title: Kinetics of pramlintide degradation in aqueous solution as a function of temperature and pH.
abstract: The stability of the 37-amino acid peptide pramlintide, in aqueous solution, was studied as a function of pH and temperature. Samples of pramlintide formulated as a parenteral product were exposed to elevated temperatures and to realistic storage conditions for as long as 30 months. Pramlintide degradation was monitored by three high-performance liquid chromatography (HPLC) methods: a reversed-phase (RP-HPLC) and a strong-cation exchange (SCX-HPLC) method for percentage purity determination by area normalization, plus a second RP-HPLC method for potency determination versus external standards. The pH-rate profile for pramlintide shows increasing degradation rate constants with increasing pH over the range pH = 3.5 to 5.0. The Arrhenius expression for pramlintide degradation at pH = 4.0 over the temperature range 5 degrees C to 50 degrees C is ln(k(0))= 37.39-21.900/RT, where k(0) is the zero-order rate constant (in %/mo) for pramlintide degradation. The pramlintide parenteral product formulated at pH = 4.0 is extremely stable, with percentage purity and percentage potency loss of only approximately 2% over 30 months at 5 degrees C. The formulated pramlintide drug product has acceptable shelf life for long-term storage at 5 degrees C and up to a 30-day patient use when stored at ambient temperature.
authors.affiliation: Cabrillo Facility of Magellan Laboratories, Inc., 9250 Trade Place, San Diego, CA 92126, USA. rkenley@cabrillolabs.com
authors.forename: R A
authors.initials: RA
authors.lastname: Kenley
authors.forename: S
authors.initials: S
authors.lastname: Tracht
authors.forename: A
authors.initials: A
authors.lastname: Stepanenko
authors.forename: M
authors.initials: M
authors.lastname: Townsend
authors.forename: J
authors.initials: J
authors.lastname: L'Italien
mesh_terms: D000595:Amino Acid Sequence; D000682:Amyloid / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D002852:Chromatography, Ion Exchange / Q000379:methods; D004340:Drug Contamination; D004355:Drug Stability; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D058228:Islet Amyloid Polypeptide; D007700:Kinetics; D008969:Molecular Sequence Data; D012015:Reference Standards; D012996:Solutions; D013696:Temperature; D013997:Time Factors; D014867:Water / Q000737:chemistry / Q000378:metabolism
chemical_list: D000682:Amyloid; D058228:Islet Amyloid Polypeptide; D012996:Solutions; D014867:Water; C105254:pramlintide