An industrial perspective on co-crystals: Screening, identification and development of the less utilised solid form in drug discovery and development.

Active pharmaceutical ingredients are commonly marketed as a solid form due to ease of transport, storage and administration. In the design of a drug formulation, the selection of the solid form is incredibly important and is traditionally based on what polymorphs, hydrates or salts are available for that compound. Co-crystals, another potential solid form available, are currently not as readily considered as a viable solid form for the development process. Even though co-crystals are gaining an ever-increasing level of interest within the pharmaceutical community, their acceptance and application is still not as standard as other solid forms such as the ubiquitous pharmaceutical salt and stabilised amorphous formulations. Presented in this chapter is information that would allow for a co-crystal screen to be planned and conducted as well as scaled up using solution and mechanochemistry based methods commonly employed in both the literature and industry. Also presented are methods for identifying the formation of a co-crystal using a variety of analytical techniques as well as the importance of confirming the formation of co-crystals from a legal perspective and demonstrating the legal precedent by looking at co-crystalline products already on the market. The benefits of co-crystals have been well established, and presented in this chapter are a selection of examples which best exemplify their potential. The goal of this chapter is to increase the understanding of co-crystals and how they may be successfully exploited in early stage development.

Above room temperature spin crossover in thioamide-functionalised 2,6-bis(pyrazol-1-yl)pyridine iron(ii) complexes.

This work describes the synthesis of two novel functionalised 2,6-bis(pyrazol-1-yl)pyridine (bpp) ligands, namely 2,6-bis(pyrazol-1-yl)pyridine-4-carbothioamide (bppCSNH2) and N-methyl-2,6-bis(pyrazol-1-yl)pyridine-4-carbothioamide (bppCSNHMe). The corresponding solvated or non-solvated Fe(ii) salts, [Fe(bppCSNH2)2]X2 and [Fe(bppCSNHMe)2]X2 (X = BF4- or ClO4-) were synthesised and their properties measured by SQUID magnetometry, Evans NMR, differential scanning calorimetry and single crystal X-ray diffraction. In the solid state [Fe(bppCSNH2)2]2+ salts persist in the low spin state below 350 K. The structure of [Fe(bppCSNH2)2](BF4)2·2MeNO2 shows a network of intermolecular interactions responsible for the low spin state stabilisation, relative to the prototypical [Fe(bpp)2]2+ spin crossover (SCO) salts. By contrast the complexes of bppCSNHMe both display abrupt SCO above 300 K. [Fe(bppCSNHMe)2](BF4)2·MeNO2 requires solvent loss before SCO can be observed centred at 332 K. The non-solvated [Fe(bppCSNHMe)2](ClO4)2 shows SCO centred at 325 K. Analysis of solvated and non-solvated crystal structures suggests that cooperativity is facilitated by thioamide-group interactions with neighbouring pyrazolyl and pyridyl moieties.

Studying weak inter-actions in crystals at high pressures: when hardware matters.

The quality of structural models for 1,2,4,5-tetra-bromo-benzene (TBB), C6H2Br4, based on data collected from a single crystal in a diamond anvil cell at 0.4 GPa in situ using two different diffractometers belonging to different generations have been compared, together with the effects of applying different data-processing strategies.

Hysteretic spin crossover driven by anion conformational change.

A new air stable FeIII spin crossover (SCO) complex has been synthesized. The compound undergoes abrupt SCO near room temperature with T1/2 (↓) = 244 K and T1/2 (↑) = 278 K. Structural studies of the complex in the high spin and low spin state show that the strong cooperativity and thus the wide hysteresis is driven by an unprecedented anionic conformational change.

Controlled production of the elusive metastable form II of acetaminophen (paracetamol): a fully scalable templating approach in a cooling environment.

A scalable, transferable, cooling crystallisation route to the elusive, metastable, form II of the API acetaminophen (paracetamol) has been developed using a multicomponent "templating" approach, delivering 100% polymorphic phase pure form II at scales up to 120 g. Favourable solubility and stability properties are found for the form II samples.

Absorbate-induced piezochromism in a porous molecular crystal.

Atmospherically stable porous frameworks and materials are interesting for heterogeneous solid-gas applications. One motivation is the direct and selective uptake of pollutant/hazardous gases, where the material produces a measurable response in the presence of the analyte. In this report, we present a combined experimental and theoretical rationalization for the piezochromic response of a robust and porous molecular crystal built from an extensively fluorinated trispyrazole. The electronic response of the material is directly determined by analyte uptake, which provokes a subtle lattice contraction and an observable bathochromic shift in the optical absorption onset. Selectivity for fluorinated absorbates is demonstrated, and toluene is also found to crystallize within the pore. Furthermore, we demonstrate the application of electronic structure calculations to predict a physicochemical response, providing the foundations for the design of electronically tunable porous solids with the chemical properties required for development of novel gas-uptake media.

Inclusion of trans-resveratrol in methylated cyclodextrins: synthesis and solid-state structures.

The phytoalexin trans-resveratrol, 5-[(1E)-2-(4-hydroxyphenyl)ethenyl]-1,3-benzenediol, is a well-known, potent antioxidant having a variety of possible biomedical applications. However, its adverse physicochemical properties (low stability, poor aqueous solubility) limit such applications and its inclusion in cyclodextrins (CDs) has potential for addressing these shortcomings. Here, various methods of the attempted synthesis of inclusion complexes between trans-resveratrol and three methylated cyclodextrins (permethylated α-CD, permethylated ß-CD and 2,6-dimethylated ß-CD) are described. Isolation of the corresponding crystalline 1:1 inclusion compounds enabled their full structure determination by X-ray analysis for the first time, revealing a variety of guest inclusion modes and unique supramolecular crystal packing motifs. The three crystalline inclusion complexes were also fully characterized by thermal analysis (hot stage microscopy, thermogravimetric analysis and differential scanning calorimetry). To complement the solid-state data, phase-solubility studies were conducted using a series of CDs (native and variously derivatised) to establish their effect on the aqueous solubility of trans-resveratrol and to estimate association constants for complex formation.

Lisinopril dihydrate: single-crystal x-ray structure and physicochemical characterization of derived solid forms.

Screening for new solid forms of the antihypertensive lisinopril was performed by recrystallization of the commercial form, lisinopril dihydrate, from various solvents and by exposing the product of its dehydration to a series of vapors under controlled conditions. Modifications other than the dihydrate encountered in the study included new anhydrous and amorphous forms, with intrinsic dissolution rates significantly greater than that of the dihydrate. Further physicochemical characterization included constant and programmed temperature powder X-ray diffraction, differential scanning calorimetry, thermogravimetry, and Fourier transform infrared spectroscopy. In the course of this study, the single-crystal X-ray structure of lisinopril dihydrate, [a = 14.550(2), b = 5.8917(8), c = 14.238(2) Å, ß = 112.832(3)° at T = 173(2) K, space group P21 , Z = 2], was determined for the first time, revealing its double zwitterionic character in the solid state.

Inclusion of the insecticide fenitrothion in dimethylated-ß-cyclodextrin: unusual guest disorder in the solid state and efficient retardation of the hydrolysis rate of the complexed guest in alkaline solution.

An anhydrous 1:1 crystalline inclusion complex between the organophosphorus insecticide fenitrothion [O,O-dimethyl O-(3-methyl-4-nitrophenyl)phosphorothioate] and the host compound heptakis(2,6-di-O-methyl)-ß-cyclodextrin (DIMEB) was prepared and its structure elucidated by single-crystal X-ray diffraction. This revealed two independent host molecules in the asymmetric unit. In one of these, the cavity is occupied by two disordered guest components (distinguishable as rotamers with respect to the P-OAr bond) while in the other, three distinct guest components with site-occupancies 0.44, 0.29 and 0.27 appear, the last having a reversed orientation relative to all the other components. Kinetic studies of the alkaline hydrolysis of fenitrothion in the presence of DIMEB showed a remarkable reduction of 84% in the rate of this reaction relative to that for the free substrate, a value exceeding those previously attained with the native hosts, ß- and γ-cyclodextrin, and fully methylated ß-cyclodextrin.

Effect of cyclodextrins on the reactivity of fenitrothion.

The hydrolysis reaction of fenitrothion was studied in water containing 2% dioxane and in the presence of native cyclodextrins (α-, ß- and γ-CD) and two commercially available modified derivatives, namely, permethylated ß- and α-cyclodextrin (TRIMEB and TRIMEA, respectively). The kinetics of the reaction in the presence of TRIMEA could not be measured because the complex formed is insoluble and precipitated even at low concentration. On the other hand, the reaction is only weakly affected by the presence of α-CD. The hydrolysis reaction is inhibited by all the other cyclodextrins. From the kinetic data the association equilibrium constants for the formation of the 1:1 inclusion complexes were determined as 417, 511 and 99M(-1) for ß-CD, TRIMEB and γ-CD, respectively. Despite the differences in the association constants for ß- and γ-CD, the observed inhibition effect is about the same and this is due to the fact that the rate of hydrolysis in the cavity of γ-CD is smaller than that in the cavity of ß-CD. The strongest inhibitor is TRIMEB and this result is consistent with the known structure of the complex in the solid state.

Enantiotropically related albendazole polymorphs.

In the present study we report the solid-state properties of albendazole (ABZ) re-crystallized from different solvents for comparison with the commercially available form. Crystalline phases were characterized as to thermal behavior, X-ray diffractometry, both on powder and single crystal, and solubility in methanol or 0.1 N HCl. The relevant thermodynamic parameters were calculated from solubility measurements at different temperatures. The re-crystallization of ABZ both from methanol and N,N-dimethylformamide afforded a new stable polymorph form (Form II) enantiotropically related to the commercially available ABZ (Form I), the latter being the metastable form at ambient temperature. Both forms proved to be physically quite stable, likely due to a high-energy barrier for the activation of the interconversion. ABZ in the solid state represents a rather complex system in which the molecular structural differences that could be associated with the polymorphism are of at least four possible types, or combinations of these: (a) tautomeric; (b) different conformations of either or both of the side-chains attached to the bicyclic ring system; (c) the occurrence of molecular disorder or its absence; (d) no essential difference in molecular structure but different hydrogen bonding arrangements in the two polymorphs.

Solid-state structures and thermal properties of inclusion complexes of the organophosphate insecticide fenitrothion with permethylated cyclodextrins.

The X-ray crystal structures and thermal stabilities of the inclusion complexes formed between the organophosphate insecticide fenitrothion [O,O-dimethyl O-(3-methyl-4-nitrophenyl) phosphorothioate] and the host compounds TRIMEA and TRIMEB (permethylated alpha- and beta-cyclodextrins, respectively) are reported. In the complex (TRIMEA)(2).fenitrothion 1, the guest phosphate ester group is disordered and the molecule is fully encapsulated within a novel TRIMEA dimer in which the secondary rims of the two host molecules are in close contact. In contrast, the complex TRIMEB.fenitrothion 2 is monomeric and the guest molecule is statistically disordered over two positions, with the phosphate group inserted in the host cavity in both cases. Thermal analysis indicated gradual and partial loss of the guest in 1 during heating between 130 degrees C and the melting point of the complex (approximately 200 degrees C), whereas complex 2 displayed significant mass loss only after fusion of the complex at 161 degrees C.

Effect of peracetylation on the conformation of gamma-cyclodextrin.

The well-known, fourfold symmetry of the gamma-CD molecule in its solid inclusion complexes is lost on peracetylation, which yields a highly distorted host molecule in which self-inclusion of acetyl residues divides the macrocyclic cavity into two distinct sub-cavities that accommodate solvent molecules.