Superior Plasticity and Tabletability of Theophylline Monohydrate

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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

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Molecular Pharmaceutics

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Superior plasticity and tabletability of theophylline monohydrate

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Shao-Yu Chang and Changquan Calvin Sun*

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

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

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MN 55455

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10

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*Corresponding author

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Changquan Calvin Sun, Ph.D.

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9-127B Weaver-Densford Hall

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308 Harvard street S.E.

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Minneapolis, MN 55455

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Email: [email protected]

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Tel: 612-624-3722

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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

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Abstract

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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.

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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

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31

Keyword. Theophylline, plasticity, tabletability, hydrate,


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33


INTRODUCTION

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

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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.

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performance of pharmaceutical powders,

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compressibility and compactibility.

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molecular and crystal structure.

41

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

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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.

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

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

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

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

Some

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

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

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

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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

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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


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

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been known for some time.

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

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origin of the distinct tableting behavior of THa and THm.

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MATERIALS AND METHODS

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Materials

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

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

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

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

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

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

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Methods

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Hydration Kinetics

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

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

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

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

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to the chamber for the hydration reaction to continue.

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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

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


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

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

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

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

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corresponding samples.

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Particle Size Analysis

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

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

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

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

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

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

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Powder X-ray Diffractometer (PXRD)

90

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

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

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

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

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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

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THm. 17, 18

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Thermogravimetric Analysis (TGA)



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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

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

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

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Compaction Behavior

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

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

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

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

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

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

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further tested.

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

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

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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

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=

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

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of fine sand paper.

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True Density Determination

(1)

20


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

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

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data

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

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measurement.

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

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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,

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= 1 − −

126

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

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

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

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

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

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

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

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= 1 −

− ln

(2)

(3)

134 135

Hardness Measurement by Macroindentation

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

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

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



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

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

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accurate identification of the indent boundary.

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

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

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

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calculated using equation (4). 25

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=

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

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H = H0 ! "

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

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triplicated.

24

The area of indents was determined using a calibrated

(4)

(5)

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In-die Elastic Recovery

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

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compaction pressure, respectively, using equation (6).

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ER%= 100(h - h0)/ h0

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

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

158

deterioration of tablet strength.

(6)

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Crystal Structure Analysis

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

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

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

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by crystal structure visualization.

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Results and Discussion

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

Complete

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

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matching the theoretical weight gain for 100% conversion.

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

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

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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


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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

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-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%,

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

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

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

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

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

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

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

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

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

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

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

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

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

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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),

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corresponding to surface moisture.

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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

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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

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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

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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

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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

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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.


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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



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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


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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

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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

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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

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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 Theophylline Monohydrate

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