Mark D. Eddleston

Screening for polymorphs of cocrystals: a case study

A comprehensive crystal form screen was performed on the phenazine:mesaconic acid system using a variety of techniques including solution based approaches, dry and liquid assisted grinding, thermal methods and sublimation. A novel approach to preparing pharmaceutical cocrystals involving crystallisation at a solvent–solvent interface was also employed, and produced a new thermodynamically stable polymorph of the anhydrous cocrystal. In total, three anhydrous polymorphs, a monohydrate and a DMSO solvate were obtained from the screen, and the crystal structures of Form II (the thermodynamically stable polymorph) and the hydrate were determined. Traditional solution based approaches to polymorphism screening were found to have limitations when applied to this cocrystal system due to differences in the solubilities of phenazine and mesaconic acid in many solvents. Furthermore, several cocrystal preparation methods were required in order to isolate all of the crystal forms that were identified during the study, confirming the need for a multi-technique approach when screening for polymorphs of cocrystals.

Polymorph Identification and Crystal Structure Determination by a Combined Crystal Structure Prediction and Transmission Electron Microscopy Approach

Electron diffraction offers advantages over X-ray based methods for crystal structure determination because it can be applied to sub-micron sized crystallites, and picogram quantities of material. For molecular organic species, however, crystal structure determination with electron diffraction is hindered by rapid crystal deterioration in the electron beam, limiting the amount of diffraction data that can be collected, and by the effect of dynamical scattering on reflection intensities. Automated electron diffraction tomography provides one possible solution. We demonstrate here, however, an alternative approach in which a set of putative crystal structures of the compound of interest is generated by crystal structure prediction methods and electron diffraction is used to determine which of these putative structures is experimentally observed. This approach enables the advantages of electron diffraction to be exploited, while avoiding the need to obtain large amounts of diffraction data or accurate reflection intensities. We demonstrate the application of the methodology to the pharmaceutical compounds paracetamol, scyllo-inositol and theophylline.

An Investigation of the Causes of Cocrystal Dissociation at High Humidity

The dissociation at high humidity of cocrystals formed between caffeine and theophylline with a series of dicarboxylic acids is investigated and found to be driven by the partial dissolution of the acid, rather than by the formation of caffeine/theophylline hydrate. It is shown that partial dissociation occurs under all humidity conditions, and that cocrystals of compounds which do not form hydrates also dissociate by this mechanism. The observations made in this study indicate that cocrystal instability at high humidity will be a widespread issue, especially for cocrystals where the two coformers have widely differing aqueous solubilities, as is likely for systems where cocrystallisation is being used as means of improving the aqueous solubility, or dissolution rate, of a compound.

Determination of the Crystal Structure of a New Polymorph of Theophylline

A new approach to crystal structure determination, combining crystal structure prediction and transmission electron microscopy, was used to identify a potential new crystal phase of the pharmaceutical compound theophylline. The crystal structure was determined despite the new polymorph occurring as a minor component in a mixture with Form II of theophylline, at a concentration below the limits of detection of analytical methods routinely used for pharmaceutical characterisation. Detection and characterisation of crystallites of this new form were achieved with transmission electron microscopy, exploiting the combination of high magnification imaging and electron diffraction measurements. A plausible crystal structure was identified by indexing experimental electron-diffraction patterns from a single crystallite of the new polymorph against a reference set of putative crystal structures of theophylline generated by global lattice energy minimisation calculations.

On the polymorphism of griseofulvin: identification of two additional polymorphs.

In this paper, we present an investigation of the polymorphism of griseofulvin. In addition to the only reported crystalline form (form I), two new polymorphic forms (II and III) have been identified and characterized by differential scanning calorimetry and powder X-ray diffraction. Reasons why these two polymorphs were isolated during the present study, but not detected during the numerous previous studies on this drug, are also discussed.

Use of in situ atomic force microscopy to follow phase changes at crystal surfaces in real time.

AFM of cocrystals: Atomic force microscopy can be used to observe phase changes at crystal surfaces where the transformation is accompanied by a change in the spacing between layers of molecules. The conversion of a metastable polymorph of the caffeine-glutaric acid cocrystal into the thermodynamically stable form was analyzed continuously in situ using intermittent-contact-mode atomic force microscopy.

Sonocrystallization Yields Monoclinic Paracetamol with Significantly Improved Compaction Behavior

Ultrasound-assisted crystallization (sonocrystallization) was used to prepare a mixture of nano- and micrometer-sized crystals of the monoclinic form of paracetamol-a widely used analgesic known for its particularly problematic mechanical behavior under compression (i.e. poor tabletability). The nano- and micrometer-sized crystals yielded a powder which exhibits elastic moduli and bulk cohesions that are significantly higher than those observed in samples consisting of macrometer-sized crystals, thus leading to enhanced tabletability without the use of excipients, particle coating, salt, or cocrystal formation. Experimental compaction and finite element analysis were utilized to rationalize the significantly improved compaction behavior of the monoclinic form of paracetamol.

Electrospun Polymer Blend Nanofibers for Tunable Drug Delivery: The Role of Transformative Phase Separation on Controlling the Release Rate

Electrospun fibrous materials have a wide range of biomedical applications, many of them involving the use of polymers as matrices for incorporation of therapeutic agents. The use of polymer blends improves the tuneability of the physicochemical and mechanical properties of the drug loaded fibers. This also benefits the development of controlled drug release formulations, for which the release rate can be modified by altering the ratio of the polymers in the blend. However, to realize these benefits, a clear understanding of the phase behavior of the processed polymer blend is essential. This study reports an in depth investigation of the impact of the electrospinning process on the phase separation of a model partially miscible polymer blend, PVP K90 and HPMCAS, in comparison to other conventional solvent evaporation based processes including film casting and spin coating. The nanoscale stretching and ultrafast solvent removal of electrospinning lead to an enhanced apparent miscibility between the polymers, with the same blends showing micronscale phase separation when processed using film casting and spin coating. Nanoscale phase separation in electrospun blend fibers was confirmed in the dry state. Rapid, layered, macroscale phase separation of the two polymers occurred during the wetting of the fibers. This led to a biphasic drug release profile from the fibers, with a burst release from PVP-rich phases and a slower, more continuous release from HPMCAS-rich phases. It was noted that the model drug, paracetamol, had more favorable partitioning into the PVP-rich phase, which is likely to be a result of greater hydrogen bonding between PVP and paracetamol. This led to higher drug contents in the PVP-rich phases than the HPMCAS-rich phases. By alternating the proportions of the PVP and HPMCAS, the drug release rate can be modulated.

Cocrystal Dissociation in the Presence of Water: A General Approach for Identifying Stable Cocrystal Forms

In previous studies, cocrystals have been shown to be susceptible to dissociation at high humidity because of differences in the solubilities of the two coformer molecules, especially when these molecules can form hydrates. Contrastingly, however, the propensity of the pharmaceutically active compound caffeine to hydrate formation is reduced by cocrystallization with oxalic acid. Here, the stability of the oxalic acid cocrystal of caffeine is investigated from a thermodynamic perspective through the use of aqueous slurries of caffeine hydrate and oxalic acid dihydrate. Conversion to the anhydrous caffeine-oxalic acid cocrystal occurred under these conditions confirming that this form is thermodynamically stable in an aqueous environment. The slurry methodology was further developed as a general approach to screening for cocrystals that are not susceptible to dissociation at high humidity. In this manner, cocrystals of the hydrate-forming molecules theophylline, carbamazepine, and piroxicam that are stable at high humidity, indefinitely avoiding hydrate formation, were identified.

Cocrystal dissociation and molecular demixing in the solid state

A new cocrystal containing caffeine and theophylline was found to dissociate on heating, with caffeine and theophylline molecules spontaneously demixing and recrystallizing as separate phases, in a solid-solid transition likely driven by an increase in entropy. The morphology and composition of the resulting crystals was determined by transmission electron microscopy.