Superior Plasticity and Tabletability of ... - ACS Publications

Subscriber access provided by UB + Fachbibliothek Chemie | (FU-Bibliothekssystem)

Article

Superior plasticity and tabletability of theophylline monohydrate Shao-Yu Chang, and Changquan Calvin Sun Mol. Pharmaceutics, Just Accepted Manuscript • Publication Date (Web): 26 Apr 2017 Downloaded from http://pubs.acs.org on May 1, 2017

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 free 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 accessible to all readers and 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.

Molecular Pharmaceutics 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 27 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

2

Superior plasticity and tabletability of theophylline monohydrate

3

4

Shao-Yu Chang and Changquan Calvin Sun*

5

6

Pharmaceutical Materials Science and Engineering Laboratory, Department of Pharmaceutics, College of

7

Pharmacy, University of Minnesota, 9-127B Weaver-Densford Hall, 308 Harvard street S.E., Minneapolis,

8

MN 55455

9

10

11

12

*Corresponding author

13

Changquan Calvin Sun, Ph.D.

14

9-127B Weaver-Densford Hall

15

308 Harvard street S.E.

16

Minneapolis, MN 55455

17

Email: [email protected]

18

Tel: 612-624-3722

19

Fax: 612-626-2125

1 ACS Paragon Plus Environment

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

20

Page 2 of 27

Abstract

21

A theophylline monohydrate (THm) powder, with particle size and shape substantially similar to

22

a theophylline anhydrate powder, was prepared by vapor mediated phase conversion. The elimination of

23

possible contributions by particle size and shape to tableting properties made it possible to

24

unambiguously identify the role of bonding area and bonding strength on powder tableting performance.

25

It was also shown that accurate true density is essential for correct analysis and understanding of tableting

26

behavior of THm.

27

explained by its unique ladder-like structure, where rigid molecular dimers (rungs) weakly connect to

28

more rigid water chains (rails). The low energy barrier for moving rigid dimers down the rigid water

29

chain enables facile propagation of dislocations in THm crystals when subjected to an external stress.

Experimental evidence revealed surprisingly high plasticity of THm.

This is

30

31

Keyword. Theophylline, plasticity, tabletability, hydrate,


Page 3 of 27 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

32

33


INTRODUCTION

The establishment of material structure-property relationship is of paramount importance in 1

34

material research in different fields, including pharmaceutical development.

35

structure can more greatly influence the physico-chemical and mechanical properties than the molecular

36

structure. Crystal engineering is, therefore, playing an increasingly important role in materials science

37

research.

38

performance of pharmaceutical powders,

39

compressibility and compactibility.

40

molecular and crystal structure.

41

overcoming powder tableting problems requires a clear understanding of the relationship between crystal

42

structure and mechanical properties. 1, 9

43

2

In fact at times, crystal

Material mechanical properties, e.g., elasticity and plasticity, have been related to tableting

8

5-7

3, 4

which can be systematically analyzed using tabletability,

These mechanical properties, in turn, are influenced by both the

As a result, the development of an effective engineering strategy for

Incorporation of water in crystal lattice often leads to a different crystal structure, which is 10

44

expected to impact pharmaceutically important properties, including mechanical properties.

45

hydrates were found to exhibit better compaction properties than corresponding anhydrates, such as p-

46

hydroxybenzoic acid, where the crystalline water molecules act both as “molecular lubricant” to improve

47

crystal plasticity and “molecular glue” to improve bonding strength. 11 It is of value to explore whether

48

or not such beneficial effects by crystal hydration are of general applicability.

Some

49

Theophylline anhydrate (THa) was shown to be very plastic and exhibited excellent tabletability

50

due to its structural features that lead to multiple slip mechanisms.12 However, theophylline monohydrate

51

(THm) was reported to exhibit even better tableting performance than THa.

52

studies was crystallized from water and, although not mentioned by the authors, likely had a different

53

particle size and shape from those of THa. As such, it remains unclear whether or not the superior

54

tableting performance of THm was due to the different particular properties or differences in mechanical

55

properties.15,

16

13, 14

THm in the previous

Even if the superior tabletability of THm was attributed to the unique mechanical 3 ACS Paragon Plus Environment


Page 4 of 27

56

properties of THm, its structural origin is hitherto unknown, despite the fact that the structure of THm has

57

been known for some time.

58

and THm while minimizing possible contributions from particle size and shape, 2) identify the structural

59

origin of the distinct tableting behavior of THa and THm.

60

MATERIALS AND METHODS

61

Materials

The goals of this study were to 1) compare tableting performance of THa

62

Theophylline anhydrate was obtained from BASF Chemical Co. (Ludwigshafen, Germany).

63

Theophylline monohydrate was prepared by placing theophylline anhydrate in a sealed chamber of 93%

64

relative humidity (RH) over a saturated KNO3 solution. Complete conversion to THm was indicated when

65

sample weight reached a constant value in three consecutive measurements over a period of 15 days.

66

Magnesium stearate was purchased from Tyco Healthcare/Mallinckrodt (Surrey, United Kingdom).

67

Methods

68

Hydration Kinetics

69

As-received THa was dried in an oven at 70 oC for 4 h to remove surface moisture. Accurately

70

weighed, dry THa (~24 g) was evenly placed in three aluminum boats, with surface area of ~40 cm2 and

71

sample thickness of ~6 mm, and stored in a sealed 93% RH chamber.

72

periodically removed from the chamber, weighed, and gently stirred with a spatula before being returned

73

to the chamber for the hydration reaction to continue.

74

Identification of A Suitable RH for Conditioning Powders

The powder sample was

75

In order to reduce the difference in surface moisture before compression, powders were

76

equilibrated at a common RH, at which both THa and THm are kinetically stable. For this purpose, the


Page 5 of 27 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


77

physical stability of THa powder at 75% RH (saturated NaCl solution) and 52% RH (saturated

78

Mg(NO3)2·6H2O solution), and THm powder at 52%, 43% (saturated K2CO3 solution) and 32% RH

79

(saturated MgCl2 solution) were evaluated by monitoring the change of sample weight for at least 50 days.

80

Weight gain of THa samples or weight loss of THm samples indicated unwanted physical instability of

81

corresponding samples.

82

Particle Size Analysis

83

The particle size of THa and THm was determined using a particle size analyzer (Microtrac SIA,

84

Montgomeryville, PA). Approximately ~20 mg of each powder was suspended in IsoparTM G Fluid ( ~5

85

ml) and sonicated for 20 seconds to fully disperse particles. Solubility of theophylline in this medium

86

was negligible. The suspension was added into a sample delivery controller (SDC, Montgomeryville, PA)

87

and circulated. A high speed camera captured image of particles in focus and the area equivalent

88

diameter of each particle was determined using image analysis software. All experiments were triplicated.

89

Powder X-ray Diffractometer (PXRD)

90

The powder X-ray diffraction (PXRD) patterns of THa and THm were obtained using an X-ray

91

diffractometer (Bruker AXS D5005, Madison, WI) with Cu Kα radiation generated at 40 mA and 45 kV.

92

Each powder was placed into a sample holder and pressed by a glass slide to ensure co-planarity between

93

surfaces of the powder and the sample holder. Samples were scanned over the 2θ range of 5˚ - 35˚ in

94

0.04˚ increments with a counting time of 1s at each step. The experimental PXRD patterns of both

95

powders were verified with the theoretical PXRD patterns calculated from crystal structures of THa and

96

THm. 17, 18

97

Thermogravimetric Analysis (TGA)



Page 6 of 27

98

The water content of THa and THm was determined using a thermogravimetry analyzer (TGA

99

Q50, TA Instruments, New Castle, DE, USA). Powders (2-3 mg) were quickly transferred from a RH

100

chamber to an open aluminum pan and were immediately heated to 300 ˚C at a rate of 10 ˚C/min under

101

dry nitrogen purge at a flow rate of 50 mL/min.

102

Compaction Behavior

103

Aliquots of powder (~200 mg) were loaded into a die and compressed using 8 mm round and flat

104

faced punches on a Zwick Materials Testing Machine (Model 1485; Zwick-Roell, Ulm, Germany) over

105

the compaction pressure range of 25 - 350 MPa at the punch velocity of 2 mm/min without holding at the

106

peak pressure. The punches and die were externally lubricated with a 5% (w/v) suspension of magnesium

107

stearate in ethanol and dried with a fan before each tablet compaction. Three tablets were prepared at

108

each compaction pressure. They were stored in 52% RH overnight to allow relaxation before being

109

further tested.

110

Tablet diameter, D, and thickness, T, were measured using a digital caliper (0.01 mm accuracy),

111

and tablets were weighed using an analytical balance (0.01 mg accuracy). Tablet breaking force, F, was

112

obtained using a texture analyzer (TA-XT2i, Texture Technologies Corp., NY) at a testing speed of 0.01

113

mm/s. Tensile strength, , was calculated according to equation (1). 19

114

=

115

To avoid errors in tablet thickness determination due to flashing, tablets were gently polished on a piece

116

of fine sand paper.

117

True Density Determination

(1)

20


Page 7 of 27 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


118

It is imperative to obtain accurate powder true densities, ρt, in powder compaction research,

119

because even a small error in ρt can have profound impact on the analysis of results of powder tableting

120

data

121

for anhydrous powders, such as THa, but unfit for THm, which undergoes dehydration during

122

measurement.

123

Quantachrome Instruements, Boynton Beach, Florida). For THm powders ρt was obtained by fitting

124

tablet density (ρ) vs. compaction pressure (P) data with equation (2), 22

20, 21

.

The commonly employed helium pycnometry for measuring powder true density is suitable

Therefore, the ρt of THa was measured using helium pycnometry (Ultrapyc 1200e,

125

= 1 − −

126

where the parameter, 1/C, is related to material plasticity. A lower 1/C value corresponds to higher

127

plasticity. The parameter, εc, describes the critical powder porosity at which a continuous 3D network of

128

particle-particle contact is formed. 23 True densities were also calculated from single crystal structures for

129

comparison. The true density values calculated from single crystal structures are expected to be slightly

130

higher than those derived from data fitting because single crystal structures were obtained at sub-ambient

131

temperatures and crystals were assumed to be perfect, while real crystal contain defects. Tablet porosity

132

(ε) was calculated from ρ and ρt according to equation (3).

133

= 1 −

− ln

(2)

(3)

134 135

Hardness Measurement by Macroindentation

136

A spherical stainless indenter (3.18 mm in diameter), attached to a texture analyzer (TA-XT2i,

137

Texture Technologies Corp., NY), was used to indent tablet at the middle of the round tablet face. The

138

indenter traveled downward at a speed of 0.01 mm/min to attain a force (F) that was 60% of the fracture



Page 8 of 27

139

force of a tablet prepared under the same compaction conditions. The force was maintained for 3 min 24.

140

The indented tablet surface was gently rubbed against a piece of graphite-coated paper to assist the

141

accurate identification of the indent boundary.

142

digital microscope (x200 magnification, Dino-Lite™ Pro AM413MT; AnMo Electronics Corporation,

143

Taiwan). The circular indent was fitted by a three-point method and the projected area, A, was calculated

144

using DinoCapture™ software (V2.0 AnMo Electronics Corporation, Taiwan). Hardness, H, was

145

calculated using equation (4). 25

146

=

147

The hardness - porosity data were fitted using equation (5). 26

148

H = H0 ! "

149

where H0 is the hardness extrapolated to zero porosity and b is an constant. Hardness measurements were

150

triplicated.

24

The area of indents was determined using a calibrated

(4)

(5)

151

152

153

In-die Elastic Recovery

Tablet in-die elastic recovery was calculated from tablet thickness, h0 and h, under peak and zero 28

154

compaction pressure, respectively, using equation (6).

155

ER%= 100(h - h0)/ h0

156

ER reflects the interplay between elastic energy stored in particles during compaction and elastic modulus.

157

A higher ER means a higher extent of elastic recovery upon decompression, which usually leads to more

158

deterioration of tablet strength.

(6)

29


Page 9 of 27

159

Crystal Structure Analysis

160

The THa (Reference code: BAPLOT) and THm (Reference code: THEOPH01) cifs were

161

downloaded from Cambridge Structural Database and analyzed using Mercury (v3.7, Cambridge

162

Crystallographic Data Centre, Cambridge, UK). Primary slip systems in THa and THm were identified

163

by crystal structure visualization.

164

Results and Discussion

165

The hydration kinetics of as-received THa at 93% RH is shown in Figure 1.

Complete

166

conversion to THm was achieved after ~140 hours (6 days), with the final weight gain of 9.99% exactly

167

matching the theoretical weight gain for 100% conversion.

168

confirmed by PXRD, which agreed with the calculated PXRD and no extraneous peaks could be observed

169

(Figure S1). Particle size distributions of THa and THm were similar (Table 1). No significant change in

170

particle morphology was observed by both optical microscopy (Figure S2) and SEM (Figure S3).

Complete phase conversion was also

11 10 9

Weight change (%)

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


8 7 6 5 4 3 2 1 0 0

50

100

150

200

250

300

Time (hrs)

171 172

Figure 1. Conversion kinetics from theophylline anhydrate (THa) to theophylline monohydrate (THm) at

173

93% RH (n = 3). The dashed line indicates expected weight gain for complete conversion. 9 ACS Paragon Plus Environment


174

175

Table 1. Particle size for theophylline anhydrate (THa) and monohydrate (THm). Standard deviations are

176

in parentheses. THa

THm

D10 [(µm)

21.4 (1.0)

20.2 (0.1)

D50 (µm)

38.2 (1.8)

36.3 (0.6)

D90 (µm)

70.2 (5.4)

65.2 (2.9)

177

b

a

0.3

1 0

THm (52% RH)

Weight change (%)

-1

Weight change (%)

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 10 of 27

-2 -3

THm (43% RH)

-4 -5 -6 -7

0.2

THa (75% RH)

0.1

THa (52% RH)

0.0

-8

THm (32% RH)

-9 -0.1

-10 0

10

20

30

40

50

60

0

10

20

30

40

50

60

Time (Days)

Time (Days)

178 179

Figure 2. Phase stability, monitored by weight change, of a) theophylline monohydrate (THm) at 52%,

180

42% and 32% RH, and b) theophylline anhydrate (THa) at 75% and 52% RH.

181

To identify a common RH where both THa and THm are kinetically stable, both materials were

182

stored at various THs at room temperature. At 32% RH, THm underwent rapid weight loss indicating

183

facile dehydration to THa (Figure 2a). At 43% RH, THm dehydrated at a slower rate than at 32% RH,

184

which is consistent with the expectation that faster dehydration occurred at a lower storage RH. At 52%

185

RH, THm was stable for at least 50 days (Figure 2a). THa did not undergo detectable weight change 10 ACS Paragon Plus Environment

Page 11 of 27 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


186

when exposed to 52% for 50 day (Figure 2b). However the weight of THa increased by 0.15% at 75% RH

187

after 60 days (Figure 2b), indicating very slow hydration kinetics. As a result, THa and THm were found

188

to be both kinetically stable at 52% RH, even after prolonged storage. This was confirmed by PXRD data,

189

which showed no sign of phase conversion for both THa and THm (Figure 3). Therefore, 52% RH was

190

chosen for storing all powders prior to compaction and all tablets before strength testing throughout this

191

study. For tablets compressed at the highest compaction pressure of 350 MPa, no detectable phase

192

change was evident by XRD data (Figure 3). Thus, a phase change was ruled out as an explanation for

193

the difference in tabletability of THm and THa.

THa (Cal.) THa powder (52% RH) THa tablet (52% RH)

THm (Cal.) THm powder (52% RH) THm tablet (52% RH) 5

10

15

20

25

30

35

2 theta

194 195

Figure 3. X-ray diffraction profiles for powders and tablets of THa and THm, respectively, after storing

196

at 52% RH for 24 h.

197

The TGA thermogram of THa showed about 0.15% weight loss up to 120 ˚C (Figure 4),

198

corresponding to surface moisture.

199

theoretically calculated weight loss (9.08%), indicating dehydration occurred during the brief exposure of

200

the sample to the ambient environment of 15% RH during sample preparation.

However weight loss of THm was 7.88%, which is less than



THa

100

Weight change (%)

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 12 of 27

95

THm

90 20

40

60

80

100

120

140

160

180

200

Temperature (°C)

201 202

Figure 4. TGA thermograms of theophylline anhydrate (THa) and theophylline monohydrate (THm).

203

Both samples were stored in a 52% RH chamber for a day prior to thermal analysis.

204

205

206

True Density and crystal plasticity

Key crystallographic information of THa and THm from the previously published structures is 17, 18

207

summarized in Table 2.

208

orthorhombic THa to monoclinic THm with an expanded unit cell volume that more than sufficiently

209

compensates additional mass of water, leading to lower true density of THm. True density values of THa

210

and THm from helium pycnometry and fitting compression data are also included for comparison.

The incorporation of water leads to a change in the crystal structure from

211

The true densities of THa and THm obtained from fitting the P-ρ data using equation (1) were

212

1.46 ± 0.02 g/cm3 and 1.43 ± 0.001 g/cm3, respectively (Figure 5). Fitting was excellent for both sets of

213

data as indicated by high coefficients of correlation R2 (> 0.99). The fitted true density of THa is about

214

2% lower than the true density calculated from crystal structure (1.493 g/cm3, Table 2). True density

215

determined by helium pycnometry was 1.49 ± 0.0008 g/cm3, which is nearly identical to that calculated 12 ACS Paragon Plus Environment

Page 13 of 27 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


216

from crystal structure (Table 2).

217

measurement, the slightly lower true density form fitting is likely caused by the presence surface moisture

218

(0.75% when equilibrated at 52% before tableting). For THm, the fitted true density is about 3% lower

219

than the calculated density from the crystal structure.

220

crystal structure was solved at a much lower experimental temperature (-100 ˚C); and 2) surface moisture

221

effect similar to that observed in THa. Thus, true density values of THa and THm obtained by fitting

222

were considered sufficiently accurate and used for subsequent calculations of tablet porosity.

223

Table 2. Key crystallographic information for theophylline anhydrate (THa)17 and monohydrate (THm)18.

224

Standard deviations are stated in parentheses.

Since surface moisture is removed during helium pycnometry

18

This value is reasonable considering 1) the

THa Crystal class

Orthorhombic

Monoclinic

Z

4

4

Space group

Pna21

P21/n

a (Å)

24.612 (2)

4.468 (2)

b (Å)

3.8302 (4)

15.355 (5)

c (Å)

8.501 (5)

13.121 (5)

β (˚)

90

97.792 (7)

Volume (Å3)

801.38 (12)

891.9 (6)

Temperature (K)

293

173 (2)

Calculated density (g/cm3)

1.493

1.476

1.49 (0.0008)

1.52 (0.017)

1.46 (0.015)

1.43 (0.001)

Measured density (g/cm3) a Fitted density (g/cm3) b 225 226 227

a. b.

THm

Measured by helium pycnometry at room temperature Obtained by fitting room temperature compression data using equation 2. 13 ACS Paragon Plus Environment


228

350

Compaction pressure (MPa)

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 14 of 27

300 THa

THm

250 200 150 100 50 0 0.9

1.0

1.1

1.2

1.3

1.4

1.5

3

229

Tablet density (g/cm )

230

Figure 5. True density fitting of tablet density – compaction pressure by the Sun equation for

231

theophylline anhydrate (THa) and theophylline monohydrate (THm)

232

The plasticity parameter, 1/C, of THm (166 ± 21 MPa) generated by data fitting is much lower

233

than that of THa (646 ± 181 MPa). This means that, although THa is known to be very plastic, THm is

234

even more plastic than THa. The greater plasticity of plastic THm is expected to allow more permanent

235

deformation under the same stress than the less plastic THa. To solidify this point, we also determined H0

236

of both THm and THa because a material with a lower H0 is more plastic. H of both THa and THm

237

decayed exponentially as predicted by equation (5) (Figure 6, R2 > 0.99 for both). The H0 of THa (217.6

238

± 3.8 MPa) was significantly higher than that of THm (155.5 ± 2.2 MPa). Thus, THm is more plastic

239

than THa by this measure as well.


Page 15 of 27

300

Hardness (MPa)

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


100

THm

THa 10 0.00

0.05

0.10

0.15

0.20

0.25

0.30

0.35

Porosity

240

241

Figure 6. Hardness of theophylline anhydrate (THa) and theophylline monohydrate (THm).

242

243

244

Compactibility

Tablet tensile strength, σ, usually decreases exponentially with increasing porosity, as described

245

by the Ryshkewitch equation (7). 30

246

σ=σ0 ! "

247

where σ0 is the tensile strength extrapolated to zero porosity and b is an empirical constant. 31 σ0 could be

248

used to quantify bonding strength in this case, because THm and THa possess substantially similar

249

particle size and shape, which would result to the same bonding area at zero porosity.

250

compactibility of both THa and THm obeyed the Ryshkewitch equation (Figure 7, R2 > 0.98 for both).

251

Both the σ0 and b of THa (6.87 ± 0.40 MPa and 10.06 ± 0.3) were higher than that of THm (4.29 ± 0.11

252

MPa, and 4.80 ± 0.24). The lower bonding strength of THm is consistent with its lower true density,

(7)

32

The



Page 16 of 27

253

similar to some polymorphic systems 33 but different from the p-HBA anhydrate and monohydrate system

254

11

255

bonding area for THm is larger than that of THa because of the higher plasticity of THm, even at the

256

same porosity. Thus, the lower bonding strength of THm is superseded by the positive effect of larger

257

bonding area on σ. With decreasing porosity, the σ of THa increased faster than THm. Consequently, the

258

two compactibility curves cross approximately at porosity of 0.09, below which σ of THa is higher than

259

that of THm. At low porosities, the difference in the actual bonding area is minimal, and the higher

260

bonding strength of THa dominates the bonding area-bonding strength interplay. This is different from

261

the earlier work that suggested THm exhibited higher σ at the entire porosity range, and σ0 of THm is

262

higher than that of THa. 13 This contradiction may have been caused by using a poor estimate of the true

263

density in the calculation of the tablet porosity of THm in the earlier work. Although not specified by

264

those authors, the true density of THm was likely measured using helium pycnometry, the prevailing

265

method at that time. If so, the measured true density would be higher due to dehydration of THm during

266

the course of measurement.

267

helium pycnometry (1.52 g/cm3), the compactibility curve of THm shifted to the right hand side to the

268

extent that it no longer intersects compactibility curve of THa (Figure S4), which is the same as that

269

reported in the literature. 13

.

At porosities greater than 0.1, σ of THm is higher than THa. This is attributed to the fact that the

22

In fact, when using the higher value of the true density measured by


Page 17 of 27

10

Tensile strength (MPa)

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


THm 1

THa

0.1 0.00

0.05

0.10

0.15

0.20

0.25

Porosity

270 271

Figure 7. Compactibility of theophylline anhydrate (THa) and theophylline monohydrate (THm).

272

Compressibility

273

Compressibility is reflected in the plot of tablet porosity as a function of compaction pressure.

274

Other things being equal and under identical compaction condition, a more compressible material forms

275

tablets with lower porosity. When a powder is compressed, it undergoes volume reduction through

276

particle rearrangement, fragmentation of particles, and plastic deformation.34 The porosity of both THa

277

and THm tablets decreased with the increasing compaction pressure as expected (Figure 8). At 25 MPa,

278

tablet porosity of THa and THm was nearly identical, which is consistent with the expected similar

279

powder packing for two powders with essentially the same particle size and shape. However, tablet

280

porosity diverged with increasing pressure. The porosity of THm tablets was significantly lower than that

281

of THa at pressure ≥ 50 MPa. The faster elimination of pores in THm tablets is in keeping with the

282

higher plasticity of THm. Lower porosity means larger bonding area in a THm tablet than in a THa tablet

283

at a given compaction pressure, which favors higher tablet strength.



0.25

0.20

Porosity

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 18 of 27

0.15

0.10 THa 0.05 THm 0.00 0

50

100

150

200

250

300

350


284 285

Figure 8. Compressibility of theophylline anhydrate (THa) and theophylline monohydrate (THm).

286

Tabletability

287

Tablet tensile strength of both THa and THm increased with increasing compaction pressure

288

(Figure 9).

289

deformation of particles, which leads to larger bonding area between adjacent particles. The tabletability

290

profiles of THa and THm converge with increasing compaction pressure. At 25 and 50 MPa, the tensile

291

strength of THm tablets was nearly two fold that of THa. At the compaction pressure ~300 MPa, tensile

292

strength of THa and THm tablets became essentially the same. This observation is consistent with the

293

observation that THa have stronger bonding strength (Figure 7), which gradually dominates the bonding

294

area – bonding strength (BABS) interplay when difference in bonding area diminishes at higher pressures.

295

The excellent tabletability of THa obtained in this work is in agreement with the previous report. 12 It is

296

attributed to its high plasticity resulting from the presence of multiple slip mechanisms in the crystal.

297

Surprisingly, the presence of water in the crystal structure even further improves tableting performance.

This is expected because higher compaction pressure causes more permanent plastic


Page 19 of 27

35

298

According to the BABS interplay model,

299

higher tabletability of THm due to its higher plasticity.

the larger bonding at lower pressures is responsible for the

6

5

Tensile strength (MPa)

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


4

THm 3

2

1

THa 0 0

300 301

50

100

150

200

250

300

350

400


Figure 9. Tabletability of theophylline anhydrate (THa) and theophylline monohydrate (THm).

302

An understanding of the impact of interparticular bonding area on different tabletability of THa

303

and THm requires consideration of the tablet tensile strength normalized by tablet porosity, i.e.,

304

compactibility analysis (Figure 7), and tablet porosity as a function of compaction pressure, i.e.,

305

compressibility analysis (Figure 8). As discussed above, THm exhibits lower bonding strength but larger

306

bonding area when compressed at the same compaction pressure. At low pressures, the larger bonding

307

area (due to higher plasticity) in THm tablets dominates the BABS interplay. Therefore, tablet tensile

308

strength is higher for THm. At high pressures, the dominance of bonding area is less prominent because

309

both approach zero porosity. As a result, the bonding strength plays a more important role, which is

310

reflected as the convergence of tensile strength at pressures higher than 300 MPa (Figure 9).

311



312

In-die elastic recovery

313

Elastic recovery during decompression tends to reduce bonding area developed during

314

compression. For both THa and THm, in-die elastic recovery increased with increasing compaction

315

pressure (Figure 10). A higher compaction pressure induces more extensive plastic deformation between

316

particles, but it also leads to more stored elastic energy in particles. As a result, higher elastic recovery is

317

observed. At all compaction pressures, THa underwent higher degree of in-die elastic recovery than THm.

318

This contributes to higher porosity and weaker THa tablets at the same compaction pressures, despite of

319

the higher bonding strength of THa (Figure 7). 36

THa

5

In-die elastic recovery (%)

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 20 of 27

4

3

THm 2

1

0 0

50

100

150

200

250

300

350

400


320 321

Figure 10. In-die elastic recovery of theophylline anhydrate (THa) and theophylline anhydrate (THm)

322

tablets as a function of compaction pressure.

323

Crystal Structural origin of superior plasticity of THm

324 325

To explain the high plasticity of THm, it is useful to compare the crystal structures of THa and THm for structural insight, especially slip mechanism responsible for plastic deformation.

Slip planes 20

ACS Paragon Plus Environment

Page 21 of 27 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


37

326

can be identified by either visual inspection of crystal packing or attachment energy calculation.

327

planes typically have the lowest attachment energy, which is defined as the energy released in attaching a

328

new layer of molecules to a growing crystal face. It was previously shown that theophylline molecules in

329

THa form V-shaped hydrogen-bonded rigid columns, which stack to form flat layers. 12 When subject to

330

stress, columns are able to slide more easily than the classical stacking flat sheets structure of plastic

331

crystals.

332

external stress induced slip in the crystal less directionally dependent. Slip of the stacking layers is also

333

possible to accommodate plastic deformation.

334

deformation, which contributes to its excellent tabletability. 12

38-40

Slip

Additionally, columns in adjacent layers in THa lie at the angle of 111.61˚, which makes

Thus, THa responds to stress through facile plastic

a

b

c

c

b

b a

a Layer 1

Layer 2

Layer 1

Layer 2

2.900 2.744 2.726

2.763 3.205

335 336

Figure 11. Crystal structure of theophylline monohydrate a) along a axis, layers 1 and 2 are indicated by

337

red and blue planes, respectively; b) rotating 48.2˚ along b axis in the direction of dotted arrow.

338

Molecules are shown in red and blue colors for layer 1 and 2, respectively



339

Page 22 of 27

The better tabletability of THm than THa (Figure 8), despite its lower bonding strength (Figure 6), 35

340

suggests larger bonding area in THm tablets dominates the bonding area-bonding strength interplay.

341

Therefore, THm must exhibit even greater plasticity than THa. This requires a more effective plastic

342

deformation mechanism of the THm crystal.

343

molecule into the THm crystal lattice leads to approximately 11% expansion in unit cell volume (Table 2).

344

This process can potentially introduce additional defects to the crystal lattice. However, the THa powder

345

consisted of polycrystalline particles, likely because it was manufactured through dehydrating

346

monohydrate crystals. Thus, the potentially higher defect concentration in THm cannot fully explain its

347

significantly higher plasticity than THa. An inspection of the THm crystal structure revealed that water

348

molecules are bonded through O-H···O hydrogen bonds to form water chains running in the

349

direction (Figure 11). Theophylline dimers, with an inversion center and fortified through two N-H···O

350

hydrogen-bonds, connect to water molecules in two parallel water chains on either side through N-H···O

351

hydrogen-bonds (Figure 11a). Such dimers stack along adjacent water chains to form a ladder like

352

structure.

353

layer but shifted to the side by half of the width of the ladder. Dimers in adjacent layers lie at an angle of

354

158.81˚ (Figure 11b).

355

molecule in the adjacent layers through a C-H···O hydrogen bond. Since these layers are not flat, facile

356

slide between layers is unlikely. Therefore, this type of structures is expected to lead to low plasticity and,

357

hence, poor tableting performance if these layers are rigid.

358

high plasticity, shown by its lower H0 and 1/C than THa, this structure must allow facile propagation of

359

dislocations through a mechanism not recognized before.

During the hydration process, the incorporation of water

Lateral repetition of such ladders forms a layer. Adjacent layers are mirror images of this

Each theophylline molecule in a dimer connects with another theophylline

41-43

Since THm actually exhibits excellent

360

Because hydrogen bonds between dimer and water is weak (N-O distance is 2.900 Å) compared

361

to hydrogen bonds between the dimers (N-O distance is 2.763 Å) or between adjacent water molecules

362

within the water chain (O-O distance is 2.744 and 2.726 Å), water chains and the dimers serve as sturdy

363

rail and rungs, respectively. The C-H···O hydrogen bonds (C-O distance of 3.205 Å) between dimers in 22 ACS Paragon Plus Environment

Page 23 of 27 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


364

neighboring layers are the weakest among all hydrogen bonds. Thus, when subjected to an external stress,

365

the rigid ladders can be displaced along the direction from their position at rest with little

366

resistance since only the weak N-H···O hydrogen bonds are necessary to be overcome for plastic

367

deformation. More importantly, the displacement of the dimeric rungs will propagate through the rigid

368

pillars easily because only a few dimers are involved for a dislocation to move along the water chains in

369

the THm crystal (Figure 12a-c). Hence, plastic deformation can take place under a stress much lower

370

than that required to simultaneously move the entire column as in THa.

371

a

b

F

F

c

F

372 373

Figure 12. Illustration of crystal deformation of theophylline monohydrate (THm): a) Initial state when

374

subject to stress; b) When the hydrogen bonds (blue dotted line) of theophylline dimers were overcome,

375

the dimers were consecutively displaced and moved forwards along water chains; c) Theophylline dimer

376

moved to the other end of the crystal at the end of the deformation process.

377

Conclusion



Page 24 of 27

378

The use of theophylline anhydrate and monohydrate with nearly identical particle size and shape

379

allowed identification of the role of bonding area and bonding strength on powder tableting performance.

380

Accurate true density is essential for correct analysis and understanding of tableting behavior of THm.

381

THm displayed surprisingly high plasticity and superior tabletability, which is explained by its unique

382

structure, consisting of rigid molecular rungs weakly connecting to rigid rails of water chains. Such

383

unique structure enables facile propagation of dislocations with minimum resistance when subjected to an

384

external stress.

385

simulation, will facilitate its application in crystal engineering to solve challenges related to mechanical

386

properties of organic crystals.

Better understanding of this mechanism of plastic deformation, e.g., by computer

387

388

Supporting Information

389

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

390

Powder X-ray diffractograms, polarized light microscopic images, scanning electron microscopic images,

391

effects of erroneous true density on compactibility of THm and THa.

392

393

Acknowledgements

394

Portions of this work were carried out in the Characterization Facility, University of Minnesota, which

395

receives partial support from NSF through the MRSEC program, and the Minnesota Nano Center, which

396

receives partial support from the NSF through the NNCI program.

397

398

References 24 ACS Paragon Plus Environment

Page 25 of 27 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

399 400 401 402 403 404 405 406 407 408 409 410 411 412 413 414 415 416 417 418 419 420 421 422 423 424 425 426 427 428 429 430 431 432 433 434 435 436 437 438 439 440 441 442 443 444 445


1. Sun, C. C. Materials Science Tetrahedron—A Useful Tool for Pharmaceutical Research and Development. J. Pharm. Sci. 2009, 98, (5), 1671-1687. 2. Desiraju, G. R. Crystal engineering: from molecule to crystal. Journal of the American Chemical Society 2013, 135, (27), 9952-9967. 3. Hiestand, E. N. Mechanical Properties of Compacts and Particles that Control Tableting Success. J. Pharm. Sci. 1997, 86, (9), 985-990. 4. Jain, S. Mechanical properties of powders for compaction and tableting: an overview. Pharm. Sci. Technolo. Today 1999, 2, (1), 20-31. 5. Joiris, E.; Martino, P.; Berneron, C.; Guyot-Hermann, A.-M.; Guyot, J.-C. Compression Behavior of Orthorhombic Paracetamol. Pharm Res 1998, 15, (7), 1122-1130. 6. Tye, C. K.; Sun, C.; Amidon, G. E. Evaluation of the effects of tableting speed on the relationships between compaction pressure, tablet tensile strength, and tablet solid fraction. J. Pharm. Sci. 94, (3), 465-472. 7. Patel, S.; Kaushal, A. M.; Bansal, A. K. Compression physics in the formulation development of tablets. Critical Reviews™ in Therapeutic Drug Carrier Systems 2006, 23, (1). 8. Bag, P. P.; Chen, M.; Sun, C. C.; Reddy, C. M. Direct correlation among crystal structure, mechanical behaviour and tabletability in a trimorphic molecular compound. CrystEngComm 2012, 14, (11), 3865-3867. 9. Reddy, C. M.; Rama Krishna, G.; Ghosh, S. Mechanical properties of molecular crystalsapplications to crystal engineering. CrystEngComm 2010, 12, (8), 2296-2314. 10. Khankari, R. K.; Grant, D. J. Pharmaceutical hydrates. Thermochimica Acta 1995, 248, 61-79. 11. Sun, C. C.; Grant, D. J. Improved tableting properties of p-hydroxybenzoic acid by water of crystallization: a molecular insight. Pharm. Res. 2004, 21, (2), 382-386. 12. Chattoraj, S.; Shi, L.; Sun, C. C. Understanding the relationship between crystal structure, plasticity and compaction behaviour of theophylline, methyl gallate, and their 1: 1 co-crystal. CrystEngComm 2010, 12, (8), 2466-2472. 13. Agbada, C.; York, P. Theophylline hydrate/anhydrous system: effects of water of hydration on mechanical properties of compacted beams. J. Pharm. Pharmacol. 1990, 42, (S1), 76P-76P. 14. Suihko, E.; Lehto, V.-P.; Ketolainen, J.; Laine, E.; Paronen, P. Dynamic solid-state and tableting properties of four theophylline forms. Int. J. Pharm. 2001, 217, (1), 225-236. 15. Khomane, K. S.; Bansal, A. K. Effect of particle size on in-die and out-of-die compaction behavior of ranitidine hydrochloride polymorphs. AAPS PharmSciTech 2013, 14, (3), 1169-1177. 16. Garekani, H. A.; Ford, J. L.; Rubinstein, M. H.; Rajabi-Siahboomi, A. R. Formation and compression characteristics of prismatic polyhedral and thin plate-like crystals of paracetamol. Int. J. Pharm. 1999, 187, (1), 77-89. 17. Ebisuzaki, Y.; Boyle, P. D.; Smith, J. A. Methylxanthines. I. Anhydrous theophylline. Acta Crystallographica Section C: Crystal Structure Communications 1997, 53, (6), 777-779. 18. Sun, C.; Zhou, D.; Grant, D. J.; Young Jr, V. G. Theophylline monohydrate. Acta Crystallographica Section E: Structure Reports Online 2002, 58, (4), 0368-0370. 19. Fell, J. T.; Newton, J. M. Determination of tablet strength by the diametral-compression test. Journal of Pharmaceutical Sciences 1970, 59, (5), 688-691. 20. Paul, S.; Chang, S.-Y.; Sun, C. C. The phenomenon of tablet flashing—its impact on tableting data analysis and a method to eliminate it. Powder. Technol. 2017, 305, 117-124. 21. Sun, C. C. Quantifying errors in tableting data analysis using the Ryshkewitch equation due to inaccurate true density. J. Pharm. Sci. 2005, 94, (9), 2061-2068. 22. Sun, C. C. A novel method for deriving true density of pharmaceutical solids including hydrates and water-containing powders. J. Pharm. Sci. 2004, 93, (3), 646-653.



446 447 448 449 450 451 452 453 454 455 456 457 458 459 460 461 462 463 464 465 466 467 468 469 470 471 472 473 474 475 476 477 478 479 480 481 482 483 484 485 486 487 488 489 490

Page 26 of 27

23. Sun, C. C. Microstructure of tablet—pharmaceutical significance, assessment, and engineering. Pharm. Res. 2016, 1-11. 24. Patel, S.; Sun, C. C. Macroindentation hardness measurement—modernization and applications. Int. J. Pharm. 2016, 506, (1), 262-267. 25. Tabor, D., The Hardness of Metals, Clarendon. Oxford: 1951. 26. Soroka, I.; Sereda, P. J. Interrelation of hardness, modulus of elasticity, and porosity in various gypsum systems. Journal of the American Ceramic Society 1968, 51, (6), 337-340. 27. Holman, L.; Leuenberger, H. The relationship between solid fraction and mechanical properties of compacts—the percolation theory model approach. Int. J. Pharm. 1988, 46, (1-2), 35-44. 28. Sun, C. C.; Grant, D. J. W. Influence of elastic deformation of particles on Heckel analysis. Pharm. Dev. Technol. 2001, 6, (2), 193-200. 29. Sun, C. C.; Hou, H. Improving mechanical properties of caffeine and methyl gallate crystals by cocrystallization. Crystal Growth and Design 2008, 8, (5), 1575-1579. 30. Ryshkewitch, E. Compression strength of porous sintered alumina and zirconia. Journal of the American Ceramic Society 1953, 36, (2), 65-68. 31. Roberts, R. J.; Rowe, R. C.; York, P. The relationship between the fracture properties, tensile strength and critical stress intensity factor of organic solids and their molecular structure. Int. J. Pharm. 1995, 125, (1), 157-162. 32. Sun, C. C. Mechanism of moisture induced variations in true density and compaction properties of microcrystalline cellulose. Int. J. Pharm. 2008, 346, (1–2), 93-101. 33. Upadhyay, P.; Khomane, K. S.; Kumar, L.; Bansal, A. K. Relationship between crystal structure and mechanical properties of ranitidine hydrochloride polymorphs. CrystEngComm 2013, 15, (19), 39593964. 34. Wray, P. E. The physics of tablet compaction revisited. Drug. Dev. Ind. Pharm. 1992, 18, (6-7), 627-658. 35. Osei-Yeboah, F.; Chang, S.-Y.; Sun, C. C. A critical Examination of the Phenomenon of Bonding Area - Bonding Strength Interplay in Powder Tableting. Pharm. Res. 2016, 33, (5), 1126-1132. 36. Rowe, R. C.; Roberts, R. J. Pharmaceutical Powder Compaction Technology. Marcel Dekker, New York 1996. 37. Sun, C. C.; Kiang, Y. H. On the identification of slip planes in organic crystals based on attachment energy calculation. Journal of Pharmaceutical Sciences 2008, 97, (8), 3456-3461. 38. Chattoraj, S.; Shi, L.; Chen, M.; Alhalaweh, A.; Velaga, S.; Sun, C. C. Origin of deteriorated crystal plasticity and compaction properties of a 1: 1 cocrystal between piroxicam and saccharin. Crystal Growth & Design 2014, 14, (8), 3864-3874. 39. Reddy, C. M.; Padmanabhan, K. A.; Desiraju, G. R. Structure− property correlaJons in bending and brittle organic crystals. Crystal growth & design 2006, 6, (12), 2720-2731. 40. Krishna, G. R.; Devarapalli, R.; Lal, G.; Reddy, C. M. Mechanically Flexible Organic Crystals Achieved by Introducing Weak Interactions in Structure: Supramolecular Shape Synthons. Journal of the American Chemical Society 2016, 138, (41), 13561-13567. 41. Sun, C.; Grant, D. W. Influence of Crystal Structure on the Tableting Properties of Sulfamerazine Polymorphs. Pharm. Res. 2001, 18, (3), 274-280. 42. Ahmed, H.; Shimpi, M. R.; Velaga, S. P. Relationship between mechanical properties and crystal structure in cocrystals and salt of paracetamol. Drug. Dev. Ind. Pharm. 2016, 1-9. 43. Khomane, K. S.; Bansal, A. K. Weak hydrogen bonding interactions influence slip system activity and compaction behavior of pharmaceutical powders. J. Pharm. Sci. 2013, 102, (12), 4242-4245.

491


Page 27 of 27 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


Table of Contents Graphic: Title: Superior plasticity and tabletability of theophylline monohydrate

Authors: Shao-Yu Chang and Changquan Calvin Sun*

ACS Paragon Plus Environment

Superior Plasticity and Tabletability of ... - ACS Publications

Recommend Documents