title: Drug-excipient compatibility testing using a high-throughput approach and statistical design.
abstract: The aim of our research was to develop a miniaturized high throughput drug-excipient compatibility test. Experiments were planned and evaluated using statistical experimental design. Binary mixtures of a drug, acetylsalicylic acid, or fluoxetine hydrochloride, and of excipients commonly used in solid dosage forms were prepared at a ratio of approximately 1:100 in 96-well microtiter plates. Samples were exposed to different temperature (40 degrees C/ 50 degrees C) and humidity (10%/75%) for different time (1 week/4 weeks), and chemical drug degradation was analyzed using a fast gradient high pressure liquid chromatography (HPLC). Categorical statistical design was applied to identify the effects and interactions of time, temperature, humidity, and excipient on drug degradation. Acetylsalicylic acid was least stable in the presence of magnesium stearate, dibasic calcium phosphate, or sodium starch glycolate. Fluoxetine hydrochloride exhibited a marked degradation only with lactose. Factor-interaction plots revealed that the relative humidity had the strongest effect on the drug excipient blends tested. In conclusion, the developed technique enables fast drug-excipient compatibility testing and identification of interactions. Since only 0.1 mg of drug is needed per data point, fast rational preselection of the pharmaceutical additives can be performed early in solid dosage form development.
authors.affiliation: F. Hoffmann-La Roche Ltd., Pharmaceutical and Analytical R & D, Basel, Switzerland. nicole.wyttenbach@roche.com
authors.forename: Nicole
authors.initials: N
authors.lastname: Wyttenbach
authors.forename: Christian
authors.initials: C
authors.lastname: Birringer
authors.forename: Jochem
authors.initials: J
authors.lastname: Alsenz
authors.forename: Martin
authors.initials: M
authors.lastname: Kuentz
mesh_terms: D001241:Aspirin / Q000737:chemistry / Q000592:standards; D002851:Chromatography, High Pressure Liquid; D003627:Data Interpretation, Statistical; D004339:Drug Compounding / Q000379:methods / Q000592:standards / Q000706:statistics & numerical data; D004344:Drug Incompatibility; D004355:Drug Stability; D004356:Drug Storage; D005079:Excipients / Q000737:chemistry* / Q000592:standards; D005473:Fluoxetine / Q000737:chemistry / Q000592:standards; D006358:Hot Temperature; D006813:Humidity; D004364:Pharmaceutical Preparations / Q000737:chemistry* / Q000592:standards; D013997:Time Factors
chemical_list: D005079:Excipients; D004364:Pharmaceutical Preparations; D005473:Fluoxetine; D001241:Aspirin