Supply and Demand in the Ball Mill: Competitive Cocrystal Reactions

Article pubs.acs.org/crystal

Supply and Demand in the Ball Mill: Competitive Cocrystal Reactions Franziska Fischer,†,‡ Dominik Lubjuhn,† Sebastian Greiser,†,‡ Klaus Rademann,‡ and Franziska Emmerling*,† †

BAM Federal Institute for Materials Research and Testing, R.-Willstätter-Strasse 11, 12489 Berlin, Germany Department of Chemistry, Humboldt-Universität zu Berlin, B.-Taylor-Strasse 2, 12489 Berlin, Germany

‡

S Supporting Information *

ABSTRACT: The stability of different theophylline cocrystals under milling conditions was investigated by competitive cocrystal reactions. To determine the most stable cocrystal form under milling conditions, the active pharmaceutical ingredient theophylline was either ground with two similar coformers (benzoic acid, benzamide, or isonicotinamide), or the existing theophylline cocrystals were ground together with a competitive coformer. All competitive reactions were investigated by in situ powder X-ray diffraction disclosing the formation pathway of the milling processes. On the basis of these milling reactions, a stability order (least to most stable) was derived: tp/bs < tp/ba < tp/ina < bs/ina.

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INTRODUCTION In the last few years, intensive investigation of cocrystals has led to a broad application of these materials. Cocrystallization can improve unique physicochemical properties of the material.1−5 Aakeröy introduced a definition of the term “cocrystal” in 2005. Cocrystals are multicomponent, crystalline phases consisting only of discrete, neutral molecular species, which are solid at ambient conditions.6 A new crystal lattice is formed, which is stabilized via noncovalent, intermolecular interactions between these molecules,7−12 leading to an alteration of distinct physicochemical properties including melting point, stability against physical and chemical stress, water solubility, or dissolution behavior.4,13−17 Cocrystals are of particular interest in pharmaceutical research, since the solubility and the dissolution behavior of an active pharmaceutical ingredient (API) is closely connected with its bioavailability. Next to the solubility, the stability against humidity and the compressibility of an API can be improved by cocrystallizing it with an appropriate coformer.18−22 Several synthesis strategies, ranging from freeze-drying and spray-drying to the formation from melt or solution are employed to synthesize cocrystals with customized properties.23−27 Especially mechanochemical reactions, solid state reactions which are induced by mechanical energy, e.g., grinding in a ball mill approach, have become an established synthesis method for cocrystals.28 The method bares many advantages compared to other synthesis methods.29−32 Mechanochemistry represents a very effective and sustainable method. No or only small amounts of solvents are required, and the reactions proceed quantitatively at room temperature within short reaction periods. Despite intensive investigations, a fundamental understanding of the mechanochemical mechanisms is still lacking.33,34 First insights in the mechanochemical cocrystal formation were obtained by in situ measurements of theobromine/oxalic © 2016 American Chemical Society

acid and carbamazepine/saccharin cocrystals using synchrotron X-ray powder diffraction.35,36 The setup was extended by the combination with Raman spectroscopy, allowing the evaluation of the formation pathway of cocrystals on the crystalline and molecular level.37 These experiments can reveal the synthesis pathways of milling reactions including amorphous states and intermediate phase, but the knowledge of the underlying driving forces and the stabilities of cocrystals is still insufficient. Although intensive work focuses on the theoretical prediction of cocrystallization products,38−41 until now, it has not been possible to predict these crystal structures reliably due the complexity of crystallization processes.42−45 Only the combination of theoretical prediction and experiments permits all possible crystalline forms to be found. Typically, the hierarchy of intermolecular synthons is evaluated on the basis of Cambridge Structural Database entries to get information about preferred cocrystal structures.46−50 Only a few studies concentrate on stability tests, using exchange reactions, which offer the direct comparison of the stability among different cocrystals.51−53 For pharmaceutical applications, it is important to characterize all possible modifications of an API preventing conversion during the storage of the API. In this work, we conducted multicomponent milling reactions to assess the thermodynamic stability of theophylline (tp) cocrystals. To minimize kinetic inhibition, we chose the coformers benzoic acid (bs), benzamide (ba), and isonicotinamide (ina) shown in Scheme 1, which exibit comparable homosynthons in their pure crystal structures. In situ X-ray diffraction investigations of all milling reactions provide new Received: June 17, 2016 Revised: August 5, 2016 Published: August 19, 2016 5843

DOI: 10.1021/acs.cgd.6b00928 Cryst. Growth Des. 2016, 16, 5843−5851

Crystal Growth & Design

Article

insights into the formation pathways and allow ranking the stability under mechanochemical conditions of the compounds.

Scheme 1. Molecular Structure of Reactants in the Grinding Experiments

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EXPERIMENTAL SECTION

Materials. Benzamide (ba), C7H7NO (99%, Aldrich Chemistry, Germany), benzoic acid (bs), C7H6O2 (99%, Acros Organics, Belgium), isonicotinamide (ina), C6H6N2O (99.5%, Acros Organics, Belgium), and theophylline (tp), C7H8N4O2 (99+%, Acros Organics, Belgium) were purchased commercially and were used without further purification. For polymorphic compounds, the most stable form at ambient condition was used. Synthesis of the Pure Cocrystals. The milling syntheses were conducted by neat grinding in a ball mill (MM400, Retsch, Germany) at 30 Hz for 25 min. A 10 mL steel vessel with two steel balls (10 mm diameter, 4 g) was used for a total load of 1 g. Theophylline/Benzamide (tp/ba). tp (597.9 mg, 1 equiv) and ba (402.1 mg, 1 equiv) were weighed into a grinding jar, and the reaction mixture was ground for 25 min at 30 Hz. Afterward the product was investigated using powder X-ray diffraction (PXRD). Theophylline/Benzoic Acid (tp/bs). tp (596.0 mg, 1 equiv) and bs (404.1 mg, 1 equiv) were weighed into a grinding jar, and the reaction mixture was ground for 25 min at 30 Hz. Afterward the product was investigated using PXRD. Theophyllin/Isonicotinamide (tp/ina). tp (596.0 mg, 1 equiv) and ina (404.1 mg, 1 equiv) were weighed into a grinding jar and the

Figure 1. Powder XRD patterns of the cocrystals (a) theophylline/benzamide (tp/ba), (b) theophylline/benzoic acid (tp/bs),58 (c) theophylline/ isonicotinamide (tp/ina), and (d) benzoic acid/isonicotinamide (ba/ina) and the corresponding reactants. 5844



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Figure 2. Crystal structures of the cocrystals (a) theophylline/benzamide (tp/ba), (b) theophylline/benzoic acid (tp/bs),58 (c) theophylline/ isonicotinamide (tp/ina), and (d) benzoic acid/isonicotinamide (ba/ina). The hydrogen atoms not involved in the hydrogen bonding were omitted for clarity. Green dashed lines indicate hydrogen bonds. Raman Spectroscopy. Raman measurements were performed on a Raman RXN1 analyzer (Kaiser Optical Systems, France). The spectra were collected using a laser with a wavelength of λ = 785 nm and a contactless probe head (working distance 1.5 cm, spot size 1.0 mm). Raman spectra were recorded with an acquisition time of 5 s and five accumulations. NIR excitation radiation at λ = 785 nm and an excitation intensity of 6.6 W/cm2 were performed. ssNMR. 1H NMR measurements were performed on a Bruker AVANCE 600 spectrometer using a 2.5 mm double-bearing magic angle spinning (MAS) probe (Bruker Biospin) and applying a spinning speed of 27.5 kHz. The 1H rotor-synchronized echo experiment with an echo time of 2·Tr = 0.073 ms were used to suppress existent background signals. The spectra were recorded with a π/2 pulse lengths of 3.0 μs, π pulse lengths of 6.0 μs, a recycle delay of 60 s, and an accumulation number of 8. In the case of pure sa, the signal was not sufficient for the 1H rotor-synchronized echo experiment. Two 1H MAS NMR measurements with recycle delays of 60 s and 300 s were performed.

reaction mixture was ground for 25 min at 30 Hz. Afterwards the product was investigated using PXRD. Competitive Milling Synthesis. The competitive milling syntheses were conducted by neat grinding stoichiometric amounts of tp and two additional coformers (ba, bs, or ina) in a ball mill (MM400, Retsch, Germany) at 30 Hz for 25 min. A 10 mL steel vessel with two steel balls (10 mm diameter, 4 g) was used for a total load of 1 g. Stability Milling Synthesis. The stability milling syntheses were conducted by neat grinding stoichiometric amounts of an existing cocrystal and a competitive coformer in a ball mill (MM400, Retsch, Germany) at 30 Hz for 25 min. A 10 mL steel vessel with two steel balls (10 mm diameter, 4 g) was used for a total load of 1 g. XRD Measurements. The products were investigated by PXRD. The obtained powder patterns of the pure cocrystals did not show any residues of the reactants. All PXRD experiments were carried out using a D8 diffractometer (Bruker AXS, Karlsruhe, Germany) in transmission geometry (Cu−Kα1 radiation, λ = 1.54056 Å). The crystal structures were solved based on the PXRD pattern using the open source program FOX for indexing and structure solution.54 The program CHEKCELL was used to confirm the unit cell and the space group.55 FOX uses global-optimization algorithms to solve the structure by performing trials in direct space. This search algorithm uses random sampling coupled with simulated temperature annealing to locate the global minimum of the figure-of-merit factor. The crystal structure of the cocrystals was solved by the simulated annealing procedure on a standard personal computer within 12 h, finding the deepest minimum of the cost function several times during the procedure. To complete the structure determination, the structural solution obtained from Monte Carlo/simulated annealing was subsequently subjected to a Rietveld refinement employing the TOPAS software.56 CCDC-1443668 (tp/ina) contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.cdc.cam.ac.uk/data_request/cif. Synchrotron Measurements. In situ XRD measurements were performed at the microfocus beamline μSpot (BESSY II, Helmholtz Centre Berlin for Materials and Energy, Germany) in transmission geometry. The powder patterns were collected using a wavelength of 1.0000 Å using a Si (111) double-crystal monochromator. A twodimensional MarMosaic CCD X-ray detector with 3072 × 3072 pixels was used to record the scattering intensity. In a typical experiment, XRD patterns were collected for 30 s. The obtained scattering images were processed and converted into diagrams of scattered intensities versus scattering vector q (q = 4π/λ sin θ) employing an algorithm from the FIT2D software.57 For the graphical representations, q values were transformed to the diffraction angle 2θ (Cu). The in situ monitoring of the competitive syntheses was conducted by neat grinding in a mini mill PULVERISETTE 23 (Fritsch, Germany) at 50 Hz for 25 min with similar reactant charges as in the laboratory experiments. A 10 mL self-constructed Perspex vessel with two steel balls (10 mm) was used for a total load of 1 g. The powder patterns were collected directly during the grinding process.

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RESULTS AND DISCUSSION Syntheses and Characterization of the Model Compounds. Our investigations focus on cocrystals of tp with the coformers ba, bs, and ina. Although they are not isomorphic and different in nature (acid, base, neutral), these coformers were chosen due to their structural similarity (Scheme 1, Table S1). The cocrystal reactants reveal similar starting conditions for the competitive milling reactions. For instance, they provide similar hydrogen bonds, which have to be broken during the cocrystallization. All cocrystals can be synthesized by neat grinding of the reactants in an equimolar ratio. The corresponding PXRD patterns depicted in Figure 1 show the completeness of the cocrystallization processes. On the basis of the corresponding powder pattern, the crystal structure of the cocrystal tp/ina could be solved and refined. The crystal structures of the cocrystals which were observed in milling experiments are shown in Figure 2. The cocrystals were stabilized by intermolecular hydrogen bonds and π−π stacking. All tp cocrystals show the same amide-pseudo amide hydrogen bonding motif, which was described in detail by Eddleston.59 In the tp/ina cocrystal this motif is extended by a hydrogen bond between the amino group within the amide of the coformer and a carbonyl oxygen atom of tp. The tp/ba cocrystal shows additionally a third interaction between the amino group within the amide of ba and the ternary amine of tp. For further characterization, the cocrystal products were investigated via Raman spectroscopy, solid-state NMR (ssNMR) spectroscopy, and melting point determination. Raman and ssNMR spectra were recorded to identify a possible salt formation during the cocrystallization. 5845



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Table 1. Crystallographic Data of the tp/ba, tp/bs, tp/ina, and bs/ina Cocystal58,61 crystal

tp/ba

tp/bs

tp/ina

bs/ina

formula M [g/mol] crystal system space a [Å] b [Å] c [Å] α [°] β [°] γ [°] V [Å3] Z method T [K] salt Tm [°C]

(C7H8N4O2)(C7H6NO) 301.30 tetragonal P41 10.2815 10.2815 26.1608 90 90 90 2765.44 8 PXRD 293 no 130.6

(C7H8N4O2)(C7H6O2) 302.28 monoclinic P21/n 6.98713(59) 25.1082(25) 8.60835(83) 90 108.5578(50) 90 1431.67 4 PXRD 293 no 135.7

(C7H8N4O2)(C6H6N2O) 302.28 monoclinic P21/c 3.830583(32) 16.61709(19) 21.54658(23) 90 99.78699(87) 90 1351.55 4 PXRD 293 no 194.1

(C7H6O2):(C6H6N2O) 244.24 monoclinic C2/c 22.379(4) 5.1507(8) 20.540(3) 90 96.927 90 2350.31 8

Evaluating for instance the spectra of the tp/ba cocrystal, it can be assumed that the cocrystal is formed by neutral molecules. When tp forms a salt with an amino base, the stretching bands of the carbonyl groups at 1665 and 1707 cm−1 shift by 30−40 cm−1 to lower frequencies in the Raman spectra. Additionally, the Raman band of the secondary amine at 3123 cm−1 would disappear based on the deprotonation. In the case of the tp/ba cocrystal the carbonyl stretching bands shift by 22 and 17 cm−1, and the Raman signal of the secondary amine occurs at 3118 cm−1 in the cocrystal spectrum (Figure S2).60 The small changes in the positions of the Raman signal reveal that the cocrystallization proceeds without a salt formation. These results are backed by 1H ssNMR data. Here, the chemical shift of the acidic proton of tp has to be considered. In pure tp this proton causes a ssNMR signal at 14.5 ppm (Figure S7). In the cocrystal the signal is shifted to 13.0 ppm. The highfield shift indicates that the regarded proton is not as strongly bridged as in pure tp. Since the tp molecules are neutral in the pure form, they are also uncharged in the cocrystal.60 The other cocrystals were investigated similarly. On the basis of the slight shifts of the signals in the Raman and ssNMR spectra, it can be assumed that all compounds consist of neutral molecules and are cocrystals with respect to the definition given by Aakeröy. To evaluate the thermal stability the melting points of the cocrystals were determined. Here, it can be observed that the tp/ina cocrystal has the highest melting point with 194.1 °C. The tp/ba cocrystal shows the lowest thermal stability with a melting point at 130.6 °C. The collected data of these investigations and the lattice constants of the cocrystals are shown in Table 1. Competitive and Stability Experiments. In order to find the favored cocrystals, three types of competitive milling reactions were performed as depicted in Figure 3: (A) grinding a stoichiometric mixture of tp, coformer1, and coformer2, (B) grinding the cocrystal tp/coformer1 with a stoichiometric amount of coformer2, (C) grinding the cocrystal tp/coformer2 in an equimolar ratio with coformer1. For these experiments the coformers ba, bs, and ina were used. Previous mechanochemical investigations, where theobromine competes with other APIs to cocrystallize with anthranilic acid, revealed that the most stable cocrystal cannot always be formed in milling synthesis due to kinetic inhibition. In this study, we can monitor coformer exchange reactions to build the most stable

no 163.5

Figure 3. Schematic representation of the milling reactions with a stoichiometric mixture of the compounds (A), or an existing cocrystal with a competitive coformer (B + C).

cocrystal of the system as pertains the grinding environment employed. Theophylline−Benzoic Acid−Isonicotinamide. The milling process of tp, bs, and ina leads to the cocrystallization of the coformers, while tp remains unreacted. An exchange reaction accompanied by the recrystallization of tp can be observed during the milling process of the respective tp cocrystal with the appropriate coformer, resulting in the same product as in the grinding reaction of the pure reactants (Scheme S1). These results are in accordance with Etter’s rules concerning the acidity of the reactants. The rule describes that the best hydrogen donor interacts with the best hydrogen acceptor.62 Furthermore, the bs/ina cocrystal is stabilized via more hydrogen bonds per molecule than the tp/bs or the tp/ ina cocrystal leading to an increased stability. The cocrystal is defined by a strong hydrogen bond between the best hydrogen donor (acidic group of bs) and the pyridine nitrogen atom of ina representing the best hydrogen acceptor (Figure 4, violet).61 The strength of this interaction is reflected in the 1 H ssNMR spectrum of the bs/ina cocrystal (Figure S10), where the signal of the acidic proton of bs is low-field shifted by 2.4 ppm. This shift clearly shows that the proton is strongly bridged in the cocrystal due to the strength of the interaction between the acidic group of bs and the pyridine nitrogen atom of ina. Each ina molecule is connected to a second bs molecule via a hydrogen bond between the amide group of ina and the carbonyl oxygen atom of bs (Figure 4, blue). Additionally, a R22(8) dimer (Figure 4, orange) between the amide groups of two ina molecules is formed. Raman and ssNMR measurements reveal that the molecules interact strongly in the bs/ina cocrystal. It can be assumed that these strong hydrogen bonds 5846



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3.30 min (residuals of bs can be monitored up to 10.00 min) and the formation of the final product starts after 9.00 min of grinding, it can be supposed that the 1:1 bs/ina cocrystal is formed from the 2:1 cocrystal precursor. The reflections of this 2:1 intermediate vanish after 14.30 min. During the grinding experiment starting from the tp/ina cocrystal and bs the same intermediate phase could be observed. Compared to the other two reactions bs is not provided directly in the reaction starting from tp/bs and ina, but it is released during the milling synthesis continuously leading to the direct formation of the thermodynamically favored 1:1 cocrystal of bs and ina. Since the formation of the 2:1 intermediate cocrystal depends on the amount of bs provided in the reaction, it can be assumed that the cocrystal formation is controlled by the supply of building blocks. On the basis of the Raman spectra of the bs2/ina cocrystal a salt formation can be excluded. Therefore, a preferred formation based on a salt formation in the bs2/ina cocrystal can be ruled out. When the bs/ina cocrystal is milled with pure tp, no changes in the powder patterns during the grinding process are observable (Figure S17). Theophylline−Benzamide−Isonicotinamide. In this system, the tp/ina cocrystal is always formed next to pure ba unaffected by the starting materials, either the pure components (A in Figure 3), the tp/ba cocrystal with ina (C in Figure 3), or the tp/ina cocrystal with ba (Scheme S1). This indicates that the tp/ina cocrystal is the thermodynamically most stable cocrystal in this ternary system. According to Etter’s rules a ba/ ina cocrystal is expected, because ina represents with a pKa value of 3.7 the strongest hydrogen donor and ba (pKa = 13.3) the best hydrogen acceptor. Until now, all mechanochemical or solvothermal syntheses with various different parameters of this cocrystal were unsuccessful. The tp/ina cocrystal reveals three different types of hydrogen bonds. Each tp molecule is connected to two ina molecules via hydrogen bonds. One hydrogen bond is formed between the acidic imidazolic nitrogen atom from a tp molecule and the oxygen atom from the amide group of the ina molecule. An

Figure 4. Crystal structure of the bs/ina cocrystal seen along the baxis. The hydrogen atoms not involved in the hydrogen bonding were omitted for clarity. Green dashed lines indicate hydrogen bonds.

also contribute to a preferred formation of the bs/ina cocrystal in the grinding experiments. The three kinds of competitive reactions were investigated by using the in situ monitoring with synchrotron XRD to evaluate the formation pathway of the milling processes in detail. Here, a Perspex grinding jar was used as reaction vessel since it is transparent for synchrotron radiation. The powder patterns of the reaction mixture were collected every 30 s during the grinding process. These investigations reveal that the 2:1 bs/ina cocrystal is formed as an intermediate phase, both for synthesis from the pure reactants and the tp/ina cocrystal with bs (Figure S15). Starting with the three pure reactants, the intermediate can be observed after a milling time of 1.30 min (Figure 5a). Since most of the reflections of bs and ina are observed until

Figure 5. Synthesis process of competitive reactions followed by synchrotron XRD with the starting materials: (a) pure educts tp, bs, and ina (left); (b) tp/ina and bs (middle); and (c) tp/bs and ina (right). 5847



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back this assumption. Since both cocrystals reveal the R22(9) pseudo amide−amide synthon the ssNMR signal of the involved, acidic proton of tp can be considered. In the tp/ba cocrystal this proton causes a signal at 13.0 ppm (Figure S7). In the tp/ina cocrystal it is considerably low-field shifted at 14.2 ppm (Figure S9) indicating that the hydrogen interactions in the tp/ina cocrystal are stronger than in the tp/ba cocrystal. The in situ monitoring shows that by milling the three pure components together, the tp/ina cocrystal is formed gradually from its educts, while ba persists during the complete milling process. As presented in Figure 7a the first reflections of the tp/ ina cocrystal can be observed after a milling time of 4.00 min, and the reflections of tp and ina vanish after 14.30 min completely. During the synthesis starting from the tp/ba cocrystal and ina, the product is formed only after 6.00 min. The conversion into the tp/ina cocrystal proceeds in a similar period (Figure 7b). The tp/ba cocrystal is more stable than the pure reactants, and higher mechanochemical energy is needed to start the reaction leading to the longer induction period. In the last grinding experiment the tp/ina cocrystal and ba were chosen as starting materials, but no reaction could be observed during the whole grinding time. Theophylline−Benzamide−Benzoic Acid. When tp is milled with bs and ba in an equimolar ratio, tp cocrystallizes with ba, whereas bs stays stable. Since the tp/bs cocrystal converts into the tp/ba cocrystal and pure bs during the grinding process with ba, and the tp/ba cocrystals remains constant within the milling reaction with bs (Scheme S1), it can be assumed that the tp/ba cocrystal is more stable under milling conditions than the tp/bs cocrystal. The interaction with the basic ba is preferred over bs, since tp possesses an acidic hydrogen atom. According to Etter’s rules a cocrystal of ba and bs is expected, as ba represents the strongest base and bs the strongest acid in this system. In these experiments, no ba/ bs cocrystal could be observed. Although the structure of a ba/ bs cocrystal remains unsolved, the density of a ba/bs cocrystal could be estimated to be similar to the densities of the reactants

additional hydrogen bond is formed between the amide group of an ina molecule and the carbonyl group of a tp molecule, resulting in a R22(9) dimer (Figure 6, orange). The third

Figure 6. Crystal structure of the tp/ina cocrystal seen along the aaxis. The hydrogen atoms not involved in the hydrogen bonding were omitted for clarity. Green dashed lines indicate hydrogen bonds.

hydrogen bond (violet) between the amide group of an ina molecule and the second carbonyl group of a tp molecule leads to a chain-structure motive. Additionally, the cocrystal is stabilized via π−π stacking between the tp molecules and the ina molecules, respectively. The hydrogen bonds of the tp/ina cocrystal are considerable shorter hydrogen bonds compared to the tp/ba cocrystal leading to a more efficient packing, a higher density (1.49 g·cm−3 versus 1.45 g·cm−3), and a better thermal stability proved by differential scanning calorimetry (DSC) measurements (see Figures S11−S14).60 The 1H ssNMR data

Figure 7. Synthesis process of competitive reactions followed by synchrotron XRD with the starting materials: (a) pure educts tp, ba, and ina (left); (b) tp/ba and ina (middle); and (c) tp/ina and ba (right). 5848



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Figure 8. Synthesis process of competitive reactions followed by synchrotron XRD with the starting materials: (a) pure educts tp, ba, and bs (left); (b) tp/ba and bs (middle); and (c) tp/bs and ba (right).

ba (1.31 g·cm−3) and bs (1.32 g·cm−3).63,64 On the basis of the higher density of the tp cocrystal with ba (1.45 g·cm−3), it can be assumed that the packing of a tp/ba cocrystal is obviously more efficient than the ba/bs cocrystal leading to a higher stability of tp/ba. The in situ monitoring displays that grinding all three pure components of the ternary system together leads to an gradual formation of the tp/ba cocrystal after 3.30 min, while the reflections of bs are still observable. Simultaneously, a tp/ba/bs phase is built, which could not be observed in the laboratory experiments by neat grinding in the steel vessels. This ternary phase could only be received in the steel jar by liquid-assisted grinding supporting the idea that polymers can influence the fate of the grinding product.65 The powder patterns of the product phase depicted in Figure 8a contain a reflection at 2θ = 11.9°, which cannot be assigned to an already described cocrystal or other crystalline phase. Since grinding can lead to a transformation into another polymorphic form, the powder pattern of the product phase was also compared to the powder patterns of all polymorphs of tp and ba. No accordance could be observed. Neither high-resolution data of this product recorded in the laboratory nor ex situ investigations reveal this reflection. Therefore, it can be supposed that this reflection is caused by a very unstable crystalline phase, which decomposes when opening the grinding jar. In the in situ milling synthesis of the tp/ba cocrystal with bs the formation of the ternary tp/ba/bs phase can be observed after 8.00 min, while the reflections of the reactants decrease slightly. The amount of the tp/ba/bs phase is significantly higher than in the first described reaction of the pure compounds. The same products are also formed, when the tp/bs cocrystal is milled with ba. However, an intermediate can be observed in this reaction between a milling time of 5.00 and 16.00 min, which is also characterized by the intensive, unknown reflection at 2θ = 11.9°. As shown in Figure 8 the induction time for both reactions is longer than in the milling synthesis starting with the pure components. It can be

concluded that the cocrystals are energetically more favored than pure tp, bs,and ba.

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CONCLUSION Solid state cocrystallization offers a facile and efficient way to screen cocrystals. Herein, we investigated the possibility to evaluate the stability of cocrystals based on a set of competitive milling reactions. Our results reveal that under mechanochemical conditions cocrystal former exchange reactions proceed in order to form the most stable cocrystal product if kinetic inhibition can be excluded. To probe the stability of the new tp/ina cocrystal, comparable coformers were chosen with respect to their size and molecular structure, intermediates, and cocrystal products of the reaction. It can be assumed that the thermodynamically most stable cocrystal product is formed in all conducted multicomponent grinding experiments as pertains the grinding environment employed. On the basis of our result we postulate the following mechanochemical stability order of the investigated cocrystals: tp/bs < tp/ba < tp/ina < bs/ina. In situ measurements were performed to evaluate and understand the pathways of the competitive grinding reactions. In the formation process of the bs/ina cocrystal, an intermediate 2:1 cocrystal of bs and ina could be observed. The presence of this intermediate depends on the starting materials. The intermediate is formed, when bs is offered in pure form in the grinding jar. No intermediate was observed in reactions starting from the tp/bs cocrystal with ina. Here, bs is released continuously and the thermodynamically more stable 1:1 bs/ ina cocrystal is formed directly. The results indicate that carefully chosen mechanochemical experiments offer not only new cocrystals but are also capable of deriving stability data.

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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.6b00928. 5849



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(16) Lipert, M. P.; Rodríguez-Hornedo, N. Mol. Pharmaceutics 2015, 12, 3535−3546. (17) Sanphui, P.; Devi, V. K.; Clara, D.; Malviya, N.; Ganguly, S.; Desiraju, G. R. Mol. Pharmaceutics 2015, 12, 1615−1622. (18) Arora, K. K.; Thakral, S.; Suryanarayanan, R. Pharm. Res. 2013, 30, 1779−1789. (19) Sun, C. C. J. Pharm. Sci. 2009, 98, 1671−1687. (20) Seefeldt, K.; Miller, J.; Alvarez-Nunez, F.; Rodriguez-Hornedo, N. J. Pharm. Sci. 2007, 96, 1147−1158. (21) Surov, A. O.; Manin, A. N.; Churakov, A. V.; Perlovich, G. L. Mol. Pharmaceutics 2015, 12, 4154−4165. (22) Sanphui, P.; Mishra, M. K.; Ramamurty, U.; Desiraju, G. R. Mol. Pharmaceutics 2015, 12, 889−897. (23) Eddleston, M. D.; Patel, B.; Day, G. M.; Jones, W. Cryst. Growth Des. 2013, 13, 4599−4606. (24) Alhalaweh, A.; Kaialy, W.; Buckton, G.; Gill, H.; Nokhodchi, A.; Velaga, S. P. AAPS PharmSciTech 2013, 14, 265−276. (25) Gao, Y.; Olsen, K. W. Mol. Pharmaceutics 2014, 11, 3056−3067. (26) Seefeldt, K.; Miller, J.; Alvarez-Núñez, F.; Rodríguez-Hornedo, N. J. Pharm. Sci. 2007, 96, 1147−1158. (27) Maheshwari, C.; Jayasankar, A.; Khan, N. A.; Amidon, G. E.; Rodriguez-Hornedo, N. CrystEngComm 2009, 11, 493−500. (28) Braga, D.; Maini, L.; Grepioni, F. Chem. Soc. Rev. 2013, 42, 7638−7648. (29) James, S. L.; Adams, C. J.; Bolm, C.; Braga, D.; Collier, P.; Frišcǐ ć, T.; Grepioni, F.; Harris, K. D.; Hyett, G.; Jones, W.; et al. Chem. Soc. Rev. 2012, 41, 413−447. (30) Boldyreva, E. Chem. Soc. Rev. 2013, 42, 7719−7738. (31) Cinčić, D.; Frišcǐ ć, T.; Jones, W. Chem. - Eur. J. 2008, 14, 747− 753. (32) Fucke, K.; Myz, S. A.; Shakhtshneider, T. P.; Boldyreva, E. V.; Griesser, U. J. New J. Chem. 2012, 36, 1969−1977. (33) Caira, M. R.; Nassimbeni, L. R.; Wildervanck, A. F. J. Chem. Soc., Perkin Trans. 2 1995, 2213−2216. (34) Etter, M. C.; Reutzel, S. M.; Choo, C. G. J. Am. Chem. Soc. 1993, 115, 4411−4412. (35) Fischer, F.; Scholz, G.; Batzdorf, L.; Wilke, M.; Emmerling, F. CrystEngComm 2015, 17, 824−829. (36) Halasz, I.; Puškarić, A.; Kimber, S. A. J.; Beldon, P. J.; Belenguer, A. M.; Adams, F.; Honkimäki, V.; Dinnebier, R. E.; Patel, B.; Jones, W.; Štrukil, V.; Frišcǐ ć, T. Angew. Chem., Int. Ed. 2013, 52, 11538− 11541. (37) Batzdorf, L.; Fischer, F.; Wilke, M.; Wenzel, K. J.; Emmerling, F. Angew. Chem., Int. Ed. 2015, 54, 1799−1802. (38) Arlin, J. B.; Price, L. S.; Price, S. L.; Florence, A. J. Chem. Commun. 2011, 47, 7074−7076. (39) Price, S. L. Chem. Soc. Rev. 2014, 43, 2098−2111. (40) Issa, N.; Karamertzanis, P. G.; Welch, G. W. A.; Price, S. L. Cryst. Growth Des. 2009, 9, 442−453. (41) Cruz-Cabeza, A. J.; Day, G. M.; Jones, W. Chem. - Eur. J. 2008, 14, 8830−8836. (42) Schammé, B.; Couvrat, N.; Malpeli, P.; Delbreilh, L.; Dupray, V.; Dargent, É.; Coquerel, G. Int. J. Pharm. 2015, 490, 248−257. (43) Bhardwaj, S. P.; Arora, K. K.; Kwong, E.; Templeton, A.; Clas, S.-D.; Suryanarayanan, R. Mol. Pharmaceutics 2013, 10, 694−700. (44) Baird, J. A.; Van Eerdenbrugh, B.; Taylor, L. S. J. Pharm. Sci. 2010, 99, 3787−3806. (45) Descamps, M.; Dudognon, E. J. Pharm. Sci. 103, 2615−2628. (46) Shattock, T. R.; Arora, K. K.; Vishweshwar, P.; Zaworotko, M. J. Cryst. Growth Des. 2008, 8, 4533−4545. (47) Kavuru, P.; Aboarayes, D.; Arora, K. K.; Clarke, H. D.; Kennedy, A.; Marshall, L.; Ong, T. T.; Perman, J.; Pujari, T.; Wojtas, L.; Zaworotko, M. J. Cryst. Growth Des. 2010, 10, 3568−3584. (48) Bis, J. A.; Vishweshwar, P.; Weyna, D.; Zaworotko, M. J. Mol. Pharmaceutics 2007, 4, 401−416. (49) Moragues-Bartolome, A. M.; Jones, W.; Cruz-Cabeza, A. J. CrystEngComm 2012, 14, 2552−2559. (50) Aakeröy, C. B.; Epa, K.; Forbes, S.; Schultheiss, N.; Desper, J. Chem. - Eur. J. 2013, 19, 14998−15003.

Molecular structures and crystallographic data of compounds, Raman and solid-state NMR spectra, DSC-TG and further in situ XRD measurements (PDF) Accession Codes

CCDC 1443668 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.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We are grateful to S. Reinsch for DSC-TG measurements. ABBREVIATIONS API, active pharmaceutical ingredient; ba, benzamide; bs, benzoic acid; DSC-TG, differential scanning calorimetry and thermogravimetric analysis; ina, isonicotinamide; MAS, magic angle spinning; PXRD, powder X-ray diffraction; tp, theophylline; ssNMR, solid-state NMR

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REFERENCES

(1) Thakuria, R.; Delori, A.; Jones, W.; Lipert, M. P.; Roy, L.; Rodriguez-Hornedo, N. Int. J. Pharm. 2013, 453, 101−125. (2) Elder, D. P.; Holm, R.; Lopez de Diego, H. Int. J. Pharm. 2013, 453, 88−100. (3) Sinha, A. S.; Maguire, A. R.; Lawrence, S. E. Cryst. Growth Des. 2015, 15, 984−1009. (4) Schultheiss, N.; Newman, A. Cryst. Growth Des. 2009, 9, 2950− 2967. (5) Frišcǐ ć, T.; Jones, W. Cryst. Growth Des. 2009, 9, 1621−1637. (6) Aakeröy, C. B.; Salmon, D. J. CrystEngComm 2005, 7, 439−448. (7) Aakeröy, C. B.; Fasulo, M. E.; Desper, J. Mol. Pharmaceutics 2007, 4, 317−322. (8) Etter, M. C.; Frankenbach, G. M. Chem. Mater. 1989, 1, 10−12. (9) Frišcǐ ć, T.; Jones, W. J. Pharm. Pharmacol. 2010, 62, 1547−1559. (10) Zaworotko, M. J. Cryst. Growth Des. 2007, 7, 4−9. (11) Aitipamula, S.; Banerjee, R.; Bansal, A. K.; Biradha, K.; Cheney, M. L.; Choudhury, A. R.; Desiraju, G. R.; Dikundwar, A. G.; Dubey, R.; Duggirala, N.; Ghogale, P. P.; Ghosh, S.; Goswami, P. K.; Goud, N. R.; Jetti, R. R. K. R.; Karpinski, P.; Kaushik, P.; Kumar, D.; Kumar, V.; Moulton, B.; Mukherjee, A.; Mukherjee, G.; Myerson, A. S.; Puri, V.; Ramanan, A.; Rajamannar, T.; Reddy, C. M.; Rodríguez-Hornedo, N.; Rogers, R. D.; Row, T. N. G.; Sanphui, P.; Shan, N.; Shete, G.; Singh, A.; Sun, C. C.; Swift, J. A.; Thaimattam, R.; Thakur, T. S.; Kumar Thaper, R.; Thomas, S. P.; Tothadi, S.; Vangala, V. R.; Variankaval, N.; Vishweshwar, P.; Weyna, D. R.; Zaworotko, M. J. Cryst. Growth Des. 2012, 12, 2147−2152. (12) Baldrighi, M.; Cavallo, G.; Chierotti, M. R.; Gobetto, R.; Metrangolo, P.; Pilati, T.; Resnati, G.; Terraneo, G. Mol. Pharmaceutics 2013, 10, 1760−1772. (13) Smith, A. J.; Kavuru, P.; Wojtas, L.; Zaworotko, M. J.; Shytle, R. D. Mol. Pharmaceutics 2011, 8, 1867−1876. (14) Qiao, N.; Wang, K.; Schlindwein, W.; Davies, A.; Li, M. Z. Eur. J. Pharm. Biopharm. 2013, 83, 415−426. (15) Shayanfar, A.; Asadpour-Zeynali, K.; Jouyban, A. J. Mol. Liq. 2013, 187, 171−176. 5850



Article

(51) Abourahma, H.; Urban, J. M.; Morozowich, N.; Chan, B. CrystEngComm 2012, 14, 6163−6169. (52) Mukaida, M.; Sugano, K.; Terada, K. Chem. Pharm. Bull. 2015, 63, 18−24. (53) Alsirawan, M. B.; Vangala, V. R.; Kendrick, J.; Leusen, F. J.; Paradkar, A. Cryst. Growth Des. 2016, 16, 3072−3075. (54) Favre-Nicolin, V.; Cerny, R. J. Appl. Crystallogr. 2002, 35, 734− 743. (55) Laugier, J.; Bochu, B. Chekcell, 2001. (56) Topas Version 5, General Profile and Structure Analysis Software for Powder Diffraction Data (User Manual); Bruker AXS: Karlsruhe, 1999−2014. (57) Hammersley, A. P.; Brown, K.; Burmeister, W.; Claustre, L.; Gonzalez, A.; McSweeney, S.; Mitchell, E.; Moy, J.-P.; Svensson, S. O.; Thompson, A. W. J. Synchrotron Radiat. 1997, 4, 67−77. (58) Heiden, S.; Trö bs, L.; Wenzel, K. J.; Emmerling, F. CrystEngComm 2012, 14, 5128−5129. (59) Eddleston, M. D.; Arhangelskis, M.; Fábián, L.; Tizzard, G. J.; Coles, S. J.; Jones, W. Cryst. Growth Des. 2016, 16, 51−58. (60) Fischer, F.; Greiser, S.; Schmidt, M. U.; Emmerling, F. Acta Crystallogr., Sect. C: Struct. Chem. 2016, 72, 217−224. (61) Aakeröy, C. B.; Beatty, A. M.; Helfrich, B. A. Angew. Chem., Int. Ed. 2001, 40, 3240−3242. (62) Etter, M. C. Acc. Chem. Res. 1990, 23, 120−126. (63) Penfold, B.; White, J. C. Acta Crystallogr. 1959, 12, 130−135. (64) Sim, G.; Robertson, J. M.; Goodwin, T. Acta Crystallogr. 1955, 8, 157−164. (65) Hasa, D.; Schneider Rauber, G. S.; Voinovich, D.; Jones, W. Angew. Chem., Int. Ed. 2015, 54, 7371−7375.

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