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.

01 Jun 2011·Drug Development and Industrial PharmacyQ4 · MEDICINE

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

Q4 · MEDICINE

Article

Author: Kalle Sigfridsson ; A. Carlsson ; M. Ahlqvist ; A. Fridstrom

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 pK(a) 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.

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Indication	Highest Phase	Country/Location	Organization	Date
Gastrointestinal dysfunction	Discovery	United Kingdom	AstraZeneca PLC	-
Gastrointestinal dysfunction	Discovery	Sweden	AstraZeneca PLC	-
Gastrointestinal dysfunction	Discovery	United Kingdom	AstraZeneca PLC	-
Gastrointestinal dysfunction	Discovery	Sweden	AstraZeneca PLC	-

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