Matti Ahlqvist

Water dynamics in channel hydrates investigated using H/D exchange.

The dynamics and interactions of water with different channel hydrates were studied. Caffeine 4/5-hydrate, theophylline monohydrate and sodium cromoglycate were used as model compounds. The hydrogen/deuterium (H/D) exchange of the different hydrates following exposure to deuterium oxide vapour was studied using FT-Raman spectroscopy. The aim of the work was to (1) investigate the potential for H/D exchange studies to provide information about channel hydrates and (2) correlate the mobility of the water molecules inside lattice channels with structural parameters of the specific hydrates. The rate of exchange in the three different compounds was shown to vary considerably with caffeine 4/5 hydrate undergoing exchange much more rapidly than either sodium cromoglycate or theophylline monohydrate, with exchange in the latter compound being extremely slow. Based on the known crystal structures, it was possible to rationalise the results and to draw conclusions about the mechanism of exchange for the model compounds. It was found that the mobility of the water molecules in a channel hydrate is very dependent on the dimensions of the hydrate channel. Thus H/D-exchange studies may provide very useful structural and energetic information about channel hydrates.

Early development evaluation of AZD8081: a substrate for the NK receptors

The purpose of the present study was to find out if AZD8081, a dual neurokinin (NK)1/2 receptor antagonist, was suitable for development of an oral, solid immediate release (IR) formulation and in a further perspective also as an oral extended release (ER) formulation. AZD8081 is a base with pKa values <2.5 and about 8.5. The measured intrinsic solubility is about 0.1 mg/mL and the solubility in FaSSIF (fasted simulated small intestinal fluid) is about 3.2 mg/mL. Aqueous buffer solutions are stable for at least 1 month between pH 1–7 up to 37°C. In the solid-state, a mixture of amorphous and crystalline substance showed significant chemical instability in the initial stress testing studies. No degradation was, however, observed for highly crystalline material at similar conditions. It is concluded that the impurity profile and/or the present solid-state of the batches affect the stability of the substance. The amorphous contribution of the substance is the main cause to the observed degradation in solid-state. Crystalline AZD8081 is polymorphic with two known monotropic forms, form A and form B. Both forms are only slightly hygroscopic ansolvates with melting points of approximately 108°C and 117°C, respectively. Form B is the more stable of the two forms and is therefore most suited for further development. The candidate is suitable for development of standard IR formulations since no specific limitations of significance for formulation development were identified. In addition, the good stability in human intestinal fluid and in colon slurry makes AZD8081 a suitable candidate for ER formulation.

Preformulation investigation and challenges; salt formation, salt disproportionation and hepatic recirculation

Abstract A compound, which is a selective peroxisome proliferator activated receptor (PPAR) agonist, was investigated. The aim of the presented studies was to evaluate the potential of the further development of the compound. Fundamental physicochemical properties and stability of the compound were characterized in solution by liquid chromatography and NMR and in solid‐state by various techniques. The drug itself is a lipophilic acid with tendency to form aggregates in solution. The neutral form was only obtained in amorphous form with a glass‐transition temperature of approximately 0 °C. The intrinsic solubility at room temperature was determined to 0.03 mg/mL. Chemical stability studies of the compound in aqueous solutions showed good stability for at least two weeks at room temperature, except at pH 1, where a slight degradation was already observed after one day. The chemical stability in the amorphous solid‐state was investigated during a period of three months. At 25 °C/60% relative humidity (RH) and 40 °C/75% RH no significant degradation was observed. At 80 °C, however, some degradation was observed after four weeks and approximately 3% after three months. In an accelerated photostability study, degradation of approximately 4% was observed. Attempts to identify a crystalline form of the neutral compound were unsuccessful, however, salt formation with tert‐butylamine, resulted in crystalline material. Results from stability tests of the presented crystalline salt form indicated improved chemical stability at conditions whereas the amorphous neutral form degraded. However, the salt form of the drug dissociated under certain conditions. The drug was administered both per oral and intravenously, as amorphous nanoparticles, to conscious dogs. Plasma profiles showed curves with secondary absorption peaks, indicating hepatic recirculation following both administration routes. A similar behavior was observed in rats after oral administration of a pH‐adjusted solution. The observed double peaks in plasma exposure and the dissociation tendency of the salt form, were properties that contributed to make further development of the candidate drug challenging. Options for development of solid dosage forms of both amorphous and crystalline material of the compound are discussed. Graphical abstract Figure. No Caption available.

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

&NA; 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. Graphical abstract Figure. No Caption available.