title: Moisture transfer from stopper to product and resulting stability implications.
abstract: Since the stability of a freeze-dried product is often sensitive to the level of moisture, control of residual moisture by attention to the secondary drying phase of the freeze-drying process is of considerable importance. However, several reports in the literature as well as our own experience suggest that low residual moisture immediately after manufacture does not ensure low moisture throughout the shelf life of the product. Equilibration of the product with moisture in the stopper can lead to significant increases in product water content. This research is a study of the kinetic and equilibrium aspects of moisture transfer from stopper to product at 5 degrees C, 25 degrees C, and 40 degrees C for two amorphous materials: vancomycin (highly hygroscopic) and lactose (moderately hygroscopic). Stoppers are 13 mm butyl rubber (#1816, West Co.) slotted freeze-drying stoppers which were studied: (a) "U"-with no treatment; (b) "SV1"-steam-sterilized followed by 1 hr vacuum drying; and (c) "SV8"-steam sterilized followed by 8 hrs vacuum drying. No evidence was found for moisture transmission through the stopper. Rather, the product moisture content increases with time and reaches an apparent equilibrium value characteristic of the product, amount of product, and stopper treatment method ("SV1" much greater than "U" greater than "SV1"). As a first approximation, the rate of approach to "equilibrium" depends only on temperature (t1/2 approximately 10 months at 5 degrees C to approximately 4 days at 40 degrees C) with the "equilibrium" water content being independent of temperature. The "equilibrium" moisture content increases as the dose decreases and is larger for vancomycin than for lactose. The "equilibrium" moisture contents range from 5.0% (25 mg vancomycin, "SV1" stoppers) to 0.68% (100 mg lactose, "SV8" stoppers).
authors.affiliation: Lilly Research Laboratories, Eli Lilly & Co., Indianapolis, IN.
authors.forename: M J
authors.initials: MJ
authors.lastname: Pikal
authors.forename: S
authors.initials: S
authors.lastname: Shah
mesh_terms: D001688:Biological Products / Q000302:isolation & purification*; D004349:Drug Packaging / Q000295:instrumentation; D004355:Drug Stability; D020724:Elastomers; D005612:Freeze Drying; D007700:Kinetics; D012408:Rubber; D013696:Temperature; D013816:Thermodynamics; D014867:Water / Q000032:analysis
chemical_list: D001688:Biological Products; D020724:Elastomers; D014867:Water; D012408:Rubber; C017098:butyl rubber