Mechanochemical synthesis and structural characterisation of a theophylline-benzoic acid cocrystal (1 : 1)

Heiden, Sebastian; Tröbs, Lisa; Wenzel, Klaus-Jürgen; Emmerling, Franziska

doi:10.1039/c2ce25236h

Cited by 40 publications

(32 citation statements)

References 19 publications

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“…46,47 In cocrystal preparation, namely theophylline cocrystals, slow evaporation of solvent continues to be the most used technique. 1,[18][19][20][21][23][24][25][26][27][33][34][35]38 Other methods such as neat grinding, 28,48 mixing in a slurry 17,29 and freeze-drying 15 are also possible. Over the past few years Liquid Assisted Grinding (LAG) [6][7][8] has gained some importance in the synthesis of cocrystals, including cocrystals of theophylline.…”

Section: Introductionmentioning

confidence: 99%

X-ray and NMR Crystallography Studies of Novel Theophylline Cocrystals Prepared by Liquid Assisted Grinding

Fernandes

Sardo

Mafra

et al. 2015

Crystal Growth & Design

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Two new cocrystals of, theophylline were pared by liquid assisted grinding. While compound 1 (theophylline:4-aminosalicylic acid 2:1) was characterized by single crystal X-ray diffraction, the crystal structure of compound 2 (theophylline:4-aminobenzoic acid 1:1) was determined by combining. X-ray: powder diffraction (XRPD), solid-state NMR and DFT calculations. The use of 1D/2D H-1 high resolution solid-state NMR techniques provided structural insight on local length scales revealing internuclear proximities and relative orientations between the building blocks of compound 2, thus providing information on the type of hydrogen bond synthons, formed. DFT - calculations were also employed to generate meaningful structures and calculate NMR H-1 and C-13 chemical shifts to further validate the XRPD model. Compound 2 shows an unusual structure, in which the amino groups do not participate in hydrogen bonds, While compound exhibits an extended hydrogen-bonding network, in which planar subunits can be recognized

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Section: Introductionmentioning

confidence: 99%

X-ray and NMR Crystallography Studies of Novel Theophylline Cocrystals Prepared by Liquid Assisted Grinding

Fernandes

Sardo

Mafra

et al. 2015

Crystal Growth & Design

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“…Coffein ist eine bei der Untersuchung von pharmazeutischen Kokristallen häufig verwendete Modellverbindung, die Kokristalle mit Carbonsäuren bildet;100, 101 zugleich gibt es zahlreiche Berichte in der Literatur, dass Coffein keine Kokristalle mit Benzoesäure bildet 102. 103 Zum Beispiel wurden in einer jüngsten Studie die Bemühungen von vier Laboratorien geschildert, diesen schwer fassbaren Kokristall durch Trockenmahlen, flüssigkeitsunterstütztes Mahlen und lösungsvermittelte Phasenumwandlung herzustellen 104. Nachdem alle Versuche erfolglos blieben, wurden CSP‐Verfahren eingesetzt,105, 106 um die mögliche Existenz eines 1:1‐Kokristalls von Coffein und Benzoesäure zu bewerten, mit dem Ergebnis, dass die Bildung dieses Kokristalls thermodynamisch günstig sein sollte.…”

Section: Aktuelle Fälle Von Verschwundenen Polymorphen Und Schwer unclassified

Verschwundene Polymorphe: eine Neubetrachtung

2015

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Vor knapp zwanzig Jahren beschrieben Dunitz und Bernstein eine Auswahl faszinierender Fälle von “verschwundenen” Polymorphen. Der Umstand, dass eine früher einmal hergestellte Kristallform nicht mehr erhalten werden kann, ist natürlich frustrierend und kann zu einem ernsten Problem für den Festkörperchemiker werden. In diesem Aufsatz werden aktuelle Fälle und Beispiele von verschwundenen Polymorphen (sowie das Vorkommen schwer auffindbarer Kristallformen) besprochen, um die fortdauernde Bedeutung dieser oft problematischen und zugleich immer wieder faszinierenden Erscheinung in der Festkörperforschung zu demonstrieren. Einige dieser Fälle standen im Zentrum von Patentstreits. Der Aufsatz beleuchtet daher auch die komplexe Beziehung zwischen Kristallchemie und Rechtsfragen.

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“…Hence, theophylline is a good model molecule to research cocrystal formation and investigate the cocrystallization mechanism. According to the literature, the cocrystals of theophylline have been successfully prepared with several carboxylic acids, such as glutaric acid, oxalic acid, and benzoic acid [10,27,28]. Benzoic acid (BA) occurs naturally in many plants and serves as an intermediate in the biosynthesis of many secondary metabolites [29].…”

Section: Introductionmentioning

confidence: 99%

“…Benzoic acid is a good non-toxic cocrystal coformer because of the carboxyl group in its structure, which can form many kinds of cocrystals with different APIs. The 1:1 theophylline-benzoic acid cocrystal has been reported to be prepared via neat grinding and slow evaporation [27,30]. These two methods are mostly commonly used in cocrystal screening, however are not conducive for robust scaling because of the inherent limitations of the techniques and solution crystallization most widely used to achieve large-scale production of crystals [13,31].…”

Section: Introductionmentioning

confidence: 99%

Preparation of Theophylline-Benzoic Acid Cocrystal and On-Line Monitoring of Cocrystallization Process in Solution by Raman Spectroscopy

et al. 2019

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Pure theophylline-benzoic acid cocrystal was prepared via slurry and cooling crystallization in solution to overcome the disadvantages of existing preparation methods. The target cocrystal was characterized by powder X-ray diffraction (PXRD), thermalgravimetric analysis (TGA), differential scanning calorimetry (DSC) and Raman spectroscopy. The slurry and cooling cocrystallization process in solution was monitored via on-line Raman spectroscopy. The results obtained from on-line Raman monitoring can exhibit the transformation process from raw materials (theophylline and benzoic acid) to cocrystal and show the cocrystal formation rate. Comparing each transformation process under different conditions in slurry crystallization, we found that suspension density of raw materials and temperature both have an impact on the theophylline-benzoic acid cocrystal formation rate. It could be concluded that the cocrystal formation rate increased with the increase of suspension density of raw materials. Further under the same suspension density, higher temperature will accelerate theophylline-benzoic acid cocrystal formation. Meanwhile, various data from the cocrystallization process in cooling crystallization, including nucleation time, nucleation temperature and suitable cooling ending point can be gained from results of on-line Raman monitoring.

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Mechanochemical synthesis and structural characterisation of a theophylline-benzoic acid cocrystal (1 : 1)

Cited by 40 publications

References 19 publications

X-ray and NMR Crystallography Studies of Novel Theophylline Cocrystals Prepared by Liquid Assisted Grinding

X-ray and NMR Crystallography Studies of Novel Theophylline Cocrystals Prepared by Liquid Assisted Grinding

Verschwundene Polymorphe: eine Neubetrachtung

Preparation of Theophylline-Benzoic Acid Cocrystal and On-Line Monitoring of Cocrystallization Process in Solution by Raman Spectroscopy

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