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

• Published in: European journal of pharmaceutical sciences Vol. 128; pp. 128 - 136
• Main Authors: Sigfridsson, Kalle, Lindsjö, Martin, Paulsson, Stefan
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.02.2019
• Subjects: Drug delivery; Drug development; Photostability; Preformulation; Solid-state stability; Stability; Drug delivery; Stability; Drug development; Photostability; Solid-state stability; Preformulation
• ISSN: 0928-0987; 1879-0720
• DOI: 10.1016/j.ejps.2018.11.028

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. [Display omitted]