1 Qualitative and quantitative characterization of composition

Subscriber access provided by UNIV OF DURHAM

Qualitative and quantitative characterization of composition heterogeneity on the surface of spray dried amorphous solid dispersion particles by an advanced surface analysis platform with high surface-sensitivity and superior spatial resolution Sonal V Bhujbal, Dmitry Zemlyanov, Alex-Anthony Cavallaro, sharad mangal, Lynne S. Taylor, and Qi Tony Zhou Mol. Pharmaceutics, Just Accepted Manuscript • DOI: 10.1021/acs.molpharmaceut.8b00122 • Publication Date (Web): 11 Apr 2018 Downloaded from http://pubs.acs.org on April 16, 2018

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

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

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

Molecular Pharmaceutics

1

Qualitative and quantitative characterization of composition heterogeneity on the surface

2

of spray dried amorphous solid dispersion particles by an advanced surface analysis

3

platform with high surface-sensitivity and superior spatial resolution

4

Sonal V. Bhujbal1, Dmitry Y. Zemlyanov2, Alex Cavallaro3, Sharad Mangal1, Lynne S. Taylor1,

5

Qi (Tony) Zhou1*

6

1

7

Stadium Mall Drive, West Lafayette, IN 47907, USA

8

2

9

47907, USA

Department of Industrial and Physical Pharmacy, College of Pharmacy, Purdue University, 575

Birck Nanotechnology Center, Purdue University, 1205 West State Street, West Lafayette, IN

10

3

11

*Corresponding Author: Qi (Tony) Zhou, Tel.: +1 765 496 0707, Fax: +1 765 494 6545, E-

12

mail: [email protected]

13

Keywords: Amorphous solid dispersions, spray drying, surface composition heterogeneity,

14

surface characterization, XPS, ToF-SIMS

15

Short title: Surface analysis platform for spray dried ASD

Future Industries Institute, University of South Australia, Mawson Lakes, SA 5095, Australia

ACS Paragon Plus Environment

1

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

Page 2 of 29

16 17

ABSTRACT

18

Surface composition critically impacts stability (e.g. crystallization) and performance (e.g.

19

dissolution) of spray dried amorphous solid dispersion (ASD) formulations; however traditional

20

characterization techniques such as Raman and infrared spectroscopies may not provide useful

21

information of surface composition on the spray dried ASD particles due to low spatial

22

resolution, high probing depth and lack of quantitative information. This study presents an

23

advanced surface characterization platform consisting of two complementary techniques: X-ray

24

photoelectron spectroscopy (XPS) and time-of-flight secondary ion mass spectrometry (ToF-

25

SIMS). Such a platform enables qualitative and quantitative measurements of surface

26

composition for the fine spray dried ASD particles with ultra-surface-sensitivity (less than 10 nm

27

from the surface) and superior spatial resolution (approximately 250 nm for ToF-SIMS). Both

28

XPS and ToF-SIMS demonstrated that the polymer (PVPVA) was dominantly enriched on the

29

surface of our spray dried naproxen-PVPVA ASD particles. Of a particular note was that XPS

30

could differentiate two batches of spray dried ASD particles with a subtle difference in surface

31

composition produced by varying feed solution solvents. This advanced surface characterization

32

platform will provide essential surface information to understand the mechanisms underlying the

33

impact of surface composition on stability (e.g. crystallization) and functionality (e.g.

34

dissolution)

in

future


studies.

2

Page 3 of 29 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


35 36

Graphic abstract

37

38


3


39

Page 4 of 29

INTRODUCTION

40

Oral dosage forms are the most popular dosage administration route for pharmaceutical

41

products because of lower manufacturing cost, easier administration and higher patient

42

compliance as compared with parenteral administrations.1,2 For orally administered medications

43

to be absorbed systemically with sufficient bioavailability, drug solubilization and dissolution are

44

essential steps, and can be limiting factors for drugs with low aqueous solubility and high

45

permeability. Based on the aqueous solubility and membrane permeability of drugs, the

46

Biopharmaceutics Classification System (BCS) categorizes drugs into four classes, viz. Class I

47

(highly soluble and highly permeable), Class II (low soluble and highly permeable), Class III

48

(highly soluble and low permeable) and Class IV (low soluble and low permeable).3

49

Unfortunately, a high percentage (> 60%) of drugs in the development pipeline are in the BCS

50

Class II category.4,5 Several formulation strategies have been applied to increase the solubility

51

and/or dissolution rate of this class of drugs, such as salt formation, amorphous solid dispersions

52

(ASDs),

53

Formulating BCS Class II drugs into amorphous solid dispersions (ASDs) is one of the more

54

widely used strategies for enhancing drug solubility and dissolution.7,8

nanoparticles,

cyclodextrin

complexation,

microemulsions,

and

co-crystals.6

55

In an amorphous dispersion formulation, the active pharmaceutical ingredient (API) is

56

dispersed in a matrix,9 which is typically a polymer and may contain other components. When

57

the drug is in the amorphous state, no energy is needed to break the crystal lattice during

58

solubilization.10 Hence, compared to the crystalline form, amorphous drugs generally can

59

achieve higher apparent solubility and faster dissolution.11 Dispersion in a hydrophilic polymer

60

matrix can further enhance the dissolution rate, particularly at low drug loadings. Several

61

techniques can be used to produce ASD formulations including spray drying, hot melt extrusion,


4

Page 5 of 29 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


62

quench cooling from the melt, solvent evaporation, and electrospinning/spraying. Over the past

63

decade, spray drying has increasingly been used to manufacture ASD particles, particularly for

64

the thermo-labile molecules that are not suitable for hot melt extrusion.12,13 In spray drying to

65

produce an ASD, the feed solution containing the drug and polymer is atomized into fine

66

droplets and rapidly dried into particles where the drug is typically trapped in the amorphous

67

form.14 Spray drying is used for the commercial manufacture of several ASD formulations15 and

68

is a continuous process with a scale-up capability.16

69

As ASDs typically contain drug in a high energy state, there is a risk for the drug to

70

convert to a more stable crystalline state. Such unwanted crystallization can compromise the

71

solubility/dissolution/bioavailability advantages of ASDs.17 The polymers used to formulate

72

ASDs typically confer some protection against crystallization by decreasing drug nucleation and

73

growth rates, through effects such as reducing the drug chemical potential, forming specific

74

interactions such as hydrogen bonds with the drug, decreasing matrix mobility, and increasing

75

the glass transition temperature (Tg).18,19 Studies have shown that phase separation of the drug

76

and polymer in the dispersion can promote the crystallization of the drug.20,21 Thus, it is

77

considered crucial to characterize and maintain a homogenous dispersion of drug and polymer in

78

the formulation in order to ensure physical stability.22 However, the spray drying process can

79

produce particles with a heterogonous dispersion of components with differentiated physical and

80

chemical properties. Zhou et al., showed that the poorly water-soluble compounds, rifampicin23

81

or azithromycin,24 were enriched on particle surfaces when they were co-spray dried with the

82

water-soluble drug, colistin, from a co-solvent system of water and ethanol. For ASDs, if the

83

drug is enriched on the surface of the spray dried particles, crystallization is likely to be

84

facilitated, particularly when the particle surfaces are exposed to moisture.25,26 Teerakapibal et


5


Page 6 of 29

85

al., demonstrated that surface coatings with gelatin could inhibit surface crystallization of

86

amorphous films of indomethacin or nifedipine.27 Hence, there is a need to characterize and

87

understand the heterogeneous distribution of various components in spray dried ASD particles,

88

especially at particle surfaces, with an aim of optimizing the formulation and processing

89

conditions to achieve a homogeneous distribution and ensure the physical stability.28

90

Although there are some reports of macroscopic phase separation in the bulk of

91

ASDs,26,29 studies on spray dried particle surfaces are scarce. Characterization of the composition

92

of the first few molecular layers of the surface of fine spray dried particles is extremely

93

challenging because of the relatively small particle size (ranging from a few microns to tens of

94

microns).30,31 To provide meaningful surface information on such fine particles, measurement

95

techniques with both high surface-sensitivity and superior spatial resolution are required.

96

Unfortunately, many of the common characterization techniques such as Raman or infrared (IR)

97

spectroscopies typically have a low spatial resolution, a high probing depth of a few microns,32,33

98

and hence, for spray dried particles, provide bulk-level information with low surface sensitivity.

99

Therefore, there is a need to develop advanced characterization tools with high surface-

100

sensitivity and superior spatial resolution to better understand the properties of spray dried

101

particles.

102

The surface characterization platform developed in this study consists of two

103

complementary measurements:

X-ray photoelectron spectroscopy (XPS) and time-of-flight

104

secondary ion mass spectrometry (ToF-SIMS) for fine spray dried ASD particles. This platform

105

enables qualitative and quantitative measurements of chemical species on the surface of spray

106

dried ASD particles with both ultra-high surface sensitivity (top 10 nm) and nanometer-scale

107

spatial resolution (approximately 250 nm for ToF-SIMS). Naproxen, a weakly acidic drug (pKa


6

Page 7 of 29 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


108

of 4.15, logP of 3.18, melting point 153°C and aqueous absolute solubility of 15.9 mg/L at

109

25°C)34 was used as the model drug. Kollidon® VA 64 (PVPVA), a copolymer of 1-vinyl-2-

110

pyrrolidone and vinyl acetate in a ratio of 6:4 by mass, was used as the model polymer. The

111

surface composition information obtained by this advanced platform will be critical to

112

understand and optimize the stability of spray dried ASD formulations.

113 114

Supplement Figure 1: Chemical structures of: (A) Naproxen and (B) PVPVA (1-vinyl-2-

115

pyrrolidone and vinyl acetate in a ratio of 6:4 by mass).

116

EXPERIMENTAL SECTION

117

Materials

118

Naproxen was purchased from Attix Pharmaceuticals (Toronto, Ontario, Canada).

119

Kollidon® VA 64 (PVPVA) was supplied by BASF Corporation (Florham Park, New Jersey,

120

USA). Methanol and acetone (HPLC grade) were purchased from Sigma–Aldrich (St. Louis,

121

Missouri, USA).

122

Spray Drying

123

A Büchi 290 spray dryer (Büchi Labortechnik AG, Falwil, Switzerland) was used to


7


Page 8 of 29

124

prepare spray dried ASDs. For Batch 1, equal amounts (500 mg each) of naproxen and PVPVA

125

were weighed and dissolved in co-solvent containing equal volumes of methanol and acetone to

126

obtain a total solids concentration of 50 mg/mL. The key operating parameters during spray

127

drying were slightly modified from the literature35: inlet temperature 50 ± 2°C; outlet

128

temperature 30 ± 2°C; aspirator 35 m3/h; atomizer setting 700 L/h; feed rate 12 mL/min. The

129

spray dried samples were kept in a desiccator with silica gel until analysis. For Batch 2, equal

130

amounts (500 mg each) of naproxen and PVPVA were dissolved in a co-solvent containing

131

methanol and acetone in a 1:9 volumetric ratio. The spray drying processing parameters for

132

Batch 2 were the same to those for Batch 1. The composition of the co-solvent was changed with

133

an expectation to generate different surface compositions of drug and polymer on the spray dried

134

particle surfaces. This was because naproxen has a higher solubility in acetone than in methanol,

135

while PVPVA has similar solubility in acetone and methanol. It was hypothesized that the

136

advanced surface characterization platform developed here can differentiate the subtle change on

137

surface composition caused by different co-solvent systems.

138

Powder x-ray diffraction (P-XRD)

139

P-XRD (Rigaku Smartlab™ diffractometer, Rigaku Americas, Texas, USA) with Cu-Kα

140

radiation source and a D/tex ultra-detector was used to determine drug crystallinity. The samples

141

were spread uniformly on a glass slide and placed in the measurement chamber. The samples

142

were scanned over 2θ range of 5° to 40° with a voltage of 40 kV and a current of 44 mA.

143

Scanning electron microscopy (SEM)

144

A field emission scanning electron microscope (NOVA nanoSEM, FEI Company,

145

Hillsboro, Oregon, USA) was used to evaluate the morphology of spray-dried ASD particles. A

146

small amount of sample was spread on an adhesive carbon tape attached to a stainless-steel stub.


8

Page 9 of 29 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


147

Pressurized air was used to remove excessive powders. These samples were then coated with

148

platinum by a sputter coater (208 HR, Cressington Sputter Coater, Watford, UK). An inbuilt

149

software was used to capture the images.

150

Particle size distribution

151

Scanning electron microscopy images were used to determine the particle size of the

152

samples.36 Three different SEM images were evaluated using the ImageJ software (National

153

Institute of Health, Rockville, Maryland, USA) and the Martin’s diameter of approximately 150

154

randomly-selected particles was measured for each sample. D10, D50 and D90 were calculated.

155

Time-of-flight secondary ion mass spectrometry (ToF-SIMS)

156

Time-of-flight secondary ion mass spectrometry (nanoToF instrument, Physical

157

Electronics Inc., Chanhassen, Minnesota, USA) was used to analyze the surface composition of

158

the particle surface. In ToF-SIMS analysis, the surface of a solid sample is bombarded with a

159

beam of primary ions. This results in the extraction and emission of atomic and molecular

160

secondary ions from the outer layers of solid surface (sputtering).37,38 The mass of these

161

secondary ions is measured by co-relating it with their time of flight to the detector. Such an

162

analysis cycle can be repeated at higher frequencies to obtain a comprehensive mass spectrum.

163

The high transmission, high mass resolution of time-of-flight mass spectrometer along with the

164

ability to detect ions of different masses simultaneously makes it suitable for secondary ion

165

analysis.37,38 The process described by Zhou et al.39 was used in the current study with a few

166

minor modifications. The instrument was operated at 30 kV energy and equipped with a pulsed

167

liquid metal 79+Au primary ion gun. Electron flood gun and 10 eV Ar+ ions provided dual charge

168

neutralization. An “unbunched” Au1 instrument setting was used to optimize spatial resolution

169

while performing surface analysis. A positive SIMS mode was used to collect raw data from


9


Page 10 of 29

170

several locations typically using a 100 × 100 µm2 raster area, with 2 min acquisitions. Five

171

randomly selected areas of interest were imaged per sample to collect a representative data set

172

for purposes of statistical interrogation.

173

WincadenceN software (Physical Electronics Inc., Chanhassen, Minnesota, USA) was

174

used to generate high-resolution surface composition overlays. Region-of-interest analyses were

175

performed on the collected raw image. Mass spectra were extracted specifically from within the

176

boundaries of the particles of interest which allowed the surface chemistry of the particle to be

177

extracted from the background signals. Characteristic peak fragments for naproxen and PVPVA

178

were selected to be [C14H15O3+] [~231 atomic mass unit (amu)] and [C6H9NO+] (~112 amu),

179

respectively (Figure 1). These characteristic fragments formed the basis of calibration and peak

180

selection from the resulting spectra of samples. The surface chemistry of the particles was semi-

181

quantitatively compared by normalizing the integrated peak values of the selected symbol ions to

182

the total secondary ion intensity.


10

Page 11 of 29

A1

70000 185

Boxcar binning

Intensity

60000 50000 40000 30000 20000 10000

158

0 100

120

140

171

160

180

200

A2 40000 275

Intensity Boxcar binning

[C14H15O3+] 30000

20000 231 253

10000

243

0 200

B1

220

Boxcar binning

112

Intensity

240

280

300

15000 138

124

10000

5000

150 105 108

0 100

B2 1

260

[C6H9NO+]

20000

120 117

164 176

134

120

140

160

190

180

200

3500 207

Boxcar binning

3000

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


2500 2000 1500 233

1000 500 202

183

0 200

216

221

220

259

240

260

280


300

11


184

Figure 1: ToF-SIMS spectra of (A) naproxen and (B) PVPVA.

185

X-ray photoelectron spectroscopy (XPS)

Page 12 of 29

186

X-ray photoelectron spectroscopy (XPS) (AXIS Ultra DLD spectrometer, Kratos

187

Analytical Inc., Manchester, UK) with monochromic Al Kα radiation (1486.6 eV) was used for

188

quantitative surface composition study of the ASDs. In XPS analysis, the surface of the sample is

189

irradiated with an X-ray beam. The photons cause core-level electrons to be emitted with a

190

specific kinetic energy, which is measured by an energy analyzer. Such generated photoelectron

191

spectrum contains the photoemission peaks of all elements (but H and He). The shift of the core-

192

level peaks due a chemical bond with another atom(s), which is often referred to as a chemical

193

shift, helps to identify the chemical state of an element. The inelastic mean free path of the

194

photoelectrons in a solid is in the range of a few nanometers, and therefore, the XPS information

195

depth is limited to approximately 10 nm (for Al Kα radiation of 1486.6 eV). XPS has been used

196

for characterization of complex organic material such as peptides40 and drugs.41

197

The XPS spectra were collected at constant pass energy (PE) mode using PE of 20 and 160 eV

198

for high-resolution and survey spectra, respectively. To avoid non-homogeneous electric charge

199

of non-conducting powder and achieve better resolution, a commercial Kratos charge neutralizer

200

was employed. Typical full width at half maximum of the photoemission peak from a metal (Au

201

7f or Ag 3d) is ~0.35 eV at PE of 20 eV. Binding energy (BE) values refer to the Fermi

202

edge. The binding energy scale was calibrated using Au 4f7/2 at 84.0 eV and Cu 2p3/2 at 932.67

203

eV. A double-sided sticking Cu tape was used to place powder samples on stainless steel sample

204

holder. XPS data was processed using a CasaXPS software. Curve-fitting of the O 1s, N 1s and C

205

1s regions was performed to determine the relative fractions of PVPVA and naproxen in ASD

206

formulations.26,42–44 The model O 1s, N 1s and C 1s peaks obtained from the pure materials,


12

Page 13 of 29 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


207

PVPVA and naproxen, were used for curve fitting. The fractional area of the components

208

corresponds to the number of atoms of interest (PVPVA and naproxen) in the near-surface

209

region. Figure 2 shows the example of the C 1s peak curve fitting by the PVPVA and naproxen

210

components for the sample of Batch 1. Atomic concentrations of the elements in near-surface

211

region was calculated following a Shirley background subtraction and by considering

212

corresponding Scofield atomic sensitivity factors and inelastic mean free path (IMFP) of

213

photoelectrons using standard procedures in the CasaXPS software.39 Supplement Figure 2

214

shows the reference spectra and curve-fit using O1s. At least five replicates were measured and

215

results

were

averaged.

216 217

Figure 2: Example of the C 1s peak curve-fit for the sample of Batch 1.


13


Page 14 of 29

218 219

Supplement Figure 2: Example of the O 1s peak curve-fit: (a) PVPVA (reference spectrum); (b)

220

NAP (reference spectrum); (c) Batch 1 (PVPVA component is blue, NAP component is red), (d)

221

Batch 2 (PVPVA component is blue, NAP component is red).

222

Statistical analysis

223

Data are presented as mean ± standard deviation (SD). The statistical analysis was

224

conducted by an independent t-test using SPSS™ software (SPSS Inc. IBM Corporation, New

225

York, NY, USA).


14

Page 15 of 29 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

226


RESULTS AND DISCUSSION

227

Two batches of naproxen-PVPVA ASD solids were prepared by spray drying. The

228

purpose of preparing two batches was to generate spray dried particles with subtle difference in

229

surface composition by adjusting the components of the co-solvents. The hypothesis was that the

230

advanced surface characterization platform would be able to measure subtle differences in the

231

surface composition of the spray dried ASD particles.

232

Crystallinity of the samples was evaluated using P-XRD (Supplement Figure 3). As-

233

supplied naproxen showed sharp peaks indicating its crystalline nature. In contrast, solid

234

dispersions of naproxen-PVPVA did not exhibit any crystalline peaks, which demonstrated both

235

batches of spray dried particles were amorphous.

236

Naproxen Batch 1 Batch 2

237 238

Supplement Figure 3: Power X-ray diffraction patterns of supplied naproxen, Batch 1 ASD

239

(Naproxen _PVPVA spray dried from methanol and acetone in volumetric ratio of 1:1) and


15


Page 16 of 29

240

Batch 2 ASD (Naproxen _PVPVA spray dried from methanol and acetone in volumetric ratio of

241

1:9).

242

SEM images of the spray-dried ASD samples are shown in Supplement Figure 4. The

243

spray dried particles from both batches had very similar particle shape, size and surface texture.

244

SEM images are not capable of providing any information on surface composition.

245

246 247

Supplement Figure 4: Representative scanning electron microscopy images of: (A) Batch 1:

248

Naproxen _PVPVA spray dried from methanol and acetone in volumetric ratio of 1:1; (B) Batch

249

2: Naproxen _PVPVA spray dried from methanol and acetone in volumetric ratio of 1:9.

250 251

Table 1 shows the particle size information of the formulations. The values indicate two

252

spray dried batches had similar particle sizes. For industrial manufacturing, a larger size for

253

spray dried particles is preferable rather than the fine particles generated herein. However, in the

254

present study, very small sizes were intentionally generated for the spray dried particles to test


16

Page 17 of 29


1 2 3 255 the capability of the surface characterization platform for extremely fine particles. 4 5 6 256 7 8 257 Table 1: Particle sizes (n = 150) and surface compositions as measured by XPS (n = 5) and ToF9 10 11 258 SIMS (n = 5) of Batch 1 ASD (Naproxen _PVPVA spray dried from methanol and acetone in 12 13 259 volumetric ratio of 1:1) and Batch 2 ASD (Naproxen _PVPVA spray dried from methanol and 14 15 260 acetone in volumetric ratio of 1:9). 16 17 18 261 19 20 21 Formulation Particle size (µm) XPS (C 1s spectra) ToF-SIMS (% normalized counts) 22 % Surface % Surface 23 Composition Composition m/z 231 m/z 112 (Theoretical) (Measured) 24 D10 D50 D90 (Naproxen) (PVPVA) 25 Naproxen PVPVA Naproxen PVPVA 26 0.5 ± 0.2 Batch 1 0.1 ± 0.0 1.1 ± 0.1 54 46 12 ± 2 88 ± 2 0.008 ± 0.002 0.025 ± 0.002 27 28 Batch 2 0.1 ± 0.1 0.5 ± 0.1 1.0 ± 0.1 54 46 9 ± 2* 91 ± 2* 0.003 ± 0.001** 0.025 ± 0.001 29 30 31 262 * p < 0.05, ** p < 0.01, significantly different to Batch 1 32 33 263 ToF-SIMS images are shown in Figure 3. The focusing capability of the ion beams used 34 35 36 264 in ToF-SIMS along with the nature of energy transfer from the primary ion beam to the particle 37 38 surface results in a controlled removal of the fragment only from the uppermost surface.37,38 For 265 39 40 266 solid surfaces, about 95% of the sputtering occurs from the top one or two molecular monolayers 41 42 43 267 (approximately 1 nm). This enables characterization of the solid surface chemistry with ultra44 45 268 high surface-sensitivity, a wide mass range, high mass resolution, and a lateral resolution in 46 47 nanometer range (approximately 250 nm in this study).37,38 269 48 49 50 270 In Figure 3, the green signals represent exclusive mass fragment of naproxen, and the red 51 52 271 signals represent exclusive mass fragment of PVPVA. Qualitative image analysis of both 53 54 55 272 formulations indicated a heterogeneous surface composition on the surface of spray dried 56 57 58 59 17 ACS Paragon Plus Environment 60


Page 18 of 29

273

particles with an abundance of PVPVA. Table 1 shows the % normalized counts as measured by

274

ToF-SIMS. Normalized counts can be defined here as the count of the selected secondary ions of

275

each component divided by the total count of ions recorded. Integrated peak values of the

276

selected ions have been normalized to the total secondary ion intensities. Since, these values are

277

percentages over the total ion signals of all species, percentage normalized counts do not give a

278

measure of absolute surface coverage of the component. However, these can be considered as a

279

useful tool for studying relative changes as they enabled a semi-quantitative comparison of

280

surface compositions between two batches wherein naproxen content was found significantly

281

higher (p < 0.01) on the particle surfaces of Batch 1; while no difference was measured in

282

PVPVA between two batches (Table 1). To confirm the observed dominant distribution of

283

PVPVA on the particle surfaces and the difference in surface composition between two

284

formulations as measured by ToF-SIMS, the surface composition was further evaluated by XPS.

285


18

Page 19 of 29 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


A

B

C

D

286 287

Figure 3: Distributions of naproxen (green) and PVPVA (red) measured by ToF-SIMS on the

288

particles surfaces of: (A) Naproxen; (B) PVPVA; (C) Batch 1: Naproxen _PVPVA spray dried

289

from methanol and acetone in volumetric ratio of 1:1; and (D) Batch 2: Naproxen _PVPVA

290

spray dried from methanol and acetone in volumetric ratio of 1:9 (scale bar represents 10 µm).

291

XPS provides quantitative information regarding chemical composition of the top

292

approximately 10 nm of a particle surface. The XPS data (Table 1) demonstrated that PVPVA is

293

considerably enriched on the particle surface for both formulations, indicating heterogeneity in


19


Page 20 of 29

294

component distribution within the spray dried particles. For example, for the Batch 1, the

295

theoretical concentration of PVPVA was approximately 45% (calculated by normalizing the

296

relative carbon atom proportion in the formulation); while the measured surface concentration

297

was 88 ± 2% (as determined by curve-fits of the C 1s). XPS data also clearly differentiated the

298

varying surface compositions between two batches (p< 0.05), even though the difference was

299

subtle (e.g. naproxen 12 ± 2% for Batch 1 and 9 ± 2% for Batch 2). We further confirmed these

300

subtle differences and surface enrichment of PVPVA using O1s (94 ± 3% surface is PVPVA for

301

Batch 1 and 98 ± 2% for Batch 2, p = 0.029). To verify the quantitation by XPS, physical

302

mixtures of spray dried pure drug and pure PVPVA were prepared at ratios of 25:75, 50:50, and

303

75:25. The differences in XPS data for physical mixtures between theoretical and measured

304

values for each ratio is less than 10%, showing the measurement accuracy. In addition, the XPS

305

data were in good agreement with the ToF-SIMS results, which enabled qualitative and

306

quantitative measurements in surface composition for the spray dried ASD particles.

307

Solvent choice is an important factor which is known to impact the surface composition

308

of spray dried particles45 and thus an underlying cause of different surface composition of the

309

two batches could have been the varying solubilities of naproxen and PVPVA in the varying

310

ratios of co-solvents used for the two batches. When a droplet of a solution is being spray dried,

311

the solvent from the outer layers of the droplet is evaporated first. When such a solvent system

312

contains two or more components, the substance with higher solubility in the solvent may have a

313

higher diffusion as the solute molecules tend to diffuse towards the particle core.46 In contrast,

314

the substances with relatively less solubility reach supersaturation rapidly and precipitate,

315

whereby precipitated material has a much lower rate of diffusion, and thus tends to concentrate

316

on the particle surface as the solvent is being evaporated.47 Similarly, in this case, a higher


20

Page 21 of 29 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


317

solubility of naproxen in co-solvent system used for Batch 2 could have led to a lower

318

concentration on the particle surface.

319

Vehring et al. have discussed the correlation of Peclet number for a component of interest

320

on its surface enrichment.47 Peclet number (Pei) given by the following equation, depends on the

321

processes of diffusion and solvent evaporation.

322 323

(1)

324 325

Here k is the solvent evaporation rate and Di is the diffusivity of the component of interest in

326

the solvent system. Simulations by Vehring et al. suggested that higher Peclet number would be

327

associated with higher surface enrichment. When the drying kinetics are faster than the

328

component diffusivity, the component tends to concentrate on the outer surface. The higher

329

molecular weight of the PVPVA relative to the naproxen, is likely to lead to low polymer

330

diffusivity its subsequent surface enrichment. The difference in the formulation surface

331

composition observed in this study could have been a combination of one or more of these

332

factors. Chen et al. showed surface tension may also impact surface composition of spray dried

333

ASD particles because solutes with lower surface tension may concentrate on the air-liquid

334

interface when droplets are formed so as to assemble a surface with low free energy.48 Thus, it is

335

important to note that the process of spray drying is complex with several material properties and

336

processing conditions affecting the particle surface composition. Hence, further systematic

337

studies are warranted to unveil the true mechanisms of such heterogeneity surfaces of spray dried

338

ASD particles.


21


Page 22 of 29

339

In future studies, exposure of the inner surface of these particles by cryo-SEM, as

340

discussed in the work of Gamble et al. may provide a complete picture of drug-polymer

341

distribution in the particle.49 This method involves freezing the samples with liquid nitrogen and

342

subsequently fracturing them to expose the inner surface of the particles. In addition, mass

343

balance of these analysis methods could be investigated to test their ability to detect and quantify

344

the degradation products generated by the sample.

345

CONCLUSION

346

In the present study, an advanced surface composition analysis platform consisting of

347

ToF-SIMS and XPS measurements was developed. This platform had superior surface sensitivity

348

(top 10 nm of the surface) and high spatial resolution (approximately 250 nm for ToF-SIMS),

349

enabling both qualitative and quantitative measurements of compositions on the uppermost

350

surface of spray dried ASD fine particles. It is noteworthy that even a subtle change in surface

351

composition could be differentiated by the developed surface characterization platform between

352

two batches of ASD particles spray dried with a difference feed solvent composition. The

353

advanced surface characterization platform developed in this study will be very useful to

354

understand mechanisms by which process parameters affect surface composition and study the

355

underlying impacts of surface composition on the stability (e.g. crystallization) and functionality

356

(e.g. dissolution) of ASDs in future studies.

357

ACKNOWLEDGEMENTS

358

Qi (Tony) Zhou is supported by the National Institute of Allergy and Infectious Diseases

359

of the National Institutes of Health under Award Number R01AI132681. The content is solely

360

the responsibility of the authors and does not necessarily represent the official views of the

361

National Institutes of Health. Qi (Tony) Zhou is a recipient of the Ralph W. and Grace M.


22

Page 23 of 29 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


362

Showalter Research Trust Award. The authors are grateful for the scientific and technical

363

assistance of the Australian Microscopy & Microanalysis Research Facility at the Future

364

Industries Institute, University of South Australia.

365

REFERENCES

366

1.

367 368

Mahay H. Oral chemotherapy: Patient advantages and challenges. Pharm Times. 2009;75(8):64-65.

2.

Chandrasekhar R, Hassan Z, AlHusban F, Smith AM, Mohammed AR. The role of

369

formulation excipients in the development of lyophilised fast-disintegrating tablets. Eur J

370

Pharm Biopharm. 2009;72(1):119-129. doi:10.1016/j.ejpb.2008.11.011.

371

3.

Zakeri-Milani P, Barzegar-Jalali M, Azimi M, Valizadeh H. Biopharmaceutical

372

classification of drugs using intrinsic dissolution rate (IDR) and rat intestinal permeability.

373

Eur J Pharm Biopharm. 2009;73(1):102-106. doi:10.1016/j.ejpb.2009.04.015.

374

4.

375 376

Babu NJ, Nangia A. Solubility advantage of amorphous drugs and pharmaceutical cocrystals. Cryst Growth Des. 2011;11(7):2662-2679. doi:10.1021/cg200492w.

5.

Xie T, Taylor LS. Dissolution Performance of High Drug Loading Celecoxib Amorphous

377

Solid Dispersions Formulated with Polymer Combinations. Pharm Res. 2016;33(3):739-

378

750. doi:10.1007/s11095-015-1823-y.

379

6.

Jatwani S, Rana AC, Singh G, Aggarwal G. An overview on solubility enhancement

380

techniques for poorly soluble drugs and solid dispersion as an eminent strategic approach.

381

Int J Pharm Sci Res. 2012;3(4):942-956.

382

7.

Van Den Mooter G. The use of amorphous solid dispersions: A formulation strategy to

383

overcome poor solubility and dissolution rate. Drug Discov Today Technol.

384

2012;9(2):e79-e85. doi:10.1016/j.ddtec.2011.10.002.


23


385

8.

386 387

9.

Chiou WL, Riegelman S. Pharmaceutical applications of solid dispersion systems. J Pharm Sci. 1971;60(9):1281-1302. doi:10.1002/jps.2600600902.

10.

390 391

Leuner C, Dressman J. Improving drug solubility for oral delivery using solid dispersions. Eur J Pharm Biopharm. 2000;50(1):47-60. doi:10.1016/S0939-6411(00)00076-X.

388 389

Page 24 of 29

Hancock BC, Zografi G. Characteristics and significance of the amorphous state in pharmaceutical systems. J Pharm Sci. 1997;86(1):1-12. doi:10.1021/js9601896.

11.

Vaka SRK, Bommana MM, Desai D, Djordjevic J, Phuapradit W, Shah N. Excipients for

392

Amorphous Solid Dispersions. In: Shah N, Sandhu H, Choi DS, Chokshi H, Malick AW,

393

eds. Amorphous Solid Dispersions: Theory and Practice. New York, NY: Springer New

394

York; 2014:123-161. doi:10.1007/978-1-4939-1598-9_4.

395

12.

396 397

Patel RP, Patel MP, Suthar AM. Spray Drying Technology : An Overview. Indian Jourbal Sci Technol. 2009;2(10):44-47. doi:10.1017/CBO9781107415324.004.

13.

Crowley MM, Zhang F, Repka MA, et al. Pharmaceutical applications of hot-melt

398

extrusion:

399

doi:10.1080/03639040701498759.

400

14.

Part

I.

Drug

Dev

Ind

Pharm.

2007;33(9):909-926.

Bohr A, Boetker JP, Rades T, Rantanen J, Yang M. Application of spray-drying and

401

electrospraying/electospinning for poorly watersoluble drugs: A particle engineering

402

approach. Curr Pharm Des. 2014;20(3):325-348.

403

15.

404 405

soluble drugs. Acta Pharm Sin B. 2014;4(1):18-25. doi:10.1016/j.apsb.2013.11.001. 16.

406 407

Huang Y, Dai W-G. Fundamental aspects of solid dispersion technology for poorly

Singh A, Van den Mooter G. Spray drying formulation of amorphous solid dispersions. Adv Drug Deliv Rev. 2016;100:27-50. doi:10.1016/j.addr.2015.12.010.

17.

Baghel S, Cathcart H, O’Reilly NJ. Polymeric Amorphous Solid Dispersions: A Review


24

Page 25 of 29 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


408

of Amorphization, Crystallization, Stabilization, Solid-State Characterization, and

409

Aqueous Solubilization of Biopharmaceutical Classification System Class II Drugs. J

410

Pharm Sci. 2016;105(9):2527-2544. doi:10.1016/j.xphs.2015.10.008.

411

18.

Purohit HS, Taylor LS. Phase separation kinetics in amorphous solid dispersions upon

412

exposure

413

doi:10.1021/acs.molpharmaceut.5b00041.

414

19.

to

water.

Mol

Pharm.

2015;12(5):1623-1635.

Kou X, Zhou L. Stability of Amorphous Solid Dispersion. In: Shah N, Sandhu H, Choi

415

DS, Chokshi H, Malick AW, eds. Amorphous Solid Dispersions: Theory and Practice.

416

New York, NY: Springer New York; 2014:515-544. doi:10.1007/978-1-4939-1598-9_16.

417

20.

Shamblin SL, Zografi G. The effects of absorbed water on the properties of amorphous

418

mixtures

419

doi:10.1023/A:1018960405504.

420

21.

containing

sucrose.

Pharm

Res.

1999;16(7):1119-1124.

Matsumoto T, Zografi G. Physical Properties of Solid Molecular Dispersions of

421

Indomethacin with Poly(vinylpyrrolidone) and Poly(vinylpyrrolidone-co-vinyl-acetate) in

422

Relation to Indomethacin Crystallization. Pharm Res. 1999;16(11):1722-1728.

423

22.

Qian F, Huang J, Hussain MA. Drug–Polymer Solubility and Miscibility: Stability

424

Consideration and Practical Challenges in Amorphous Solid Dispersion Development. J

425

Pharm Sci. 2010;99(7):2941-2947.

426

23.

Zhou Q, Gengenbach T, Denman JA, Yu HH, Li J, Chan HK. Synergistic Antibiotic

427

Combination Powders of Colistin and Rifampicin Provide High Aerosolization Efficiency

428

and Moisture Protection. AAPS J. 2014;16(1):37-47. doi:10.1208/s12248-013-9537-8.

429 430

24.

Zhou Q, Loh ZH, Yu J, et al. How Much Surface Coating of Hydrophobic Azithromycin Is Sufficient to Prevent Moisture-Induced Decrease in Aerosolisation of Hygroscopic


25


Page 26 of 29

431

Amorphous Colistin Powder? AAPS J. 2016;18(5):1213-1224. doi:10.1208/s12248-016-

432

9934-x.

433

25.

Rumondor ACF, Marsac PJ, Stanford LA, Taylor LS. Phase behavior of poly

434

(vinylpyrrolidone) containing amorphous solid dispersions in the presence of moisture.

435

Mol Pharm. 2009;86(1):47-60. doi:10.1021/mp900050c.

436

26.

Wang W, Zhou QT, Sun S-P, et al. Effects of Surface Composition on the Aerosolisation

437

and Dissolution of Inhaled Antibiotic Combination Powders Consisting of Colistin and

438

Rifampicin. AAPS J. 2015;18(2):372-384. doi:10.1208/s12248-015-9848-z.

439

27.

440 441

Teerakapibal R, Gui Y, Yu L. Gelatin Nano-coating for Inhibiting Surface Crystallization of Amorphous Drugs. Pharm Res. 2018;35(1). doi:10.1007/s11095-017-2315-z.

28.

Puri V, Dantuluri AK, Kumar M, Karar N, Bansal AK. Wettability and surface chemistry

442

of crystalline and amorphous forms of a poorly water soluble drug. Eur J Pharm Sci.

443

2010;40(2):84-93. doi:10.1016/j.ejps.2010.03.003.

444

29.

Vasanthavada M, Tong WQ, Joshi Y, Kislalioglu MS. Phase behavior of amorphous

445

molecular dispersions I: Determination of the degree and mechanism of solid solubility.

446

Pharm Res. 2004;21(9):1598-1606. doi:10.1023/B:PHAM.0000041454.76342.0e.

447

30.

Lin, Yu-Wei; Wong, Jennifer; Qu, Li; Chan, Hak-Kim; Zhou Q (Tony). Powder

448

production and particle engineering for dry powder inhaler formulations. Curr Pharm

449

Des. 2015;21(27):3902-3916.

450

31.

Zhou QT, Qu L, Larson I, Stewart PJ, Morton DA V. Improving aerosolization of drug

451

powders by reducing powder intrinsic cohesion via a mechanical dry coating approach. Int

452

J Pharm. 2010;394(1-2):50-59. doi:10.1016/j.ijpharm.2010.04.032.

453

32.

Chan KLA, Kazarian SG. New opportunities in micro-and macro-attenuated total


26

Page 27 of 29 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


454

reflection infrared spectroscopic imaging: spatial resolution and sampling versatility. Appl

455

Spectrosc. 2003;57(4):381-389.

456

33.

Vankeirsbilck T, Vercauteren A, Baeyens W, et al. Applications of Raman spectroscopy

457

in pharmaceutical analysis. TrAC - Trends Anal Chem. 2002;21(12):869-877.

458

doi:10.1016/S0165-9936(02)01208-6.

459

34.

460 461

National Center for Biotechnology Information. PubChem Compound Database. doi:156391.

35.

Paudel A, Van Den Mooter G. Influence of solvent composition on the miscibility and

462

physical stability of naproxen/PVP K 25 solid dispersions prepared by cosolvent spray-

463

drying. Pharm Res. 2012;29(1):251-270. doi:10.1007/s11095-011-0539-x.

464

36.

Shekunov BY, Chattopadhyay P, Tong HHY, Chow AHL. Particle size analysis in

465

pharmaceutics: Principles, methods and applications. Pharm Res. 2007;24(2):203-227.

466

doi:10.1007/s11095-006-9146-7.

467

37.

Benninghoven A. Chemical Analysis of Inorganic and Organic Surfaces and Thin Films

468

by Static Time‐of‐Flight Secondary Ion Mass Spectrometry (TOF‐SIMS). Angew

469

Chemie Int Ed English. 1994;33(10):1023-1043. doi:10.1002/anie.199410231.

470

38.

Sodhi RNS, Ontario SI, Chemistry A. Time-of-flight secondary ion mass spectrometry

471

(TOF-SIMS):—versatility

472

2004;129(6):483-487.

473

39.

in

chemical

and

imaging

surface

analysis.

Analyst.

Zhou Q (Tony), Denman J, Gengenbach T, et al. Characterization of the Surface

474

Properties of a Model Pharmaceutical Fine Powder Modified with a Pharmaceutical

475

Lubricant to Improve Flow via a Mechanical Dry Coating Approach. J Pharm Sci.

476

2011;100(8):3421-3430.


27


477

40.

Page 28 of 29

Jedlicka SS, Rickus JL, Zemlyanov DY. Surface Analysis by X-ray Photoelectron

478

Spectroscopy of Sol−Gel Silica Modified with Covalently Bound Peptides. J Phys Chem

479

B. 2007;111(40):11850-11857. doi:10.1021/jp0744230.

480

41.

Song Y, Zemlyanov D, Chen X, et al. Acid-Base Interactions of Polystyrene Sulfonic

481

Acid in Amorphous Solid Dispersions Using a Combined UV/FTIR/XPS/ssNMR Study.

482

Mol Pharm. 2016;13(2):483-492. doi:10.1021/acs.molpharmaceut.5b00708.

483

42.

Wei G, Mangal S, Denman J, et al. Effects of Coating Materials and Processing

484

Conditions on Flow Enhancement of Cohesive Acetaminophen Powders by High-Shear

485

Processing With Pharmaceutical Lubricants. J Pharm Sci. 2017;106(10):3022-3032.

486

doi:10.1016/j.xphs.2017.05.020.

487

43.

Mangal S, Gengenbach T, Millington-Smith D, Armstrong B, Morton DAV, Larson I.

488

Relationship between the cohesion of guest particles on the flow behaviour of interactive

489

mixtures. Eur J Pharm Biopharm. 2016;102:168-177. doi:10.1016/j.ejpb.2016.03.012.

490

44.

Zhou Q, Qu L, Gengenbach T, et al. Investigation of the extent of surface coating via

491

mechanofusion with varying additive levels and the influences on bulk powder flow

492

properties. Int J Pharm. 2011;413(1-2):36-43. doi:10.1016/j.ijpharm.2011.04.014.

493

45.

Bhardwaj V, Trasi N, Zemlyanov DY, Taylor LS. Surface area normalized dissolution to

494

study differences in itraconazole-copovidone solid dispersions prepared by spray-drying

495

and

496

doi:https://doi.org/10.1016/j.ijpharm.2018.02.005.

497

46.

498 499

hot

melt

extrusion.

Int

J

Pharm.

2018.

Vehring R. Pharmaceutical particle engineering via spray drying. Pharm Res. 2008;25(5):999-1022. doi:10.1007/s11095-007-9475-1.

47.

Vehring R, Foss WR, Lechuga-Ballesteros D. Particle formation in spray drying. J


28

Page 29 of 29 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


500 501

Aerosol Sci. 2007;38(7):728-746. doi:10.1016/j.jaerosci.2007.04.005. 48.

Zhen C, Yang K, Huang C, Zhu A, Yu L, Qian F. Surface enrichment and depletion of the

502

active ingredient in spray dried amorphous solid dispersions. Pharm Res. 2018;35:38.

503

doi:https://doi.org/10.1007/s11095-018-2345-1.

504

49.

Gamble JF, Ferreira AP, Tobyn M, et al. Application of imaging based tools for the

505

characterisation of hollow spray dried amorphous dispersion particles. Int J Pharm.

506

2014;465(1-2):210-217. doi:10.1016/j.ijpharm.2014.02.002.

507


29

1 Qualitative and quantitative characterization of composition

Recommend Documents