Knowing When To Stop—Trapping Metastable Polymorphs in

Article pubs.acs.org/crystal

Knowing When To StopTrapping Metastable Polymorphs in Mechanochemical Reactions Hannes Kulla,†,‡ Sebastian Greiser,† Sigrid Benemann,† Klaus Rademann,‡ and Franziska Emmerling*,† †

Federal Institute for Materials Research and Testing (BAM), Richard-Willstätter-Str. 11, 12489 Berlin, Germany Department of Chemistry, Humboldt-Universität zu Berlin, Brook-Taylor-Str. 2, 12489 Berlin, Germany

‡

S Supporting Information *

ABSTRACT: The cocrystal formation of pyrazinamide (PZA) with malonic acid (MA) was studied in situ. The mechanochemical reaction proceeds via conversion of a crystalline intermediate (PZA:MA II) into the thermodynamically more stable form (PZA:MA I) upon further grinding. The information derived from in situ powder X-ray diffraction (PXRD) enabled the isolation of this new metastable polymorph. On the basis of the PXRD data, the crystal structure of the 1:1 cocrystal PZA:MA II was solved. The polymorphs were further characterized and compared by Raman spectroscopy, solid-state NMR spectroscopy, differential thermal analysis/thermogravimetric analysis, and scanning electron microscopy. Our study demonstrates how monitoring mechanochemical reactions by in situ PXRD can direct the discovery and isolation of even short-lived intermediates not yet accessed by conventional methods.

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INTRODUCTION In the search for improved active pharmaceutical ingredients (APIs), formation of cocrystals and their polymorphs represents an increasingly important approach.1,2 Cocrystals are defined as crystalline materials composed of at least two neutral molecules in the same crystal lattice.3 Their stabilization by non-covalent intermolecular forces such as hydrogen bonds,4,5 π−π stacking,6 or halogen bonds7,8 offers the opportunity to influence physiochemical properties like solubility, bioavailability, and stability without altering the pharmaceutical activity of the API.9−12 Pharmaceutical cocrystals consist of at least one API and an appropriate coformer.13,14 The original assumption that cocrystals may be less prone to polymorphism than their individual components was not confirmed.15−17 Polymorphs are compounds consisting of the same chemical composition but distinct crystal structures.18 These different crystalline forms can differ significantly in their physiochemical properties. Therefore, procedures for producing a variety of polymorphic forms have been established.19−25 In recent years, mechanochemistry has been increasingly exploited for the screening of cocrystals and their polymorphs. This trend can be attributed to the introduction of liquid-assisted grinding (LAG), where small amounts of solvents are added to the reaction mixture.26,27 Under these conditions, the reactions generally proceed faster and the products are more crystalline compared with neat grinding.26,28 Previous studies suggested that the polarity and amount of solvent used during LAG can change the polymorphic outcome.29−32 Despite the intensive research in this area, prediction and crystallization of polymorphs remain a challenge.33−37 The similar crystal energies of polymorphs hamper their isolation in pure form because of spontaneous © 2017 American Chemical Society

interconversion. However, these metastable forms offer great potential for improving solubility and bioavailability.38 To obtain metastable intermediates by grinding, an understanding of the formation pathways is crucial, as this will help to adjust the reaction conditions. First ex situ studies of mechanochemical reactions suggest a stepwise formation process.39−41 However, an interruption of the reaction process is not suitable if reactions proceed quickly or short-lived or air-sensitive intermediates are formed. In comparison to a continuous experiment, different products may be obtained in an interrupted process.42 Recently, in situ setups using powder X-ray diffraction (PXRD) and Raman spectroscopy to study milling syntheses were introduced to prevent these problems. These studies reveal stepwise formation processes via amorphous42−45 or crystalline solids.29,45−47 The products can be formed directly within minutes48 or after a long induction time.49 Monitoring of mechanochemical reactions in real time by situ diffraction reveals new solid forms that are difficult or impossible to access by conventional solution methods.43,50,51 Although cocrystals of the antituberculosis drug pyrazinamide have been well-studied52−54 and four pyrazinamide polymorphs (α−δ) have been described,55,56 only one polymorphic cocrystal with succinic acid has been reported to date.57,58 Herein, an in situ investigation of the grinding reaction of pyrazinamide (PZA) with malonic acid (MA) is presented. The mechanochemical cocrystal formation proceeds via the transformation of a crystalline intermediate (PZA:MA II) into a more stable form (PZA:MA I) upon further grinding. Knowing Received: October 26, 2016 Revised: January 19, 2017 Published: January 20, 2017 1190

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under an Ar/synthetic air flow. For correction of the buoyancy effect, a second heating and cooling cycle performed under the same conditions was subtracted.

the reaction course from in situ PXRD data allowed the metastable Form II to be isolated under laboratory conditions by an adjustment of the reaction time. On the basis of the XRD pattern, the crystal structure of the cocrystal PZA:MA II was solved. Both polymorphs were characterized by Raman spectroscopy, solid-state NMR spectroscopy (ssNMR), differential thermal analysis (DTA) coupled with thermogravimetric (TG) analysis, and scanning electron microscopy (SEM). Slurry experiments confirmed the assignment of the kinetic and thermodynamic products from the in situ reaction process.

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RESULTS AND DISCUSSION Characterization of PZA:MA Cocrystals (1:1). A screening for new cocrystals of pyrazinamide (PZA) and malonic acid (MA) was performed by neat and liquid-assisted grinding with solvents of different polarity (acetone, acetonitrile, diethyl ether, ethanol, n-heptane, and water) and various reactant stoichiometries. Only Form I of the 1:1 cocrystal of PZA:MA that was previously obtained from solution58 was detected in the PXRD patterns after 20 min of grinding at 50 Hz (Figure S1). For this reaction time, neither a change of solvent nor different ratios of reactants led to any new solid form. The cocrystal formation was then studied with in situ PXRD and Raman spectroscopy to discover possible short-lived intermediates. Indeed, a new metastable form was observed in the X-ray powder pattern having reflections distinguishable from those of the already existing 1:1 cocrystal of PZA:MA Form I. With the knowledge from the in situ investigations, we were able to isolate this intermediate and solve the crystal structure from its powder pattern. The PXRD patterns of both forms and of the reactants PZA and malonic acid are shown in Figure 1. The new metastable Form II can be easily distinguished from the known stable Form I in the PXRD patterns.

EXPERIMENTAL SECTION

Materials. Pyrazinamide, C5H5N3O, and malonic acid, C3H4O6, (≥99%) were purchased from Merck (Germany) and used without further purification. Milling Synthesis. The polymorph screening was performed by neat grinding and liquid-assisted grinding in a conventional ball mill (Pulverisette 23, Fritsch) at 50 Hz for 20 min. PZA (542 mg, 1 equiv) and MA (458 mg, 1 equiv) were weighed into a steel jar (10 mL) with two 10 mm steel balls. For LAG experiments, 200 μL of the chosen solvent was added, and the vessel was immediately closed. In order to obtain Form II of the PZA:MA cocrystal, grinding was performed for 2 min at 50 Hz either by adding a polar solvent like ethanol or acetonitrile in a Perspex jar or by neat grinding in a steel vessel. Slurry Experiments. Slurry experiments were conducted to assign the thermodynamically stable polymorph. Therefore, 100 mg of one cocrystal form or a mixture of Form I (50 mg) and Form II (50 mg) was slurried in 1 mL of n-heptane for 3 days. Afterward, the solid phase was separated by filtration and analyzed using PXRD. X-ray Diffraction. Dried products were characterized by PXRD. The measurements were performed on a diffractometer (D8 Discover, Bruker AXS) in transmission geometry (Cu Kα1 radiation, λ = 1.54056 Å). The data were collected in the 2θ range 5−60° using a step size of 0.009°. The structure of PZA:MA Form II was solved using DASH.59 The indexing procedure and the Rietveld refinement of the final structure were conducted with TOPAS.60 Rietveld refinement of the Form II cocrystal powder pattern revealed the presence of ca. 1% pyrazinamide in the sample. CCDC 1491221 contains the supplementary crystallographic data for the 1:1 cocrystal of pyrazinamide:malonic acid Form II. The data can be obtained free of charge from the Cambridge Crystallographic Data Centre via www. cdc.cam.ac.uk/data_request/cif. In situ XRD measurements were performed at the μSpot beamline (BESSY II, Helmholtz Centre Berlin for Materials and Energy). A detailed description of the setup can be found in ref 46 The synthesis was conducted with a conventional ball mill (Pulverisette 23) for 20 min at 50 Hz in a Perspex jar. Every 30 s a PXRD pattern was recorded and processed with FIT2D.61 The obtained scattering vector (q) values were converted to the diffraction angle 2θ (Cu Kα1) to provide a comparison to laboratory XRD experiments. The resulting patterns (2θ vs intensity) were analyzed, plotted, and background-corrected using EVA.62 Spectroscopy. Raman spectra were recorded on a Raman RXN1 analyzer (Kaiser Optical Systems) employing a laser (λ = 785 nm) with an acquisition time of 5 s and five accumulations. The ssNMR measurements were performed on a Bruker AVANCE 600 spectrometer using a MAS probe operating at a speed of 25 kHz. 1 H NMR spectra were recorded with a π/2 pulse length of 2.75 μs, a recycle delay of 300 s, and an accumulation number of 8. For background suppression, an empty rotor was measured. Adamantane (chemical shift 1.78 ppm) was used as a secondary field standard. SEM. SEM experiments were carried out with a ZEISS SUPRA 40 scanning electron microscope (Carl Zeiss AG). The measurements were performed with an acceleration voltage of 10 kV and a working distance between 6.0 mm and 6.1 mm. DTA-TG. DTA-TG measurements were performed on a SETARAM TAG24 thermobalance. Cocrystals were heated at a rate of 10 K/min to 573 K and afterward cooled at 30 K/min in an open Pt crucible

Figure 1. Measured PXRD patterns of PZA:MA Form I and Form II and the corresponding reactants.

A Rietveld refinement of the Form II cocrystal PXRD pattern displayed a minor impurity of 1% pyrazinamide in the sample. The pure isolation was hampered by the very short time window in which all of the reactants are already converted but the metastable form has not yet transformed into the more stable Form I (see Figure 7). However, Form II of the PZA:MA cocrystal can be obtained purely either by neat grinding for 2 min in a steel vessel or by liquid-assisted grinding for 2 min with polar solvents like ethanol or acetonitrile in a Perspex jar at 50 Hz. The crystal structure of the new polymorph is presented in Figure 2. The final Rietveld refinement shows good agreement of the simulated and measured XRD patterns (Figure S2). The PZA:MA Form II cocrystal crystallizes in the triclinic spacegroup P1̅ with Z = 2, a = 11.9379(3) Å, b = 8.28142(15) 1191

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Figure 4. SEM images of PZA:MA I and II powders at different magnifications.

surfaces of Form I seem to be smoother, which may be attributed to the longer milling time. Since hydrogen atom positions cannot be determined absolutely on the basis of PXRD data, the solid forms of PZA:MA were further investigated by ssNMR and Raman spectroscopy to exclude salt formation. The Raman spectra of both polymorphs and the respective reactants appear similar (Figure 5a). However, small shifts in the Raman bands of pyrazinamide at 1025 and 1054 cm−1 that can be assigned to the C−N and C−C stretching vibrations63 are observed in the Raman spectra of the cocrystals (Figure 5b). The polymorphs can be differentiated on the basis of the Raman signal of Form I at 1106 cm−1. Since the Raman bands of the PZA:MA cocrystals are only slightly shifted in comparison to those of pyrazinamide, salt formation can be excluded. This presumption is confirmed by ssNMR measurements, where only minor changes for both forms in comparison to pyrazinamide are revealed (Figure 6). Hence, cocrystal formation of pyrazinamide with malonic acid is likely. In comparison with malonic acid, the carboxylic acid protons in Form II are slightly deshielded from 12.4 to 13.3 ppm. The ssNMR spectrum of Form I contains two signals at 11.7 and 14.3 ppm belonging to the two heterosynthons in the crystal structure of PZA:MA I. Stability and Phase Transformations. To assess the thermodynamically favored polymorph, slurry experiments with n-heptane were conducted. Independent of the form used as the starting material, powder patterns of the dried products only showed the presence of Form I. Therefore, Form I is assumed to be thermodynamically more stable than Form II. However, DTA-TG measurements show no difference in the thermal behaviors of the polymorphs (Figures S3 and S4). Both forms melt at about 113 °C and start to sublime above 150 °C. The polymorphs are monotropically related, as no thermal event was observed below their melting points. A difference in the stability of Form II was noticed depending on the jar material used for the synthesis. While the product obtained in a Perspex jar was stable for at least 1 year, the product synthesized in a steel jar almost completely converted to Form I during the same time (Figure S5). This is probably due to the higher impact of steel compared with Perspex. Apparently, if a certain threshold of energy is exceeded, the conversion to Form I continues slowly in the solid state. The transformation to Form I can be induced by grinding within minutes, as indicated by in situ measurements. Real-Time in Situ Investigation of the PZA:MA Cocrystal. In situ studies were carried out using PXRD

Figure 2. (a) Hydrogen-bonding motif. (b) Structure of the 1:1 PZA:MA Form II cocrystal, viewed along the c axis.

Å, c = 5.38375(13) Å, α = 107.4040(8)°, β = 95.5407(12)°, γ = 96.2522(10)°, and V = 500.165 Å3. Two molecules of PZA and MA form a twisted tetramer (Figure 2a). In this malonic acid forms a homosynthon by means of O−H···O (distance of 2.619 Å) hydrogen-bonding interactions on one side and a hetereosynthon with the amide group of pyrazinamide via N−H···O (distance of 2.757 Å) and O−H···O (distance of 2.760 Å) hydrogen bonds on the other side. The polymorphic forms show different hydrogen-bonding interactions. The crystal structure of Form I was previously described in detail.58 In Form I, one molecule of malonic acid forms two heterosynthons, one with the amide group and another with a second PZA molecule with the aromatic nitrogen. The infinite chains created this way stack into parallel sheets by π−π interactions (Figure 3a). In Form II, tetrameric units are stacked along the a axis in a staggered arrangement (Figure 3b). The crystallite morphologies of the final powders obtained by liquid-assisted grinding with ethanol are depicted in Figure 4. The SEM images indicate cuboid-shaped particles with similar sizes for both polymorphs. Compared with Form II, the particle

Figure 3. (a) 1D chain motif in the PZA:MA I cocrystal. (b) Tetramer arrangement in the PZA:MA II cocrystal. 1192

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Figure 5. (a) Raman spectra of the PZA:MA Form I and Form II cocrystals and the respective reactants. (b) Enhanced image between 980 and 1140 cm−1.

formation is also observed after 30 s as the pyrazinamide bands at 1025 and 808 cm−1 shift to 1021 and 814 cm−1. (Figure S7). On the basis of the Raman signal at 1106 cm−1, the formation of Form I is revealed after 2.5 min. Full conversion can be followed by the decreasing intensity of the Raman band at 1526 cm−1. The difference in reaction times in comparison with the PXRD data can be explained by the fact that Raman spectroscopy is more sensitive than X-ray diffraction, and hence, products may be detected earlier and reactants longer. Nevertheless, the Raman data for the neat grinding reaction progress are in good agreement with the time-resolved powder patterns (Figure S8). The same two-step process observed for liquid-assisted grinding of pyrazinamide with malonic acid was found for neat grinding (Figure 7b), but without the addition of solvent the reaction proceeds much slower. Form II is only formed after 1.5 min (stage 2) and pure between 10.5 and 13.5 min (stage 3). Under neat conditions, full conversion of reactants to Form I takes 16 min in total. This demonstrates how mechanochemical reactions can be accelerated by adding small amounts of solvent.26 However, the time window for pure isolation of Form II is independent of the reaction conditions, which indicates that the reaction is kinetically controlled. Once Form II is formed, recrystallization to the more stable Form I occurs within 2 min. In solution these processes may be even faster, making the detection and isolation of Form II even harder if not impossible. Mechanochemistry may therefore be a suitable method for synthesizing metastable solid forms.43,45,65 In this regard, in situ investigations are a valuable tool for the elucidation of mechanochemical reaction pathways leading to new solid forms by optimizing reaction conditions. Especially metastable forms may otherwise be simply overlooked.

Figure 6. Solid-state NMR spectra of the PZA:MA Form I and Form II cocrystals and the respective reactants.

combined with Raman spectroscopy to evaluate the mechanochemical formation pathway of the PZA:MA polymorphs. Reactants with a total load of 1 g were weighed into a Perspex jar and ground in a ball mill for 20 min at 50 Hz. The timeresolved PXRD results for neat and liquid-assisted grinding of PZA with malonic acid are depicted in Figure 7. Under liquid-assisted grinding conditions, the starting materials (Figure 7a, stage 1) readily convert into a new phase within 30 s (stage 2). After 2 min all of the reactants are consumed, and the PZA:MA cocrystal Form II can be obtained purely (stage 3). However, upon further grinding rapid conversion of the metastable form to the more stable Form I takes place (stage 4). The reaction is complete after 4.5 min, where only reflections belonging to Form I can be observed in the PXRD patterns (stage 5). The purity is confirmed by a Rietveld refinement of the final product (Figure S6). It is therefore not surprising that the polymorph screening with different solvents for a reaction time of 20 min did not result in any new solid form. According to Ostwald’s rule of stages64 Form II can be regarded as kinetically favored and Form I as the thermodynamic product. In the Raman spectra, cocrystal

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CONCLUSION

In the present study, the cocrystal formation of pyrazinamide with malonic acid by grinding in an equimolar ratio was monitored by in situ PXRD and Raman spectroscopy. In situ PXRD data revealed a two-step mechanism in which a metastable phase (Form II) converts quickly into the more stable Form I upon further grinding. The new metastable polymorph was successfully isolated by optimizing the reaction conditions derived from the in situ investigations. The crystal 1193

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Figure 7. Time-resolved powder patterns for (a) liquid-assisted grinding with ethanol and (b) neat grinding of pyrazinamide with malonic acid (molar ratio of 1:1). The diffraction patterns of reactants and products are given below and above the time-resolved diffraction patterns. The development of the phases during the milling process is depicted on the right side.

structure of the 1:1 pyrazinamide:malonic acid Form II cocrystal was solved from powder diffraction data. Salt formation could be excluded because signals in the Raman and solid-state NMR spectra are only slightly shifted in comparison to the reactants. Slurry experiments corroborate the assignment of Form II as the kinetic product and Form I as the thermodynamic product. This is in good agreement with the reaction progress monitored by in situ PXRD. While often the outcome of the reaction can be simply controlled by the choice of solvent, the present study underlines the importance of reaction time. Since this parameter is often only considered in terms of full conversion of reactants, there is a need for timeresolved in situ measurements to fill the gap. In this way, in situ investigations of mechanochemical formation pathways will enable the discovery and isolation of even short-lived intermediates.

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PXRD patterns from neat grinding and LAG experiments, Rietveld refinement of the crystal structure, DTATG measurements, and in situ Raman data for neat and LAG experiments (PDF) Accession Codes

CCDC 1491221 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 e-mailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, U.K.; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Franziska Emmerling: 0000-0001-8528-0301

ASSOCIATED CONTENT

Author Contributions

S Supporting Information *

The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.cgd.6b01572. 1194

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Notes

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The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We are grateful to S. Reinsch for DTA-TG measurements. ABBREVIATIONS API, active pharmaceutical ingredient; DTA-TG, differential thermal analysis and thermogravimetric analysis; PZA, pyrazinamide; LAG, liquid-assisted grinding; MA, malonic acid; MAS, magic-angle spinning; PXRD, powder X-ray diffraction; SEM, scanning electron microscopy; ssNMR, solid-state NMR

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Crystal Growth & Design

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DOI: 10.1021/acs.cgd.6b01572 Cryst. Growth Des. 2017, 17, 1190−1196