Development of a Suitable Salt Form for a GPR40 Receptor Agonist

Abstract

AMG 837 (1) is a novel GPR40 agonist selected for clinical development for the treatment of type 2 diabetes. A lysine salt was initially identified as a development form. However, due to the poor crystallinity and severe hygroscopicity of this form, investigations on the free acid form of the drug substance and salt screening were conducted to identify an acceptable physical form for long-term development. A sodium and calcium salt were identified as potentially viable phases, and polymorph screening was conducted on both. The quality attributes of the salts were then compared to determine which phase would be preferred for development.

Solid Form Selection and Process Development of KO-947 Drug Substances

“…Oral administration of KO-947 was originally targeted and a polymorph screening on the free base was conducted with the aim of findign a suitable form for oral solid dosage formulations. Various screening techniques such as slurry, thermal heating–cooling, solvent evaporation, antisolvent precipitation, and grinding were employed and 11 forms were identified from these efforts and the X-ray powder diffraction (XRPD) patterns are shown in Figure . The thermal properties of these forms were then characterized with differential scanning calorimetry (DSC) and thermal gravimetric analysis (TGA) under matching conditions and the data are summarized in Table .…”

Development of a Synthetic Process for K-8986, an H1-Receptor Antagonist

“…First, we screened suitable salt forms of the target. To select acceptable counterions for API, the Generally Regarded as Safe (GRAS) lists, Orange Book Database, and other excellent reviews were consulted. , Hydrochloric acid, citric acid, fumaric acid, maleic acid, phosphoric acid, and sulfuric acid were selected for preliminary salt screening of 6 . To obtain binary mixtures, the molar ratio of 6 and acid was adjusted to 1:1 or 1:2 because 6 contains two basic nitrogen atoms in its piperazine moiety.…”

Free Fatty Acid Receptor 1 (FFAR1) as an Emerging Therapeutic Target for Type 2 Diabetes Mellitus: Recent Progress and Prevailing Challenges

“…In addition, the synthetic challenges of AMG 837 triggered a number of related studies in enantioselective and scalable synthesis. The unfavorable physical properties (low melting temperature, poor solubility, and stability) of the free acid form, as well as the severe hygroscopicity and poor crystallinity of the initially identified lysine salt, prompted systematic salt screening to be conducted, and ultimately, the stable crystalline hemicalcium salt dihydrate form was identified for long‐term development …”

“…The unfavorable physical properties (low melting temperature, poor solubility, and stability) of the free acid form, as well as the severe hygroscopicity and poor crystallinity of the initially identified lysine salt, prompted systematic salt screening to be conducted, and ultimately, the stable crystalline hemicalcium salt dihydrate form was identified for long-term development. 124 Based on the favorable preclinical profiles, AMG 837 has reached in phase I clinical trials, however, no further progress has been disclosed, possibly because of safety signals. It is speculated that AMG 837 has a reasonable possibility to permeate the CNS, because the structural analog 32 (5 mg/kg) revealed a brain to plasma ratio of 0.6 in rats.…”