Prediction of mefenamic acid crystal shape by random forest classification

Purpose: This study describes the development and application of machine-learning models to the prediction of the crystal shape of mefenamic acid recrystallized from organic solvents. Method: Mefenamic acid crystals were grown in 30 different solvents and categorized according to crystal shape as either polyhedral or needle. A total of 87 random forest classification models were trained on this data. Initially, 3 models were built to assess the efficacy of this method. These models were trained on datasets containing Molecular Operating Environment (MOE) descriptors for the solvents and crystal shapes labels obtained by visual inspection of microscope images. The subsequent 84 models tested prediction accuracy for individual solvents that were sequentially excluded from the model training sets. In total, three different sets of MOE descriptors (one set that contained all available 2D descriptors, a second set that focused on molecular structure and a third set that focused on physical properties) were investigated to determine which of these three sets of descriptors resulted in the highest overall prediction accuracy across the different solvents. Results: For the initial three models, the highest prediction accuracy of crystal shape observed was 93.5% as assessed by 4-fold cross-validation. When solvents were sequentially excluded from training data, 32 out of 84 models predicted the shape of mefenamic acid crystals for the excluded solvent with 100% accuracy and a further 21 models had prediction accuracies from 50-100%. Reducing the feature set to only solvent physical property descriptors and supersaturations resulted in higher overall prediction accuracies than the models using atom count, bond count, and pharmacophore descriptors and the models using all solvent molecular descriptors. For the 8 solvents on which the models performed poorly (<50% accuracy), further characterisation of crystals grown in these solvents resulted in the discovery of a new mefenamic acid solvate. However, all other crystals were the previously known form I. Conclusion: Random forest classification models using solvent physical property descriptors can reliably predict crystal morphologies for mefenamic acid crystals grown in 20 out of the 28 solvents included in this work. Poor prediction accuracies for the remaining 7 solvents may be an indication that the factors not adequately covered by the training data result in these solvents being outliers

Crystal Structure and Twisted Aggregates of Oxcarbazepine Form III

Polymorphism and crystal habit play vital roles in dictating the properties of crystalline materials. Here, the structure and properties of oxcarbazepine (OXCBZ) form III are reported along with the occurrence of twisted crystalline aggregates of this metastable polymorph. OXCBZ III can be produced by crystallization from the vapor phase and by recrystallization from solution. The crystallization process used to obtain OXCBZ III is found to affect the pitch, with the most prominent effect observed from the sublimation-grown OXCBZ III material where the pitch increases as the length of aggregates increases. Sublimation-grown OXCBZ III follows an unconventional mechanism of formation with condensed droplet formation and coalescence preceding nucleation and growth of aggregates. A crystal structure determination of OXCBZ III from powder X-ray diffraction methods, assisted by crystal structure prediction (CSP), reveals that OXCBZ III, similar to carbamazepine form II, contains void channels in its structure with the channels, aligned along the c crystallographic axis, oriented parallel to the twist axis of the aggregates. The likely role of structural misalignment at the lattice or nanoscale is explored by considering the role of molecular and closely related structural impurities informed by crystal structure prediction

Philosophie für Kinder als Zuhören. Vermeidung von Fallstricken der Instrumentalisierung

Since its inception in the seventies, philosophy for children (P4C) curricula have been under attack from various sides. As Maughn Gregory points out in his paper dealing with various criticisms, P4C attracted “overlapping and conflicting criticism” from religious and social conservatives to educational psychologists, philosophers, and critical theorists (Gregory 2011, 199). Conservative criticism of P4C often goes against the grain of philosophy and liberal education in general and can probably be seen as an age-old dispute constantly resurfacing against the effort of philosophers, while psychologists’ arguments that philosophical thinking is beyond children of certain age are today easily refuted by the work of Kieran Egan (2002) and Alison Gopnik (2009). Critical theorists’ critique, however, seems to go deeper than all other criticisms by raising intellectually pertinent problem of philosophy education: that instead of fulfilling its promise of liberating subjects it in fact interpellates them into free market ideology. As Gert Biesta (2011) tries to show, P4C curricula “are supposed to develop a range of skills, including cognitive and thinking skills, moral and social skills, and democratic skills” (Ibid. 310) and thereby instrumentalize philosophy in order to achieve a certain goal, a dubious and alarming undertaking that “can be characterized as ideological” (Ibid. 309). In order for P4C to tackle this problem of instrumentalization of philosophy (raised also in Vansieleghem (2005)) the present paper suggests that P4C curricula should be seen (and in certain cases reformed) as promoting a Socratic dialogue with children, whereby the emphasis lies on listening to a child and giving her a voice, and not on “teaching skills”. This paper thus argues that it is precisely through philosophical dialogue that a child can be heard as a child, since such a dialogue intrinsically presupposes recognition of the conversational partner as an equal interlocutor. P4C curricula can thus be regarded as an important part of emerging field of “Pedagogy of Listening” (cf. Rinaldi 2001).Od zasnivanja u 70-im godinama 20. stoljeća, kurikulum filozofije za djecu bio je napadnut s raznih strana. Kao što Maughn Gregory ističe u njegovom članku o tim kritikama, filozofija za djecu privukla je »preklapajuće i proturječne kritike« od religijskih i društvenih konzervativaca do edukacijskih psihologa, filozofa i kritičkih teoretičara (Gregory 2011, 199). Konzervativna kritika filozofije za djecu često ide protiv struje filozofije i liberalnog obrazovanja općenito te se može promatrati kao stari spor koji se konstantno pojavljuje unatoč naporu filozofa, dok se argumenti psihologa da filozofijsko mišljenje nije moguće kod djece određene dobi danas lako pobijaju istraživanjima Kierana Egana (2002) i Alison Gopnik (2009). S druge strane, čini se da kritika kritičkih teoretičara seže dublje nego druge jer razmatra intelektualno relevantan problem filozofskog obrazovanja: umjesto da ispuni svoje obećanje da će osloboditi subjekte, ustvari ih interpelira u ideologiju slobodnog tržišta. Kao što Gert Biesta nastoji pokazati, kurikuli filozofije za djecu »trebaju razviti spektar vještina, uključujući kognitivne vještine i vještine mišljenja, moralne i društvene vještine te demokratske vještine« (Biesta 2011, 310) te na taj način instrumentaliziraju filozofiju da bi postigli određeni cilj, što je dvojben i alarmantan pothvat koji se »može okarakterizirati kao ideološki« (ibid., 309). Da bi se uhvatilo u koštac s problemom instrumentalizacije filozofije (o čemu raspravlja i Vansieleghem (2005)), ovaj rad sugerira da kurikuli filozofije za djecu trebaju promovirati sokratski dijalog s djecom (te u nekim slučajevima biti reformirani u tom smjeru), gdje se naglasak stavlja na slušanje djeteta te davanje glasa, a ne na »nastavne vještine«. Ovaj rad stoga tvrdi da upravo kroz filozofski dijalog dijete može biti saslušano kao dijete, jer takav dijalog intrinzično pretpostavlja prepoznavanje partnera u razgovoru kao ravnopravnog sugovornika. Tako se kurikuli filozofije za djecu mogu smatrati važnim dijelom rastućeg polja »pedagogije slušanja« (v. Rinaldi 2001).Depuis sa création dans les années 70, le programme éducatif de philosophie a été attaqué de divers côtés. Comme le souligne Maughn Gregory dans son article consacré à ces critiques, la philosophie pour les enfants a attiré des « critiques qui s’imbriquent et se contredisent », partant des conservateurs religieux et sociaux et allant jusqu’aux psychologues de l’éducation, philosophes et théoriciens critiques (Gregory 2011, 199). La critique conservatrice de la philosophie pour les enfants va souvent à l’encontre du courant de la philosophie et de l’éducation libérale en général et peut être vue comme un vieux conflit qui réapparait constamment malgré l’effort des philosophes, bien que les arguments du psychologue, selon lesquelles une pensée philosophique chez les enfants d’un certain âge n’est pas possible, aient été facilement réfutés par les recherches de Kieran Egan (2002) et Alison Gopnik (2009). Toutefois, il semblerait que la critique des théoriciens critiques va plus loin que les autres car elle met en avant un problème intellectuellement pertinent pour l’éducation philosophique : au lieu de tenir sa promesse en vue de la libération des sujets, elle interpelle à vrai dire ces mêmes sujets au sein d’une idéologie de marché libre. À la manière dont Gert Berta tente de le montrer, les programmes éducatifs de philosophie pour les enfants «sont supposés mettre en oeuvre un éventail de compétences, comportant des compétences cognitives et des compétences de la pensée, des compétences morales et sociales, et des compétences démocratiques » (Biesta 2011, 310). Ainsi, ces programmes instrumentalisent la philosophie pour arriver à leurs fins, entreprise douteuse et alarmante « qui peut être caractérisée d’idéologique » (Ibid, 309). Afin de s’attaquer au coeur du problème de l’instrumentalisation de la philosophie (problème également abordé par Vansieleghem (2005)), ce travail suggère que les programmes de philosophie pour les enfants promeuvent les dialogues socratiques avec les enfants (et, dans certains cas, soient réformés en vue de cette voie), dialogues où l’accent est mis sur l’écoute de l’enfant et sur le fait de lui donner la parole, et non sur les « compétences de l’enseignement ». Par là, ce travail stipule que c’est précisément à travers un dialogue philosophique que l’enfant peut être entendu en tant qu’enfant car un dialogue de la sorte suppose de manière intrinsèque la reconnaissance du partenaire dans la conversation comme interlocuteur égal. Ainsi, les programmes éducatifs peuvent être perçus comme une partie importante du domaine émergeant de « la pédagogie de l’écoute » (v. Rinaldi 2001).Seit ihrer Einführung in den Siebzigerjahren waren die Curricula der Philosophie für Kinder (PfK) von verschiedenen Seiten her den Angriffen ausgesetzt. Wie Maughn Gregory in seinem Artikel über die unterschiedlichen Kritiken darauf hinweist, zog die PfK „eine sich überlappende und widersprüchliche Kritik“ auf sich, von Religions- und Sozialkonservativen bis zu pädagogischen Psychologen, Philosophen und kritischen Theoretikern (Gregory 2011, 199). Die konservative Kritik an der PfK schwimmt oftmals gegen den Strom der Philosophie und der liberalen Erziehung im Allgemeinen und kann vermutlich als ein uralter Disput angesehen werden, der trotz der Bemühungen der Philosophen andauernd auftaucht, während die Argumente der Psychologen, das philosophische Denken sei für Kinder im bestimmten Alter unbegreiflich, heutzutage leicht durch das Werk von Kieran Egan (2002) und Alison Gopnik (2009) widerlegt werden. Die Kritik der kritischen Theoretiker scheint andererseits tiefer zu reichen als alle anderen Kritiken, indem sie ein intellektuell relevantes Problem der Philosophieerziehung anschneidet: dass sie, statt ihr Versprechen der Befreiung der Subjekte einzuhalten, sie in der Tat in die Ideologie des freien Markts einfügt. Wie Gert Biesta (2011) zu zeigen versucht, „sollen“ die Curricula der PfK „eine Reihe von Fertigkeiten entwickeln, einschließlich der kognitiven und Denkfertigkeiten, der moralischen und sozialen Fertigkeiten sowie der demokratischen Fertigkeiten“ (ebd., 310), und instrumentalisieren dadurch die Philosophie, um ein bestimmtes Ziel zu erreichen, was ein fragwürdiges und alarmierendes Unternehmen ist, das „sich als ideologisch charakterisieren lässt“ (ebd., 309). Damit die PfK dieses Problem der Instrumentalisierung der Philosophie in Angriff nimmt (erörtert auch von Vansieleghem (2005)), schlägt der vorliegende Artikel vor, die Curricula der PfK (in bestimmten Fällen in dieser Richtung reformiert) sollten den sokratischen Dialog mit Kindern fördern, wobei der Schwerpunkt darin liege, dem Kind zuzuhören und die Stimme zu geben, und nicht in den „Lehrfertigkeiten“. Aufgrund dessen argumentiert diese Arbeit, gerade durch den philosophischen Dialog könne ein Kind als Kind gehört werden, da ein solcher Dialog intrinsisch die Anerkennung des Gesprächspartners als eines gleichberechtigten Gesprächsteilnehmers voraussetze. Die Curricula der PfK können demnach als ein wichtiger Teil des aufstrebenden Felds der „Pädagogik des Zuhörens“ betrachtet werden (vgl. Rinaldi 2001)

Crystal structure and twisted aggregates of oxcarbazepine form III

Polymorphism and crystal habit play vital roles in dictating the properties of crystalline materials. Here, the structure and properties of oxcarbazepine (OXCBZ) form III are reported along with the occurrence of twisted crystalline aggregates of this metastable polymorph. OXCBZ III can be produced by crystallization from the vapor phase and by recrystallization from solution. The crystallization process used to obtain OXCBZ III is found to affect the pitch, with the most prominent effect observed from the sublimation-grown OXCBZ III material where the pitch increases as the length of aggregates increases. Sublimation-grown OXCBZ III follows an unconventional mechanism of formation with condensed droplet formation and coalescence preceding nucleation and growth of aggregates. A crystal structure determination of OXCBZ III from powder X-ray diffraction methods, assisted by crystal structure prediction (CSP), reveals that OXCBZ III, similar to carbamazepine form II, contains void channels in its structure with the channels, aligned along the c crystallographic axis, oriented parallel to the twist axis of the aggregates. The likely role of structural misalignment at the lattice or nanoscale is explored by considering the role of molecular and closely related structural impurities informed by crystal structure prediction

Successful computationally directed templating of metastable pharmaceutical polymorphs

A strategy of using crystal structure prediction (CSP) methods to determine which, if any, isostructural template could facilitate the first crystallization of a predicted polymorph by vapor deposition is extended to the fenamate family. Mefenamic acid (MFA) and tolfenamic acid (TFA) are used as molecules with minimal chemical differences, whereas flufenamic acid (FFA) shows greater differences in the substituents. The three crystal energy landscapes were calculated, and periodic electronic structure calculations were used to confirm the thermodynamic plausibility of possible isostructural polymorphs to experimentally obtainable crystals of the other molecules. As predicted, a new polymorph, TFA form VI, was found by sublimation onto isomorphous MFA form I, using a recently developed technique. MFA and TFA form a continuous solid solution with the structure of MFA I and TFA VI at the limits, but the isomorphous MFA/FFA solid solution does not extended to a new polymorph of FFA. The novel solid solution structure of TFA and FFA was found, and a new isomorphous polymorph TFA VII was found by sublimation onto this new solid solution template. Sublimation of TFA onto a metal surface at the early stage of deposition gave TFA form VIII. We rationalize the formation of new polymorphs of only TFA

Enabling precision manufacturing of active pharmaceutical ingredients: workflow for seeded cooling continuous crystallisations

Continuous manufacturing is widely used for the production of commodity products. Currently, it is attracting increasing interest from the pharmaceutical industry and regulatory agencies as a means to provide a consistent supply of medicines. Crystallisation is a key operation in the isolation of the majority of pharmaceuticals and has been demonstrated in a continuous manner on a number of compounds using a range of processing technologies and scales. Whilst basic design principles for crystallisations and continuous processes are known, applying these in the context of rapid pharmaceutical process development with the associated constraints of speed to market and limited material availability is challenging. A systematic approach for continuous crystallisation process design is required to avoid the risk that decisions made on one aspect of the process conspire to make a later development step or steps, either for crystallisation or another unit operation, more difficult. In response to this industry challenge, an innovative system-wide approach to decision making has been developed to support rapid, systematic, and efficient continuous seeded cooling crystallisation process design. For continuous crystallisation, the goal is to develop and operate a robust, consistent process with tight control of particle attributes. Here, an innovative system-based workflow is presented that addresses this challenge. The aim, methodology, key decisions and output at each at stage are defined and a case study is presented demonstrating the successful application of the workflow for the rapid design of processes to produce kilo quantities of product with distinct, specified attributes suited to the pharmaceutical development environment. This work concludes with a vision for future applications of workflows in continuous manufacturing development to achieve rapid performance based design of pharmaceuticals

Tautomerism unveils a self-inhibition mechanism of crystallization

Modifiers are commonly used in natural, biological, and synthetic crystallization to tailor the growth of diverse materials. Here, we identify tautomers as a new class of modifiers where the dynamic interconversion between solute and its corresponding tautomer(s) produces native crystal growth inhibitors. The macroscopic and microscopic effects imposed by inhibitor-crystal interactions reveal dual mechanisms of inhibition where tautomer occlusion within crystals that leads to natural bending, tunes elastic modulus, and selectively alters the rate of crystal dissolution. Our study focuses on ammonium urate crystallization and shows that the keto-enol form of urate, which exists as a minor tautomer, is a potent inhibitor that nearly suppresses crystal growth at select solution alkalinity and supersaturation. The generalizability of this phenomenon is demonstrated for two additional tautomers with relevance to biological systems and pharmaceuticals. These findings offer potential routes in crystal engineering to strategically control the mechanical or physicochemical properties of tautomeric materials

Prediction of mefenamic acid crystal shape by random forest classification

Research problem: Crystal shape is one of the key attributes affecting the bulk particle properties of a crystalline material as well as its downstream manufacturability1. However, the prediction of experimental crystal shapes remains very challenging. This research aims to explore the potential application of machine learning algorithms to solve this problem

Reversible, two-step single-crystal to single-crystal phase transitions between desloratadine forms I, II, and III

Single-crystal to single-crystal polymorphic transformations in molecular solids are relatively rare, with changes in crystal structure more commonly leading to destruction of the parent crystal. However, the structural basis for such transitions is of considerable interest given the changes in material properties that can result. The antihistamine desloratadine displays a two-step, reversible single-crystal to single-crystal phase transition during heating/cooling cycles between three conformational polymorphs: the low temperature form I, a polytypic intermediate form II, and the high temperature form III. The two-step transition involves a sequential flipping of the piperidine rings of desloratadine molecules in the crystals, which induce reversible micrometer-scale contraction on heating and expansion on cooling of the largest face of a desloratadine single crystal. Distinct, slow-moving phase boundaries, originating on the (001) face of the crystal, were observed sweeping through the entire crystal in hot-stage microscopy, suggesting a single nucleation event. Computational spectroscopy, using periodic DFT-D phonon calculations, reproduces the experimental variable-temperatureTHz-Raman spectra and rules out the possibility of the phase transformations occurring via any classical soft mode. A combination of variable-temperature powder X-ray diffraction, solid-state NMR, and computational spectroscopy provides a detailed molecular description of the phase transitions, indicating a first-order diffusionless process between I → II and II → III, wherein both conformational changes and lattice distortions occur simultaneously in the crystal lattice. The study indicates that a nucleation and growth mechanism is compatible with concerted movements producing a conformational change in organic molecular crystals