Impact Is ImportantâSystematic Investigation of the Influence of

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Impact Is ImportantSystematic Investigation of the Influence of Milling Balls in Mechanochemical Reactions Franziska Fischer,†,‡ Nicole Fendel,†,‡ Sebastian Greiser,†,‡ Klaus Rademann,†,‡ and Franziska Emmerling*,† †

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

‡

S Supporting Information *

One reliable approach is the collision theory which is based on the statistical nature of the mechanochemical process. Here, the reaction rate as displayed in eq 1 depends on three aspects: the reaction probability at a given mechanical energy impact per contact (Km), the contact probability of the particles within a collision with the milling body per time (P), and the contact area of the different reactants (S).2,35

ABSTRACT: A newly established in situ technique using Raman spectroscopy was employed for the detailed kinetic investigation of mechanochemical reaction pathways. This approach was applied for the systematic investigation of the direct influence of colliding balls on the reaction rate constants of a mechanochemical cocrystallization reaction. As a model reaction, the mechanochemical cocrystallization of felodipine and the coformer imidazole was investigated. Keeping the total ball mass constant by varying the number of milling balls, our study reveals that the impact of each single collision has a more significant influence on the reaction kinetics than expected.

v = K mPS

Parallels were also drawn to high-pressure torsion to evaluate the kinetics of the milling reaction.2 Delogu established a connection between milling and high-pressure torsion. The concept describes individual collisions. Delogu proposed that the powder experiences the same conditions as under highpressure torsion at one collision.36,37 Under high-pressure torsion the whole sample encounters the same pressure and temperature conditions. During grinding, the milling balls hit only a small fraction of the sample. The milling synthesis is therefore a statistic and discontinuous process.38,39 Delogu also assumed that in a mechanochemical reaction the kinetics is defined by the number of impacts of the balls. The typical collision proceeds in about 1 ms, whereas the transformation induced by mechanical stress takes place in about 10 ns.40−44 Consequently, the reaction is finished before the collision is completed. However, according to Delogu, the transformation occurs only when the milling balls have a minimal energy to induce the mechanically activated reaction.2 Stolle and Takacs contributed substantially by investigating the effect of milling parameters on organic and inorganic reactions.45,46 Focusing on the reaction yield or the jar temperature, Stolle identified the milling frequency, the milling time, the size and number of milling balls, and the grinding material as crucial factors on the formation of the product.47−49 Recently, experimental setups were introduced by us and others for in situ monitoring of grinding reactions in conventional ball mills under real conditions.50−52 With respect to the understanding of mechanochemical kinetics, this setup marks a break-through experiment in mechanochemistry, since the formation pathways of the reactions can be elucidated. The development of the in situ monitoring with Raman spectroscopy and X-ray diffraction of mechanochemical reaction is the basis for a better understanding of the fundamental

M

echanochemistry is evolving into a highly popular synthesis approach in different areas.1−4 The charm of this green, facile, and widely applicable method relying simply on grinding material in suitable mortars or mills has attracted materials scientists, chemists, physicists, and pharmacists.5−9 In pharmaceutical research, mechanochemically synthesized cocrystals are intensively studied.10−15 Cocrystals are multicomponent crystalline phases consisting of organic, uncharged molecules. These compounds comprise typically an active pharmaceutical ingredient (API) and a so-called cofomer. Via cocrystallization a new crystal lattice is formed. It is stabilized by intermolecular forces including hydrogen bonds, halogen bonds, or π−π-stacking.16−20 New crystal structures lead also to new physicochemical properties such as solubility and physical or chemical stability. Therefore, cocrystals are of interest in pharmacy and agriculture, since the water solubility of an active substance can be altered in a customized way.21−25 For these reactions, ball mills are used, in which the mechanical force is provided by the impact of steel or ceramic balls on the material in the milling jar.2 The reaction conditions can be altered either by grinding solid compounds (neat grinding) or by adding small amounts of liquids to the reaction mixture (liquid assisted grinding, LAG). In contrast to the popularity and success of mechanochemical syntheses, progress in understanding selective reaction pathways is lacking. This understanding is a prerequisite for the rational syntheses of novel compounds. Most difficult is the prediction and the description of the reaction kinetics during the milling synthesis. Mechanochemical kinetics and mechanisms were thoroughly investigated; nevertheless, a general applicable model has not been found yet.26−34 © 2017 American Chemical Society

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Received: December 21, 2016 Published: March 17, 2017 655

DOI: 10.1021/acs.oprd.6b00435 Org. Process Res. Dev. 2017, 21, 655−659

Organic Process Research & Development

Communication

mechanisms and kinetics during the milling process.51 Based on the time-resolved in situ data the formation pathways, mechanism, reaction rate constants, and the apparent activation energy of the synthesis become available.53−56 In this study, we combine the systematic investigation of milling parameters with the new in situ Raman technique for a detailed understanding of the milling process. We explore the influence of the number of milling balls on the reaction rate constants. It should be elucidated whether the number of impacts is a rate-determining factor for the kinetics of the reaction. A cocrystal of the API felodipine (fel) and the coformer imidazole (imi) serves as suitable model system, since it is obtained via neat grinding and the Raman signals of the individual reactants and the cocrystal are clearly distinguishable. The mechanochemical formation under real conditions was followed by in situ Raman spectroscopy. The data allow determining the ball-depending reaction rate constants of the cocrystallization reaction. The individual mass of the milling balls was varied in different syntheses, whereas the overall mass of the milling balls was kept constant by adjusting the number of balls. Based on these conditions, the total energy impact on the whole sample was equal in each single milling experiment. The individual mass of the milling balls turned out to be directly proportional to the reaction rate constants. Figure 1 shows the X-ray powder diffraction (XRPD) patterns of the cocrystal and the respective reactants. After milling the reactants in an equimolar ratio for 30 min at 50 Hz with two steel balls (each 4 g in mass, 10 mm in diameter,

standard parameters) in a ball mill (Pulverisette 23, Fritsch, Germany), the XRPD pattern of the product shows no residuals of the reactants in the powder pattern. Based on the powder data of the felodipine−imidazole (fel:imi) cocrystal the crystal structure was solved and refined (Figure S1). The compound crystallizes in the space group P1̅ (Figure 2) and is

Figure 2. (a) Structure motif of the fel:imi cocrystal showing the hydrogen bonds (green dashed lines), (b) crystal structure along the aaxis. The hydrogen atoms not involved in hydrogen bonding have been omitted for clarity. (c) Raman signals chosen for the kinetic evaluation of the mechanochemical cocrystallization of fel (blue) and imi (red).

stabilized via two hydrogen bonds (see SI). The crystallographic data of the cocrystal are summarized in Table S1. Based on Raman and solid-state NMR spectroscopy data (Figure S3), a salt formation can be excluded, and the cocrystal contains only neutral molecules. As expected, the melting point of the cocrystal (127.5 °C) ranges between the melting points of the pure reactants (Figures S4−S6). The formation pathway of the fel:imi cocrystal was investigated by in situ Raman spectroscopy. For the synthesis a transparent grinding jar (Perspex) was used. Typically, the syntheses were conducted in a ball mill (Pulverisette 23, Fritsch, Germany) at 50 Hz for 30 min. Raman spectra were recorded every 30 s with an acquisition time of 5 s and five accumulations during the milling process. The spectra reveal a continuous cocrystallization process of fel and imi without any

Figure 1. (a) Powder X-ray diffraction patterns and (b) Raman spectra of the felodipine−imidazole (fel:imi) cocrystal and the reactants. 656



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intermediate. The Raman bands selected for the kinetic analysis of the mechanochemical cocrystallization process were carefully chosen to avoid superimposition of the spectra of the reactants among each other and with those of the Perspex jar. The most suitable Raman signals occur at 1484, 1620, and 1703 cm−1. The latter can be attributed to the carbonyl stretching of the ethyl ester of fel, whereas the signal at 1620 cm−1 is caused by the CC vibration within the dihydropyridine ring. The signal at 1484 cm−1 is attributed to the C−H deformation of fel.57−59 The intensities of the selected Raman signals decrease with a prolonged milling time (Figure 3a). Plotting the intensities in

Table 1. Specification of the Milling Balls Used in the in Situ Investigation of the Cocrystallization of fel and imia milling balls number

single mass (g)

diameter (mm)

k (min−1)

s.d. (min−1)

2 6 16 32 236

4 1.38 0.5 0.25 0.034

10 7 5 4 2

0.24 0.04 0.028 0.0026 0.0018

0.04 0.02 0.007 0.0008 0.0006

a

Experimentally determined reaction rate constants (k) for different milling balls (s.d. = standard deviation).

balls. Based on the experimental setup, a decreasing number of balls was used with increasing mass of an individual ball, which means that the number of balls and consequently the number of collisions decrease (Figure 4, Figure 4a with a logarithmic scale is illustrated in Figure S8.). The collision number depends on two aspects: the milling frequency (which was kept constant at 50 Hz) and the number of milling balls. These results are in contrast with those of Stolle et al. The authors have shown that the mechanochemical synthesis of 5-arylidene barbituric acid derivates leads to higher yields using smaller milling balls.48 This comparison elucidates that the reaction kinetics have to be regarded separately from the reaction yield. (B) Our results reveal also that not only the number of collisions determines the kinetics of the mechanochemical reaction, but also the energetic impact per collision. Until now, it was supposed that every impact with a critical energy activates the mechanochemical transformation.2 However, our results show that the reaction gets faster with an increasing energy input per collision. More precisely, the reaction rate constant k and the mass of the single balls msingle are proportional under the condition that the total mass of all balls is constant (eq 2). k ∝ msingle

(2)

In conclusion, one collision with a high energy impact leads to a faster reaction than two collisions with each the half mass of the first one. The energy impact and the number of collisions are not related linearly. This effect can also be connected to the heat development during the milling process. Larger milling balls with a higher mass probably lead to a reinforced temperature rise within the milling jar as compared to smaller milling balls.47 In a recent study we could show that the temperature of the jar plays a critical role for the kinetics of a mechanochemical reaction. Even small variations of the environmental temperature cause noticeable changes of the reaction rate constants.55,60 Although the reaction rate constants decrease rapidly with lighter milling balls, no critical mass could be determined at which no transformation was activated. Ultimately, accepting a long milling period, a successful synthesis seems possible without any milling balls. Here, the crystallites of the reactants act as milling balls themselves. Our study underlines the potential of in situ Raman investigations for elucidating the kinetics of mechanochemical reactions. Here, the mechanochemical cocrystallization of fel and imi was chosen as a model reaction. For the first time, we could demonstrate that the energy input of a single collision during mechanochemical reactions has a higher influence than the number of collisions.

Figure 3. (a) Raman spectra recorded during the mechanochemical cocrystallization of fel with imi with 16 milling balls (each 0.5 g). The Raman signals at 1484, 1620, and 1703 cm−1 were chosen to monitor the progress of the reaction (assignment see text). The signal at 1725 cm−1 can be attributed to the Perspex jar. (b) Plot of the Raman intensities according to a first-order reaction of the Raman band at 1484 cm−1. A comparison with the plots of the Raman bands at 1620 and 1703 cm−1 is depicted in Figure S7.

accordance to a first-order reaction led to a good fit (Figure 3b). The slope is equivalent to the rate constant of the cocrystallization reaction. In the following, the reaction was conducted with different milling balls differing in single mass and size. In order to keep the total mass of the milling balls constant at 8 g, the amount of balls was adjusted (Table 1). The total ball mass was chosen for a direct comparison to the standard parameters. While the other reaction parameters were kept constant, it is possible to measure the direct influence of the impact of each collision on the reaction rate constants. Each experiment was repeated six times. The following two major results were obtained. (A) The cocrystal reaction proceeds faster with larger, heavier milling 657



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Figure 4. Determined reaction rate constants of the mechanochemical cocrystallization of fel with imi in dependence of (a) the single masses of the milling balls and (b) the number of milling balls (which is connected to the number of collisions during grinding).

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(13) Frišcǐ ć, T.; Jones, W. Cryst. Growth Des. 2009, 9, 1621. (14) Braga, D.; Maini, L.; Grepioni, F. Chem. Soc. Rev. 2013, 42, 7638. (15) Tan, D.; Loots, L.; Friscic, T. Chem. Commun. 2016, 52, 7760. (16) 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. (17) Aakeröy, C. B.; Fasulo, M. E.; Desper, J. Mol. Pharmaceutics 2007, 4, 317. (18) Etter, M. C.; Frankenbach, G. M. Chem. Mater. 1989, 1, 10. (19) Frišcǐ ć, T.; Jones, W. J. Pharm. Pharmacol. 2010, 62, 1547. (20) Zaworotko, M. J. Cryst. Growth Des. 2007, 7, 4. (21) McNamara, D. P.; Childs, S. L.; Giordano, J.; Iarriccio, A.; Cassidy, J.; Shet, M. S.; Mannion, R.; O’Donnell, E.; Park, A. Pharm. Res. 2006, 23, 1888. (22) Good, D. J.; Rodríguez-Hornedo, N. Cryst. Growth Des. 2009, 9, 2252. (23) Trask, A. V.; Motherwell, W. D. S.; Jones, W. Int. J. Pharm. 2006, 320, 114. (24) Trask, A. V.; Motherwell, W. D. S.; Jones, W. Cryst. Growth Des. 2005, 5, 1013. (25) Chieng, N.; Hubert, M.; Saville, D.; Rades, T.; Aaltonen, J. Cryst. Growth Des. 2009, 9, 2377. (26) Thiessen, P. A.; Meyer, K.; Heinicke, G. Grundlagen der Tribochemie; Akademie-Verlag: Berlin, 1967. (27) Boldyrev, V. V.; Avvakumo, E.; Gusev, G. M. Dokl. Akad. Nauk SSSR 1969, 184, 119. (28) Kaupp, G.; Naimi-Jamal, M. R. CrystEngComm 2005, 7, 402. (29) Bowden, F. P.; Tabor, D. The friction and lubrication of solids; Clarendon Press: Oxford, 1958. (30) Bowden, F. P.; Yoffe, A. D. Fast reactions in solids; Academic Press: New York, 1958. (31) Boldyrev, V. V. Powder Technol. 2002, 122, 247. (32) Urakaev, F. K.; Boldyrev, V. V. Powder Technol. 2000, 107, 93. (33) Urakaev, F. K.; Boldyrev, V. V. Powder Technol. 2000, 107, 197. (34) Boldyrev, V. V.; Tkacova, K. J. Mater. Synth. Process. 2000, 8, 121.

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.oprd.6b00435. Experimental data, powder diffraction, and NMR and Raman data (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Klaus Rademann: 0000-0003-3084-3917 Franziska Emmerling: 0000-0001-8528-0301 Notes

The authors declare no competing financial interest.

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ABBREVIATIONS API, active pharmaceutical ingredient; fel, felodipine; imi, imidazole; LAG, liquid-assisted grinding; NMR, nuclear magnetic resonance; s.d., standard deviation; XRPD, X-ray powder diffraction

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REFERENCES

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