Relationships among crystal structures, mechanical properties, and

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Relationships among crystal structures, mechanical properties, and tableting performance probed using four salts of diphenhydramine Chenguang Wang, Shubhajit Paul, Kunlin Wang, Shenye Hu, and Changquan Calvin Sun Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.7b01153 • Publication Date (Web): 02 Oct 2017 Downloaded from http://pubs.acs.org on October 4, 2017

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Crystal Growth & Design

Relationships among crystal structures, mechanical properties, and tableting performance probed using four salts of diphenhydramine

Chenguang Wang, Shubhajit Paul, Kunlin Wang, Shenye Hu, 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


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Abstract Clear understanding of the relationships among crystal structure, mechanical properties, and tableting performance is of enormous importance for successful development of tablet products. This study was aimed at systematically examining such relationships using four salts of diphenhydramine (DPH), a first-generation H-receptor antagonist, i.e., hydrochloride (DPH-HCl), citrate (DPH-Cit), saccharinate (DPH-Sac), and acesulfamate (DPH-Acs). The conformation and intermolecular interactions of DPH as well as crystal packing in the four salts were considerably different. Both the energy framework and visualization of the crystal structure revealed the greatest plasticity of DPH-Acs, which was characterized by drastically different intermolecular interactions in orthogonal directions. This was consistent with its facile bending behavior and the lowest hardness. The most plastic DPH-Acs also exhibited the best tabletability, which was accompanied by greater compressibility and compactibility as well as smaller elastic recovery than other three salts.

Among the three hard brittle DPH salts, higher crystal hardness

corresponded to poorer tabletability. This work demonstrates the technological feasibility of understanding or even predicting tableting performance based on crystal structures and mechanical properties.


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Introduction Active pharmaceutical ingredients (API) often display deficient pharmaceutical properties that hinder their successful development into tablets.

Among several strategies,

crystal engineering is effective for addressing this problem by designing a solid form exhibiting the desired pharmaceutical properties.1 Salt formation has been widely utilized to alter important pharmaceutical properties of APIs, including crystallinity, melting point, solubility, dissolution rate, bioavailability, chemical/physical stability, taste, and mechanical properties.2 Nearly half of the small molecule drugs are commercialized as salts.3 A protocol for screening a preferred salt form based on thorough physicochemical characterization is available.4 The counterion cost, method of crystallization, and yield during scale up and manufacture are also factors to consider.5 Cocrystallization is another common engineering approach that compliments salt formation to expand the solid-state landscape of drugs. Salts and cocrystals are in many ways similar and they may be viewed as a broad class of materials with a continuum of chemical structures involving proton transfer.6 Despite their similarities, the ionization state of molecules can have a significant impact on the relative stabilities of crystal lattice energy.7 In addition, cocrystals tend to be less prone to solvate formation, which is an advantage for pharmaceutical applications, reliable structure prediction, and supramolecular synthesis of APIs.8

Also

importantly, they are classified into distinct groups of solid forms by regulatory agency.9 Among the key properties of an API, mechanical property is a well-recognized but relatively poorly studied property, which has recently attracted growing interest in the field of crystal engineering.10-15 Appropriate mechanical properties are important for several important processes, e.g., tablet compaction and milling, during the manufacture of oral solid dosage forms.16-19 Initial research on mechanical properties of crystals in the context of tableting



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suggested that tablet tensile strength at zero porosity linearly correlated with melting point for Llysine salts.20 The sulfamerazine polymorph with flat layered structure, or active slip planes, corresponded to much better tabletability than the polymorph exhibiting ‘zig-zag’ layered structure.20 The correlation between crystal structure and tableting performance was further demonstrated using a homologous series of parabens, polymorphs and cocrystals.19,

21, 22

Subsequent work further solidified the correlation among crystal structure, mechanical properties, and tableting performance by also including mechanical properties of polymorphs and cocrystals through qualitative crystal bending and quantitative nanoindentation experiments.23, 24 The general observations in previous research suggested that more plastic crystals usually showed better tabletability, which is consistent with the bonding area and bonding strength (BABS) model.25, 26 This is rationalized by the formation of larger bonding area, which favors better tabletability, between crystals that undergo more permanent plastic deformation under the same compaction conditions and with similar particulate properties. The BABS model also suggests that higher bonding strength, which may be indicated by a higher melting point or stronger intermolecular interactions, also favors better tabletability. The foundational prior research has collectively suggested connections among crystal structure, crystal mechanical properties, and tabletability, which justifies the efforts of solving tabletability problems of drugs through crystal engineering.

However, an example that

comprehensively tests the above-mentioned relationships in pharmaceutical salts is still missing. In this study, we examined such relationships using four salts of diphenhydramine (DPH, Scheme 1), a first-generation H-receptor antagonist. DPH is a commonly used antihistamine drug for treating symptoms associated with allergy and aiding sleep. The DPH hydrochloride salt (DPH·HCl) and citrate salt (DPH·Cit) are used in the immediate and extended release 4 ACS Paragon Plus Environment

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tablets, respectively. We synthesized two new salts with saccharin (DPH·Sac) and acesulfame (DPH·Acs) in an effort to mask the bitter taste of DPH for oral delivery. The molecular structure of diphenhydramine (DPH), hydrochloride (HCl), citric acid (Cit), saccharin (Sac) and acesulfame (Acs) are shown in Scheme 1.

Scheme 1. Chemical structures of a) diphenhydramine, b) hydrochloric acid, c) citric acid, d）saccharin, and e) acesulfame.

Experimental Section Materials DPH·HCl (Baikang Pharmaceutical Co., Ltd, Liaoyuan, Jilin, China), DPH·Cit (Luxin Pharmaceutical Co., Ltd, Jinan, Shandong, China), sodium saccharin salt hydrate (Na·Sac, Sigma–Aldrich, St. Louis, MO), and acesulfame potassium (K·Acs, Tokyo Chemical Industry Co., Ltd, Japan) were used as received. The pKa value of DPH, Sac, and Acs are 8.98, 1.6 and 2.0, respectively. They easily form DPH·Sac and DPH·Acs salts as expected from the large ∆pKa (>3). We prepared the bulk powders (~30 g batch size) of DPH·Sac and DPH·Acs through the anion exchange reaction between equi-molar DPH·HCl and Na·Sac or K·Acs in water.27 Single Crystal X-ray Diffraction (SCXRD)



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The crystal structures of DPH·HCl (JEMJOA), DPH·Cit (FOXTAN), and DPH·Acs were reported in the literature.

28-30

However, the space group and unit cell parameters for DPH·HCl

were incorrectly assigned and three-dimensional coordinates for DPH·Cit were unavailable from the current Cambridge crystallographic database entry. Therefore, their crystal structures were re-determined in this work. 200 mg DPH·HCl was dissolved in 15 mL of methanol with a few drops of water in a 20 mL glass vial to form a clear solution. The vial was covered with parafilm with a small hole introduced in the middle. The vial was then left in a fume hood undisturbed to allow slow evaporation at room temperature. DPH·Cit single crystals were prepared by slow evaporation of a 20 mL isopropyl alcohol solution (5 mg/mL) at ambient conditions following a similar procedure. A mixture of 1:1 stoichiometric amount of DPH·HCl (0.1 mmol) and Sac·Na (0.1 mmol) was suspended in 10 mL of water in a 20 mL glass vial. The vial was slightly heated to obtain a clear solution, which was hot filtered, allowed to cool to room temperature, and then followed by slow evaporation. Crystals suitable for single crystal X-ray diffraction (SCXRD) experiment were obtained within one week. SCXRD experiments were performed on a Bruker D8 Venture diffractometer (Bruker AXS Inc., Madison, Wisconsin) equipped with a Bruker PHOTON-II CMOS detector. The data collection was done with a MoKα radiation source (IµS 3.0 microfocus tube). Data integration was performed with the SAINT program, the SADABS program was used for scaling and absorption correction and XPREP was used for space group determination and data merging. Crystal structure was solved using SHELXT intrinsic phasing methods and refined using ShelXle program (a graphical user interface for SHELXL).31

The hydrogen atoms were placed

geometrically from the difference Fourier map and allowed to ride on their parent atoms in the 6 ACS Paragon Plus Environment

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refinement cycles.

All non-hydrogen atoms were refined with anisotropic displacement

parameters. Attachment energy calculation The attachment energy was calculated by the crystal growth module in the Materials Studio 7.0. (Accelrys Software Inc., San Diego, CA, USA) using Dreiding force field and Qeq charges at fine quality. The “Ewald” electrostatic summation method and “atom based” van der Waals summation was chosen. In addition, a minimum dhkl was set at ‘1.0 Å’. Crystal structure analysis To identify hydrogen-bond patterns and molecular conformation, Mercury (V.3.9, Cambridge Crystallographic Data Centre, Cambridge, UK) was utilized.

Hirshfeld 2D

fingerprint plot was constructed using CrystalExplorer (V.17, University of Western Australia). For the calculation of intermolecular interaction energy, B3LYP-D2/6-31G(d,p) model based on dispersion-corrected density functional theory was employed. The “energy framework” was constructed based on the total intermolecular interaction energy, which included electrostatic, polarization, dispersion, and exchange-repulsion components with scale factors of 1.057, 0.740, 0.871 and 0.618, respectively.32 Powder X-Ray Diffractometry (PXRD) Powders were characterized on a powder X-ray diffractometer (D8 Advance; Bruker AXS, Madison, WI) with Cu Kα radiation (1.54059Å). Samples were scanned between 5 to 35° 2θ with a step size of 0.02° and a dwell time of 1.0 s/ step. The tube voltage and amperage were set at 40 kV and 40 mA, respectively. Thermal analyses 7 ACS Paragon Plus Environment


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Powder samples (∼3 mg) were loaded into sealed aluminum pans and heated in a differential scanning calorimeter (Q1000, TA Instruments, New Castle, DE) at a rate of 10 °C/min under a continuous 25 mL/min nitrogen purge. The instrument was equipped with a refrigerated cooling system. Temperature and enthalpy were calibrated using high purity indium. To measure volatile content in a solid, samples (∼3 mg) were placed in an open aluminum pan and heated from room temperature to 300 °C at 10 °C/min under 50 mL/min nitrogen purge on a thermogravimetry analyzer (Q500, TA Instruments, New Castle, DE). Dynamic Water Vapor Sorption Isotherm Water sorption isotherms of the materials were obtained using an automated vapor sorption analyzer (Intrinsic DVS, Surface Measurement Systems Ltd., Allentown, PA) at 25 °C. The nitrogen flow rate was 50 mL/min. Each sample was first dried with dry nitrogen purge until a constant weight was obtained. Then, the sample was exposed to a series of relative humidities (RH) from 0% to 95% with the step size of 5% RH. At each specific RH, sample was assumed having reached equilibration when either dm/dt ≤ 0.002% or maximum equilibration time of 6h was met. The RH was then changed to the next target value. Nanoindentation Nanoindentation data were collected using a nanoindenter (NanoIndenter® XP, MTS Systems Corporation, Oak Ridge, TN) equipped with TestWorks® 4 (v. 4.09A) software. A standard Berkovich diamond indenter tip was used. Experiments were performed under the displacement control mode at a constant rate of 5 nm/s with a maximum displacement of 1000 nm (hold for 10 s). It was assumed that the Poisson ratio was 0.30 for all four salts. The unloading portion of the force - displacement curve was used to calculate the E and H according


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to the Oliver–Pharr method.

33

The unloading curve was used to determine stiffness of the

crystal, which was used to derive contact depth between the tip and the crystal, from which projected area of contact was calculated from a predetermined area function for the tip used in this work. equations.

The hardness and reduced elastic modulus were calculated using appropriate 33

Before and after the experiment, the tip area function was determined by

conducting a series of indentations (n = 10) on a fused silica standard with a modulus of 70.0 GPa and hardness of 9.5 GPa. Only the most dominating crystal face was indented for each salt. Powder compaction Compaction of the four DPH salts was conducted on a compaction simulator (Presster, Metropolitan Computing Corp., NJ), simulating a 10 stations Korsch XL100 press with a 9.5 mm diameter flat-faced round tooling. A sieve cut between #80 and #120 mesh (USA standard sieves), i.e., 125-180µm size fraction, of each powder was used for tableting. Tablets were prepared over a compaction pressure range of 25-300 MPa at a speed of 30 ms dwell time (corresponding to 41570 tablets/h). Tablets were stored in a tightly closed glass vial overnight and then broken diametrically on a texture analyzer (Texture Technologies Corp., Surrey, UK). Tablet tensile strength was calculated using Eqn. (1).34

= .. (1) Where F, D, and h are the breaking force, tablet diameter, and thickness, respectively. The true density of individual DPH salts was measured by helium pycnometrry (Quantachrome Instruments, Ultrapycnometer 1000e, Byonton Beach, Florida). An accurately weighed sample (1-2 g) was placed into the sample cell. The measurement was allowed to 9 ACS Paragon Plus Environment


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repeat up to a maximum of 100 times. The experiment was terminated when the coefficient of variation of five consecutive measurements is below 0.005%. measurements was reported as true density of the sample.

The mean of the last five

The compact porosity (ε) was

determined from Eqn. (2):

= 1 −

(2)

Where tablet density was calculated from tablet weight, diameter, and thickness.

Results and discussion Solid state characterization Before assessning the tableting performance of DPH salts, the solid-state purity and stability of the powders were verifed by PXRD, DSC, TGA, and DVS (Figure 1). The calculated PXRD patterns from the crystal structures matched well with the experimental PXRD patterns for all DPH salts, comfirming their phase purity (Figure 1a). The relative variations in peak intensity are attributed to the phenomenon of preferred orientation of crystals during data collection. Therefore, milling did not cause phase change in all four salts. Similarly, no detectable phase changes occurred during compaction (data not shown). The phase purity of these samples was also supported by the flat baseline and single melting peak in their DSC thermograms. The melting point of DPH salts followed the order: DPH·HCl (170.6 oC) ＞ DPH·Cit (151.3 oC) ＞ DPH·Acs (122.3 oC) ＞ DPH·Sac (119.9 oC) (Figure 1b). No weight loss was detected for DPH·Acs and DPH·Sac when melted (Figure 1c). Weight loss accompanied melting for DPH·Cit and DPH·HCl, which may be attributed to the escape of citric acid and HCl


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from the melt, respectively (Figure 1c). All salts were stable against RH up to 75% (Figure 1d). Among the four salts, DPH·Cit was the most stable against elevated RH, with no deliquescence even at 95% RH. Overall, no moisture-induced solid phase changes are expected for these salts under normal manufacturing and storage conditions. (a)

(c)

(b)

(d)

Figure 1. Solid state characterization for DPH salts a) PXRD patterns (experimental and calculated from crystal structures), b) DSC, c) TGA, and d) moisture sorption behavior.

Conformation of DPH



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Key crystallographic information of the four DPH salts is summarized in Table 1. More detailed crystallographic data and parameters for structure refinement of three newly solved structures are summarized in Tables S1-3.

We started crystal structure analysis from an

examination of molecular conformation, which plays a crucial role in crystal packing patterns. The DPH structures showed distinct and flexible conformations in the four salts (Figure 2a). The torsion angle of N-C(3)-C(4)-O are -37.49 o, -94.31 o, 73.52 o, and 56.88 o for DPH·HCl, DPH·Cit, DPH·Sac, and DPH·Acs, respectively. Other selected torsion angles are summarized in Table S4. The interplanar angle between two phenyl rings was significantly smaller in DPH·Acs (80.5 o) than in DPH·HCl (106.2 o), DPH·Cit (98.6 o), and DPH·Sac (108.8 o). Table 1. Crystallographic parameters of DPH salts. DPH·HCl

DPH·Cit

DPH·Sac

DPH·Acs a

C17H22ClNO

C23H29NO8

C24H26N2O4S

C21H26N2O5S

Formula weight

291.80

447.47

438.53

418.50

Crystal system

Orthorhombic

Monoclinic

Monoclinic

Monoclinic

Pna21

P21/c

P21/c

P21/n

a/Å

10.7556(11)

21.229(3)

13.013(2)

9.0159(6)

b/Å

14.0355(10)

9.6695

18.663(4)

5.9880(4)

c/Å

10.5063(10)

11.1075

9.0999(15)

38.346(3)

β/°

90

91.327(4)

91.848

96.416(3)

Z

4

4

4

4

1586.0(2)

2279.5(4)

2208.9(7)

2057.2(2)

Density (Mg/m3)

1.222

1.304

1.319

1.351

Packing coefficient

0.688

0.678

0.687

0.696

1522795

1544102

1544101

1504526

Compound Chemical formula

Space group

Volume (Å3)

CCDC a

. Detailed single crystal preparation and crystal parameters of DPH·Acs were reported in ref.29.


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The 2D fingerprint plot of Hirshfeld surface (distribution of distance from a point on the surface to the nearest nucleus outside (de) or inside (di) the surface) were generated to compare the chemical environment of DPH in those four salts (Figure S1). The single longest spike in the Hirshfeld diagram of DPH·HCl corresponds to the charge-assisted hydrogen bond, N+-H···Cl(H⋅⋅⋅Cl, 8.8%). There are two longest spikes in the DPH·Cit diagram, the upper one corresponds to H···O (de＞di, 20.3%) contact and the lower one corresponds to H···H (di=de, 57.2%) contact. The two salts (DPH·Sac and DPH·Acs) show considerably similar diagrams, where all three longest spikes are caused by H···O (16.8 % vs. 19.8 %), H-H (55.3% vs. 58.4%), C-H (21.0% vs. 18.5%) and N⋅⋅⋅H (3.8% vs. 2.8%) contacts. The major difference is that DPH·Sac shows much more scattered points in the upper region than DPH·Acs, suggesting longer contact (large di) and consequently less efficient packing (Figure S1 c & d). This is consistent with the higher density of DPH·Acs (1.351 g/cm3) and packing coefficient (69.6 %) than DPH·Sac (1.319 g/cm3 and 68.7 %). The C⋅⋅⋅C interaction in DPH·Sac is 2.2 %, which is much higher than DPH·HCl (0.4 %), DPH·Acs (0.4 %), and DPH·Cit (0 %, which indicates the absence of π⋅⋅⋅π interactions). All above analyses confirmed that salt formation significantly changed the conformation of DPH and the intermolecular interaction type, number, and strength.



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Figure 2. a) Overlay of DPH in DPH·HCl (green), DPH·Cit (magenten), DPH-Ace (red), and DPH·Sac (blue) crystal structures. b) Relative contribution of different intermolecular interactions of DPH in the four salts.

Crystal packing and energy framework analysis Intermolecular interactions and architecture of crystal packing, was analyzed using “energy framework”,35 which was used to identify slip planes and predict crystal mechanical behavior.36 The asymmetric unit of orthorhombic DPH·HCl (space group Pna21) contained 1:1 ratio of DPH+ and Cl-. Calculated interaction energies are summarized in Table S5. The onedimensional chains formed by DPH+ and chloride, which interact through charge assisted hydrogen bonds, N+-H···Cl- (d(D---A), θ(D−H…A): 3.001 Å) and C-H···Cl- (3.512 Å, 3.551 Å, 3.558 Å), run parallel to the c axis (Figures 3a,b). Adjacent chains interlock to form two-dimensional layers parallel to the (0 1 0) plane (Figure 3b). The intralayer interaction energies were large (Figure 3c). The layers stack to form the three-dimensional packing (Figure 3c). Layers interact through C-H···π and C-H···Cl- (3.775 Å) interactions, which immobilize layers to hinder slip 14 ACS Paragon Plus Environment

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between layers. Both visualization and attachment energy calculation suggested (0 1 0) is the most likely slip plane (Table S6). However, the large interlayer interaction energies suggests the sliding between the (0 1 0) planes is energetically unfavorable. The energy cost for sliding along the likely slip plane (0 1 0) is much larger than other salts (Tables S6, 8, 10, 12). Additionally, the rough surface of the layers also hinders the layer slip. The similarly large attachment energies lead to a relative isotropic energy framework and a rigid 3D structure. Therefore, DPH·HCl is expected to be hard and brittle.

(a)

(c)

(b)

Figure 3. a) A chain composed of DPH+ and Cl- running along c axis, b) two-dimensional layer structure along the ac plane, c) energy framework. A likely layer (shaded in pink) is shown and a possible slip plane of (010) is indicated (dashed line). The intermolecular interaction energy threshold was set at 10 kJ/mol.

The asymmetric unit of the monoclinic DPH·Cit (space group P21/c) comprised of DPH+ and citrate anion at 1:1 ratio (Z=4). Calculated interaction energies are summarized in Table S7.



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A proton transferred from the tricarboxylic acid to the ammonium of DPH. Citrates connect to form a layer through a number of hydrogen bonds of C-H···O (2.593 Å, 2.660 Å), C-H···O (2.573 Å) arranged in R22(10) and R24(16) motifs (Figure 4a). The citrate layers are sandwiched by DPH+ layers, where they interact through N+-H···O (2.927 Å, 2.858 Å) to form a R21 (5) motif (Figure 4a). The diphenyl groups of DPH oriented above and below the H bonded layer, rendering the surface of the layer hydrophobic, which is consistent with its known low solubility and non-hygroscopicity. Interactions between adjacent DPH+ layers are non-specific van der Waals and C-H···π interactions.

Both visualization (Figure 4b) and attachment energy

calculation (Table S8) suggest (1 0 0) as the likely slip plane. This is consistent with the energy framework of DPH·Cit (Figure 3b), which suggests relatively weaker interactions between the DPH+ layers.

However, the energy framework of DPH·Cit is overall relatively isotropic,

characterized by comparable intermolecular interactions (Table S7 and Figure 4b). Therefore, sliding along any direction is not expected to be significantly favored energetically. Thus, similar to DPH·HCl, the DPH·Cit crystal is expected to be hard and brittle. (a)

(b)


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Figure 4. a) Hydrogen bonding motifs in DPH-Cit salt, R22(10), R24(16) and R21(5). b) Crystal packing and energy framework viewed into the b axis. A likely layer (shaded in pink) is shown and a possible slip plane of (100) is indicated (dashed line). The intermolecular interaction energy threshold was set at 5 kJ/mol. Orange lines indicate energies corresponding to repulsive interactions.

The asymmetric unit (Z=4) of the monoclinic DPH·Sac (space group P21/c) consists of DPH+ and Sac- at 1:1 ratio, which interact through N+-H···O=S (2.720 Å) hydrogen bond and π---π stacking (Figure 5a). Calculated interaction energies are summarized in Table S9. Such DPH+- Sac- units interact through C-H···O=S (3.242, 3.241 Å) to form a 3D structure, where layers parallel to (0 0 1) plane may be visually identified. Since only weak C-H···O=S (3.327 Å) hydrogen bonds are observed between the layers, (0 0 1) is likely the slip plane in DPH·Sac. Although the attachment energy of the (1 0 0) plane was the lowest (Table S10), the molecules slide along (1 0 0) is unlikely because of the steric hindrance between layers. The visually identified slip planes is supported by the energy framework (Figure 5b), where intralayer bonding energy is much greater than the interlayer interaction energy for DPH-Sac assembly (Figure 5b). However, the rough topology of the layers hinders facile slip along directions other than b axis. Therefore, plasticity of DPH·Sac remains poor.



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(a)

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(b)

Figure 5. a) Asymmetric unit of of DPH·Sac and b) crystal packing diagram and energy framework of DPH·Sac salt viewed along b axis. A likely layer (shaded in pink) is shown and a possible slip plane of (001) is indicated (dashed line). The intermolecular interaction energy threshold was set at 10 kJ/mol.

The asymmetric unit of the monoclinic DPH·Acs (Z=4) (space group P21/n) consists of DPH+ and Acs- at 1:1 ratio that interact through N+-H···O (2.738 Å) and C-H···O (3.285 Å) hydrogen bonds (Figure 6a). Calculated interaction energies are summarized in Table S11. The DPH+ - Acs- units interact through C-H···O=S (3.411 Å) and C-H···O=S (3.305 Å, 3.355 Å) weak hydrogen bonds to form the 3D structure. Both the visualization and attachment energy calculation suggest (0 0 1) as the likely active slip plane. Only weak π⋅⋅⋅π and hydrogen bonding interactions are present between adjacent layers (Figure 6b) while the attachment energy of the parallel (0 0 2) plane was the lowest (Table S12). Crystal energy framework shows anisotropy where molecules within (0 0 1) planes exhibit stronger interactions than those between them (Figure 6b).

Thus, all three methods suggested (0 0 1) as the likely slip plane. Overall, both

energy considerations and visualization suggest good plasticity of the DPH·Acs crystal. 18 ACS Paragon Plus Environment

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(a)

(b)

Figure 6. a) Asymmetric unit of DPH·Acs, b) crystal packing diagram and energy framework of DPH·Acs salt. A likely layer (shaded in pink) is shown and a possible slip plane of (001) is indicated (dashed line). The intermolecular interaction energy threshold was set at 5 kJ/mol.

Mechanical properties of DPH salts Mechanical properties of DPH salts were first characterized quantitatively by a threepoint bending method.10, 33 The experiment was carried out using forceps and a needle under an optical microscope.

The block-shaped DPH·HCl and needle-shaped DPH·Cit crystals both

broke into two parts with flat cleaved surface. DPH·Sac crystals also fractured but the fracture planes were rugged. In contrast, DPH·Acs crystals were flexible and bendable (Figure 7).37



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Figure 7. Mechanical deformation behavior of DPH salts during crystal bending experiments.

Although the crystal bending experiment is useful for qualitatively classifying crystals according to their deformation behavior, e.g., brittle or bending crystals, it is incapable of further quantitatively distinguishing crystals within the same class.

In addition, crystal size and

orientation of crystal during the test also influence the results.38 Thus, we also employed nanoindentation to quantify the mechanical properties of the four DPH salts.39 Representative force - displacement curves during the loading and unloading are shown in Figure 8. The extracted parameters, E and H, are summarized in Table 2. The indentation force required for the indenter tip to reach the same penetration depth followed the descending order: DPH·HCl ＞ DPH·Sac ＞ DPH·Cit ＞ DPH·Acs. Accordingly, DPH·Acs had the lowest H (0.30±0.04 GPa) and E (8.59±0.59 GPa), which is consistent with its unique plastic bending behavior (Figure 7d). The H of crystals followed the descending order of DPH·HCl > DPH·Sac＞ DPH·Cit ＞ DPH·Acs. E among the DPH salts followed the order of DPH·HCl > DPH·Cit ≈ DPH·Sac＞ DPH·Acs. Melting point was reported to correlate roughly linearly with E in a previous study


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involving a series of dicarboxylic acids.40 However, this relationship was not observed in this study.

Table 2. Crystal mechincal properties determined by nanoindentation (n=8) DPH salts

Hardness (GPa)

Elastic modulus (GPa)

DPH·HCl

0.86±0.29

11.91±3.03

DPH·Cit

0.48±0.03

9.54±0.87

DPH·Sac

0.76±0.25

9.50±3.46

DPH·Acs

0.30±0.04

8.59±0.59

Figure 8. Representative load - displacement curves of DPH salts.

Combined with crystal structure analysis, nanoindentation served as a powerful tool to probe the relationship between crystal structure and mechanical properties.

Successful



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development of such relationship requires the understanding of relative orientation during nanoindentation experiments because of the anisotropy in most molecular crystals. The practice of using the nanoindentaion results obtained from a major face to represent the whole crystal mechanical property may be misleading for high anisotropic crystals. In some cases, rank order of crystal plasticity could be qualitatively predicted from an analysis of crystal structure alone based on the presence or absence of slip planes.14, 20 Based on the presence of possible slip planes in crystal structures and corresponding interlayer interaction energies, plasticity of the four salts was ranked: DPH·HCl＞DPH·Cit＞DPH·Sac＞DPH·Acs. This predicted rank order slightly differs from that based on measured H, i.e., DPH·HCl ＞ DPH·Sac ＞ DPH·Cit ＞ DPH·Acs. This inconsistency may be in part attributed to anisotropy of organic crystals. The potential face-dependency of E and H is illustrated in Figure 9, where H can be very different when indentation is made at a direction parallel to the flat slip planes and perpendicular to them.11

Therefore, measurements on the predominant face may not completely describe

mechanical properties of a crystal. This effect is minimized for milled crystals since fracture more likely occur to reduce the longest dimension of a crystal. Overall, the connection between crystal structure and mechanical properties is clear, where crystals with flat slip planes tend to be more plastic. It is interesting to note that the order or crystal density, DPH·HCl < DPH·Cit < DPH·Sac < DPH·Acs (Table 1), is exactly reversed from the plasticity order based on slip plane analysis.


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Figure 9. Schematic representive the potential anisotropy of crystal mechanical. During nanoindentation experiments, the movement of molecule layers along the a direction is much more difficult than the b direction.

Tableting performance of DPH salts Having established the relationship between crystal structure and mechanical properties, the final step was to evaluate their connection to powder tableting performance. In order to minimize the potential effects of particle size, a sieve cut of 125 - 180µm was used in all compaction studies. Tablet strength depends on the contributions from both bonding area and bonding strength. Therefore, tableting performance can be assessed using, tabletability (tensile strength vs. compaction pressure), compressibility (porosity vs. compaction pressure), and compactibility profiles (tensile strength vs. porosity).25,

26

Figure 10a shows the tabletability

profiles of these four salts. In all cases, an initial rise was followed by a decrease in tensile strength above 150 MPa, indicating overcompression of these salts at pressures above 150 MPa. The overcompression phenomenon occurs when excessive elastic recovery during unloading process deteriorates bonding among particles, which weakens the tablet.41, 42 The degree of outof-die elastic recovery (ER) (Figure 10b) followed the order of DPH·Sac ≈ DPH·Cit > DPH·HCl > DPH·Acs.

The most plastic DPH·Acs also exhibited the lowest ER, i.e., elimination of

bonding area due to elastic recovery is the least for DPH·Acs. 23 ACS Paragon Plus Environment


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Based on the maximum attainable tensile strength, tabletability followed the order: DPH·Acs > DPH·Sac > DPH·Cit > DPH·HCl (Figure 10a). DPH·HCl exhibited the worst tableting performance where lamination was observed above 250 MPa. The observed rank order of tabletability is consistent with the mechanical properties characterized by both bending and nanoindentation experiments, where the most plastic DPH·Acs exhibited the best tabletability, while the least plastic DPH·HCl showed the poorest tabletability. The intermediate tabletability of DPH·Sac and DPH·Cit corresponded to their intermediate H and E (Table 2). To further understand contributions from bonding area and bonding strength to the observed tabletability, compressibility and compactibility profiles were also examined (Figures 10c,d). In the pharmaceutically relevant pressure range, i.e., 100-300 MPa, tablet porosity followed the order of DPH·HCl ≈ DPH·Cit > DPH·Acs ≈ DPH·Sac. Thus, the bonding area contribution to the observed tabletability is greater for DPH·Acs and DPH·Sac. For each pair of salts with similar compressibility, the one exhibiting higher tensile strength had higher bonding strength. Therefore, bonding strength of DPH·Acs is greater than DPH·Sac and that of DPH·Cit is greater than DPH·HCl. It is interesting to note that compressibility of DPH·Acs is the best in the entire pressure range. At pressures lower than 100 MPa, porosity between DPH·HCl and DPH·Acs is similar and lowest. The divergence of compressibility between DPH·Acs and DPH·HCl may be attributed to the higher elastic recovery of DPH·HCl (Figure 10b). The lower porosity of DPH·Acs than DPH·Sac below 100 MPa may be attributed to the higher plasticity of DPH·Acs, due to the presence of active slip plane. When normalized by porosity, DPH·Acs exhibited the highest tensile strength, indicating its highest bonding strength (Figure 10d). Normally, an exponential relationship between tablet strength and porosity is expected for intact tablets.43 However, for overcompressed tablets, this relationship was not followed due to the 24 ACS Paragon Plus Environment

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weakening effects of defects in the tablet in the overcompression pressure region (Figure 10d). In absence of overcompression, tablet tensile strength either increases or stays constant with increasing compaction pressure. A symptom of overcompression is the decrease in tensile strength at a higher compaction pressure, as can be seen in Figure 10a. It is worth to mention that all four salts exhibited overcompression phenomenon.44,

45

Excluding data in the

overcompression region, the compactibility follows the descending order of DPH·Acs > DPH·Sac > DPH·Cit > DPH·HCl. This order to is the same as the order of plasticity measured by H but is different from that of melting point (DPH·HCl > DPH·Cit > DPH·Acs > DPH·Sac) or enthalpy of fusion (DPH·Cit ≈ DPH·HCl > DPH·Acs > DPH·Sac). This observation suggests that the bulk powder compaction behavior of the four salts is more reliably predicted from crystal mechanical properties than from thermal properties.



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(a)

(b)

(c)

(d)

Figure 10. Tableting performance of DPH salts. a) tabletability, b) tablet elastic recovery profiles, c) compressibility, and d) compactibility profiles (points corresponding to overcompressed tablets are circled)

Conclusions The correlation between crystal structures, mechanical properties, and tableting performance of molecular crystals was systematically examined in this work with the aid of several advanced techniques. The analyses of molecular conformation, and crystal packing, as well as the construction of energy framework based on intermolecular interaction strength 26 ACS Paragon Plus Environment

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provided a wealth of information on crystal structure, including the identification of active slip planes. Qualitative bending experiment and quantitative nanoindentation study complement each other to provide comprehensive information on crystal mechanical properties. Compaction simulation led to full characterization of tableting performance. This study confirmed the long held view that highly plastic crystals tend to exhibit better tabletability, which can be explained from an analysis of contributions from bonding area and bonding strength. Thus, this work illustrates the technological feasibility of understanding or even predicting tableting performance of pharmaceutical crystals using the complementary tools employed in this work.

Supporting Information

The Supporting Information is available free of charge on the ACS Publications website. 2D fingerprint plot of Hirshfeld surface, Crystal data and structure refinement of three DPH salts, Intermolecular interaction energy of four DPH salts, Attachment energy of four DPH salts. Three newly crystal structures determined in this work (CCDC #1522795, 1544101, 1544102) and

DPH-Acs

(1504526)

can

be

obtained

free

of

charge

via

www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected]. Acknowledgments The authors thank the Minnesota Supercomputing Institute (MSI) at the University of Minnesota for providing resources that contributed to the research results reported in this paper.

References (1) Saha, S.; Desiraju, G. R., σ‐hole and π‐hole synthon mimicry in third‐generation crystal engineering: design of elastic crystals. Chem. Eur. J. 2017, 23, 4936-4943.



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(2) Wouters, J.; Quéré, L., Pharmaceutical Salts and Co-crystals. ed.; Royal Society of Chemistry: 2011. (3) Stahl, P. H.; Wermuth, C. G., Handbook of pharmaceutical salts: properties, selection and use. Chemistry International 2002, 24, 21. (4) Korn, C.; Balbach, S., Compound selection for development–Is salt formation the ultimate answer? Experiences with an extended concept of the “100mg approach”. Eur. J. Pharm. Sci. 2014, 57, 257-263. (5) Berge, S. M.; Bighley, L. D.; Monkhouse, D. C., Pharmaceutical salts. J. Pharm. Sci. 1977, 66, 1-19. (6) Childs, S. L.; Stahly, G. P.; Park, A., The salt− cocrystal continuum: the influence of crystal structure on ionization state. Mol. Pharm. 2007, 4, 323-338. (7) Mohamed, S.; Tocher, D. A.; Price, S. L., Computational prediction of salt and cocrystal structures—does a proton position matter? Int. J. Pharm. 2011, 418, 187-198. (8) Aakeröy, C. B.; Fasulo, M. E.; Desper, J., Cocrystal or salt: does it really matter? Mol. Pharm. 2007, 4, 317-322. (9) Guidance for industry-regulatory classification of pharmaceutical cocrystals. https://www.fda.gov/ucm/groups/fdagov-public/@fdagov-drugsgen/documents/document/ucm516813.pdf (May, 2017), (10) Panda, M. K.; Ghosh, S.; Yasuda, N.; Moriwaki, T.; Mukherjee, G. D.; Reddy, C. M.; Naumov, P., Spatially resolved analysis of short-range structure perturbations in a plastically bent molecular crystal. Nat. Chem. 2015, 7, 65-72. (11) Reddy, C. M.; Krishna, G. R.; Ghosh, S., Mechanical properties of molecular crystals— applications to crystal engineering. CrystEngComm 2010, 12, 2296-2314. (12) Mishra, M. K.; Desiraju, G. R.; Ramamurty, U.; Bond, A. D., Studying microstructure in molecular crystals with nanoindentation: Intergrowth polymorphism in felodipine. Angew. Chem. Int. Ed. 2014, 126, 13318-13321. (13) Sanphui, P.; Mishra, M. K.; Ramamurty, U.; Desiraju, G. R., Tuning mechanical properties of pharmaceutical crystals with multicomponent crystals: voriconazole as a case study. Mol. Pharm. 2015, 12, 889-897. (14) Mishra, M. K.; Ramamurty, U.; Desiraju, G. R., Solid solution hardening of molecular crystals: tautomeric polymorphs of omeprazole. J. Am. Chem. Soc. 2015, 137, 1794-1797. (15) Azuri, I.; Meirzadeh, E.; Ehre, D.; Cohen, S. R.; Rappe, A. M.; Lahav, M.; Lubomirsky, I.; Kronik, L., Unusually large Young’s moduli of amino acid molecular crystals. Angew. Chem. Int. Ed. 2015, 54, 13566-13570. (16) Perumalla, S. R.; Shi, L.; Sun, C. C., Ionized form of acetaminophen with improved compaction properties. CrystEngComm 2012, 14, 2389-2390. (17) Perumalla, S. R.; Sun, C. C., Enabling tablet product development of 5‐fluorocytosine through integrated crystal and particle engineering. J. Pharm. Sci. 2014, 103, 1126-1132. (18) Mishra, M. K.; Ramamurty, U.; Desiraju, G. R., Mechanical property design of molecular solids. Curr. Opin. Solid State Mater. Sci. 2016, 20, 361-370. (19) Sun, C. C.; Hou, H., Improving mechanical properties of caffeine and methyl gallate crystals by cocrystallization. Cryst. Growth Des. 2008, 8, 1575-1579. (20) Sun, C.; Grant, D. J., Influence of crystal structure on the tableting properties of sulfamerazine polymorphs. Pharm. Res. 2001, 18, 274-280. (21) Feng, Y.; Grant, D. J.; Sun, C. C., Influence of crystal structure on the tableting properties of n‐alkyl 4‐hydroxybenzoate esters (parabens). J. Pharm. Sci. 2007, 96, 3324-3333. 28 ACS Paragon Plus Environment

Page 29 of 31

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


(22) 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, 3865-3867. (23) Krishna, G. R.; Shi, L.; Bag, P. P.; Sun, C. C.; Reddy, C. M., Correlation among crystal structure, mechanical behavior, and tabletability in the co-crystals of vanillin isomers. Cryst. Growth Des. 2015, 15, 1827-1832. (24) Yadav, J. A.; Khomane, K. S.; Modi, S. R.; Ugale, B.; Yadav, R. N.; Nagaraja, C.; Kumar, N.; Bansal, A. K., Correlating single crystal structure, nanomechanical, and bulk compaction behavior of febuxostat polymorphs. Mol. Pharm. 2017, 14, 866-874. (25) 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, 1126-1132. (26) Sun, C. C., Decoding powder tabletability: roles of particle adhesion and plasticity. J. Adhes. Sci. Technol. 2011, 25, 483-499. (27) Wang, C.; Perumalla, S. R.; Lu, R.; Fang, J.; Sun, C. C., Sweet berberine. Cryst. Growth Des. 2016, 16, 933-939. (28) Glaser, R.; Maartmann-Moe, K., X-ray crystallography studies and CP-MAS 13 C NMR spectroscopy on the solid-state stereochemistry of diphenhydramine hydrochloride, an antihistaminic drug. J. Chem. Soc. Perkin Trans. 2 1990, 1205-1210. (29) Wang, C.; Hu, S.; Sun, C. C., Expedited development of diphenhydramine orally disintegrating tablet through integrated crystal and particle engineering. Mol. Pharm. 2017, 14, 3399-3408 (30) Allen, F. H., The cambridge structural database: a quarter of a million crystal structures and rising. Acta Crystallogr.B Struct. Sci. 2002, 58, (3), 380-388. (31) Hübschle, C. B.; Sheldrick, G. M.; Dittrich, B., ShelXle: a Qt graphical user interface for SHELXL. J. Appl. Crystallogr. 2011, 44, 1281-1284. (32) Turner, M. J.; Grabowsky, S.; Jayatilaka, D.; Spackman, M. A., Accurate and efficient model energies for exploring intermolecular interactions in molecular crystals. J. Phys. Chem. Lett. 2014, 5, 4249-4255. (33) Oliver, W. C.; Pharr, G. M., Measurement of hardness and elastic modulus by instrumented indentation: advances in understanding and refinements to methodology. J. Mater. Res. 2004, 19, 3-20. (34) Fell, J.; Newton, J., Determination of tablet strength by the diametral‐compression test. J. Pharm. Sci. 1970, 59, 688-691. (35) Spackman, M. A.; Jayatilaka, D., Hirshfeld surface analysis. CrystEngComm 2009, 11, 19-32. (36) Turner, M. J.; Thomas, S. P.; Shi, M. W.; Jayatilaka, D.; Spackman, M. A., Energy frameworks: insights into interaction anisotropy and the mechanical properties of molecular crystals. Chem. Commun. 2015, 51, 3735-3738. (37) Reddy, C. M.; Gundakaram, R. C.; Basavoju, S.; Kirchner, M. T.; Padmanabhan, K. A.; Desiraju, G. R., Structural basis for bending of organic crystals. Chem. Commun. 2005, 39453947. (38) Uchic, M. D.; Dimiduk, D. M.; Florando, J. N.; Nix, W. D., Sample dimensions influence strength and crystal plasticity. Science 2004, 305, 986-989. (39) Varughese, S.; Kiran, M.; Ramamurty, U.; Desiraju, G. R., Nanoindentation in crystal engineering: quantifying mechanical properties of molecular crystals. Angew. Chem. Int. Ed. 2013, 52, 2701-2712. 29 ACS Paragon Plus Environment


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Page 30 of 31

(40) Mishra, M. K.; Varughese, S.; Ramamurty, U.; Desiraju, G. R., Odd–even effect in the elastic modulii of α,ω-alkanedicarboxylic acids. J. Am. Chem. Soc. 2013, 135, 8121-8124. (41) Sun, C. C., A material-sparing method for simultaneous determination of true density and powder compaction properties - Aspartame as an example. Int. J. Pharm. 2006, 326, 94-99. (42) Paul, S.; Sun, C. C., Gaining insight into tablet capping tendency from compaction simulation. Int. J. Pharm. 2017, 524, 111-120. (43) Ryshkewitch, E., Compression strength of porous sintered alumina and zirconia. J. Am. Ceram. Soc. 1953, 36, 65-68. (44) Wang, C.; Hu, S.; Sun, C. C., Expedited development of a high dose orally disintegrating metformin tablet enabled by sweet salt formation with acesulfame. Int. J. Pharm. 2017, 532, 435-443 (45) Shi, L.; Sun, C. C., Overcoming poor tabletability of pharmaceutical crystals by surface modification. Pharm. Res. 2011, 12, 3248-3255.


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For Table of Contents Use Only Manuscript Title: Relationships among crystal structures, mechanical properties, and tableting performance probed using four salts of diphenhydramine Authors: Chenguang Wang, Shubhajit Paul, Kunlin Wang, Shenye Hu, and Changquan Calvin Sun

Synopsis An analysis of crystal structures of four salts of diphenhydramine by energy framework explains their different mechanical properties and compaction behavior.


Relationships among crystal structures, mechanical properties, and

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