Real‐Time In Situ Powder X‐ray Diffraction Monitoring of Mechanochemical Synthesis of Pharmaceutical Cocrystals

Halász, Ivan; Puškarić, Andreas; Kimber, Simon A. J.; Beldon, Patrick J.; Belenguer, Ana M.; Adams, Frank D.; Honkimäki, V.; Dinnebiér, Robert E.; Patel, Bhavnita; Jones, William; Štrukil, Vjekoslav; Friščić, Tomislav

doi:10.1002/ange.201305928

Cited by 41 publications

(25 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Rates of reactant consumption are considerably faster in LAG reactions compared with NG (Table , Figure S5 in the Supporting Information), consistent with the well‐known accelerating effect of liquid additives on mechanochemical reactivity . The alcohols (added in the amount of 10 mol %) show a constant increase in reaction rate constants although LAG with water seems to be slightly faster than LAG with MeOH.…”

Section: Resultssupporting

confidence: 76%

“…Although tandem PXRD and Raman in situ monitoring experiments are readily compared by plotting on the same timescale, quantitative assessment not only provides detailed insight into the species involved in the reaction but also permits its kinetic modeling. Quantitative assessment by PXRD monitoring was possible only in systems in which crystal structures of all participating phases were known, enabling Rietveld refinement, in a similar manner as described previously . Example Rietveld refinement plots are given in the Supporting Information, section S3.…”

Section: Resultsmentioning

confidence: 99%

“…Mechanochemical milling is emerging as a versatile synthesis technique for a variety of chemical transformations, including synthesis and screening of cocrystal forms and polymorphs . Despite the long history of mechanochemistry and the use of milling in various branches of chemical and materials processing, the underlying mechanistic details of these reactions are only now becoming accessible, enabled by the recent development of in situ reaction monitoring techniques based on powder X‐ray diffraction (PXRD), Raman spectroscopy, and a combination of the two .…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Tandem In Situ Monitoring for Quantitative Assessment of Mechanochemical Reactions Involving Structurally Unknown Phases

Lukin

Stolar

Tireli

et al. 2017

Chemistry A European J

Self Cite

View full text Add to dashboard Cite

We report herein quantitative in situ monitoring by simultaneous PXRD and Raman spectroscopy of the mechanochemical reaction between benzoic acid and nicotinamide, affording a rich polymorphic system with four new cocrystal polymorphs, multiple phase transformations, and a variety of reaction pathways. After observing polymorphs by in situ monitoring, we were able to isolate and characterize three of the four polymorphs, most of which are not accessible from solution. Relative stabilities among the isolated polymorphs at ambient conditions were established by slurry experiments. Using two complementary methods for in situ monitoring enabled quantitative assessment and kinetic analysis of each studied mechanochemical reaction, even when involving unknown crystal structures, and short-lived intermediates. In situ Raman monitoring was introduced here also as a standalone laboratory technique for quantitative assessment of mechanochemical reactions and understanding of mechanochemical reactivity. Our results provide an important step toward a complete and high-throughput quantitative approach to mechanochemical reaction kinetics and mechanisms, necessary for the development of the mechanistic framework of milling reactions.

show abstract

Section: Resultssupporting

confidence: 76%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Tandem In Situ Monitoring for Quantitative Assessment of Mechanochemical Reactions Involving Structurally Unknown Phases

Lukin

Stolar

Tireli

et al. 2017

Chemistry A European J

Self Cite

View full text Add to dashboard Cite

show abstract

“…Mechanochemical processes have been investigated on the macroscopic scale, where the spectroscopic signal results from an ensemble of a large number of molecules. For instance, the selective dissociation or bimolecular reactions of polymers and the co-crystallization behaviour of organic (pharmaceutical) compounds under mechanical force have been monitored using mass spectrometry 7 , electron spin resonance spectroscopy 8 , vibrational spectroscopy 9 and X-ray diffraction 10 . However, the detailed mechanisms behind mechanochemical processes remain poorly understood at the molecular level.…”

mentioning

confidence: 99%

Force-induced tautomerization in a single molecule

et al. 2016

View full text Add to dashboard Cite

Heat transfer, electrical potential and light energy are common ways to activate chemical reactions. Applied force is another way, but dedicated studies for such a mechanical activation are limited, and this activation is poorly understood at the single-molecule level. Here, we report force-induced tautomerization in a single porphycene molecule on a Cu(110) surface at 5 K, which is studied by scanning probe microscopy and density functional theory calculations. Force spectroscopy quantifies the force needed to trigger tautomerization with submolecular spatial resolution. The calculations show how the reaction pathway and barrier of tautomerization are modified in the presence of a copper tip and reveal the atomistic origin of the process. Moreover, we demonstrate that a chemically inert tip whose apex is terminated by a xenon atom cannot induce the reaction because of a weak interaction with porphycene and a strong relaxation of xenon on the tip as contact to the molecule is formed

show abstract

“…Next or our interest in fundamental aspects of mechanochemcial reactions where we have studied these reactions by in situ reaction monitoring using synchrotron powder Xray diffraction. [16][17][18] We were also interested if a change of the tautomeric form of each of the hydroxypyridines would occur upon cocrystal (or salt) formation.…”

Section: Introductionmentioning

confidence: 99%

Solid-State Supramolecular Assembly of Salicylic Acid and 2-Pyridone, 3-Hydroxypyridine or 4-Pyridone

et al. 2017

Self Cite

View full text Add to dashboard Cite

Mechanochemical milling of equimolar mixtures of salicylic acid with three hydroxy derivatives of pyridine provided three new phases. With 2-hydroxypyridine, which is in fact present as 2-pyridone, a discrete cocrystal supramolecular assembly is formed. 3-hydroxypyridine and salicylic acid formed a salt and an extended network of hydrogen bonds while the product of the reaction of 4-hydroxypyridine (present as 4-pyridone) and salicylic acid remained structurally uncharacterized. All three hydroxypyridines retain the tautomeric form as in their respective pure phases upon cocrystal formation. Where possible, reaction profiles have been extracted from in situ monitoring via Rietveld refinement to show direct product formation which could be well described using the first-order reaction rate law.

show abstract

Real‐Time In Situ Powder X‐ray Diffraction Monitoring of Mechanochemical Synthesis of Pharmaceutical Cocrystals

Cited by 41 publications

References 47 publications

Tandem In Situ Monitoring for Quantitative Assessment of Mechanochemical Reactions Involving Structurally Unknown Phases

Tandem In Situ Monitoring for Quantitative Assessment of Mechanochemical Reactions Involving Structurally Unknown Phases

Force-induced tautomerization in a single molecule

Solid-State Supramolecular Assembly of Salicylic Acid and 2-Pyridone, 3-Hydroxypyridine or 4-Pyridone

Contact Info

Product

Resources

About