Profoundly Improved Plasticity and Tabletability of Griseofulvin by in

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Profoundly improved plasticity and tabletability of griseofulvin by in-situ solvation and desolvation during spherical crystallization Hongbo Chen, Chenguang Wang, and Changquan Calvin Sun Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.9b00053 • Publication Date (Web): 27 Feb 2019 Downloaded from http://pubs.acs.org on March 3, 2019

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Crystal Growth & Design

Profoundly improved plasticity and tabletability of griseofulvin by insitu solvation and desolvation during spherical crystallization Hongbo Chen, Chenguang Wang, and Changquan Calvin Sun*

Pharmaceutical Materials Science and Engineering Laboratory, Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, USA

*Corresponding author Changquan Calvin Sun, Ph.D. 9-127B Weaver-Densford Hall 308 Harvard Street S.E. Minneapolis, MN 55455 Email: [email protected] Tel: 612-624-3722 Fax: 612-626-2125

1 ACS Paragon Plus Environment

Crystal Growth & Design 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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Griseofulvin (GSF) is a high dose drug exhibiting poor flowability and tabletability, which

3

makes formulating a high drug loading tablet challenging. In using spherical crystallization to

4

improve flowability, the spherical agglomerates (SA) of GSF were found to have profoundly

5

improved tabletability over the as-received GSF. An improved plasticity of GSF SA was observed

6

despite its identical crystal structure and larger particle size when compared to the as-received GSF.

7

Tracking solid forms during the process revealed the formation of a GSF solvate with

8

dichloromethane, the bridging liquid for spherical agglomeration. With subsequent desolvation

9

during drying, nanoporous GSF crystals were obtained, which could be plastically deformed more

10

easily and exhibited much improved tabletability.


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11 12


Introduction Successful tablet manufacturing requires the powder blends to meet several criteria,

13

including adequate tabletability, flowability, uniformity, and free from sticking to punches.1,

2

14

Particle engineering and crystal engineering are two effective approaches to overcome inherent

15

problematic physical or mechanical properties and, thereby, enable successful tablet

16

development.3-5 Common methods to improve powder flowability and tabletability of active

17

pharmaceutical ingredients (API) have recently been summarized.6

18

flowability include making spherical granules,7, 8 increasing size,3 reducing surface roughness,9

19

reducing cohesion by nano-coating,10 and changing surface chemistry.11 Methods to improve

20

tabletability, such as surface polymer coating,12 size reduction,13 increasing roughness,14

21

cocrystallization,15 and crystal hydration,16 mainly rely on increasing bonding area among

22

particles.17 Typically, flowability enhancement by size enlargement and surface smoothing by

23

granulation also leads to deteriorated tabletability.18

Methods to improve

24

In comparison to common granulation methods, spherical crystallization (SC) stands out

25

as an efficient way to simultaneously improve flowability and tabletability.19-21 SC is a method

26

that transforms fine crystals into compact spherical agglomerates (SA).22 Such spherical crystal

27

agglomerates exhibit good flowability because of the large size and spherical shape.8, 23, 24 While

28

a systematic investigation remains incomplete, the improved tabletability by SC, is commonly

29

attributed to the enhanced interparticle contacts due to fragmentation of agglomerates,21, 25 smaller

30

primary crystals19 and easier plastic deformation.26 Spherical crystals are commonly produced by

31

either spherical agglomeration22 or quasi-emulsion solvent diffusion (QESD)27. In the spherical

32

agglomeration, three solvents, good solvent, poor solvent, and bridging liquid, are used. During

33

this process, the API is dissolved in a good solvent, followed by adding the drug solution to a

34

miscible poor solvent to induce immediate precipitation of fine API crystals. Then, a bridging 3 ACS Paragon Plus Environment


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liquid is added to facilitate agglomeration of primary fine API crystals into large spherical

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agglomerates through the surface tension effect.28 The polarity of solvents is important in the SA

37

process. The good and poor solvents should have similar polarity and they are miscible. When they

38

mix through molecular diffusion, API precipitates out because of the reduced interactions with the

39

good solvent due to the affinity between the poor and good solvent molecules. The faster the

40

mixing between good and poor solvents, the faster the crystallization and finer primary crystals,

41

which will subsequently form agglomerates by the bridging liquid. In general, the polarity of the

42

bridging liquid should be different from the poor solvent, and hence they are immiscible. This

43

ensures that the bridging liquid is available for collecting small API crystals into agglomerates.29

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Griseofulvin (GSF), an antifungal drug with dose as large as 1 g, is marketed as high drug

45

loading tablets (up to 500 mg per tablet).

Pure GSF shows poor powder flowability and

46

tabletability. In an effort to improve flowability of GSF by spherical agglomeration to enable the

47

development of a high dose tablet,1 we surprisingly found simultaneously and profoundly

48

improved tabletability; the mechanism of which was investigated.

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Materials and methods

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Materials

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Griseofulvin was obtained from GSK Glaxo laboratories, London, UK. Microcrystalline

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cellulose (Avicel PH102; FMC Biopolymers, Newark, DE), dimethylformamide (DMF, Sigma-

53

Aldrich, St. Louis, MO), dichloromethane (DCM, Fisher Scientific, Fair Lawn, NJ), ultrapure

54

deionized water (0.066 μS/cm, Thermo Scientific, USA) were used as received. All crystallization

55

experiments were performed using glass beakers.

56

Spherical crystallization

57

Construction of ternary phase diagram


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DMF, water, and DCM were used as the good solvent, poor solvent and bridging liquid for

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preparing spherical GSF crystals using the spherical agglomeration method from a preliminary

60

screening study. A ternary phase diagram was constructed to identify the agglomeration zone by

61

the following process.30 DMF and DCM were cooled to 0 oC in an ice-bath and then combined in

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volume ratios of 1:9, 2:8, 3:7, 4:6, 5:5, 4:6, 7:3, 8:2, and 9:1. A 5 mL aliquot of each was

63

transferred to a screw capped vial, and water was added dropwise with intermittent mixing. When

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the clear mixed solvents became turbid, the volume of water was noted. To obtain the

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agglomeration zone on the phase diagram, 1 g of GSF was dissolved in 7 ml of DMF. The DMF

66

solution was poured into water with DMF:water volume ratios of 7:17.5, 7:30, 7:40, 7:60 and 7:80,

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where the API precipitated. Then, DCM was added dropwise until a paste-like product was

68

observed, and the volume of DCM was noted. A ternary phase diagram, including agglomeration

69

zone, miscible and immiscible regions, was then constructed.

70

Preparation of spherical agglomerates of GSF

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To prepare spherical agglomerates of GSF, 9 g of GSF was dissolved in 60 mL of DMF at

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120 oC to obtain a clear solution. The solution was poured into 270 mL of water in a 500 mL glass

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beaker, which was immersed in an ice bath and agitated with an overhead stirrer at 600 rpm. After

74

5 min agitation, DCM was added dropwise until fine crystals were transformed into large

75

agglomerates. The system was agitated for another hour, and the agglomerates were collected and

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dried in a 60 oC oven for 4 hours.

77

Powder X-ray Diffractometry (PXRD)

78

A powder X-ray diffractometer (PANalytical X'pert pro, Westborough, MA) with Cu Kα

79

radiation (1.54059 Å) was used to characterize powders. Samples were scanned between 5 to 35°

80

2θ with a step size of 0.02° and a dwell time of 1 s/step. The tube voltage and amperage were set

81

at 40 kV and 40 mA, respectively. The diffraction patterns of the powders were compared to the 5 ACS Paragon Plus Environment


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original powder and the calculated PXRD pattern from the single crystal structure of GSF (CCDC

83

refcode: GRISFL06).31

84

Single Crystal X-ray Diffractometry

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Single crystal X-ray diffraction experiment was carried out on a Bruker-AXS Venture

86

Photon-II diffractometer (Bruker AXS Inc., Madison, Wisconsin) equipped with a Photon-II

87

(CMOS) detector. The data collection was performed using Mo Kα radiation at 100 K. A suite of

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software from Bruker, including APEX3, SADABS, SAINT and XPREP was used to analyze the

89

collected data. The crystal structure was solved and refined using Bruker ShelXle. Direct-methods

90

solution was applied to place non-hydrogen atoms from the E-map. All non-hydrogen atoms were

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refined with anisotropic displacement parameters. Hydrogen atoms that involved in hydrogen

92

bonding were located from the residual peaks in the Fourier map, otherwise were generated

93

geometrically.

94

Thermal Analyses

95

Powder samples (3−5 mg) were loaded into hermetic aluminum pans and heated from 30

96

to 240 °C at a heating rate of 10 °C/min on a differential scanning calorimeter (Q1000, TA

97

Instruments, New Castle, DE) under a continuous nitrogen purge at a flow rate of 50 mL/min. DSC

98

cell parameter was calibrated with indium for heat flow and indium and cyclohexane for

99

temperature. To measure any volatile content in a solid, a thermogravimetry analyzer (Q500, TA

100

Instruments, New Castle, DE) was applied to analyze the samples (3∼10 mg) placed in an open

101

aluminum pan. The samples were heated from room temperature to 300 °C at 10 °C/min under 25

102

mL/ min nitrogen purge.

103

Powder Flowability


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Powder flowability was measured using a ring shear cell tester (RST-XS; Dietmar Schulze,

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Wolfenbüttel, Germany), with a 10 mL cell at 1 and 3 kPa pre-shear normal stresses. The

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unconfined yield strength (fc) and major principal stress (σn) were obtained from each yield locus

107

by drawing Mohr’s circles. Flowability index (ffc) was calculated using Eq. (1):

108

𝑓𝑓c = 𝑓c

𝜎𝑛

(1)

109 110

Powder tabletability

111

A universal material test machine (model 1485, Zwick/Roell, Germany) was used to

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prepare tablets with compaction pressure ranging from 25 to 350 MPa at speed of 4 mm/min. The

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punch tip and die wall was lubricated using magnesium stearate. Tablets were relaxed under

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ambient environment for at least 24 h before being broken diametrically using a texture analyzer

115

(TA-XT2i; Texture Technologies Corporation, Scarsdale, NY). Tablet tensile strength was

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calculated from the breaking force and tablet dimensions following the standard procedure.32

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True density of powders was measured using a helium pycnometer (Quantachrome

118

Instruments, Ultrapycnometer 1000e, Byonton Beach, FL). The sample cell was filled with

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accurately weighed powders (1-2g). The measurement was stopped when the coefficient of volume

120

variation of the last five consecutive measurements was below 0.005%. Otherwise, the experiment

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terminates automatically at a maximum of 100 measurements. The mean and standard deviation

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of the last five measurements were reported.

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Scanning electron microscopy (SEM)

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An ion-beams sputter (IBS/TM200S; VCR Group Inc., San Clemente, CA) was used to

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was sputter-coated a thin layer platinum (thickness ~ 75 Å) onto the samples. Scanning electron

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microscopy (JEOL 6500F; JEOL Ltd., Tokyo, Japan) operated at SEI mode with an acceleration 7 ACS Paragon Plus Environment


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voltage of 5kV was used to evaluate particle morphology and surface feathers and a high vacuum

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(10-4-10-5 Pa) was maintained during the imaging process.

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In-die Heckel analysis

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A universal material test machine (model 1485, Zwick/Roell, Germany) was used to

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prepare tablets (about 200mg) with compaction pressure 300 MPa at speed of 4 mm/min (n=3).

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The force and normal strain during the compression are exported. Both GSF SA and as-received

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were analyzed using the Heckel equation,33 Eq. (2):

134

― ln (1 ― 𝐷) = 𝐾𝑃 + 𝐴

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where P is the compaction pressure, K is the slope of the linear portion of the Heckel plot, and A

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is the y-axis intercept of the linear portion. D is the relative density calculated using Eq. (3)

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D=1―

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The reciprocal of K, which is termed mean yield pressure (Py), is a parameter that can be used to

139

quantify plasticity of the powder. A lower Py indicates higher plasticity of a powder. The

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measurement was triplicated.

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Out-of-die Kuentz–Leuenberger (KL) equation

(2)

tablet density

(3)

true density

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The Kuentz–Leuenberger (KL) equation, Eq. (4)34 was applied to obtain the plasticity

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parameter, 1/C, by fitting tablet porosity – pressure data. A lower 1/C value indicates higher

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plasticity of the powder. The parameter, εc, describes the critical powder porosity at which the

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powder starts to gain rigidity or strength.

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𝑃 = 𝐶[𝜀 ― 𝜀𝑐 ― 𝜀𝑐𝑙𝑛(𝜀𝑐)

147

Out-of-die Hardness determination by macroindentation

1

𝜀

(4)


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

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XT2i, Texture Technologies Corp., NY), was used to indent the cylindrical tablet at the center of

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a flat face. During loading, the indenter was moved downward at a speed of 0.01 mm/min, and

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the indenting force was set around 60% of the breaking force of the tablet prepared at the same

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compaction pressure and maintained for 3 min. The indented area was measured using a calibrated

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digital microscope (×200 magnification, Dino-Lite Pro AM413MT; AnMo Electronics

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Corporation, Taiwan). A three-point method was used to identify the circular indented area and

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the projected area, A, was calculated using DinoCapture software (V2.0 AnMo Electronics

156

Corporation, Taiwan). To more accurately determine the indented area, the contrast between the

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indent and surrounding flat tablet surface was enhanced by gently rubbing the tablet face against

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a piece of graphite-coated paper. Tablet hardness, H, was calculated using Eq. (5):

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𝐻=𝐴

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H0, hardness at zero porosity, was obtained by extrapolating the function to zero porosity.

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Energy framework of crystal structures

162

The pairwise intermolecular interaction energy was estimated using CrystalExplorer and

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Gaussian09W with experimental geometry of GSF Form I.31, 35, 36 The hydrogen positions were

164

normalized to standard neutron diffraction values before calculation using the B3LYP-D2/6-

165

31G(d,p) electron densities model. The total intermolecular interaction energy for a given

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molecule is the sum of the electrostatic, polarization, dispersion, and exchange-repulsion

167

components with scale factors of 1.057, 0.740, 0.871, and 0.618, respectively. Intermolecular

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interaction between two molecules was ignored, when the closest atom - atom distance was more

169

than 3.8 Å. The interaction energies were graphically presented as a framework by connecting

𝐹

(5)



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centers of mass of molecules with cylinder thickness proportional to the total intermolecular

171

interaction energies, where interaction energies below -5 kJ/mol were omitted for clarity.

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Results and discussion

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Ternary Phase Diagram

174 175

Figure 1. Ternary phase diagram of GSF in water-DMF-DCM solvents system

176 177

The ternary phase diagram (Figure 1) pertaining to SA of GSF in this work revealed a

178

distinct agglomeration zone for producing spherical crystal agglomerates (shaded region). This

179

zone is in the immiscible region neighboring the miscible zone, where free bridging liquid (DCM)

180

was available to collect small primary GSF crystals into large SA. No agglomerates were obtained

181

in the miscible zone. Outside the shaded area in the immiscible zone, a paste-like product was

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formed because of excess amount of bridging liquid.

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Particulate properties

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The microscopic images and particle size analysis revealed the particle shape and size after

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the spherical agglomeration process. The as-received GSF consisted of irregular crystals with size

186

ranging 1 - 10 µm, while the agglomerates were round with size ranging 300 - 600 µm (Figure 2).


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Moreover, no weight loss was detected for SA before 153 oC (boiling point of DMF) by thermal

188

gravimetric analysis (Figure S1), indicating negligible residual solvent.

(a)

(b)

189 190

Figure 2. Microscopic images of GSF (a) as-received and (b) SA.

191 192

Powder flowability and tabletability

193

The flowability of the powder is an important powder property in tablet manufacturing. At

194

normal stresses of 1 and 3 kPa, the ffC values of GSF SA were similar to those of Avicel PH102

195

(Figure 3a), which suggests their adequate flowability for high speed tableting.37 The flow property

196

of the as-received GSF, on the other hand, was much poorer than that of Avicel PH102 (Figure

197

3a). The much improved flowability of the GSF SA is a consequence of the large size and round

198

shape.23

a)

b)

199 11 ACS Paragon Plus Environment


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Figure 3. (a) Flowability profiles of as-received GSF, GSF SA and Avicel PH102 (n=1); (b)

201

tabletability profiles of as-received GSF, GSF SA and GSF SA milled (n=3).

202 203

Similar to a previous study,38 intact tablets of as-received GSF could not be obtained, due

204

to lamination, over the entire pressure range between 25 and 350 MPa. The problematic

205

tabletability of GSF is attributed to minimal plasticity due to a lack of active slip planes in its

206

crystal structure.38 Surprisingly, the GSF SA exhibited excellent tabletability with the highest

207

tensile strength around 5 MPa at ~300 MPa (Figure 3b). The profoundly improved tabletability

208

could not be explained by any changes in solid state form, because the GSF SA were phase pure

209

GSF Form I, the same as the as-received GSF.

210

Another commonly cited mechanism to explain improved tabletability of spherical crystals

211

is extensive fracture of agglomerates during compaction,21, 25 which exposes fresh surfaces for

212

developing a network of interparticle bonding. This mechanism is reasonable for lubricated

213

powders where coating of particles by poorly bonding lubricant weakens bonding strength. In that

214

case, generation of particle surfaces free from such deleterious effect by fragmentation improves

215

tablet tensile strength through higher bonding strength according to the bonding area – bonding

216

strength model.17, 18, 39 However, this explanation is not appropriate, because GSF powders were

217

not mixed with any lubricant. The external lubrication of tooling could not have affected

218

interparticulate bonding strength. In addition, fragmentation of agglomerates during compaction

219

unlikely reduced GSF to the size of as-received GSF, which is very small (1 - 10 µm). Thus, larger

220

bonding area due to smaller particle also does not explain the improved tabletability. To verify

221

this point, GSF SA were milled and then compressed. The milled GSF SA exhibited similar

222

tabletability profile as the un-milled agglomerates (Figure 3b). Hence, in-situ particle 12 ACS Paragon Plus Environment

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223

fragmentation can be excluded as a main mechanism to the profoundly increased tabletability.

224

Therefore, a different mechanism must have caused significantly larger interparticulate bonding

225

area, which led to the striking improvement in tabletability.

226 227

Role of plasticity in the improved tabletability of GSF agglomerates

228 229

To seek an explanation for the improved tabletability, the plasticity of the different GSF

230

powders was assessed by Heckel analysis of in-die compressibility data. A lower value of the

231

plasticity parameter, Py, from such an analysis indicates higher plasticity of the material. Results

232

show that the Py followed the order of: GSF SA ≈ GSF SA milled < as-received GSF (Table 1),

233

which corresponded well with the order of tabletability: GSF SA ≈ GSF SA milled > as-received

234

GSF. This data supports the premise that the improved tabletability of GSF SA resulted from

235

increased plasticity. The Py values of all three materials are higher than that of Avicel PH102, a

236

commonly used plastic excipient with a Py value of ~ 62 MPa,

237

tabletability.18 However, the higher plasticity of agglomerated GSF cannot be attributed to a

238

change in particle size, since the Py of the milled GSF agglomerates is the same as that of un-

239

milled agglomerates.

240

Table 1. Plasticity parameters of as received GSF and GSF SA from in-die and out-of-die data

241

analyses. Sample name

As-received GSF

Py (MPa), n=3 143.0 ±5.3

242

a

40

and exhibiting excellent

GSF SA

GSF SA milled

107.9 ±1.3

106.4 ±2.3

1/C (MPa) a

450.0 ± 208.5 (R2=0.98) 143.4 ± 38.4 (R2=0.99) --

H0 (MPa) a

435 ± 21 (R2=0.98)

333 ± 18 (R2=0.98)

--

Parameters were derived for mixtures containing 20% Avicel PH102 13 ACS Paragon Plus Environment


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To further verify the different plasticity between the two powders using out-of-die data,

244

physical mixtures of GSF (80%) and Avicel PH102 (20%) were studied. Avicel P102 was used,

245

because pure as-received GSF could not be compressed into intact tablets. The tabletability of the

246

mixture containing GSF SA outperformed that containing as-received GSF (Figure 4a). Although

247

the relative order in tabletability of the mixture and pure GSF did not change, the tabletability

248

difference between the two mixtures was much smaller than that between pure GSF powders. The

249

tensile strength extrapolated to zero porosity, which is a parameter to infer apparent bonding

250

strength, was lower for the mixture containing GSF SA. Thus, the better tabletability of the GSF

251

SA mixture was not due to higher bonding strength between the particles (Figure 4b). However,

252

at the same compaction pressure, tablets of the mixture containing GSF SA exhibited significantly

253

lower porosity (Figure 4c), indicating higher plasticity. In fact, the plasticity parameter, 1/C, from

254

the KL analysis of the mixture containing GSF SA was lower than the mixture containing the as-

255

received GSF (Table 1), confirming the higher plasticity of SA.

256


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a)

b)

c)

d)

257 258 259

Figure 4. (a) Tabletability, (b) compactibility, (c) compressibility, and (d) hardness profiles of GSF (80%) and Avicel PH102 (20%) mixture.

260 261

The hardness at zero porosity, H0, is also a measure of plasticity of the powder, where a

262

lower H0 value relates to a higher plasticity.41 By this measure, the mixture containing GSF SA

263

was also more plastic because of its lower H0 (Figure 4d, Table 1). Therefore, results from all

264

complementary methods confirm the higher plasticity of the GSF SA. The higher plasticity, in

265

turn, leads to larger bonding area and higher tabletability for the mixture containing GSF SA.

266 267

Origin of superior plasticity of GSF SA



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At this point, the underlying reason for the superior plasticity remained elusive. Because

269

GSF SA had a crystal structure identical to the as-received GSF, as shown by the nearly identical

270

PXRD patterns (Figure 5a) and DSC thermograms (Figure 5b).

271

However, scanning electronic microscope (SEM) images revealed intriguing difference in

272

the structures of the two powders, where many nanopores with opening size of ~500 nm were

273

clearly observed in GSF SA but absent in the as-received GSF (Figures 6 and S2). These nanopores

274

can collapse during compression to make particles more deformable, which leads to larger

275

interparticulate contact area in the tablet.

a)

b)

276 277 278

Figure 5. (a) PXRD patterns of calculated GSF Form I, as-received GSF, GSF SA, calculated GSF-DCM and GSF SA before drying; (b) DSC profiles of as-received GSF and GSF SA.

279 280

The collapse of nanopores after compaction was verified by observing GSF agglomerate

281

crystals exposed to the fracture surface of a tablet prepared at 250 MPa (mixture containing 20%

282

Avicel PH102) after breaking diametrically (Figure 6). It is interesting to note that small nanosized

283

particles also appeared on the tablet fracture surface of the GSF SA (Figure 6). These nanosized

284

particles indicate possible fragmentation of the porous GSF crystals, either during compaction or 16 ACS Paragon Plus Environment

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285

during tablet breaking.

In contrast, no obvious changes to the as-received GSF crystals were

286

observed (Figure 6). Thus, the as-received GSF crystals undergo largely reversible, elastic

287

deformation during compaction, which correlates to its extremely poor tabletability (Figure 3b).

(a)

(b)

(c)

(d)

288 289

Figure 6. SEM images at (x10,000 magnification) of GSF (a) as-received crystals, (b) SA, and

290

tablet fracture surface of (c) GSF-Avicel mixture, and (d) GSF SA-Avicel mixture.

291

The origin of the nanopores in GSF SA is attributed to the solvation and desolvation

292

process during the spherical agglomeration process. The formation of a DCM solvate is confirmed

293

by the PXRD patterns of the fresh prepared GSF SA, which matched the calculated pattern of

294

GSF-DCM solvate (Figure 5a).42 While the GSF molecules are closely packed in GSF Form I

295

(Figure 7a), they form a hexagonal reticular structure fortified through a series of C-H...O (3.347,

296

3.348, 3.484, 3.476, 3.478 Å) and C-H...π (3.664 Å) interactions. The voids in the solvate are filled

297

by DCM molecules, which interact with GSF through C-H...O (3.284, 3.361, 3.364 Å) weak

298

hydrogen bonds (Figure 7b). The weak interaction strength between DCM and GSF is consistent

299

with the observed relatively facile desolvation process, which goes to completion at 60 oC in 4 h

300

(Table S1). The open structure of the desolvated GSF-DCM crystal, with 18.6% of void by volume, 17 ACS Paragon Plus Environment


Page 18 of 23

301

is unstable (Figure 7c), as suggested by the calculated large lattice energy difference (~20 kcal/mol)

302

between GSF Form I (-94.24 kcal/mol) and GSF anhydrous (-73.98 kcal/mol). Driven by such a

303

large energy difference, fast spontaneous collapse of the desolvated structure to Form I is expected,

304

which induced cracks and generated nanopores in GSF crystals. A similar mechanism was

305

previously reported for acetaminophen, which also led to significantly improved tabletability.43-45

306

Although we only studied DCM solvate of GSF in this work, it is likely that the solvation -

307

desolvation of other GSF solvates, such as GSF-chloroform, GSF-benzene, GSF dioxane,42, 46-48

308

can achieve a similar effect. This is being investigated in our laboratory.

a)

b)

c)

309 310

Figure 7. Energy framework of (a) GSF Form I and (b) GSF-DCM solvate. The (c) desolvated

311

GSF-DCM with large void is also shown for comparison. The energy threshold for the energy

312

framework is set at −22 kJ/mol.

313 18 ACS Paragon Plus Environment

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Conclusion

315

The spherical GSF Form I agglomerates, prepared by the spherical crystallization process,

316

exhibited not only good flowability as expected but also surprisingly excellent tabletability without

317

a change in the solid form. The latter is attributed to the in-situ formation of a DCM solvate and

318

subsequent desolvation during drying, which generates nanopores and makes the GSF crystals

319

more deformable by collapse of pores during compaction. Such superior deformability leads to

320

large interparticular bonding area and stronger tablets. This mechanism for enhancing crystal

321

plasticity may be useful to improve tabletability of other poorly compressible APIs that can form

322

a solvate or hydrate.

323

Supporting Information

324

Thermogravimetric analysis, high magnification of agglomerates image of GSF DCM solvate and

325

intermolecular interaction energies are provided. The crystallographic data of GSF DCM solvate,

326

CCDC 1890455, can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by

327

emailing [email protected], or by contacting the Cambridge Crystallographic Data

328

Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

329

Acknowledgements

330

Part of this work was carried out in the Characterization Facility, University of Minnesota, which

331

receives partial support from NSF through the MRSEC program. H.C. thanks the Chinese

332

Scholarship Council for partial financial support.

333 334

References 19 ACS Paragon Plus Environment


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For Table of Contents Use Only

449 450 451

Profoundly improved plasticity and tabletability of griseofulvin by in-situ solvation and desolvation during spherical crystallization

452 453

Hongbo Chen, Chenguang Wang, and Changquan Calvin Sun

454 455 456

Synopsis. Spherical nanoporous GSF agglomerates exhibited profoundly improved tabletability through in-situ solvation and desolvation during the process.


Profoundly Improved Plasticity and Tabletability of Griseofulvin by in

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