The crystalline salt form of a selected candidate drug showed photo-, thermal- and humidity induced form transitions.

AZ3411 was selected as a lead compound for the treatment of Inflammatory Bowel Disease (IBD). The present research aimed to perform an early pharmaceutical assessment of this NK antagonist candidate focusing on the challenging solid-state part of the evaluation. X-ray powder diffraction (XRPD), hot stage XRPD and microscopy, differential scanning calorimetry, thermogravimetrical analysis measurements, nuclear magnetic resonance spectroscopy and liquid chromatographic analysis were used to characterize AZ3411. The amorphous, free base form of AZ3411 was transformed to a poorly crystalline material by salt formation using maleic acid. Suspensions of the poorly crystalline form (type A), prepared in various solvents, exhibited phase transformation on storage. Some precipitate was identified as a new, more crystalline form (type B) of the maleate salt of AZ3411. Also, a third crystalline form was observed at high temperatures (type C). AZ3411 maleate type A, maleate type B and amorphous, free base form was stored in 40 °C/75% relative humidity (RH), 60 °C and 80 °C for three months. Form B was found to be the most chemically stable at all conditions. After three months at 40 °C/75%RH, both type A and type B had transformed to the anhydrous type C. Moreover, type B was transformed to form C at 60 °C and 80 °C, while type A remained unchanged. These results, together with the loss of water with temperature, suggest that type B is a hydrate. The relative stability between the hydrate type B and anhydrous type C depend on humidity and temperature. Moreover, the photosensitivity of maleate type A, maleate type B and amorphous free base has been investigated under three different illumination conditions. In similarity to the previous study, Form B was the most chemically stable form. However, after completion the study, at the highest energy conditions (765 W/m2, 250-800 nm), the crystalline type B had transformed to type C, while type A had lost in crystallinity. A similar photostability study was performed on solutions of pH 1 and pH 7. The degradation pattern was similar for the two pHs but appeared different from the unstressed solution stability study performed on different pHs between pH 1 and 7. Neither was there any obvious correlation between the degradation patterns obtained after the stressed thermal- and photostability studies performed on the drug substance in solid-state. The salt of AZ3411 fulfils basic requirements for further development of an oral immediate release (IR) dosage form, although the compound displays signs of light sensitivity and there may be a risk of solid-state transitions during formulation development and long-term storage.

Salt formation improved the properties of a candidate drug during early formulation development.

The purpose of this study was to investigate if AZD5329, a dual neurokinin NK1/2 receptor antagonist, is a suitable candidate for further development as an oral immediate release (IR) solid dosage form as a final product. The neutral form of AZD5329 has only been isolated as amorphous material. In order to search for a solid material with improved physical and chemical stability and more suitable solid-state properties, a salt screen was performed. Crystalline material of a maleic acid salt and a fumaric acid salt of AZD5329 were obtained. X-ray powder diffractiometry, thermogravimetric analysis, differential scanning calorimetry and dynamic vapor sorption were used to investigate the physicochemical characteristics of the two salts. The fumarate salt of AZD5329 is anhydrous, the crystallization is reproducible and the hygroscopicity is acceptable. Early polymorphism assessment work using slurry technique did not reveal any better crystal modification or crystallinity for the fumarate salt. For the maleate salt, the form isolated originally was found to be a solvate, but an anhydrous form was found in later experiments; by suspension in water or acetone, by drying of the solvate to 100-120 °C or by subjecting the solvate form to conditions of 40 °C/75%RH for 3 months. The dissolution behavior and the chemical stability (in aqueous solutions, formulations and solid-state) of both salts were also studied and found to be satisfactory. The compound displays sensitivity to low pH, and the salt of the maleic acid, which is the stronger acid, shows more degradation during stability studies, in line with this observation. The presented data indicate that the substance fulfils basic requirements for further development of an IR dosage form, based on the characterization on crystalline salts of AZD5329.

Selective Nonsteroidal Glucocorticoid Receptor Modulators for the Inhaled Treatment of Pulmonary Diseases.

A class of potent, nonsteroidal, selective indazole ether-based glucocorticoid receptor modulators (SGRMs) was developed for the inhaled treatment of respiratory diseases. Starting from an orally available compound with demonstrated anti-inflammatory activity in rat, a soft-drug strategy was implemented to ensure rapid elimination of drug candidates to minimize systemic GR activation. The first clinical candidate 1b (AZD5423) displayed a potent inhibition of lung edema in a rat model of allergic airway inflammation following dry powder inhalation combined with a moderate systemic GR-effect, assessed as thymic involution. Further optimization of inhaled drug properties provided a second, equally potent, candidate, 15m (AZD7594), that demonstrated an improved therapeutic ratio over the benchmark inhaled corticosteroid 3 (fluticasone propionate) and prolonged the inhibition of lung edema, indicating potential for once-daily treatment.

Early development evaluation of AZD2738, a substrate for the NK receptors.

The purpose of this study was to investigate whether AZD2738, a dual neurokinin NK1/2 receptor antagonist, is a suitable candidate for further development with an oral immediate release solid dosage form as a possible final product. The neutral form of AZD2738 has only been isolated as amorphous material. In order to search for a solid material with improved physical and chemical stability and more suitable solid-state properties, a salt screen was performed. Mostly crystalline material of fumarate, maleate and chloride salt of AZD2738 were obtained. X-ray powder diffractometry, thermogravimetric analysis, differential scanning calorimetry and dynamic vapor sorption were used to investigate the physicochemical characteristics of the salts. Based on the physicochemical properties, the chloride salt is preferred for continued product development. The chloride salt of AZD2738 is an anhydrate, the crystallization is reproducible, the hygroscopicity is acceptable and just one polymorph was obtained. Notably is that the two obtained polymorphs of the fumarate salt of AZD2738 are monotropically related, whereas the two identified polymorphs for the maleate salt of the compound are enantiotropic. The dissolution behavior and the stability (in aqueous solutions, formulations and solid state) of the salts were also studied and found to be satisfactory, at least at pH >3. Liquid formulations should preferable be stored frozen at pH >3.

Dimorphic (Ba[GaCl(4)](2))(3).2C(6)H(6): a case of coordination extremes.

Two new dimorphic tris[barium bis(tetrachloro gallate]) bisbenzene formed by the same molecular building blocks have been isolated and structurally characterized, showing an unprecedented inorganic as well as mixed organic/inorganic coordination.

Coordinated and clathrated guests in the 3infinity[Hg6As4]4+ bicompartmental framework: synthesis, crystal and electronic structure, and properties of the novel supramolecular complexes [Hg6As4](CrBr6)Br and [Hg6As4](FeBr6)Hg0.6.

Two new supramolecular complexes [Hg(6)As(4)](CrBr(6))Br (1) and [Hg(6)As(4)](FeBr(6))Hg(0.6) (2) have been prepared by the standard ampoule technique and their crystal structures determined. Both crystallize in the cubic space group Pa$\bar 3$ with the unit cell parameter a=12.275(1) (1) and 12.332(1) A (2), and Z=4. Their structures consist of bicompartmental, three-dimensional [Hg(6)As(4)](4+) frameworks with cavities of two different sizes occupied by guest anions of different type. The bigger cavities are filled with the octahedral MBr(6) (n-) ions (M=Cr or Fe; n=3 or 4), whereas the smaller cavities trap either Br- ions (1) or Hg(0) (2). The analysis of the host-guest contacts has allowed a classification of the octahedral guests as coordinated and the monatomic guests as clathrated. Magnetic measurements and ESR spectroscopy data have given information about the interaction between the host and guests. Band structure calculations (HF and hybrid DFT level) indicate that both 1 and 2 are non-metallic, with a band gap of approximately 1.5 eV (B3LYP), and that the interaction between the host and guests is of predominantly electrostatic character. It is shown that though the electrostatic host-guest interaction is weak it plays an important role in assembling the perfectly ordered supramolecular architectures.