactibility

20

1

Page 1 of 48

20 21

ABSTRACT

22

The present study investigated effect of manufacturing methods such as hot melt

24

extrusion (HME) and spray drying (SD) on physicochemical properties,

25

manufacturability, physical stability and product performance of solid dispersion. Solid

26

dispersions of compound X and PVP VA64 (1:2) when prepared by SD and HME

27

process were amorphous by polarized light microscopy, powder X-ray diffractometry,

28

and modulated differential scanning calorimetry analyses with a single glass transition

29

temperature. Fourier transform infrared (FT-IR) and Raman spectroscopic analyses

30

revealed similar molecular level interactions between compound X and PVP VA64 as

31

evident by overlapping FT-IR and FT Raman spectra in SD and HME solid dispersions.

32

The compactibility, tabletability, disintegration and dissolution performance were similar

33

for solid dispersions prepared by both processing techniques. Differences in material

34

properties such as surface area, morphological structure, powder densities, and flow

35

characteristics were observed between SD and HME solid dispersion. The SD solid

36

dispersion was physically less stable compared to HME solid dispersion under

37

accelerated stability conditions. Findings from this study suggest that similar product

38

performance could be obtained if the molecular properties of the solid dispersion

39

processed by two different techniques are similar. However differences in material

40

properties might affect the physical stability of the solid dispersions.

Ac ce

pt

ed

M

an

us

cr

ip t

23

41 42 2

Page 2 of 48

43

1.

44

Amorphous solid dispersion is an increasingly important formulation approach to

45

improve the dissolution rate and apparent solubility of poorly water soluble compounds

46

(Fahr and Liu, 2007; Leuner and Dressman, 2000; Vasconcelos et al., 2007). A

47

successful solid dispersion formulation should be easily processable to final

48

dosage form and remain chemically as well as physically stable upon storage.

49

Identification of appropiate formulation components is important to develop a successful

50

amorphous solid dispersion with desired release profile. In addition, methods used to

51

prepare amorphous solid dispersion can also influence each of these important

52

properties of the dispersion.

an

us

cr

ip t

INTRODUCTION

M

53

Commonly used methods for preparation of solid dispersions includes the fusion or

55

solvent processes such as hot melt extrusion (HME)(Miller et al., 2007; Zheng et al.,

56

2007; Zhu et al., 2006), spray drying (SD)(Chauhan et al., 2005; Takeuchi et al., 2004),

57

solvent co-precipitation (CP)(El-Gazayerly, 2000), and supercritical fluid

58

process(Moneghini et al., 2001). Often one method of preparation for solid dispersion is

59

arbitarily selected and then the formulation scientist modifies the formulation until

60

desired product performance is achieved. However, solid dispersions prepared by

61

different methods can have differences in physicochemical properties, which might

62

affect product performance (Patterson et al., 2007; Sethia and Squillante, 2004) and

63

manufacturability. Hence, during early stage of development it could be important to

64

understand the influence of processing technique on the solid dispersion performance

65

to ensure selection of an appropiate formulation and processing technique. Limited

Ac ce

pt

ed

54

3

Page 3 of 48

studies have been conducted so far to understand the influence of a solid dispersion

67

manufacturing technique on the physicochemical properties and performance of the

68

solid dispersion (Badens et al., 2009; Guns et al., 2011; Patterson et al., 2007; Sethia

69

and Squillante, 2004). HME and SD are the most common processing techniques used

70

to prepare amorphous solid dispersion. The objective of the current study was to

71

systematically investigate the effect of solid dispersion manufacturing methods such as

72

HME and SD on physicochemical properties and understand how these properties can

73

affectmanufacturability, physical stability and product performance of solid dispersions.

us

cr

ip t

66

an

74

In this investigative study, a weakly basic drug (referred to in this manuscipt as

76

compound X), which belongs to BCS class II category was used. The compound X has

77

poor aqueous solubility (intrinsic solubility estimated 18 g/ml), moderate hydrophobicity

78

(log P of 2.6) and pKa of 2.5 (shows pH dependant solubility). The compound X has

79

melting point of 207.6 C and decomposes above 275 C. Compound X was selected as

80

model compound because it is difficult to convert to amorphous form and has high

81

inherent tendency to crystallize. Polyvinylpyrrolidone-co-vinyl acetate 64 (PVP VA64)

82

was selected as a suitable polymeric crystallization inhibitor to prepare solid dispersion

83

based on preliminary screening studies, during which various extrusion polymers at

84

different ratios were evaluated by hot stage microscopy, DSC analysis, and accelerated

85

physical stability studies. Based on initial screening, a 1:2 compound X and PVP VA64

86

formulation was selected to prepare solid dispersions. The solid state and

87

physicochemical properties of the solid dispersions prepared by HME and SD process

Ac ce

pt

ed

M

75

4

Page 4 of 48

were thoroughly characterized to understand their influence on product performance,

89

physical stability, and manufacturability of solid dispersions.

90

2.

MATERIALS AND METHODS

91

2.1

Materials

92

Compound X was supplied by the Chemical Development department of Boehringer

93

Ingelheim Pharmaceuticals, Inc. (Ridgefield, Connecticut, U.S.A.). PVP VA 64

94

(Kollidon® VA64) and Crospovidone (Kollidon® CL) were obtained from BASF

95

(Ludwigshafen, Germany). Microcrystalline cellulose (Avicel® PH 112) was obtained

96

from FMC BioPolymer (Philadelphia, PA). Colloidal silicon dioxide (Aerosil® 200 P) was

97

obtained from Evonik Degussa Corporation (Parsippany, NJ). Magnesium stearate was

98

purchased from Mallinckrodt (Phillipsburg, New Jersey). Organic solvent of reagent

99

grade and pharmaceutical excipients of compendial grade were used as received.

100

pt

ed

M

an

us

cr

ip t

88

2.2

Preparation of solid dispersion by hot melt extrusion

102

Preliminary screening was conducted by hot stage microscopy to screen several ratios

103

of compound X and PVP VA64 as well as to identify appropriate temperature at which

104

drug dissolves in the polymer matrix.

Ac ce

101

105 106

A binary physical mixture of compound X with PVP VA 64 (1 to 2 ratio w/w) was

107

prepared by blending in a Turbula mixer for 5 minutes. This physical mixture was

108

extruded using a 9 mm mini extruder (Three-tech, Seon, Switzerland), which was 5

Page 5 of 48

equipped with twin screws and heated barrel. The extruder was heated to 180oC with

110

thermostatic control at the front and rear end of barrel to maintain desired barrel

111

temperature. The system was allowed to heat soak for ~15 minutes. The twin screws

112

were rotated to a desired speed and the powder blend was added in small amounts to

113

the extruder. The cooled extrudates were milled by passing through 18 mesh screen in

114

a quadro co-mill (Waterloo, Canada) at 500 rpm. Milled extrudates were stored in a

115

sealed aluminum pouch to keep them moisture free.

2.3

118

The PVP VA64 polymer and compound X (2:1 ratio) were dissolved in acetone to

119

prepare feed solution (2.5%W/V) for spray drying process. Formulation was spray dried

120

using a Buchi B290 mini spray dryer with inert loop (Buchi Labortechnik AG, Flowil,

121

Switzerland). The solution was sprayed at a flow rate of 10 mL/min using 40 psi

122

atomizing pressure. The aspirator pump was set at 100% and N2 gas pressure was set

123

at 4.5 bars. The inlet temperature was adjusted appropriately to achieve an outlet

124

temperature around 70 C. All spray dried material was kept in vacuum oven for

125

overnight drying at 25 C. The dried solid dispersions were stored in a sealed vial in a

126

desiccator to keep them moisture free.

Ac ce

pt

ed

M

an

117

127

Preparation of solid dispersions by spray drying

us

116

cr

ip t

109

128

Approximately 2 gram of spray dried solid dispersion slugs were prepared by applying

129

35KN of compressional force on carver press, followed by milling to minimize the

130

differences in particle size of solid dispersions obtained by spray drying and hot melt

6

Page 6 of 48

131

extrusion technique as well as to facilitate handling of spray dried solid dispersions. X-

132

ray powder diffractogram of spray dried dispersion before and after slugging showed no

133

difference indicating no change in material due to slugging and milling operation.

ip t

134

2.4

Preparation of solid dispersion tablets

136

The milled solid dispersions prepared by spray drying and hot melt extrusion process

137

were blended with 40% extragranular components in a turbula mixer for 5 min. The final

138

blend with composition given in Table 1, was compressed into 11 mm round shape

139

tablets using single station carver press. The compression force for each formulation

140

was adjusted to achieve disintegration time of not more than 15 minutes and tablet

141

hardness of ≥ 7 kP.

M

an

us

cr

135

ed

142

2.5

Characterization of solid dispersions and tablets

144

2.5.1 Chemical purity analysis

145

Quantitative assay and purity analysis of samples was done using an gradient HPLC

146

method where the eluent (A) comprised of 45mM Ammonium Hexafluorophosphate in

147

water/Methanol 95/5 (v/v) and eluent (B) comprised of Methanol/water 95/5 (v/v). The

148

analytical column Atlantis T3 C18, 3 µm, 150  4.6 mm was operated at 40oC with a

149

flow rate of 1.0 ml/minute and UV detection at 250 nm. The injection volume was 12 µl

150

and the data acquisition time was 57 minutes.

Ac ce

pt

143

151

7

Page 7 of 48

2.5.2 Powder flow

153

Powder flow was assessed by determining the Carr Index. Bulk density was determined

154

by measuring known volume of mass occupied by the drug substance. Tap density was

155

determined by mechanically tapping (raising the cylinder and allowing it to drop 1250

156

times a specified distance under its own weight) the cylinder (Vankel, Cary, NC) and

157

measuring the volume. Carr index was determined from the bulk and tap density.

cr

ip t

152

us

158

2.5.3 Specific surface area

160

Specific surface area for milled spray dried dispersions and hot melt extrusion

161

dispersions was determined by multipoint BET (Brunauer, Emmett, and Teller)

162

adsorption isotherm. Prior to testing, each sample was dried overnight (~16-18 hours)

163

under vacuum at 40oC to remove any gases and vapors that may have adsorbed on

164

surface. Krypton gas was used as an adsorbate in the dynamic flow method. The

165

relative pressure used for the isotherms ranged from 0.05 to 0.3. Analysis bath

166

temperature was 77K with an equilibration interval of 10 seconds.

M

ed

pt

Ac ce

167

an

159

168

2.5.4 Scanning electron microscopy (SEM)

169

A field emission scanning electron microscope (SEM, Hitachi model S4000,

170

Schaumburg, IL) was used to generate images. A small amount of powder was

171

sprinkled onto a double sided electrically conductive adhesive sheet which was

172

mounted on an aluminum stub (Electron Microscopy Sciences, Ft. Washington, PA).

8

Page 8 of 48

173

The samples were subsequently coated with an approximate 10 nm layer of platinum

174

using a Xenosput (Edwards XE-200, MA) and were then examined under a vacuum.

175

2.5.5 Particle size distribution

177

Samples were analyzed with the Sympatec QICPIC (Clausthal-Zellerfeld, Germany)

178

system using the Aspiros attachment. The analysis was performed using from 1 to 2

179

bar pressure with a feed rate of 15 mm/s to 30 mm/s. Multiple runs were performed

180

using sample amounts from 50 mg up to 350 mg of material. The quality of the resulting

181

data was determined by the total particle count and the percent obscuration of the

182

system.

M

an

us

cr

ip t

176

183

2.5.6 X-ray powder diffraction (XRPD)

185

XRPD analysis was performed at ambient temperature using a Bruker AXS X-Ray

186

Powder Diffractometer Model D8 Advance (Karlsruhe, Germany), at 40 mA and 40 KV

187

with CuK radiation (1.54 Å) in parallel beam mode utilizing a scintillation detector.

188

Samples were scanned over a range of 2 values from 3º to 35º with a step size of

189

0.05º (2) and a counting time of 4 or 0.6 seconds. A 1mm divergence slit was used

190

with the incident beam along with 0.12 mm soller slits in the diffracted beam path. A

191

sodium iodide scintillation detector was used.

Ac ce

pt

ed

184

192 193

2.5.7 Polarized light microscopy (PLM) 9

Page 9 of 48

Polarized light microscopy was performed using an Olympus BX51 Polarizing

195

Microscope (Westmont, IL) with objective of 20X and ocular magnification of 10X.

196

Small amount of sample was placed on the glass slide followed by addition of a drop of

197

oil and covered with cover slip and then examined for birefringence. Sample analysis

198

was done by using SPOT advanced software.

ip t

194

cr

199

2.5.8 Fourier transform Infra Red Spectroscopy (FT-IR) and Raman Spectroscopy

201

The IR analysis was performed using Nicolet FT-IR instrument from Thermo Fischer

202

Scientific (Madison, WI) with a DTGS KBr detector. Samples were mounted on a

203

Golden Gate single bounce ATR accessory with a diamond crystal 45° top plate and

204

KRS-5 condensing lenses. Samples were then firmly pressed down to make intimate

205

contact with the crystal using the anvil tip of the Golden Gate. IR data was collected and

206

processed on OMNIC software. All measurements were performed under nitrogen

207

purge.

pt

ed

M

an

us

200

Ac ce

208 209

Raman analysis was performed under nitrogen purge using a FT-Raman accessory

210

module from Thermo Fisher Scientific (Madison, WI) with a 1064 nm YAG laser and

211

InGaAs detector. Samples were placed in NMR tubes and mounted in the laser beam

212

path on a 180° geometry configuration. Raman data was collected and processed on

213

OMNIC software

214 215

Spectra of the solid dispersions were compared with spectra obtained from the pure

216

substances. 10

Page 10 of 48

217

2.5.9 Thermal analysis (mDSC and TGA)

219

Mass loss properties were characterized using a TGA Q500 from TA instruments (New

220

Castle, DE). Modulated DSC (mDSC) was performed on a DSC Q1000 by TA

221

instruments. Data analysis was done using Universal Analysis 2000 thermal analysis

222

software by TA instruments. For TGA, samples of 5-6 mg were heated at 5 C/min over

223

a temperature range of 20 to 300 C. For mDSC, samples of 2-4 mg were weighed and

224

placed in aluminum crimped pans. The samples were equilibrated at 20 C and then

225

heating-cooling-heating cycle was performed. During heating cycle the mDSC

226

parameters were modulated at 0.636 C every 60 s with heating rates of 2 C/min from

227

20 C to 230 C followed by holding the sample isothermally for 1 min. During cooling

228

cycle the samples were cooled at 2 C/min to -10 C followed by holding the sample

229

isothermally for 1 min and then the samples were subjected to heating cycle. All

230

measurements were performed under nitrogen purge.

cr

us

an

M

ed

pt

Ac ce

231

ip t

218

232

2.5.10 Dynamic Vapor Sorption measurement (DVS)

233

Dynamic gravimetric vapor sorption (DVS) of milled solid dispersions was done by the

234

DVS-HT (Surface measurement systems, Allentown, PA) using water as the solvent.

235

Approximately 5 to 20mg of sample was placed into the instrument microbalance where

236

it was dried at 25oC in a stream of dry air for sufficient time until constant weight was

237

recorded. The dried sample was then exposed to differing humidities all the way up to

11

Page 11 of 48

95% partial pressure in 10% RH step size at 25oC. Mass change using a microbalance

239

was recorded at different humidities. The equilibrium criterion was 0.0015% mass

240

change. The Adsorption/desorption isotherm curve was plotted using the DVS-HT

241

software. DVS analysis suite from Surface Measurement Systems Ltd. (UK) was used

242

for analysis and determination of the amount of monolayer water by applying the

243

Guggenheim-Anderson-Deboer (GAB) model ( de Boer, 1968) over the entire range of

244

humidity of adsorption isotherm. The GAB equation is a BET equation extended by Van

245

den Berg according to the modifications developed by Guggenheim, Andreson, and de

246

Boer (Van den Berg 1981). The presence and distribution of moisture in various forms

247

over wide relative humdity range can be determined by applying GAB model (Zografi

248

and Kontny, 1986).

249

2.5.11 Residual Solvent Analysis by Gas Chromatography

250

The residual solvents (acetone and water) were analyzed in SD and HME solid

251

dispersions using an Agilent 6890 Plus GC equipped with a split/splitless injector and

252

thermal conductivity detector (TCD). A Restek Rt®-Q-Bond plot column (30 m x

253

0.32mm x 10.0 µm film thickness) was used for the separation. Carrier gas (Helium)

254

flow-rate was 2.0 mL/min, constant flow mode. The oven was programmed from 100°C

255

(no hold) to 160 °C at 10 °C/minute, then from 160°C to 200 °C at 40°C/minute, with a

256

13 minute hold at 200°C to elute the diluent. The injector was set at 250°C. The

257

injection was run at a 30:1 split. A 4 mm ID low pressure drop, deactivated liner, with

258

deactivated glass wool, was used in the injection port. The TCD detector was set at 260

259

°C. The helium reference flow rate was set to 10 mL/minute and the helium make-up

260

flow rate was set to 8 mL/minute. Standards and samples were diluted with anhydrous

Ac ce

pt

ed

M

an

us

cr

ip t

238

12

Page 12 of 48

N,N-dimethylacetamide (Sigma-Aldrich, catalog # 271012). Linearity standards were

262

prepared covering a range from 100 ppm to 100,000 ppm (10%). Samples were

263

prepared by weighing approximately 75 mg of material and diluting with 3.0 mL of N,N-

264

dimethylacetamide. Both the standard and sample GC vials were prepared by filling the

265

vial to just below the screw cap threads in order to minimize the air space above the

266

solution.

267

2.5.12 True density of dispersions

268

The true density of milled solid dispersions powder was determined using Micromeritics

269

AccuPyc 1330 Gas pycnometer S/N-4011 (Norcross, GA). Calibration was performed

270

prior to each run. Sample was filled in 3.5 cm3 sample cup and weight of sample was

271

noted. Then true density measurement was carried out at an equilibration rate of

272

0.0050 psig/min and number of purges was set to 10.

cr us

an

M

ed

273

ip t

261

2.5.13 Compactibility of dispersions

275

Die compaction of around 200 mg milled solid dispersion powder or physical mixture

276

was done using Instron-5867 system (Massachusetts, USA) that was equipped with a 9

277

mm die and the platen travel speed was maintained at 0.05mm/second. After each run,

278

the punches and die body were cleaned and lubricated with 1.5% magnesium stearate

279

in ethanol suspension. For each sample the compression force was varied to achieve

280

porosity in the range of 5-30%. The compacts weight, hardness, and thickness were

281

measured to determine the porosity of the compact. Acquired compaction data was

282

used to assess compactibility and tabletability of solid dispersions.

Ac ce

pt

274

13

Page 13 of 48

283 284

2.5.14 Stability Study of Solid Dispersions

286

The physical stability of solid dispersions was assessed by placing the samples under

287

accelerated condition at 40 C/75% RH and 50 C/51% RH in open vials. The samples

288

exposed to 40 C/75% RH condition were tested at 24 hours. The samples exposed to

289

50 C/51% RH condition were tested at 1, 3, and 6 months. At each time point PLM and

290

XRD analysis was conducted to monitor for potential crystallization of the solid

291

dispersions.

an

us

cr

ip t

285

M

292

2.5.15 Hardness, disintegration and dissolution testing of dispersion tablets

294

The hardness testing was performed on tablets using the Schleuniger Pharmaton

295

hardness tester (Solothum, Switzerland) where a single tablet is place between the

296

moving metal platen and the diametrical force required to break the tablet was

297

measured.

pt

Ac ce

298

ed

293

299

The disintegration testing was done in this study using USP disintegration apparatus

300

(Erweka ZT 71, Germany). Disintegration test determines the amount of time required

301

for a tablet to disintegrate in the prescribed medium. The medium used was purified

302

water at 37oC.

303

14

Page 14 of 48

Dissolution of solid dispersion powders and tablets was performed using Leap OD Lite

305

UV Fiber optic system (North Brunswick, NJ). A two-step non-sink dissolution method

306

was developed to assess the performance of amorphous solid dispersions. The

307

samples were suspended in 40 mesh basket. In the first step dissolution testing was

308

conducted in 300 ml of simulated gastric fluid at pH = 2 for 30 min and in the second

309

step 600 ml phosphate buffer containing 0.15% SDS was added to make a final 900 ml

310

volume of pH = 6.5 media containing 0.1% SDS. The amount of drug released was

311

then monitored in the combined media at 330nm.

an

312

us

cr

ip t

304

313

3.

314

The solid state properties of solid dispersions prepared by HME and SD process were

315

analyzed by XRPD, mDSC, TGA, PLM, SEM, and Fourier FT-IR and FT Raman. The

316

material properties such as particle size, surface area, powder densities, and moisture

317

uptake were determined. The physical stability assessment was conducted to identify

318

the crystallization tendency of solid dispersions upon storage.The manufacturability was

319

assessed by conducting compactibility and tabletability analysis using instron. The

320

disintegration, hardness, and dissolution testing of tablets were conducted to assess

321

product performance.

Ac ce

pt

ed

M

RESULTS AND DISCUSSIONS

322 323

3.1

Chemical purity of dispersions

15

Page 15 of 48

The extrudate strength formulated in this study was at 100 mg of compound X.

325

Individual extrudate assay results ranged from 96% to 98% of target strength across

326

dispersions prepared by SD and HME process. These values were within 95% to 100%

327

of target strength. No significant degradation products were observed. The chemical

328

purity of the solid dispersions prepared by HME and SD process was acceptable.

329

3.2

331

3.2.1 PLM, XRPD, mDSC, TGA, FT-IR, and FT-Raman and Analysis

332

The solid dispersions prepared by both processes were thoroughly characterized for

333

absence of any crystalline API. Polarized light microscopy analysis did not reveal any

334

presence of birefringence material (Data not shown). These samples were also

335

evaluated by scanning electron microscopy to determine any presence of trace amounts

336

of crystalline material (see section 3.2.2). No crystal growth was seen by SEM for

337

dispersions prepared by both processes. The XRPD pattern showed a broad “halo” in

338

the range of 4 to 35 2 and no sharp diffraction peaks were observed for both SD and

339

HME solid dispersions, which is indicative of absence of long range molecular order in

340

both solid dispersion systems (Figure 1).

Ac ce

pt

ed

M

an

us

330

341

Characterization of the amorphous solid dispersions

cr

ip t

324

342

In the present study, the reversing heat signal from mDSC showed that the neat

343

polymer PVP VA64 has a glass transition temperature (Tg) of 108.5 oC (Figure 2). The

344

amorphous compound X was prepared in situ using DSC by conducting heating-quench

345

cooling-heating cycle and Tg was determined. The Tg of amorphous compound X was 16

Page 16 of 48

77 oC. For solid dispersions prepared by HME and SD process a single and similar Tg of

347

~95 oC was observed with no melting endotherm, suggesting formation of an

348

amorphous solid dispersion. Inclusion of compound X in the solid dispersion resulted in

349

a decrease in viscosity and energy consumption during HME process compared to

350

extrusion of polymer alone, suggesting that compound X is acting as a plasticizer in the

351

binary solid dispersion.

cr

ip t

346

us

352

The TGA analysis showed around 2% weight loss when HME and SD solid dispersions

354

were heated from 25 C to 300 C. In HME dispersion the residual moisture content was

355

5.03%, as determined by gas chromatography. In spray dried dispersion the residual

356

acetone content was 0.05% and moisture content was 2.65%, as determined by gas

357

chromatography. Overall minimal residual acetone or low level of moisture was present

358

after preparation of solid dispersions by SD or HME process.

ed

M

an

353

359

The mDSC, PLM, and XRPD analysis suggested formation of amorphous solid

361

dispersion by both SD and HME process for binary (Compound X and PVP VA64 – 1:2)

362

system.

Ac ce

363

pt

360

364

FT-IR and FT Raman analyses were conducted to explore the interactions between the

365

compound X and PVP VA64 in the binary solid dispersions prepared by HME and SD

366

process. Both techniques are complimentary but Raman is more sensitive to particle

367

size differences and the interference due to presence of water in the dispersion is

368

minimized (Gordon and McGoverin, 2011). Figures 3 and 4 show the IR and Raman

17

Page 17 of 48

spectra of crystalline compound X, amorphous compound X, PVP VA64, and solid

370

dispersions prepared by SD and HME process. The characteristic peaks of compound X

371

found at 1654 cm-1 (C=O stretch, Amide I) and 1530 cm-1 (-NH bending, Amide II)

372

represent the groups in the molecule which can act as hydrogen bond acceptor and

373

donor, respectively (Figure 5). The spectrum of PVP VA64 showed, among others, a

374

characteristic peak at 1652 cm-1 corresponding to C=O stretch of amide group which is

375

a strong hydrogen bond acceptor group(Van Eerdenbrugh and Taylor, 2011) (Figure 5).

376

The IR spectra of spray dried and HME solid dispersions were similar in all regions

377

(Figure 3, panel A). The C=O group of PVP VA64 can potentially form hydrogen bond

378

with the compound containing electron donor group(Van Eerdenbrugh and Taylor,

379

2011). IR spectra of the solid dispersions prepared by HME and SD process were

380

compared with amorphous compound X and PVP VA64 (Figure 3, panel B). Peak

381

broadening was observed in the 1650-1655 cm-1 region (C=O stretch) of the spectra of

382

both solid dispersions suggesting interaction between compound X and PVP VA64.

383

The peak at 1534 cm-1 region (-NH bending) in both HME and SD solid dispersions

384

showed the same reduction in peak intensity and red shift relative to the amorphous

385

compound X spectra (shifted to higher wave number). This is typical if the -NH group is

386

involved in hydrogen bonding. The FT-IR analysis suggest that both HME and SD solid

387

dispersions demonstrate similar hydrogen bonding interactions of the NH group in the

388

API with the C=O group in PVP VA64 (Figure 3, panel B).

Ac ce

pt

ed

M

an

us

cr

ip t

369

389 390

FT Raman spectra of the solid dispersions prepared by HME and SD process were also

391

compared with amorphous compound X and PVP VA64 (Figure 4). The Raman spectra

18

Page 18 of 48

of solid dispersions prepared by both processes were similar. The PVP VA64 carbonyl

393

peak at ~1670 cm-1 showed a blue shift (shifted to lower wave number) due to hydrogen

394

bonding interaction with the –NH group of compound X in HME and SD solid

395

dispersions(Figure 4, panel B). However subtle differences in shifts in the peak

396

positions and intensity were observed between HME and SD dispersions in the region

397

of carbonyl group peaks (~1660-1670 cm-1). These marginal differences might be due to

398

differences in particle size and surface area of the spray dried and HME solid

399

dispersions. Overall, overlapping Raman spectra were obtained in all regions for the

400

solid dispersions prepared by spray drying and HME process (Figure 4, panel A).

an

us

cr

ip t

392

401

In summary, the FT-IR and FT Raman analysis results suggest that similar hyrdogen

403

bonding interactions were achieved in solid dispersions prepared by SD and HME

404

process. The FT-IR and FT Raman analysis results indicate that the dispersions

405

prepared by two techniques are chemically similar at molecular level.

406

3.2.2 Morphology and particle size

407

The SEM analysis indicated that SD solid dispersion particles were primarily spheres

408

with smooth appearance and aggregated heavily (Figure 6). The majority of the

409

aggregates were in the 50 to 300 micron range and the spheres appeared to be intact.

410

When this material was further subjected to slugging and milling operation, no change in

411

the surface of spheres was seen by SEM (Figure 6).

Ac ce

pt

ed

M

402

412 413

In comparison, HME solid dispersion did not exhibit spherical shaped morphology.

414

Particles exhibited large sub angular irregularly shaped morphology with smooth 19

Page 19 of 48

415

surface and sharp edges. Most of the observed particles were in the range of 60 to 240

416

micron. The adherence of small particles to the surface of large particles was also

417

observed, which could be due to the milling of the extrudates (Figure 6).

ip t

418

The particle size analysis of SD and HME solid dispersions was conducted by

420

Sympatec QICPIC system. The cumulative number particle size analysis results (Table

421

2) indicate that slugging of SD dispersion followed by milling through same size sieve

422

minimized the differences in particle size distribution when compared with HME milled

423

granules. Similar observations were noted for the volume distribution. However, the

424

particle sizes noted for volume distribution (X50 & X90) were considerably higher then

425

what was observed by scanning electron microscopy, where individual particles are

426

examined. This overestimation could be due to the differences in characterization

427

technique employed.

us

an

M

ed

428

cr

419

In essence, amorphous dispersions comprising of binary components prepared by SD

430

and HME process resulted in material with different morphological features. These

431

differences in morphological features could affect the surface area, flow characteristics,

432

and physical stability of SD and HME solid dispersions.

Ac ce

433

pt

429

434

3.2.3 True density, surface area and powder flow

435

The true densities of SD and HME solid dispersions were similar and within 1% of each

436

other (Table 3). In comparison, the true density for the physical mixture prior to the

20

Page 20 of 48

437

preparation of the dispersion was relatively higher (1.3142 g/cm3), which is expected as

438

the crystalline material has an ordered structure.

439

The specific surface area for milled SD solid dispersion is around 22 times higher than

441

milled HME solid dispersions (Table 3). This is attributed to the differences in

442

morphological features of the solid dispersion. The SD solid dispersion consisted of

443

aggregates of smooth spheres whereas HME solid dispersion consisted of large

444

subangular irregularly shaped particles as observed by SEM analysis (see section

445

3.2.2). This difference in surface area of SD and HME solid dispersion could affect the

446

moisture uptake by the solid dispersion.

an

us

cr

ip t

440

M

447

The Carr’s compressibility index value, which is an indirect measure of powder flow,

449

showed that milled HME solid dispersion powder had a lower value than slugged and

450

milled SD solid dispersion powder, suggesting better flow of HME solid dispersion

451

(Table 3). The higher Carr index value for SD solid dispersion powder may be due to

452

presence of high level of aggregates in the powder, which could inter-lock and thereby

453

affect the flow of the powder.

pt

Ac ce

454

ed

448

455

3.2.4 Moisture sorption and desorption isotherm

456

Hygroscopicity of the amorphous dispersions prepared by SD and HME process was

457

assessed by moisture sorption isotherm where water was sorbed onto the solid

458

dispersion surfaces at steady state vapor pressure at 25oC. For both the systems, there

459

was a continuous moisture uptake through entire range of humidity. Differences in 21

Page 21 of 48

water uptake were observed between SD and HME solid dispersion during the sorption

461

cycle (Figure 7). The GAB theory was applied to the moisture sorption data to

462

determine the amount of adsorbed monolayer water in SD and HME solid dispersion. In

463

SD dispersion the amount of monolayer water was 0.002 mol/g and in HME dispersion

464

the amount of monolayer water was 0.00097 mol/g. The higher amount of monolayer

465

water in SD dispersion might be due to higher surface area (22 times) compared to

466

HME dispersion. Hysteresis was observed between the sorption and desorption

467

isotherms for solid dispersions prepared by both technique (Figure 7). As reported in an

468

earlier work, amorphous materials can take up significant amount of moisture into their

469

structure and not just on surface, which can result in a significant hysteresis between

470

the sorption and desorption isotherm(Crowley and Zografi, 2002).

M

an

us

cr

ip t

460

ed

471

3.2.5 Compactibility

473

Mechanical properties of SD solid dispersion, HME solid dispersion, and physical

474

mixture were assessed in terms of compactibility and tabletability. For each of these

475

systems, 9-mm flat faced cylindrical tablets were prepared at varying compressive loads

476

and diameteral force to break the tablet was measured at varying porosities. As shown

477

in Figure 8, for these three systems comprising of binary components the tensile

478

strength increases with decreasing porosity. Experimental data for these compactibility

479

profiles were fitted in solid lines by applying the Ryshkewitch Duckworth(Duckworth,

480

1953; Ryshkewitch, 1953) model, which showed that the tensile strength of material

481

was related to porosity

Ac ce

pt

472

482 22

Page 22 of 48

483 484

Where  = tensile strength, ε = porosity, 0 = limiting tensile strength of the material at

ip t

485

zero porosity and k = bonding capacity.

487

At any given porosity, physical mixture showed higher tensile strength compared to the

488

solid dispersions prepared by SD and HME process (Figure 8). Clearly for the physical

489

mixture, the limiting tensile strength obtained by extrapolation at zero porosity was the

490

highest (11.7 MPa) as compared to the solid dispersions prepared by SD and HME

491

process where the limiting tensile strength ranged from 4.4 Mpa to 7.5 Mpa. The

492

observed tensile strength values in the range of 6 to 23% porosity for SD and HME solid

493

dispersions were similar but lower as compared to the physical mixture (Figure 8). This

494

may be likely due to loss of lattice and weaker forces in between the glassy particles.

495

These results suggest that differences in material properties such as surface structure

496

and surface area between the solid dispersions prepared by SD and HME process did

497

not influence the compactibility of solid dispersions. Overall, the compactibility of the

498

solid dispersions prepared by SD and HME process was similar.

us

an

M

ed

pt

Ac ce

499

cr

486

500

3.2.6 Tabletability

501

Effect of polymorphic forms on tabletting properties have been previously discussed in

502

literature (Sun and Grant, 2001). In this study, the influence of changes introduced by

503

subjecting the material to SD and HME processes on tabletting was assessed. As

504

shown in Figure 9, tabletability is the ability of the material to form tablets of given 23

Page 23 of 48

strengths at different compaction force. For the physical mixture which was not

506

subjected to any process, the tabletability profile shows an increase in tensile strength

507

with an increase in compaction force. In comparison, the SD and HME solid

508

dispersions exhibited lower tabletability (Figure 9). Furthermore, no significant

509

difference in tabletabilty was seen for solid dispersions prepared by both the processes.

510

At any given compaction force, physical mixture not subjected to any process gave

511

stronger tablets as compared to material subjected to spray dried and hot melt extrusion

512

process. This suggests that for the binary physical mixture where no molecular level

513

interactions are present between the particles, plastic deformation of system due to

514

compression is greater thereby resulting in more interparticulate bonding and stronger

515

strength of tablet at a given compression force. Whereas, for the SD and HME solid

516

dispersions due to similar molecular level interactions between compound X and PVP

517

VA64, the crystal lattice for the compound X is completely absent and the material is

518

glassy. As a result, these glassy materials at the same porosity may have weak

519

interactions between the particles thereby resulting in a lower strength of the compacted

520

tablet. Overall, the tabletability of the SD and HME solid dispersion was similar.

521

Ac ce

pt

ed

M

an

us

cr

ip t

505

522

3.2.7

Physical Stability of SD and HME solid dispersions

523

Polarized light microscopy and x-ray powder diffraction techniques were employed to

524

assess crystallanity in SD and HME solid dispersions on stability. The accelerated

525

stress testing at 40 C/75% RH for one day in open dish showed presence of some

526

birefriengent crystals in SD solid dispersion whereas HME solid dispersion showed no

527

birefringence by PLM analysis (Data not shown). The physical stability assessment of 24

Page 24 of 48

solid dispersion at 50 C/51% RH showed presence of birefriengent crystals in SD solid

529

dispersion at 3 month whereas HME solid dispersion was still amorphous suggesting

530

good physical stability (Data not shown). In SD dispersion the amount of adsorbed

531

monolayer water is almost two times compared to HME dispersion (refer to section

532

3.2.4), which might be due to higher surface area (22 times) of SD dispersion. The

533

higher amount of adsorbed water in SD solid dispersion could result in better

534

plasticization of the system and thus faster crystallization compared to HME solid

535

dispersion. Studies by other researchers have shown that the adsorbed water can

536

plasticize the system thereby resulting in earlier surface crystallization (Heljo et al.,

537

2012; Tong and Zografi, 2004).

M

538

an

us

cr

ip t

528

The PLM analysis indicated that the amount of birefrigent crystals increased in SD solid

540

dispersion at 6 month 50 C/51% RH condition and also small amount of birefringence

541

was observed for HME solid dispersion (Data not shown). However when the 3 month

542

and 6 month’s stability samples were analyzed by XRPD no crystalline peaks were

543

observed in the diffractograms for both SD and HME solid dispersions suggesting the

544

level of crystallization is very small (Figure 10). Overall physical stability assessment

545

indicated that SD solid dispersion is less stable compared to HME solid dispersion.

546

Furthermore, as compared to XRPD, polarized light microscopy is more sensitive

547

technique to assess any trace changes in amorphous solid dispersions crystallanity.

Ac ce

pt

ed

539

548 549

3.2.8 Hardness, disintegration and dissolution

25

Page 25 of 48

The milled SD and HME solid dispersions were blended with 40% extragranular

551

components (Table 1) and compressed into tablets. The SD solid dispersion blend

552

when compressed at compressional force of 6 KN resulted in tablet hardness of 6.87 ±

553

0.6 Kp and a disintegration time of 5.16 ± 0.5 minutes in water at 37oC. The HME solid

554

dispersion blend when compressed at compressional force of 10 KN resulted in tablet

555

hardness of 10.26 ± 0.4 Kp and a disintegration time of 3.62 ± 0.4 minutes in water at

556

37oC. These results suggest that rapid disintegrating tablets of sufficient hardness

557

could be prepared for solid dispersions prepared by two different techniques.

us

cr

ip t

550

an

558

The in vitro drug release from SD and HME solid dispersion powder and tablets was

560

assessed using a two step dissolution methodology as compound X showed pH

561

dependent solubility. As seen in Figure 11, the release of crystalline compound X from

562

physical mixture was approximately 45% of label claim. The dissolution from HME solid

563

dispersion powder was slightly higher than SD solid dispersion powder in acid stage but

564

in buffer stage the dissolution profiles were similar for SD and HME solid dispersions

565

(Figure 11). The differences observed in acid stage might be due to differences in

566

density of the dispersions. The spray dried dispersion was less dense hence particles

567

were floating on the top of dissolution medium during early stage of dissolution, so

568

wetting of these particles might be delayed, which might affect the release of compound

569

X. Approximately 80% of compound X was released from both solid dispersion at the

570

end of 120 minutes, which is two times compared to the release obtained from physical

571

mixture. Since, the final dosage form to be developed was a tablet; the release from

572

tablet was also monitored in both the steps during in vitro dissolution testing (Figure 11).

Ac ce

pt

ed

M

559

26

Page 26 of 48

Overall the dissolution profiles from HME tablets and SD tablets were similar. The rate

574

of release from tablets was higher in acid stage and during initial stage of buffer stage

575

compared to dispersions but at the end of 120 minutes approximately 80% of label

576

claim was released similar to the dispersions. The slow disintegration of tablets during

577

initial stages of dissolution or the presence of extragranular components in the tablet

578

might have resulted in less surface crystallization of API during dissolution thereby

579

resulting in higher release from tablets compared to dispersions. In buffer stage some

580

decrease in amount of drug dissolved over time was observed from solid dispersion

581

powder and tablets prepared by SD and HME process, which suggest that

582

supersaturation was not maintained to some extent in the studied in vitro condition.

583

Overall, inspite of large differences (22 times) in surface area between the solid

584

dispersions prepared by two techniques, the dissolution performance of the SD and

585

HME solid dispersions was similar suggesting that level of interactions between

586

compound X and polymer is influencing the release performance of the dispersions. The

587

results suggest that similar molecular level interactions between components of solid

588

dispersion prepared by SD and HME process resulted in similar dissolution

589

performance.

590

4.

591

The present study investigated the effect of hot melt extrusion and spray drying

592

manufacturing methods on physicochemical properties, manufacturability, physical

593

stability, and product performance of solid dispersions. Solid dispersions of compound

594

X and PVP VA64 (1:2) when prepared by SD and HME process were amorphous by

Ac ce

pt

ed

M

an

us

cr

ip t

573

CONCLUSIONS

27

Page 27 of 48

PLM, PXRD, and mDSC analyses with a single glass transition temperature. The solid

596

state properties and dissolution performance were similar for solid dispersions prepared

597

by both processing techniques. The similarity in dissolution performance between the

598

solid dispersion prepared by two techniques could be due to similarity in interaction

599

between compound X and PVP VA64 as evident by overlapping FT-IR and FT Raman

600

spectra of SD and HME solid dispersions. The chemical purity of the dispersions

601

prepared by both the techniques was similar but the processing technique did have an

602

impact on physical characteristics of dispersions. The morphlogical characteristics,

603

surface area, bulk and tap density, and flow property of the SD and HME solid

604

dispersion were different. Also, under the accelerated stability conditions evaluated in

605

this study, dispersion prepared by SD process was physically less stable compared to

606

the dispersion prepared by the HME process. Findings from this study suggest that

607

similar product performance could be obtained if the molecular properties of the solid

608

dispersion processed by two different techniques are similar however differences in

609

material properties could affect the physical stability of the dispersions. While selecting

610

an appropiate processing technique to prepare solid dispersion, the influence of solid

611

state and material properties on various aspects of solid dispersion such as product

612

performance, physical stability and manufacturability should be considered by

613

formulators. In conclusion, a systematic evaluation of solid dispersions prepared by

614

different processing techniques can provide an early insight during initial stage of

615

development to enable selection of an appropriate lead dispersion formulation and

616

process.

Ac ce

pt

ed

M

an

us

cr

ip t

595

617 28

Page 28 of 48

617

618

4.

619

The authors would like to thank Mr. John Robson and Dr. Jim Coleman at the

620

Boehringer Ingelheim Pharmaceuticals Inc. for their technical assistance in scanning

621

electron microscopy and particle size determination by QICPIC.

cr

ip t

ACKNOWLEDGEMENTS

us

622

The authors would like to thank Dr. Thomas Offerdahl for helpful discussions on FT-IR

624

and Raman analysis.

Ac ce

pt

ed

M

an

623

29

Page 29 of 48

625

626

5.

REFERENCES

ip t

627

Badens, E., Majerik, V., Horváth, G., Szokonya, L., Bosc, N., Teillaud, E., Charbit, G.,

629

2009. Comparison of solid dispersions produced by supercritical antisolvent and spray-

630

freezing technologies. International Journal of Pharmaceutics 377, 25-34.

631

Chauhan, B., Shimpi, S., Paradkar, A., 2005. Preparation and evaluation of

632

glibenclamide-polyglycolized glycerides solid dispersions with silicon dioxide by spray

633

drying technique. European Journal of Pharmaceutical Sciences 26, 219-230.

M

an

us

cr

628

634

Crowley, K.J., Zografi, G., 2002. Water vapor absorption into amorphous hydrophobic

636

drug/poly(vinylpyrrolidone) dispersions. Journal of Pharmaceutical Sciences 91, 2150-

637

2165.

639

pt Ac ce

638

ed

635

de Boer, J.H., 1968. The dynamic character of adsorption. Oxford: Claredon Press.

640 641

Duckworth, W., 1953. Discussion of paper by E. Ryshkewitch, ‘Compressive strengths

642

of porous sintered alumina and zirconia’. Journal of the American Ceramic Society 36,

643

65-68.

644

30

Page 30 of 48

645

El-Gazayerly, O.N., 2000. Characterization and Evaluation of Tenoxicam

646

Coprecipitates. Drug Development and Industrial Pharmacy 26, 925-930.

647

Fahr, A., Liu, X., 2007. Drug delivery strategies for poorly water-soluble drugs. Expert

649

Opinion on Drug Delivery 4, 403-416.

ip t

648

cr

650

Gordon, K.C., McGoverin, C.M., 2011. Raman mapping of pharmaceuticals.

652

International Journal of Pharmaceutics 417, 151-162.

an

653

us

651

Guns, S., Dereymaker, A., Kayaert, P., Mathot, V., Martens, J., Mooter, G., 2011.

655

Comparison Between Hot-Melt Extrusion and Spray-Drying for Manufacturing Solid

656

Dispersions of the Graft Copolymer of Ethylene Glycol and Vinylalcohol. Pharmaceutical

657

Research 28, 673-682.

658

ed

M

654

Heljo, V., Nordberg, A., Tenho, M., Virtanen, T., Jouppila, K., Salonen, J., Maunu, S.,

660

Juppo, A., 2012. The Effect of Water Plasticization on the Molecular Mobility and

661

Crystallization Tendency of Amorphous Disaccharides. Pharmaceutical Research 29,

662

2684-2697.

Ac ce

663

pt

659

664

Leuner, C., Dressman, J., 2000. Improving drug solubility for oral delivery using solid

665

dispersions. European Journal of Pharmaceutics and Biopharmaceutics 50, 47-60.

666

31

Page 31 of 48

667

Miller, D.A., McConville, J.T., Yang, W., Williams, R.O., McGinity, J.W., 2007. Hot-melt

668

extrusion for enhanced delivery of drug particles. Journal of Pharmaceutical Sciences

669

96, 361-376.

ip t

670

Moneghini, M., Kikic, I., Voinovich, D., Perissutti, B., Filipović-Grčić, J., 2001.

672

Processing of carbamazepine–PEG 4000 solid dispersions with supercritical carbon

673

dioxide: preparation, characterisation, and in vitro dissolution. International Journal of

674

Pharmaceutics 222, 129-138.

us

cr

671

an

675

Patterson, J.E., James, M.B., Forster, A.H., Lancaster, R.W., Butler, J.M., Rades, T.,

677

2007. Preparation of glass solutions of three poorly water soluble drugs by spray drying,

678

melt extrusion and ball milling. International Journal of Pharmaceutics 336, 22-34.

M

676

ed

679

Ryshkewitch, E., 1953. Compression Strength of Porous Sintered Alumina and Zirconia.

681

Journal of the American Ceramic Society 36, 65-68.

Ac ce

682

pt

680

683

Sethia, S., Squillante, E., 2004. Solid dispersion of carbamazepine in PVP K30 by

684

conventional solvent evaporation and supercritical methods. International Journal of

685

Pharmaceutics 272, 1-10.

686 687

Sun, C., Grant, D.W., 2001. Influence of Crystal Structure on the Tableting Properties of

688

Sulfamerazine Polymorphs. Pharmaceutical Research 18, 274-280.

689

32

Page 32 of 48

690

Takeuchi, H., Nagira, S., Yamamoto, H., Kawashima, Y., 2004. Solid dispersion

691

particles of tolbutamide prepared with fine silica particles by the spray-drying method.

692

Powder Technology 141, 187-195.

ip t

693

Tong, P., Zografi, G., 2004. Effects of water vapor absorption on the physical and

695

chemical stability of amorphous sodium indomethacin. AAPS PharmSciTech 5, 9-16.

cr

694

us

696

Van den Berg, C., 1981. Vapor sorption equilibria and other water-starch interactions: a

698

physico-chemical approach. Ph.D. thesis. Wageningen: Agricultural University of

699

Wageningen, 106-110.

an

697

M

700

Van Eerdenbrugh, B., Taylor, L.S., 2011. An ab initio polymer selection methodology to

702

prevent crystallization in amorphous solid dispersions by application of crystal

703

engineering principles. CrystEngComm 13, 6171-6178.

ed

701

pt

704

Vasconcelos, T., Sarmento, B., Costa, P., 2007. Solid dispersions as strategy to

706

improve oral bioavailability of poor water soluble drugs. Drug Discovery Today 12,

707

1068-1075.

708

Ac ce

705

709

Zheng, X., Yang, R., Tang, X., Zheng, L., 2007. Part I: Characterization of Solid

710

Dispersions of Nimodipine Prepared by Hot-melt Extrusion. Drug Development and

711

Industrial Pharmacy 33, 791-802.

712

33

Page 33 of 48

Zhu, Y., Mehta, K.A., McGinity, J.W., 2006. Influence of Plasticizer Level on the Drug

714

Release from Sustained Release Film Coated and Hot-Melt Extruded Dosage Forms.

715

Pharmaceutical Development and Technology 11, 285-294.

716

Zografi, G., Kontny, M., 1986. The interactions of water with cellulose- and starch-

717

derived pharmaceutical excipients. Pharmaceutical Research 3, 187-194.

ip t

713

Ac ce

pt

ed

M

an

us

cr

718

34

Page 34 of 48

718 719

FIGURES

720

Figure 1. X-ray powder diffractograms of neat compound X, PVP VA64, spray dried dispersion and hot melt extruded dispersion

723 724

Figure 2. Thermograms of neat PVP VA64, spray dried dispersion and hot melt extruded dispersion

725 726 727

Figure 3. IR spectra of neat compound X, PVP VA64, spray dried dispersion and hot melt extruded dispersion. Panel A shows full spectra and panel B shows regions where intreaction between compound X and PVP VA64 was observed

728 729 730

Figure 4. Raman spectra of neat compound X, PVP VA64, spray dried dispersion and hot melt extruded dispersion. Panel A shows full spectra and panel B shows regions where intreaction between compound X and PVP VA64 was observed.

731

Figure 5. Structure of PVP VA64 and generic structure of compound X

732 733

Figure 6. Scanning electron microscopy images for spray dried dispersion and hot melt extruded dispersion

734 735

Figure 7. Sorption desorption isotherm for spray dried dispersion and hot melt extruded dispersion

736 737

Figure 8. Compactibility profile for spray dried dispersion, hot melt extruded dispersion and physical mixture

738 739

Figure 9. Tabletability profile for spray dried dispersion, hot melt extruded dispersion and physical mixture

740 741

Figure 10. X-ray powder diffractograms of neat compound X, PVP VA64, stability samples of spray dried (top) and hot melt extruded (bottom) dispersions

742 743

Figure 11. Dissolution profiles of physical mixture, spray dried and hot melt extruded dispersion and tablets

Ac ce

pt

ed

M

an

us

cr

ip t

721 722

744

35

Page 35 of 48

747 748 749

Highlights of Research Paper - Characterization and performance assessment of solid dispersions prepared by hot melt extrusion and spray drying process  Processing techniques such as hot melt extrusion and spray drying can influence physicochemical properties, manufacturability, physical stability and product performance of solid dispersion.

ip t

744 745 746

750

 Similar product performance could be obtained if the molecular properties of the solid dispersion processed by two different techniques are similar.

cr

751 752

us

753 754

 Differences in material properties could affect the processability and physical stability of the solid dispersions.

an

755 756 757

M

ed

762

pt

761

 A systematic evaluation of solid dispersions prepared by different processing techniques can provide an early insight during initial stage of development to enable selection of an appropriate lead dispersion formulation and process.

Ac ce

758 759 760

36

Page 36 of 48

Ac

ce

pt

ed

M

an

us

cr

i

*Graphical Abstract (for review)

Page 37 of 48

Ac

ce

pt

ed

M

an

us

cr

i

Figure 1 -updated

Page 38 of 48

Ac

ce

pt

ed

M

an

us

cr

i

Figure 2-updated

Page 39 of 48

Ac ce p

te

d

M

an

us

cr

ip t

Figure 3-updated

Page 40 of 48

Ac ce p

te

d

M

an

us

cr

ip t

Figure 4-updated

Page 41 of 48

Ac

ce

pt

ed

M

an

us

cr

i

Figure 5-updated

Page 42 of 48

Ac

ce

pt

ed

M

an

us

cr

i

Figure 6-updated

Page 43 of 48

Ac

ce

pt

ed

M

an

us

cr

i

Figure 7-updated

Page 44 of 48

Ac

ce

pt

ed

M

an

us

cr

i

Figure 8-updated

Page 45 of 48

Ac

ce

pt

ed

M

an

us

cr

i

Figure 9-updated

Page 46 of 48

Ac ce p

te

d

M

an

us

cr

ip t

Figure 10-updated

Page 47 of 48

Ac ce p

te

d

M

an

us

cr

ip t

Figure 11-updated

Page 48 of 48