Nate Schultheiss

Pharmaceutical Cocrystals and Their Physicochemical Properties

Over the last 20 years, the number of publications outlining the advances in design strategies, growing techniques, and characterization of cocrystals has continued to increase significantly within the crystal engineering field. However, only within the last decade have cocrystals found their place in pharmaceuticals, primarily due to their ability to alter physicochemical properties without compromising the structural integrity of the active pharmaceutical ingredient (API) and thus, possibly, the bioactivity. This review article will highlight and discuss the advances made over the last 10 years pertaining to physical and chemical property improvements through pharmaceutical cocrystalline materials and, hopefully, draw closer the fields of crystal engineering and pharmaceutical sciences.

Cocrystals of nutraceutical p-coumaric acid with caffeine and theophylline: polymorphism and solid-state stability explored in detail using their crystal graphs

Cocrystals constructed with p-coumaric acid (a phytochemical and nutraceutical compound) are investigated with xanthine compounds, caffeine and theophylline. Four cocrystals of p-coumaric acid with caffeine (1 : 1 and 1 : 2 stoichiometric ratios) and theophylline (two 1 : 1 polymorphs, Form I and Form II) were generated and their structures determined by single-crystal X-ray crystallography. The two theophylline cocrystals display synthon polymorphism, where both structures possess a carboxylic acid–imidazole heteromeric synthon; however, one polymorph also has a hydroxyl–carbonyl synthon (Form I), while in the other a hydroxyl–imidazole synthon (Form II) is present. Furthermore, the solid-state stability of the two p-coumaric acid : theophylline polymorphs was explored experimentally and computationally.

Attempted construction of minoxidil: carboxylic acid cocrystals; 7 salts and 1 cocrystal resulted

Cocrystallization experiments between the active pharmaceutical ingredient (API) minoxidil and a variety of pharmaceutically acceptable cocrystal formers (coformers) were carried out. Our initial efforts were centered around utilizing the various hydrogen bonding acceptor moieties on the minoxidil framework, e.g., N-oxide, amino-pyridine, and piperidine, to probe, with a carboxylic acid, the delicate balance of competing intermolecular interactions and determine a hierarchical ranking of supramolecular synthons within a specific cocrystallization reaction. We successfully generated eight multi-component samples, which were analyzed by single-crystal X-ray diffraction revealing the formation of one cocrystal and seven salts. In all cases the API and coformers were connected through a carboxylate/N-hydroxide synthon or its neutral analog proving to be a robust interaction (occurring in 8/8 structures), even in the presence of other potentially disruptive hydrogen bonding moieties. Interestingly, the amino-pyridine and piperidine moieties (both effective hydrogen bond acceptors) never participated in forming hydrogen bonds with a carboxylic acid.

Ten years of co-crystal synthesis; the good, the bad, and the ugly

We present seven new co-crystals based around 1,4-diiodotetrafluorobenzene that illustrate some of the progress that has been made, as well as some of the challenges that remain, in the assembly of specific solid-state architectures using non-covalent interactions and relatively simple molecular building blocks.

Nutraceutical cocrystals: utilizing pterostilbene as a cocrystal former

The nutraceutical compound pterostilbene is investigated for its propensity to form cocrystalline materials with active pharmaceutical ingredients. Three cocrystals of a 1 : 1 stoichiometric molar ratio of pterostilbene with caffeine (two polymorphs, Form I and Form II) and carbamazepine were prepared and characterized by crystallographic (XRPD, single-crystal) and thermoanalytical (TGA, DSC) techniques. Physical stability of the cocrystals with respect to relative humidity (RH) was examined and found to be dramatically improved in relationship to caffeine or carbamazepine. The carbamazepine : pterostilbene cocrystal was stable upon slurrying in water for 3 days; therefore, aqueous equilibrium solubility measurements were carried out, revealing that the cocrystal solubility was 7× lower than carbamazepine dihydrate and 2.5× lower than pterostilbene. Slurrying the caffeine : pterostilbene cocrystal (Form I) in water led to a solution that was supersaturated with respect to pterostilbene, resulting in the precipitation of pterostilbene after three days; therefore concentrations at specific time points were measured as opposed to equilibrium solubility. At five hours the concentration of the caffeine cocrystal was 33× lower than the caffeine hydrate solubility, but was 27× higher than the pterostilbene solubility.

Attempted assembly of discrete coordination complexes into 1-D chains using halogen bonding or halogen⋯halogen interactions

Attempts at creating infinite 1-D architectures using M(II)-acac complexes as building blocks and halogen bonding or halogen⋯halogen contacts failed to produce the desired motifs, and serve to illustrate how intermolecular interactions can be ranked in terms of their structural influence and supramolecular effectiveness.

Balancing intermolecular hydrogen-bond interactions for the directed assembly of binary 1 : 1 co-crystals

The synthesis of three supramolecular reactants (SR’s) containing two distinct hydrogen bonding donor/acceptor sites (pyridine–aminopyrimidine) designed to establish competitive intermolecular interactions during co-crystal assembly is described. These ditopic SR’s were allowed to react with aromatic carboxylic acids in varied stoichiometric ratios, producing nine molecular 1 : 1 co-crystals. Single crystal X-ray diffraction studies show that in each case, the participating carboxylic acid preferentially engages in heteromeric O–H⋯N/N–H⋯O hydrogen bonds with the aminopyrimidine binding site. The results can be rationalized through a hierarchical view of intermolecular interactions based upon observed structural pattern preferences, and they also establish the reliability of the aminopyrimidine as an effective supramolecular tool, even in the presence of other potential disruptive hydrogen-bonding donor/acceptor moieties.

A pyridyl-functionalized cavitand: Starting point for hydrogen-bond driven assembly of heterodimeric capsules

The directed assembly of derivatized cavitands into nano-sized supramolecular hosts is of considerable interest. This manuscript describes the synthesis and structural characterization of a pyridyl-functionalized cavitand that, in principle, can act as one half of a large number of hydrogen-bonded heterodimeric capsules when matched with a variety of suitably functionalized cavitands.

Synthesis and hydrogen-bond capabilities of an amino-pyridine functionalized cavitand

A new amino-pyridine substituted resorcinarene-based cavitand has been synthesized and employed in the hydrogen-bond directed assembly of (a) discrete pentameric units with 3,5-dinitrobenzoic acid and (b) an infinite supramolecular polymer with glutaric acid: both products have been characterized by X-ray single-crystal diffraction.

Chapter 6:Role of Co-crystals in the Pharmaceutical Development Continuum

Over the last ten years, the number publications, along with scientific conferences and workshops, outlining the advancement of design strategies, growing methods, analytical characterization techniques, and physicochemical property enhancements of co crystals has continued to increase significantly. Multi-component crystalline systems are not new to the pharmaceutical world, but only recently has the term ‘co-crystal’ been used in this field to describe materials containing two or more non-ionized components existing in one, independent crystalline lattice. Within the last decade solid-state researchers have focused on making co-crystals from pharmaceuticals, because they allow modifications to be introduced to the crystal structure of an active pharmaceutical ingredient, API (which in turn can alter its physical and chemical properties) without compromising its intended biological activity. This chapter will highlight and discuss the physical and chemical property improvements that have been achieved through co-crystalline materials of APIs, particularly focusing on stability, solubility, and bioavailability, and will attempt to put these activities within the context of the pharmaceutical development continuum.