The co-crystal approach to improve the exposure of a water-insoluble compound: AMG 517 sorbic acid co-crystal characterization and pharmacokinetics.
Co-crystals are relatively novel in the pharmaceutical field and are not reported extensively. AMG 517 is an insoluble small molecule VR1 (vanilloid receptor 1) antagonist. In animal studies, good exposure of AMG 517 is seen from a 10% (w/v) Pluronic F108 in OraPlus suspension. Investigation of the suspension formulation revealed that AMG 517 forms a co-crystal with sorbic acid, a preservative in OraPlus. This co-crystal of AMG 517 was isolated by coslurrying AMG 517 and sorbic acid; studied by DSC and XRD; and identified by solution NMR, TGA, and HPLC to be a 1:1 association of AMG 517 and sorbic acid. Single crystal structure analysis revealed a 1:1 co-crystal of AMG 517 and sorbic acid, held together by two hydrogen bonds and other noncovalent, nonionic forces. The co-crystal has better aqueous solubility initially as compared to AMG 517 free base but does revert back to a form of the free base hydrate during prolonged slurry in FaSIF (fasted simulated intestinal fluid). Pharmacokinetic evaluation of the co-crystal in rats using 10% (w/v) Pluronic F108 in OraPlus suspensions revealed that a 30 mg/kg dose in suspension had comparable exposure to a 500 mg/kg dose of the free base.
Bak
Annette
A
Department of Pharmaceutics, Amgen, Inc, One Kendall Square #1000, Cambridge, Massachusetts 02139, USA. abak@amgen.com
Gore
Anu
A
Yanez
Evelyn
E
Stanton
Mary
M
Tufekcic
Sunita
S
Syed
Rashid
R
Akrami
Anna
A
Rose
Mark
M
Surapaneni
Sekhar
S
Bostick
Tracy
T
King
Anthony
A
Neervannan
Sesha
S
Ostovic
Drazen
D
Koparkar
Arun
A
D000818:Animals; D052160:Benzothiazoles / Q000097:blood / Q000737:chemistry* / Q000493:pharmacokinetics; D002851:Chromatography, High Pressure Liquid; D003460:Crystallization; D018360:Crystallography, X-Ray; D009682:Magnetic Resonance Spectroscopy; D010316:Particle Size; D011743:Pyrimidines / Q000097:blood / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors*; D014867:Water / Q000737:chemistry
D052160:Benzothiazoles; C523409:N-(4-(6-(4-trifluoromethylphenyl)pyrimidin-4-yloxy)benzothiazol-2-yl)acetamide; D011743:Pyrimidines; D050916:TRPV Cation Channels; D014867:Water