Beruflich Dokumente
Kultur Dokumente
Pharmaceutical Development
(weiqin.tong@novartis.com)
Dr. Valentino Stella, “Deciphering the chemical degradation profile of drugs”, CPA/AAPS
meeting, Hangzhou, China, 2006
Importance of Understanding Solution Stability
• Temperature
− Arrhenius equation:
k = Ae − Ea / RT
− Underlying assumption
• Reaction mechanism does not change as a function of
temperature, i.e., Ea is independent of T
• May not be valid for some reactions, especially the complex
reactions
Factors Affecting Solution Stability
• Solvent
− pH of aqueous solvents
• Acid, base, and water catalyzed reactions, mostly hydrolysis
• Leading to various kinetic profiles: L, V, U
• More complex shapes of kinetic profiles if the compound has
(multiple)ionizable functionality
− Composition: medium effect on chemical reactions
• Non-traditional dosage forms: e.g. co-solvents, soft gel, lipid
based systems
Factors Affecting Solution Stability
• Light
• Oxygen
• Co-solutes
− Buffer salts: catalysis
− Surfactants: different environment in the micelles
− Complexation agents: different environment, e.g.
cyclodextrin
− Antioxidants and/or chelating agents
Common Degradation Routes
• Solvolysis/hydrolysis
− Most frequently encountered hydrolysis – ester
− Typically pseudofirst order
− Intramolecular catalysis and steric factors
• Photolysis/oxidation
• Racemization
− May cause substantial decrease in biological activities: e.g.
Pilocarpine, tetracycline
• Others
− e.g. decarboxylation
Solid State Stability: Effect of Excipients
• Particles • Environment
− Physical form − Temperature
− Particle size/surface area − Relative humidity
− Morphology − Packaging
− Defects concentration − Light
− Impurities − Oxygen
Solid State Stability: Physical
• Physical Changes
− Polymorphic transition
− Hydrate/solvate formation
− Dehydration/desolvation
− Crystallization of amorphous material
− Vaporization
• Effect of Excipients
− Solubilization in the amorphous matrix
• Inhibiting nucleation
• Changing Tg
− Effect on moisture level
Solid State Stability: Learning before doing
Excipient Microenvironment pH
MCC 7.31
Lactose MH 7.30
PVP 7.40
Crospovindone 7.44
Aerosil 7.10
Mg stearate 9.96
Mannitol 6.15
HPMC 7.32
Ac-di Sol 6.34
Ca stearate 8.89
L-HPC 7.52
Lactose SD 7.65
Challenges of Excipient Compatibility Studies
How to improve the quality of data and reduce the time and
material need for the studies?
Advancement in Excipient Compatibility Studies
H 2O
Sample and Data Analysis
www.symyx.com
Other Analytical Methods as Screening Tools
V: Ibuprofen: vaporization
• Forms eutectic in the presence of stearates which sublimates
• Film coating the tablets eliminate this problem