title: Early development evaluation of AZD8081: a substrate for the NK receptors.
abstract: 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.
authors.affiliation: Pharmaceutical Development, AstraZeneca R&D Mölndal, Mölndal, Sweden. carl-gustav.sigfridsson@astrazeneca.com
authors.forename: K
authors.initials: K
authors.lastname: Sigfridsson
authors.forename: M
authors.initials: M
authors.lastname: Ahlqvist
authors.forename: A
authors.initials: A
authors.lastname: Carlsson
authors.forename: A
authors.initials: A
authors.lastname: Fridström
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D001384:Azetidines / Q000008:administration & dosage* / Q000737:chemistry; D001549:Benzamides / Q000008:administration & dosage* / Q000737:chemistry; D003460:Crystallization; D003692:Delayed-Action Preparations; D004285:Dogs; D016503:Drug Delivery Systems; D004355:Drug Stability; D004356:Drug Storage; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007419:Intestinal Secretions / Q000378:metabolism; D008297:Male; D064729:Neurokinin-1 Receptor Antagonists; D018041:Receptors, Neurokinin-2 / Q000037:antagonists & inhibitors*; D012995:Solubility; D017155:Wettability; D055815:Young Adult
chemical_list: C560792:AZD 8081; D001384:Azetidines; D001549:Benzamides; D003692:Delayed-Action Preparations; D064729:Neurokinin-1 Receptor Antagonists; D018041:Receptors, Neurokinin-2