title: Improved pharmacokinetics of AMG 517 through co-crystallization part 2: analysis of 12 carboxylic acid co-crystals.
abstract: Intrinsic dissolution, powder dissolution, and the pharmacokinetics (PK) of 12 carboxylic acid co-crystals of AMG 517 were determined and compared. Dissolution studies were performed in fasted simulated intestinal fluid (FaSIF). A control dissolution experiment was conducted with the free base in FaSIF plus sorbic acid to compare with the AMG 517 sorbic acid co-crystal (SRA). Suspension formulations in 1% polyvinylpyrrolidone K25 in water were administered orally at 100 mg/kg to rats. All co-crystals were found to have faster intrinsic and powder dissolution rates in FaSIF as well as higher area under the concentration-time curves (AUC) in rat PK investigations compared with the free base. The control dissolution experiment indicates that the increase in dissolution rate of SRA over the free base is not due to the presence of sorbic acid in the dissolution medium. Linear correlation of dissolution rate and AUC among the 12 co-crystals was moderate, indicating that in vitro dissolution is a valuable method to predict whether a co-crystal will improve the exposure of a poorly soluble pharmaceutical ingredient; however, in vivo testing may be required to determine the extent.
authors.affiliation: Amgen, Inc., Cambridge, Massachusetts 02142, USA. mstanton@amgen.com
authors.forename: Mary K
authors.initials: MK
authors.lastname: Stanton
authors.forename: Ron C
authors.initials: RC
authors.lastname: Kelly
authors.forename: Adria
authors.initials: A
authors.lastname: Colletti
authors.forename: Meghan
authors.initials: M
authors.lastname: Langley
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Munson
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Peterson
authors.forename: John
authors.initials: J
authors.lastname: Roberts
authors.forename: Mary
authors.initials: M
authors.lastname: Wells
mesh_terms: D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D052160:Benzothiazoles / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D002264:Carboxylic Acids / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D002626:Chemistry, Pharmaceutical; D003460:Crystallization; D004339:Drug Compounding; D008297:Male; D011205:Povidone / Q000737:chemistry; D011208:Powders; D011743:Pyrimidines / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D013678:Technology, Pharmaceutical / Q000379:methods
chemical_list: D052160:Benzothiazoles; D002264:Carboxylic Acids; C523409:N-(4-(6-(4-trifluoromethylphenyl)pyrimidin-4-yloxy)benzothiazol-2-yl)acetamide; D011208:Powders; D011743:Pyrimidines; D011205:Povidone