What Has Carbamazepine Taught Crystal Engineers?

The antiepilepsy drug carbamazepine is one of the most studied pharmaceuticals in the world. The rich story of its solid forms, cocrystals, and formulation is a microcosm of the topical world of pharmaceutical materials. Understanding carbamazepine has required time, money, and dedication from numerous researchers and pharmaceutical companies worldwide. This wealth of knowledge provides the opportunity to reflect on progress within the crystal engineering field in general. This Perspective covers the extensive solid form landscape of carbamazepine and applies these examples to discuss and answer fundamental questions in the discipline. The story encompasses screening methods, computational solid form discovery, the power and influence of crystal engineering in understanding and controlling crystals and the amorphous state, and the environmental legacy of modern pharmaceuticals. This broad but in-depth analysis of carbamazepine is a vehicle into modern crystal engineering, not only in its own right but across the spectrum of organic materials science and pharmaceutical formulation. Discoveries of carbamazepine demonstrate the potential richness in the materials chemistry of every drug

A to Z of polymorphs related by proton transfer

The occurrence of tautomeric polymorphism in the Cambridge Structural Database (CSD) was established to be very rare in a previous study by A. J. Cruz-Cabeza and C. R. Groom (CrystEngComm, 2011, 13, 93). A decade has now elapsed and the CSD has seen a significant increase in its total number of crystal structures, useful CSD subsets have been introduced and the CSD Python API has been developed to allow for complex data mining. Given this, we wanted to revisit tautomeric polymorphs in the CSD alongside other polymorphs related by proton transfer and compare these results with those from an in-house pharmaceutical database in order to assess their prevalence and significance for pharmaceuticals. From A (amine–imine tautomeric polymorphs) to Z (zwitterionic polymorphs), here we study different types of polymorphs related by proton-transfer in the CSD, the CSD drug subset (DrugCSD), the single component drug subset of the CSD (SDrugCSD), and the GSK small molecule crystal structure database (GSD). First, we assess the potential of compounds to exist as tautomers. Whilst 51% of compounds in the CSD are capable of tautomerism, this number increases to 73% and 70% for the SDrugCSD and the GSD respectively. Tautomerism potential is, thus, more prevalent in pharmaceuticals than in common organic compounds in the CSD. Second, in mining the CSD we identify a total of 95 families of polymorphs related by proton transfer which can then be classified into six different categories depending on the type of proton transfer observed and the ionisation of species involved. The most common of such category is that of tautomeric polymorphs followed by zwitterionic polymorphs. The rarest type of proton transfer polymorphs is that of multi-zwitterionic polymorphs where two different zwitterions of the same compound are found in two different crystal structures. Overall, 3% of polymorphic compositions in the DrugCSD are found to be related by proton transfer which, although not very common, is of relevance to pharmaceuticals and drug development due to the potential impact on physical properties. Specific examples of each of the categories are discussed with calculations of lattice energies presented and consideration of ΔpKa values and likelihood of proton transfer and ionisation

Combined imaging and chromatic confocal microscopy technique to characterize size and shape of ensembles of cuboidal particles

The presence of needle- and plate-like particles has detrimental consequences on their downstream processing in the fine chemicals sector. Therefore, the ability to accurately characterize the particle size and shape is essential to quantify and predict their impact on the product processability. Nonetheless, tools to characterize both the size and shape of ensembles of cuboidal particles are seldom available. The overarching goal of this work is to provide a fast and accurate offline size and shape characterization tool. To this aim, we have designed and experimentally validated a combined imaging and chromatic confocal microscopy technique. We propose two modes of operation: one that facilitates the accurate 3D reconstruction of particles; and the other that facilitates their rapid characterization. We validate the performance of our technique using a commercial technique. We show that our technique can accurately characterize thousands of particles, making it a valuable addition to existing process analytical technology

Can molecular flexibility control crystallization? The case of <i>para</i> substituted benzoic acids.

From Europe PMC via Jisc Publications RouterHistory: ppub 2020-11-01, epub 2020-11-16Publication status: PublishedDespite the technological importance of crystallization from solutions almost nothing is known about the relationship between the kinetic process of nucleation and the molecular and crystal structures of a crystallizing solute. Nowhere is this more apparent than in our attempts to understand the behavior of increasingly large, flexible molecules developed as active components in the pharmaceutical arena. In our current contribution we develop a general protocol involving a combination of computation (conformation analysis, lattice energy), and experiment (measurement of nucleation rates), and show how significant advances can be made. We present the first systematic study aimed at quantifying the impact of molecular flexibility on nucleation kinetics. The nucleation rates of 4 para substituted benzoic acids are compared, two of which have substituents with flexible chains. In making this comparison, the importance of normalizing data to account for differing solubilities is highlighted. These data have allowed us to go beyond popular qualitative descriptors such 'crystallizability' or 'crystallization propensity' in favour of more precise nucleation rate data. Overall, this leads to definite conclusions as to the relative importance of solution chemistry, solid-state interactions and conformational flexibility in the crystallization of these molecules and confirms the key role of intermolecular stacking interactions in determining relative nucleation rates. In a more general sense, conclusions are drawn as to conditions under which conformational change may become rate determining during a crystallization process

Open questions in organic crystal polymorphism

From Springer Nature via Jisc Publications RouterHistory: received 2020-09-17, accepted 2020-09-25, registration 2020-09-30, pub-electronic 2020-10-19, online 2020-10-19, collection 2020-12Publication status: PublishedFunder: The Royal Society, Industry Fellowship in AstraZenecaPolymorphs, crystals with different structure and properties but the same molecular composition, arise from the subtle interplay between thermodynamics and kinetics during crystallisation. In this opinion piece, the authors review the latest developments in the field of polymorphism and discuss standing open questions

Polymorphism in p-Aminobenzoic Acid

We review the polymorphism of p-aminobenzoic acid (pABA), a model drugcompound whose crystallisation and polymorphic behaviour has been extensively studied in recent years. Beyond the well-known and characterised α and β forms, pABA also crystallises as a γ polymorph, which is structurally similar to the α form. In addition we also compare the newly reported δ form, obtained by high pressure crystallisation and through compression of the α-form. A structural analysis and comparison of all of the forms is presented, the conditions by which each of them is obtained summarised. Crystal structure prediction calculations have also been carried out in order to probe the solid form energy landscape of this compound. The overall picture of the polymorphism of pABA, reveals, surprisingly, the rarity of the β form