Excipient Compatibility Study:

New Challenges and Considerations in the Modern

Pharmaceutical R&D Paradigm

Wei-Qin (Tony) Tong, Ph.D.

Pharmaceutical Development
(weiqin.tong@novartis.com)

AAPS Workshop: Pharmaceutical Stability Testing to Support Global Markets

Sept. 10-12, 2007, Bethesda, MD
Modern Pharmaceutical R&D Paradigm

• Combinatorial chemistry and high-throughput

screening result in many more hits and more
development candidates.
• Properties of NCEs become less favorable for
development
• Gap between Research and Development is
disappearing:
− Profiling of pharmaceutical properties of drug candidates
becomes a routine practice
• Competition is intensifying: Time to market is money
• QbD requires more rational approaches for
formulation and process design
Importance of Stability

• Instability may cause

− A substantial loss of potency
− Undesired change in performance, i.e.
dissolution/bioavailability
− Substantial changes in physical appearance of the
dosage form causing product failures, e.g. color,
odor etc.
• Degradation products may result in adverse events
or toxicity
• Requirement for approval by regulatory agencies
New Challenges with Excipient Compatibility Study

• Drug substance availability

− Quantity
− Quality: form, purity, other physical properties
• Time constraint
− Time available to generate data with good quality that can
support right decision
− Pressure to do it right first time
• Challenges with special drug delivery systems
• Challenges with combination products
Learning before doing – Develop a knowledge base

There are critical differences between companies

at the detailed level of knowledge and their
ability to learn before doing
− knowledge of the underlying variables and their
relationship to performance
− knowledge of the future manufacturing environment and
the new variables introduced by that environment

G. Pisano, “The Development Factory”, Harvard Business School Press, 1996

Are we learning before doing?

The readily available literature is grossly

underutilized as a tool for predicting the
stability of drug candidates.
There is very little that is so new in this field
that it has not been seen (AND SOLVED)
before.

Dr. Valentino Stella, “Deciphering the chemical degradation profile of drugs”, CPA/AAPS
meeting, Hangzhou, China, 2006
Importance of Understanding Solution Stability

• Solution stability is more predictable

• More suitable for automation and high
throughput
• Most compounds are more stable in solid state
than in solution
• Many “solid state reactions” are indeed
occurring in the solution state
Factors Affecting 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

• Acting as surface catalysts

• Acting as a source for extra moisture
− Physical state and mobility of water molecules
• Altering the pH of the moisture layer
• Undergoing direct chemical reactions with the drug
− Drug:excipient ratio
− Powder mixing and packing
• Impact both physical contact of the reactive species and
the diffusion matrix (porosity and tortuosity)
• Physical mixing vs. granulation
• Granules vs. compacts
Solid State Stability: Other Factors

• 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

• Quantitative prediction of interaction is still difficult

• Known Incompatibilities

functional Group Incompatibilities Type of Reaction

primary amine mono and disaccarides amine-aldehyde and amine-acetal

ester, cyclic, lactose basic components ring opening, ester-base, hydrolysis

carbonyl, hydroxyl, silanol hydrogen bonding

aldehyde amine, carbohydrates aldehyde-amine, Schiff base or
glycosylamine formation

carboxyl bases salt formation

alcohol oxygen oxidation to aldehydes and ketones

sulfhydryl oxygen dimerization

phenol metals complexation
gelatin capsule shell cationic surfactants denaturation
Microenvironment pH of Common Excipients

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

• Drug-excipient ratio: does it reflect the final dosage form?

• Relative humidity: what conditions best mirror the influence of
water arising from difference processes?
• Temperature: what’s relevant to the real product stability per
ICH guideline?

How to improve the quality of data and reduce the time and
material need for the studies?
Advancement in Excipient Compatibility Studies

• Experimental design: study planning and data

evaluation

• Experimental set-up: sample preparation and storage

conditions

• Analytical methods and data analysis

Experimental Design
• Tiered approach:
− Prediction and preliminary screening
− Excipient compatibility set-up with various designs including
standard prototype formulations
− Testing only the stability of standard formulations
− Testing targeted samples based on issues observed with
standard formulations
− Formulation optimization
• Typical designs:
− Binary mixture at extreme ratios to cover the broad range
− N-1 approach (formulations with one excipient removed for
each sample)
Experimental Design
• Design of experiment approach:
− Main factors include time, humidity, temperature, and
excipient
− Allow the identification of both direct excipient effects and
factor interactions

Wyttenbach et al., Pharm Dev and Tech 10 (2005) 499.

Experimental Set-up: Sample Preparations

• Automation of sample preparation

− Autodose
− Solid dispersing tools
• High throughput approach
− 96-well plate
• Drug substance dissolved for easy dispersion but final
form unknown
• Require as little as 0.1 mg drug substance
• Does amorphous drug substance represent the worse
case for stability?
Experimental Set-up: Storage Conditions

50ºC Close 50(40-80ºC) / 75%RH 50(40-80ºC)/ 20% H2O

40-80ºC Close: 100%RH

H 2O
Sample and Data Analysis

• New analytical tools

• New softwares for data storage and analysis
Integrated Systems

• An Example: workstation developed by Symyx

www.symyx.com
Other Analytical Methods as Screening Tools

• DSC and HSDSC

− Thermal events usually at high T, often not predictive of chemical
interactions at RT
− Non-specific: can be misleading
• Isothermal calorimetry (Thermal Activity Monitor, TAM)
• Highly sensitive, therefore, experiments are performed at lower
T → better extrapolation to RT
• No or minimum sample treatment required
• Non-destructive
• Non-specific: can be misleading
• Non-representative conditions as in formulations
Stabilization

• Altering the properties of the solid drug

− Increasing melting point
− Choosing a non-hygroscopic form (crystal or salt form)
− Reducing solubility by choosing a less soluble salt
− Micellar inclusion
− Complexation
− Engineering of the particles (shape)
Stabilization

• Minimizing the level of moisture in the formulation

− Choice of excipients
− Co-solvents
− Manufacturing conditions
− Storage conditions
− Packaging
• Changing the micro-environment around the drug
particles in the formulation
− Adjusting the pH by using acids, bases, or buffer salts
− Incorporating complexation agents to inactivate trace metal ions
− Displacing oxygen with nitrogen or argon
− Incorporating antioxidants
Stabilization

• Physically separating the reacting species to

minimize the contact among the interacting drug(s)
and excipients, and water
• Coating with polymers/microencapsulation
• Multi-layer particles in capsule/tablet
• Tablet in a tablet
• Tablet in a capsule
Examples

I. Enzyme X: effect of temperature (momentary)

• When loosely mixed with excipients, the enzyme is stable
• When compressed, however, the frictional heat generated was
sufficient to degrade the labile substance

II: Captopril: importance of drug:excipient ratio

• Drug-excipient compatibility studies showed decomposition in the
present of Mg stearate
• However, High strength (100 mg) tablets prepared containing Mg
stearate are stable
• Lower strength (2 mg) tablets, on the other hand, showed
significant oxidative decomposition
Examples

III: Moexipril: stabilizing via new solid phase

• This n-carboxylalkyl dipeptide undergoes intramolecular
aminolysis in solution at pH’s less than 4.5 and ester hydrolysis
at pH’s greater than 10
• In the dry state most excipients were showed to be incompatible,
moisture and basic agents were the destabilizing factors
• In wet granulations, however, basic agents were found to
suppress drug degradation even in the presence of moisture
• A possible explanation is that new salt form was created through
ion exchange during the wet granulation process

Gu et al., Pharm Res 7 (1990) 379.

Examples

IV: Enalapril: sorption

• Incompatible with microcrystalline cellulose
− caused dissociation of the amine maleate, which resulted in
wicking of the oil away from the anion
− The free amine is unstable
• Compatible with Ca Phosphate
− No such preferential adsorption occurred

Cotton et al., Int J Pharm, 40 (1987) 129

Examples

V: Ibuprofen: vaporization
• Forms eutectic in the presence of stearates which sublimates
• Film coating the tablets eliminate this problem

Gordon et. al, Int J Pharm 21 (1984) 99.

Concluding Remarks

• The paradigm shifts in the pharmaceutical industry created new

challenges for the excipient compatibility studies.
• Having a fundamental understanding of the physicochemical
properties is a key component of designing rational compatibility
studies.
• Automation and high throughput methodologies should enhance
efficiency and our ability to explore broader design space.
• However, proper design and careful considerations of various
factors that can impact the study results are required so quality of
the data can be ensured to support the right decision.
 ACKNOWLEDGMENT

My colleagues at Novartis, especially

Abu Serajuddin
Rosario Lobrutto
Richard Vivilecchia
Amol Matharu
Yatindra Joshi
Alan Royce
Ping Li
Sudha Vippagunta
Colleen Ruegger

Geoff Zhang (Abbott)

Yihong Qiu (Abbott)