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Article Cite This: Cryst. Growth Des. XXXX, XXX, XXX-XXX

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Combining Crystal Structure and Interaction Topology for Interpreting Functional Molecular Solids: A Study of Theophylline Cocrystals Aditya B. Singaraju,† Kyle Nguyen,† Paula Gawedzki,† Fischer Herald,† Gavin Meyer,† Daniel Wentworth,† Dale C. Swenson,‡ and Lewis L. Stevens*,† †

Division of Pharmaceutics and Translational Therapeutics, College of Pharmacy and ‡X-Ray Diffraction Facility, Department of Chemistry, The University of Iowa, Iowa City, Iowa 52242, United States S Supporting Information *

ABSTRACT: The acoustic frequency distributions, mechanical moduli, and crystal structures for theophylline (THY) and three cocrystals are combined to illustrate how supramolecular organization and interaction topology contribute to the compaction performance of molecular solids. A novel solid form of THY, a cocrystal with 4-fluoro-3-nitrobenzoic acid (FNBA), is reported. This material adopts a 2d-layered structure and has superior tabletability relative to THY. The improved plasticity for THY− FNBA was further corroborated by Heckel analysis with THY−FNBA displaying a reduced yield pressure (Py) relative to theophylline. The performance of THY−FNBA was further compared to a structurally similar theophylline cocrystal with acetaminophen (THY−APAP). Despite structural similarity, their relative compaction performance was distinct. Powder Brillouin light scattering (p-BLS) was used as an experimental measure of the interaction topologies of these materials, and through this approach, the interlayer interaction strength is shown to be weaker relative to THY−APAP. Moreover, a THY and p-aminobenzoic acid (PABA) cocrystal was studied to contrast the performance of two columnar crystal structures, THY−PABA and THY. THY−PABA displayed a stacking structure that frustrated sli,p and the compaction performance was consequently diminished. The elasticity moduli were further determined for all materials, and both THY−APAP and THY−FNBA displayed low Young’s and shear moduli and is consistent with our compaction studies.

1. INTRODUCTION Engineering molecular solids for tailored performance requires both control of the intermolecular interaction topology (strength and spatial distribution) and identifying specific structural motifs that facilitate a desired function.1,2 For tableting in pharmaceutical solids, a traditional focus is on improving plasticity, i.e., irreversible deformation, and minimizing elastic recovery that potentially deteriorates particle− particle adhesion during the postcompression relaxation. From a structural perspective, an organizational motif reported to improve plasticity is the 2d-layered structure. The combination of strong intralayer and weak interlayer interactions facilitates a slip-mediated plasticity that may consequently improve tableting performance. The polymorphic structures of acetaminophen (APAP) provide a classic example of this tendency. The room-temperature stable polymorph of APAP (Form I) displays a herringbone structure with 3d, quasiisotropic distribution of strong hydrogen bonds which renders the material brittle with no low-energy slip planes available to © XXXX American Chemical Society

assist compactability, and thus this polymorphic form of APAP does not form viable compacts. Alternatively, the metastable polymorph of APAP (Form II) displays a reorganized hydrogen bonding network with a 2d-layered structure, and consequently improved tabletability has been observed.3 Provided the energy landscape of molecular solids is typically rich with potential alternative packing configurations (often separated by small differences in lattice energy), to be able to rationally select a specific form with expected functional performance (e.g., solubility, bioavailability, stability, and tabletability) would be a significant benefit to pharmaceutical research and reduce inefficient trial-and-error phase selection and formulation. Despite its advantageous tabletability, concerns with thermodynamic stability and potential phase conversion limits the selection of the metastable APAP form for industrial Received: September 20, 2017 Revised: October 13, 2017 Published: October 20, 2017 A

DOI: 10.1021/acs.cgd.7b01339 Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design

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crystallized in a monoclinic unit cell with a similar 2d-layered structur,e and while this material exhibited tabletability (an improvement relative to APAP Form I) the mechanical performance relative to theophylline is unknown.22 Lastly, the compaction behavior of a cocrystal of theophylline with paminobenzoic acid (PABA) is investigated. This provides opportunity to investigate the effect of having similar functionalities on the coformers (FNBA and PABA). Moreover, the THY−PABA material displays a stacking structure analogous to anhydrous theophylline. This is interesting from a crystal engineering perspective to contrast the performance of structurally similar materials to better understand how both structure and interaction topology contribute to functional property expression. To address this challenge, we utilize powder Brillouin light scattering (p-BLS) for experimental insight into the interaction topologies of our theophylline cocrystals. For the previously discussed acetaminophen polymorphs, Beyer et al. demonstrated through a computational approach that the different polymorphic forms of acetaminophen exhibited significantly different anisotropic elastic constants.23 Differences in anisotropic elasticity, a fundamental material property that is sensitive to the anisotropy of the total lattice potential, would be similarly reflected in the anisotropic sound frequencies. From our previous studies, p-BLS has been used to provide experimental input for describing differences in elastic anisotropy and intermolecular interaction strength.21,24 For our set of structurally similar theophylline cocrystals, we anticipate variation in the interaction topology to be reflected in the acoustic frequency distributions obtained from p-BLS and this novel input will aid understanding how both interaction topology and structural organization combine to influence bulk property expression.

manufacturing. Distinct from polymorphism, cocrystallization is an alternative approach employed to improve the physicochemical and biopharmaceutical properties of pharmaceutical solids.4−6 This approach proceeds through the addition of a coformer and offers access to room-temperature stable materials with no covalent modification to the parent drug molecule. Trask et al. demonstrated that cocrystallization improved the physical stability of theophylline and caffeine at higher humidity levels.7,8 Moreover, an enhancement in the dissolution rate was reported by Lee et al. for an acetaminophen cocrystal with theophylline.9 Reports of improved tabletability have been published for caffeine and acetaminophen cocrystals using with a variety of coformers being selected. This flexibility in coformer availability is a further advantage and permits expansion of our crystal engineering library; however, the rational selection of a specific coformer for a desired performance-based outcome still requires significant research. Even the successful formation of a pharmaceutical cocrystal with a given coformer is not guaranteed. Prediction of cocrystal formation can be based on logical hydrogen bonding potential between the functional groups present in the drug and the coformer; however, this accounts for a success rate of 20%.10,11 In an effort to improve this success rate, several research groups introduced additional molecular descriptors (e.g., polarity, shape, ionization constants, etc.) that may rationally be leveraged for successful coformer selection. On the basis of this approach, 218 cocrystallization screens were set up, of which 48 cocrystals were obtained, i.e., a 22% success rate.12−17 In this report, we investigate both the structure and interaction topologies of a series of theophylline cocrystals for interpreting their mechanical properties and tableting performance. Theophylline, a member of the xanthine family, has multiple potential sites for both donating and accepting hydrogen bonds. The energetics of potential hydrogen bonding synthons were reported by Sarma et al. for a series of phenol and dihydroxybenzoic acid derivatives that were successfully cocrystallized with theophylline to modify its aqueous solubility and stability at elevated relative humidity.18 Anhydrous theophylline demonstrates clear tabletability with tensile strengths reaching over 4 MPa at compaction pressures near 300 MPa.19 The crystal structure of anhydrous theophylline (CSD code: BAPLOT01) does not exhibit a layered structure, but rather a stacked organization of theophylline dimers. A previous cocrystallization of theophylline with methyl gallate afforded a 2d-layered structure; however, the cocrystal showed inferior compaction performance relative to theophylline.20 The better tabletability of anhydrous theophylline was argued by the presence of multiple slip mechanisms and its higher intrinsic bonding strength, evaluated by tensile strength extrapolated to zero porosity (σ0).20 To further examine the potential of 2d-layered cocrystals for adjusting the compaction performance of theophylline (THY), we have used a series of specifically selected coformers. On the basis of the expected synthon formation with benzoic acid and phenolic derivatives reported by Sarma et al., we cocrystallized theophylline (THY) with 4-fluoro-3-nitrobenzoic acid (FNBA) as coformer, which from our previous work had successfully formed a cocrystal with caffeine and significantly improved the compaction performance relative to either individual material.21 The THY−FNBA cocrystal exhibits a 2d-layered structure and its performance is further compared with the previously reported theophylline cocrystals with APAP. THY−APAP

2. EXPERIMENTAL SECTION 2.1. Materials. Theophylline (THY), acetaminophen (APAP), paminobenzoic acid (PABA), acetonitrile, ethanol, and methanol were purchased from Sigma-Aldrich and used as received. 4-Fluoro-3nitrobenzoic acid (FNBA) was purchased from TCI America. The molecular structures for THY and the coformers selected in this study are shown for reference in Figure 1.

Figure 1. Molecular structure of (a) theophylline, (b) 4-fluoro-3nitrobenzoic acid, (c) acetaminophen, and (d) p-aminobenzoic acid. 2.2. Methods. 2.2.1. Preparation of THY−FNBA Cocrystal. Liquid assisted grinding was used to generate the bulk form of this cocrystal. Equimolar quantities of THY and FNBA were added to a grinding jar and slightly mixed with a spatula. A few drops of methanol were added to this mixture, and the grinding was performed with the aid of two 12 mm grinding balls on a Retsch planetary mill. The duration of grinding and the frequency were adjusted to accommodate the preparation of several grams of the cocrystal. The frequency and duration for a batch of 10 g were 2000 rpm and 3 h, respectively. The product was dried at B



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50 °C overnight to remove any residual solvent. Single crystals of THY−FNBA were grown from saturated ethanol and methanol solutions. Equimolar quantities of THY and FNBA were added to the solvent and slightly heated to obtain a clear solution. The solution was filtered through a 0.22 μm filter and left undisturbed for a few days to evaporate. 2.2.2. Preparation of THY−APAP Cocrystal. The THY−APAP cocrystal was prepared using solution mediated phase transformation as reported by Lee et al.9 A slurry containing equimolar quantities of THY and APAP in acetonitrile was stirred overnight at 150 rpm. The solid phase was separated by filtration and dried at 75 °C. 2.2.3. Preparation of THY−PABA Cocrystal. The THY−PABA cocrystal was synthesized using liquid assisted grinding as reported by Fernandeset al.25 Instead of acetone, however, acetonitrile was chosen as the solvent. The obtained product was dried at 50 °C overnight to remove excess solvent. 2.2.4. Particle Size Distributions. The particle size distributions were obtained using a sieve analysis. Approximately 2 g of the material that initially passed through a 250 μm sieve was utilized for this purpose. The analysis was continued until equilibrium was reached and performed in triplicate. 2.2.5. Scanning Electron Microscopy (SEM). A Hitachi S-4800 SEM was used to determine the particle morphologies for all the materials. The powders were sputter-coated with gold−palladium mixtures. All the images were collected at an acceleration voltage of 1.0−1.8 kV. 2.2.6. Differential Scanning Calorimetry. Cocrystal formation was studied using differential scanning calorimetry, with scans performed using a TA Instruments Q20, which was calibrated with indium as a standard. Powders were heated from 25 °C to about 20 °C above their melting temperatures using a heating rate of 10 °C/min under a nitrogen purge of 40 mL/min. 2.2.7. Powder X-ray Diffraction. Room temperature powder patterns for the materials were obtained at 2θ values ranging between 7° and 45° using a Siemens D5000 diffractometer with Cu Kα X-rays (λ = 1.5418 Å). The step size and dwell time employed were 0.02° and 0.75 s, respectively. 2.2.8. Single-Crystal X-ray Diffraction. Crystal structures for THY, THY−APAP, and THY−PABA are available through the Cambridge Structural Database. A colorless, irregular prismatic crystal of THY− FNBA of dimensions 0.100 mm × 0.150 mm × 0.400 mm was used for structure determination. A Bruker Nonius Kappa CCD APEXII diffractometer (Mo Kα, λ = 0.71073 Å) was used to collect 2668 frames over a period of 44.47 h. The frames were integrated with the Bruker SAINT software package using a narrow-frame algorithm. Data were corrected for absorption effects using the multiscan method (SADABS). The crystallographic parameters for all the materials are listed in Table 1.25−27 All crystal structures were visualized using Mercury 3.7.28 2.2.9. Powder Brillouin Light Scattering (p-BLS). Powder BLS spectra for the materials were acquired in a backscattering geometry using a custom-made spectrometer. A laser operating at 532 nm

provided the incident light. A tandem Fabry−Perot interferometer (TFP-1) was used to resolve the inelastically scattered light from the Rayleigh line. Two different mirror spacings (3 mm and 7 mm) were employed to capture the three characteristic frequencies. All materials were passed through a 75 μm sieve prior to analysis. Two different samples were prepared for each material. For the spectra collected at 7 mm, 30−45 mg of the material was softly pressed into a washer affixed onto a glass slide and glued with a coverslip. While for those collected at 3 mm, no coverslip was used to avoid interference from the glass. All other parameters along with the BLS setup are described elsewhere.24 2.2.10. Powder Compaction. Prior to compaction, all powders were passed through a 250 μm sieve and stored in a desiccator with a relative humidity of 14−20%. Powder compacts (8 mm diameter, flat faced) were prepared using a die and punch assembly (Natoli, Inc.). The force needed to obtain a specific compaction pressure was predetermined. The die was loaded with 295−305 mg of the material, and the force was applied for 5 min. After the dwell time, the compacts were carefully ejected without delamination. Instances of delamination are discussed wherever applicable. The compacts were stored in the desiccator for 24 h to allow for elastic recovery. The dimensions of the compacts, thickness, and diameter were measured after this recovery period. 2.2.11. Out-of-Die Heckel Analysis. The linear portion of the force displacement curve (ε vs P) was used to estimate the yield pressures for all the materials. The Heckel equation (shown below) was used to fit the data, − ln(ε) = kP + A

where ε is the compact porosity, P is the compaction pressure, and inverse of the slope (k) gives the apparent yield pressure Py (MPa).29 2.2.12. Compact Tensile Strength. The diametrical breaking force for all the compacts was measured using a Q-Test II universal stress strain analyzer (MTS Systems Corporation) at a strain rate of 0.01 mm per second. The tensile strength was calculated using eq 2,

σ=

THY

THY− APAP

THY−FNBA

σ = σ0e−bε

P1̅ 7.023 8.782 13.17 96.89, 90.83, 115.46

4 1.39 KIGLUI

(this work)

HUMNEK

Pna21 24.612 3.8302 8.5010 90, 90, 90

P21/n 8.7337 15.3838 11.5271 90, 99.25, 90

Z ρ (measured) (g/mL) CSD code

4 1.481 BAPLOT01

(2)

(3)

where σ0 is the tensile strength extrapolated to zero porosity, ε is compact porosity, and b is a constant.30

3. RESULTS AND DISCUSSION 3.1. Cocrystal Characterization. The thermograms for THY, FNBA, and THY−FNBA are shown in Figure 2. The thermogram of THY shows a melting endotherm at 273 °C and the thermogram for FNBA shows a melting endotherm at 124 °C. The new cocrystal shows an endotherm intermediate to THY and FNBA at 188 °C, indicating the presence of a new crystalline phase. This was further corroborated by PXRD, and the presence of various peaks in the PXRD patterns indicates the crystallinity of the materials. The powder pattern for THY− FNBA was different from that of THY and FNBA. All of these powder patterns are overlaid in Figure 3. The experimental PXRD patterns for the two previously published cocrystals (THY−APAP and THY−PABA) are in good agreement with the predicted patterns obtained from the Cambridge Structural Database and are provided as Supporting Information (see Figure S1.b and S1.c, respectively). Further there was good agreement between the powder patterns of the liquid-assisted grinding product and the predicted patterns from the single crystal data for THY−FNBA. This is shown in Figure S1.a of the Supporting Information.

THY− PABA

P1̅ 16.019(2) 16.239(2) 20.369(3) 79.05(2), 73.33(2), 64.25(10) 12 1.568

space group a (Å) b (Å) c (Å) α, β, γ (deg)

2F πDT

where F is the diametrical breaking force, D is the diameter of the compact, and T is the thickness of the compacts. The Ryshkewitch equation was used to estimate the tensile strength extrapolated to zero porosity.30 Equation 3 was used to fit the compaction data,

Table 1. Comparison of Crystallographic Data for Theophylline and the Cocrystals parameter

(1)

2 1.459

C



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Figure 2. Overlay of DSC thermograms for THY, THY−FNBA, and FNBA ordered respectively from top to bottom.

Figure 3. Overlay of room temperature PXRD powder patterns obtained for THY−FNBA, THY, and FNBA. Figure 4. SEM micrographs for powder samples of (a) THY (scale bar = 1 mm), (b) THY−FNBA (scale bar = 5 μm) and (c) THY−APAP (scale bar = 100 μm). (d) THY−PABA (scale bar = 5 μm).

The particle size distributions were obtained through sieve analysis and the cumulative frequency plots are given in the Supporting Information (see Figure S3). The (d50, d90) in μm for THY, THY−APAP, THY−FNBA, and THY−PABA are (101, 168), (90, 163), (68, 156), and (73, 144), respectively.Figure 4 shows our SEM micrographs used to determine the particle morphologies. All the three cocrystals had prism-like crystal morphologies whereas theophylline particles exhibits a rod-like morphology. These micrographs were taken on the asreceived or as-prepared materials. 3.2. Crystal Structures of Theophylline and Theophylline Cocrystals. The crystal structure for anhydrous theophylline, previously reported by Ebisuzaki et al., is shown in Figure 5.27 For this material and all cocrystals, the noted hydrogen bonds are represented with a D−A distance and D−H···A angle. Catemeric N−H···N hydrogen bonds (2.83 Å, 179°) connect individual theophylline molecules into a v-shaped, 1d tape that extends approximately parallel to the [011] crystallographic direction. These v-shaped tapes are further organized into π- and C−H···O (3.34 Å, 149°) stabilized stacks that organize perpendicular to the a-crystallographic axis. Individual columns interact via C−H···O interactions (3.47 Å, 148°) to complete the three-dimensional structure. When THY is cocrystallized with FNBA, a flat-layered crystal is displayed, similar to the structures previously demonstrated

by the paraben series, caffeine−methyl gallate and theophylline−methyl gallate cocrystals.20,22,31 The asymmetric unit of THY−FNBA contains six hydrogen bonded THY and FNBA dimers each connected by a strong O−H···N hydrogen bond that connects FNBA to the basic imidazole nitrogen of theophylline and a supportive C−H···O interaction. For each dimer in the asymmetric unit, the O−H···N hydrogen bonding interactions span distances from 2.660−2.677 Å and angles from 157−179°. As shown in Figure 6a, separate dimers interact in-plane via separate theophylline molecules to form a tetramer through a set of N−H···O homosynthons with average dimensions of 2.73 Å, 157°. Beyond the asymmetric unit, multiple hydrogen bonds are observed, all being largely conserved to in-plane interactions. As shown in Figure 6b, each theophylline molecule within a tetramer either interacts with three or four different FNBA molecules through a network of C−H···O interactions and O−H···N interactions. Similarly, each FNBA molecule interacts with three THY molecules and one FNBA molecule. Apart from the intralayer network, the interlayer interactions are stabilized through dispersive forces with the interlayer centroid distance estimated from Mercury to D



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Figure 7. In-plane projection for THY−APAP.

dimers organize into 1d tapes that run parallel to the ccrystallographic axis, as shown in Figure 8a. Energetically this docking interaction for THY−PABA provides nearly 3 times the stabilization energy than that for THY−FNBA, as reported by Sarma et al.; however, this positions the pendant amine group of PABA such that no hydrogen bonding interactions are observed.18 Alternatively, for THY−FNBA, the THY homosynthon and multiple C−H···O interactions combine to

Figure 5. Crystal structure for theophylline showing columnar arrangement of stacked dimers.

Figure 6. Crystal structure for THY−FNBA (a) asymmetric unit with six THY−FNBA molecules with a layered structure and (b) in-plane projection viewed along thec-crystallographic axis with extended organization.

be 3.73 Å. The crystal structure of THY−FNBA reported here is similar to the crystal structure of THY−APAP reported by Childs et al.26 Illustrated in Figure 7, the same THY−THY N− H···O homosynthon is observed and the APAP molecules occupy similar lattice positions as the FNBA molecules. The other cocrystal investigated in this study is THY−PABA. Although FNBA and PABA are both benzoic acid derivatives, the docking of the carboxylic acid group with theophylline is distinct. The structure of THY−PABA was resolved by Fernandes et al. using a combination of powder X-ray, density functional theory (DFT), and supported using solid state NMR.25 For THY−PABA, two stronger hydrogens bonds, O− H···O (2.71 Å, 170°, to the exo-carbonyl) and N−H···O (2.701 Å, 171°), orient theophylline with respect to PABA, and these

Figure 8. Crystal structure for THY−PABA (a) THY and PABA dimers that organize parallel to thec-crystallographic axis, (b) projection in ab-crystallographic showing organization of 1d tapes into interdigitated stacks. E



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stabilize the flat-layer structure. Provided the limited in-plane interactions are available for THY−PABA, this material organizes the 1d tapes into an interdigitated stacking structure (see Figure 8b) that runs perpendicular to the ab-crystallographic plane. Overlapping tapes in separate stacks are separated by 3.34 Å, and stack-to-stack interactions are supported by two C−H···O hydrogen bonds with dimensions of (3.261 Å, 144°) and (3.376 Å, 135°). 3.3. Powder Compaction Performance. 3.3.1. Compressibility. Powdered theophylline formed intact compacts over the compaction pressure range of 30−315 MPa, whereas the compacts of the cocrystals suffered capping above compaction pressures of 175 MPa. As expected, the porosity for the three materials decreased with compaction load, which is shown in Figure 9a. THY−APAP is the most compressible material

these materials undergo a single, predominant mode of deformation which leads to saturation of the plasticity. Similar behavior was also reported previously in the parabens and paminobenzoic acid esters, which respectively displayed flat- and corrugated-layer structures.24,31 For theophylline, however, which is reported to deform through multiple slip systems, the porosity continues to decrease until 315 MPa. It can be concluded that, although the cocrystals possess a greater ease of deformation, theophylline undergoes a greater extent of deformation. The compressibility of THY−PABA is inferior to both THY−FNBA and theophylline. The interdigitated stacking structure frustrates slip and reduces compressibility which is reflected in Figure 9b. In contrast, THY−FNBA because of its layered structure can undergo plastic deformation easily. A Heckel analysis was performed to assess material plasticity based on the yield pressures (Py) obtained. Yield pressures for all materials are collected in Table 2 and ranged from 94 MPa Table 2. Comparison of out-of-Die Yield Pressures (Py) and Tensile Strength Extrapolated to Zero Porosity (σo) for THY and the Cocrystals material THY THY-APAP THY-FNBA THY-PABA

yield pressure, Py (MPa)

σ0 (MPa), R2

± ± ± ±

7.81 ± 0.19, 0.9985 3.94 ± 0.20, 0.9908 4.61 ± 0.29, 0.9683 NA

133.33 117.64 94.33 158.73

7.11 13.80 6.22 5.03

for THY−FNBA to 159 MPa for THY−PABA and the following rank order was observed: THY−FNBA < THY− APAP < THY < THY−PABA. Figure S2 included in the Supporting Information shows the Heckel plots for all the materials. Despite both THY−APAP and THY−FNBA being layered structures, these materials displayed different yield pressures, which is likely a consequence of interlayer interaction strength. Theophylline on the other hand was intermediate to the flat-layer and the interdigitated stack structures. The higher yield pressure for THY relative to the layered cocrystals is likely due to a higher critical stress required for the columns to move relative to each other versus the facile deformation for the layered structures. 3.3.2. Tabletability. The tabletability plot is shown in Figure 10a, which is a plot of tensile strength versus compaction pressure. Presence of a layered crystal structure can enhance plasticity through the introduction of low-energy slip planes and this was used to explain the improved tabletability of caffeine.33 Similar results were reported for a caffeine cocrystal with FNBA, cocrystals of profens with nicotinamide and other acetaminophen cocrystals.21,22,34 While all the above examples have shown to provide superior performance, the choice of coformer to give rise to a layered structure lacks rationale. Moreover, layered structures are not guaranteed to promote improved compaction performance and multiple examples are available. Co-crystallization of theophylline with methyl gallate deteriorated compaction performance relative to theophylline.20 A piroxicam−saccharin cocrystal, which displayed a 2dlayered structure, was the worst performer relative to either coformer.35 Further examples include polymorphic and hydrated systems where the most compressible form is not the form with higher bonding strength or vice versa.19,36,37 Overall, it is imperative to complement higher bonding area with bonding strength to achieve compacts with ideal

Figure 9. Overlay of compressibility plots for (a) THY, THY−FNBA, and THY−APAP, and (b) for THY−PABA and THY.

followed by THY−FNBA and theophylline. Even though both THY−APAP and THY−FNBA are layered structures, they display distinctly separate degrees of deformation. This is analogous to the behavior observed for the previously reported paraben series which showed different compressibilities with varying alkyl chain lengths.31 The porosities for THY−APAP and THY−FNBA reach a similar value near 175 MPa and plateau. Similar behavior was previously reported for materials undergoing plastic deformation as seen in the case of the chloro-dinitroaniline form II.32 Above 175 MPa, both the cocrystals showed capping, which is a typically associated with over compaction.33 By virtue of their layered crystal structure, F



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Figure 11. Overlay of compactability plots for THY, THY−FNBA, and THY−APAP. Tensile strengths are on a log scale.

is the least compactable material among the three materials. Despite its greater bonding area at the initial pressures, the bonding strength of THY−APAP limits its tensile strength. THY−FNBA is more compactable than THY−APAP through the entire porosity range indicating the contribution of bonding strength in the compaction performance of THY−FNBA. At higher porosities (lower pressure) THY−FNBA is more compactable than theophylline; however, with further reduction in porosity theophylline is superior to THY−FNBA. The higher bonding strength of theophylline is an important factor for its compactability. As discussed earlier, σ0 (see eq 3) is an indicator of bonding strength. The zero-porosity tensile strengths determined for all materials in this study are reported in Table 2. The σ0 for theophylline was determined to be 7.81 MPa, in good agreement with the previously reported value.19 For our material series, σ0 followed the rank order: THY > THY−FNBA > THY−APAP. The data for THY−PABA were not used for the fitting due to a lack of enough data points. 3.3.4. Mechanical Properties. The mechanical properties of organic solids depend sensitively on their structural organization. As discussed earlier, THY, THY−PABA, and the two layered structures (THY−APAP, THY−FNBA) display significant differences in their crystal packing, and we expect these distinct structural organizations to similarly reflected in the acoustic frequency distributions obtained using p-BLS. This connection was previously demonstrated by Singaraju et al. using a series of nitrobenzoic acid derivatives.39 The p-BLS spectra acquired at two different mirror spacings are shown in Figure 12 for THY and the cocrystals. A smaller mirror spacing (3 mm) provides a larger free spectral range such that the entire longitudinal frequency distribution may be observed. Further spectra acquired at larger mirror spacings (smaller free spectral range) allow resolution of the transverse frequency distribution from the Rayleigh line. Overall, this permits clear assignment of the three characteristic frequencies (νT,min νL,max, and νsep), as consistent with our previous work.24 Using these characteristic frequencies, the longitudinal, shear and Young’s moduli (M, G, and E respectively) were calculated. Refractive indices for THY (1.737)40 and all individual coformers were collected from the following references.41,42 Since the refractive indices for the cocrystals are not readily available, we used the average of refractive indices of THY and the coformer as a first order approximation. Thus, the refractive indices used in our calculation of aggregate elasticity moduli for THY−APAP, THY−FNBA, and THY−PABA were 1.678,1.662, and 1.688

Figure 10. Overlay of tabletability plots for (a) THY, THY−FNBA, and THY−APAP and (b) THY−PABA and THY.

properties. Often the performance of the compacts is either compromised by bonding area or bonding strength. To design functional materials, it is important to understand how both structure and interaction topology contribute the compaction behavior. THY−APAP compacts display superior tensile strength relative to theophylline at lower compaction pressures (P < 100 MPa) owing to its greater bonding area and at higher pressures the tablet tensile strength plateaus near 2 MPa. But the THY−FNBA compacts show greater tensile strength than theophylline throughout its compaction pressure range. The compaction performance of THY−FNBA is superior to that of the previously reported cocrystal of caffeine and FNBA.21 The tensile strength of theophylline compacts continues to increase until 315 MPa, where the tensile strength is greater than 4 MPa. Overall, our tabletability curve for theophylline agrees well with previous reports.19,20,38 All the three materials achieve a tensile strength greater than 2 MPa. While the tensile strength of THY−PABA compacts is greater than THY at low compaction pressure, it quickly plateaus as shown in Figure 10b. This limited compaction performance is likely due its poor relative compressibility and plasticity. 3.3.3. Compactability. Tensile strength is a function of compact porosity, and it is expected that tensile strength increases with decreasing porosity. A material with a higher tensile strength at a higher porosity is considered to be more compactable than a material with the same tensile strength at a lower porosity. It can be seen from Figure 11 that THY−APAP G



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expectation that the stack-to-stack C−H···O interactions in theophylline are stronger than the interlayer dispersive interactions in either THY−FNBA or THY−APAP. Furthermore, these stronger interactions reduce the plasticity of theophylline relative to THY−APAP and THY−FNBA. 3.3.5. Acoustic Frequency Distributions and Interaction Topology. Structurally similar materials are not required to express comparable bulk phase properties, and this highlights the contribution of the interaction topology, i.e., the spatial distribution of intermolecular forces, in adjusting material function. The dihalophenols reported by Mukherjee et al., 3,4dichlorophenol and 3-chloro-4-bromophenol, provide a clear example of two nearly identical crystal structures with distinctly separate bulk property expressions.44 The 3,4-dichlorophenol plastically bends under applied load, while the bromo-derivative exhibits elastic flexibility, and this material recovers its shape after removing the stress. Each material displays helical chains of molecules supported by intrachain O−H···O hydrogen bonds, and chain−chain interactions that include halogen bonding. From a structural perspective, the Br···Br Type II interactions are shorter and suggested to be stronger than the Cl···Cl interactions, and thus the Br halogen bonds frustrate plastically and stabilize the lattice under bending deformation. Computational studies reported by Turner et al., however, suggest that while interchain interactions are indeed stronger in 3-chloro-4-bromphenol, the contribution from the alternative halogen bonds is negligible.45 While hundreds of thousands of crystal structures are available through the Cambridge Structural Database and this repository offers an indispensable resource to data mine and to support establishing structure− function trends, the realization of tailored material function has been limited, partially due to an incomplete experimental access to intermolecular interaction topology. BLS is an inelastic, light scattering technique for measuring the hypersonic sound frequencies (GHz regime) of materials. Using the Brillouin-shift equation, these measured sound frequencies provide the sound velocities, and for single-crystal studies the anisotropic elastic constants may be calculated. Alternatively, if the anisotropic elastic constants are already known, calculation of the anisotropic sound velocities is a straightforward solution of the Christoffel determinant. These anisotropic sound velocities provide a clear, quantitative gauge of the intermolecular interaction potential and its spatial variation. Certainly geometric synthons are an important and recognizable contribution to the interaction topology; however, these interactions provide only a subset of the total lattice potential which further includes Coulombic, repulsive, polarization, and dispersive contributions.46 The restoring force associated with sound velocity propagation is sensitive to this total lattice potential, and thus we report here the application of powder BLS for both the characterization of the aggregate elastic moduli and as an interpretative tool to better understand the strength and distribution of the interaction topology. Through this approach, we expect to experimentally comple-

Figure 12. Overlay of the powder BLS spectra for THY and the cocrystals recorded at two different mirror spacings (a) 3 mm and (b) 7 mm. A representative assignment of the characteristic frequencies is shown for THY−PABA.

respectively. All the characteristic frequency assignments and the resultant aggregate elastic moduli are collected in Table 3. The Young’s moduli (E) calculated for the four materials ranges from 8.4 to 10.3 GPa, with THY−FNBA and THY− PABA found to be the softest and stiffest materials respectively, and the following rank order was observed: THY−FNBA < THY−APAP < THY < THY−PABA. Our Young’s moduli are reasonably consistent with the rank order of compressibilities for these materials. THY−PABA is distinctly the least compressible material of the series, and this is supported by both its crystal structure and the highest E provided from pBLS. Moreover, both of the 2d-layered materials (THY−FNBA and THY−APAP) displayed lower E values for the series consistent with weak, easily deformed, interlayer forces. The Young’s modulus for the THY intermediate is at 9.0 GPa. This value obtained is lower when compared to the values reported in the literature using beam bending and nanoindentation methods.20,43 The shear modulus provides information about the relative ease of shear deformation among materials. The shear moduli (G) determined using p-BLS provide valuable experimental insight into the compaction performance of our theophyllinebased materials. Similar to the increased compressibility, the facility for shear deformation of a 2d-layered structure is supported by THY−FNBA and THY−APAP displaying the lowest shear moduli of the series. These results are further consistent with their higher plasticity (lower yield pressures) provided through Heckel analysis. Alternatively, the staggered layer organization adopted by THY−PABA frustrates shear deformation and consequently THY−PABA has the highest G of the series. Moreover, the supramolecular assembly displayed by THY−PABA reduces plasticity, consistent with the highest Py of the series. Similar to the Young’s moduli data, theophylline displays a midrange G and is consistent with the

Table 3. Powder BLS Characteristic Frequencies and Aggregate Elastic Moduli for THY and All the Co-Crystals material

vsep (GHz)

vL,max (GHz)

vT,min (GHz)

THY THY−APAP THY−FNBA THY−PABA

13.00 14.74 13.85 14.85

25.86 31.78 33.29 34.25

6.78 4.06 3.30 5.30 H

M (GPa) 13.10 18.98 22.30 21.28

± ± ± ±

2.9 4.2 4.9 4.7

G (GPa) 3.39 3.10 2.95 3.67

± ± ± ±

0.7 0.7 0.6 0.8

E (GPa) 9.0 8.70 8.40 10.3

± ± ± ±

2.0 1.9 1.8 2.3



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Figure 13. Anisotropic sound velocities calculated for (a) APAP Form I in the ab-crystallographic plane and (b) APAP Form II in the accrystallographic plane. Both calculations used the elastic constants reported by Price et al.23

Figure 14. Comparison of the longitudinal frequency distributions obtained using p-BLS for (a) acetylsalicylic acid, (b) APAP Form I, and (c) urea. The universal anisotropy index (UAI), calculated for each material, is included. Red, dashed lines are provided to span the longitudinal frequency distributions.

ment structural data to better understand how intermolecular interaction strength and structure both influence material performance. To illustrate this connection between the anisotropy of the interaction potential and acoustic wave speeds, the anisotropic sound velocities are calculated for both Forms I and II of APAP using the elastic constants predicted by Beyer et al., and the results of this calculation are shown in Figure 13.23 For Form I of APAP, the maximum and minimum longitudinal sound speeds are approximately 4400 and 3400 m/s, respectively, and limited anisotropy is observed. This is consistent with the quasiisotropic distribution of hydrogen bonding interactions in Form I. Alternatively, for Form II, which displays significant in-plane hydrogen bonding and weaker interplane interactions, the maximum and minimum longitudinal sound speeds span a much larger range from approximately 6400 to 3000 m/s. Unfortunately, we were unable to isolate Form II of APAP to display its p-BLS spectrum; however, between these APAP polymorphs, the rearrangement and anisotropy of their respective interaction topologies, which clearly and significantly adjust the distribution of acoustic sound speeds, must similarly be reflected in the acoustic frequency distributions obtained from p-BLS. These acoustic frequency distributions thus

provide direct experimental access to the interaction topology, a relevant consideration for crystal engineering. To further support our connection of acoustic frequency distribution and interaction topology, the p-BLS spectra were collected for three materialsacetylsalicylic acid, acetaminophen (Form I) and ureawith previously reported singlecrystal elastic constants.23,47,48 Using these elastic constants, we calculated the universal anisotropy index, previously reported by Ranganathan et al.,49 for each material: 0.7 (aspirin), 1.9 (APAP, Form I), and 11.9 (urea), showing a clear increase in elastic anisotropy as expected from the their respective crystal structures. Our p-BLS spectra are collected in Figure 14, and attention is drawn to the breadth of the longitudinal frequency distributions which are increasing consistently with the calculated anisotropy index; i.e., the relative spatial distribution of interaction strengths is reflected in the span of the acoustic frequency distribution. Further studies are underway for a broad selection of molecular crystals to better establish p-BLS as an experimental technique to better quantify the intermolecular interaction anisotropy. Even for the structurally similar THY−FNBA and THY− APAP materials, our p-BLS results provide a discriminant suggesting a clear opportunity to incorporate interaction I



Article

structure exhibited by THY. The compaction performance of THY−FNBA was compared to that of THY−APAP, another flat-layered system. While structurally similar, these materials showed distinct compaction performance (different compressibility compactability and tabletability). The layered structures were more compressible than THY consistent with the weak interlayer forces. While THY may undergo a greater extent of deformation, due its potential activation of multiple slip systems, the layered THY cocrystals have a greater ease of deformation. The tensile strength of the compacts of the layered cocrystals plateau around 150 MPa, but the tensile strength of THY compacts continues to increase. From a manufacturing perspective, the cocrystals can prove to be a better option as they are more compactable at higher porosities or they possess greater tabletability at low compaction pressures. The THY−PABA cocrystal showed poor compaction properties demonstrated poor compressibility and the lowest plasticity, and thus overall this material displayed the poorest tabletability of the series. These observations were well supported by the aggregate elastic moduli calculated from our p-BLS studies. The shear moduli for the cocrystals were in good agreement with the yield pressures obtained from Heckel plots and the Young’s moduli were generally consistent with the compressibility of the materials. Moreover, p-BLS provides experimental access to the relative interaction topologies and their anisotropy. The shear frequency distribution provided clear discrimination of the structurally similar THY−FNBA and THY−APAP materials, and supported the increased plasticity and tabletability of THY−FNBA. Thus, to gain a better perspective of the compaction process and move toward a Quality by Design (QbD) approach, it is imperative to understand how crystal structure and the intermolecular interaction topology combine to modify material performance.

strength with structural arguments for a better understanding of functional materials. Both materials display a broad longitudinal frequency distribution, and the longitudinal frequency distributions are significantly broader than that displayed by theophylline; however, notably the maximum intensity in the shear frequency distribution is further red-shifted for both THY−FNBA and THY−APAP. The reduced νT,min for THY− FNBA suggests that the interlayer interaction strength is lower relative to THY−APAP, and this further supports the lower shear modulus and higher plasticity relative to THY−APAP. This directly reflects the significant differences in the speed of the transverse waves traveling in the orthogonal directions. Transverse acoustic waves with polarization along the interplane direction experience a weaker restoring force relative to those waves with polarization contained within the hydrogenbonded sheets. These weaker restoring forces manifest as (1) low-frequency transverse modes and (2) low shear elements in the elasticity tensor, an expectation consistent with the previous compaction studies reported by Karki et al. 22 These experimental inputs provide a direct gauge of the intersheet interaction strength and provides an important discriminant when comparing structurally similar materials for predicting potential compaction performance. Similar results were provided from our previous studies of p-aminobenzoates, whereby the rank-order of lowest absolute energy slip planes correlated well with the red-shifted νT,min. and increased plasticity.24 We speculate that with further development of pBLS, this technique may be used to rapidly screen cocrystals for identifying which materials that may display suitable tabletability. For theophylline, the span of the acoustic frequency distribution is larger than, e.g., that for acetylsalicylic acid, and this a clear signature of increasing interaction anisotropy; however, the extent of interaction anisotropy is less relative to the any of the theophylline cocrystals. The relative strength of intrastack versus interstack interactions are not substantially different; otherwise, the breadth of the longitudinal frequency distribution would be larger, and this is further consistent with the expectation that multiple slip systems are accessible to anhydrous theophylline. For the THY−PABA cocrystal, we see a broad longitudinal frequency distribution which suggests anisotropic interaction topology; however, the νT,min for THY− PABA is the highest of our material series (and overall the highest shear modulus); thus this interdigitated stacking structure, while possessing significant longitudinal acoustic anisotropy, does not facilitate shear deformation and thus displays the lowest plasticity of the series.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.cgd.7b01339. Overlay of experimental and predicted PXRD patterns for all individual materials and cocrystals; out-of-die Heckel plots for THY and all cocrystals; and the particlesize distribution plots, from sieve analysis, for THY and all cocrystals (PDF) Accession Codes

CCDC 1556375 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_ [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

4. CONCLUSIONS In this work, cocrystals of theophylline were specifically selected to contrast structural similarities and their connection to material mechanics and tableting performance. For crystal engineering using cocrystallization, it is important to establish a target motif to assist the selection of coformers that preferentially organize into a specific assembly. Moreover, structurally similar materials are not guaranteed to display the similar bulk property expression, and thus the interaction topology and its anisotropy is a critical component to understanding functional solids. A new solid form, THY− FNBA, was found to exhibit superior tabletability even relative to theophylline, a material already endowed with good compaction performance. Single-crystal XRD revealed the presence of a flat-layered structure, distinct from the stacking

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AUTHOR INFORMATION

Corresponding Author

*Tel: (319)-335-8823; fax: (319)-335-9349; e-mail: [email protected]. ORCID

Lewis L. Stevens: 0000-0003-2936-0926 Notes

The authors declare no competing financial interest. J



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Article

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