Excipients, which often make up the major proportion of tablet dosage forms are materials that can exist in different solid phases, such as polymorphs, hydrates, amorphous forms or mixed phases. Compendial and manufacturer specifications are typically focused on particulate and chemical attributes. However, variation of excipients at the molecular level can impact their performance characteristics, functionality, and formulation manufacturability. The objective of this presentation is to highlight the diversity of solid form variation in tableting excipients and provide a framework for categorizing their phase compositions. A secondary objective is to relate these categories of phase variation with their propensity for transformation due to manufacturing stresses.

1. Solid Form Aspects of Excipients and Their
Influence on Formulation and Process
Paul Luner, Ph.D.
Pharmaceutical Development
Boehringer Ingelheim Pharmaceuticals
Ridgefield, CT
August 30, 2012

2. Overview
QbD
• Focus on Solid Dosage Forms Critical Material Attributes
• Introduce 3 well known examples
Functionality
• Solid Form Diversity in SDF
Excipients Excipient Performance
• Phase Transformation and Batch to Batch Variability
Processing Stress Supplier Variability
• Impact of Solid Form Selection
• Impact of Excipient Transformation Global Procurement and
• Additional complexities Supply Chain
• Recommendations Process Design Space
Multi-source suppliers
2

3. Lactose Solid Forms
Aq Solution Equilibrium
35%  / 65%  Aq Lactose Controlled
Aq Lactose Suspension Spray Drying
Solution
Amorphous
Crystallize w/ a:b ratio of
< 93 °C LH20
> 93 °C input material Form Sol
(mg/ml) +
LH20 L
(~% ?)
L @ 20 °C
Crystallize H Crystalline Solid Solutions LH20 80 +
MeOH/EtOH - H20 5a/3b Amorphous
RH 160 ° C %RH Milling L 550
 (%RH) 3a/2b / 
>50% 4a/1b
L L
Anhydrous Unstable
Stable Hygroscopic Some Mechanical Properties of Lactose
Dynamic Brittle Tensile
Pure Forms Lactose
Vromans et al. Int. J. Pharm. 35:29 (1987)
6 D50 Indentation Fracture Strength
Type
Tablet Tensile Strength (MPa)
5
Hardness Index @ 0.85 SF
Amorphous
Spray Dried
Lactose
Anhydrous
4
136 High Moderate High
3
(~70% )
-Lactose Monohydrate
2
Monohydrate 68 High High Low
1
(Crystalline) 310TM
Monohydrate
0
104 High High High
10 15 20 25 30 35 SD 316 FF TM
Tablet Porosity (%)
Carlson and Hancock in Excipient Development for
Sebhatu &Alderborn, Pharmaceutical Biotechnology and Drug Delivery Systems, 2006
Eur. J. Pharm. Sci. 1999, 8 (4), 235-242. 3

4. Magnesium Stearate
The Impact of Lubricant Level Amorphous
Tablet Hardness Disintegration Time Magnesium
Stearate
Swaminathan and Kildsig 2001
RH > 70%
Ertel and Carstensen 1988
Hydration
Magnesium 100% RH
Stearate Trihydrate
(Dihydrate)
Rehydration Dehydration
>50 % RH 100 – 105 °C
Dehydration
Strickland, W. A. J.; Nelson, E.; Busse, L. W.; Higuchi, T. The Anhydrous
100 – 105 °C
Physics of Tablet Compression. IX. Fundamental Aspects of Magnesium
Tablet Lubrication. J. Amer. Pharm. 1956, 45 (1), 51-55. Stearate
Stearate:Palmitate Material Mechanical
Manufacturing And Kinetic Factors
Variation
Morphology
Crystal Form/Hydration
Affects Delamination Lubricity Affects Delamination (Blending and
Surface Area Composition)
Solid State and Impure Material
Micromeretics Die Wall Hard to Characterize
Sticking Lubrication Flow Aid
Specifications Weak Crystal
Applied in Kinetic Process
4

5. Microcrystalline Cellulose
Alkali/
Mercerization Form Method For
Form II Form I Pair Differentiation
I vs. II Raman; PXRD;
SS-NMR
I I Amorph
Ia vs. I IR; SS-NMR
> Algae/ >Higher
Bacteria Plants/Animals Amorph XPRD; SS-NMR.
I/I ~ 0.25 Content Raman, IR
Source
PXRD Simulated From
Crystal Structures Hard or Soft wood
Process
Particle
I Size
Crystallinity
I
5 10 20 30
Moisture Sorption
2-Theta
5

6. Why Worry Now?
BCS BREAKDOWN OF
US TOP 200 IR DRUGS EXCIPIENTS USUALLY THE
MAJOR COMPONENTS OF SDFs!
Unclassified
V
SI
Require
BC
BCS I 30-40% Formulation
BCS II Enablement
More Reliance on Excipients + Process
to Achieve Performance
BCS III
Function
Excipient
Formation
Form ???
 Proceesing/
DF Behavior
Environment DP
/Storage Process
6

7. Form Diversity in Excipients for SDF
Form Frequency in SDF Excipients
Number of Excipients
50
Solid Dosage Form Excipients (n=75) N=75
40
Amorphous/Crystalline Distribution
30
29.3 20
Occuring
Only as 10
Amorphous 0
One Two Three Four Five
61.3 Number of Solid Forms
(including amorphous)
9.3
Occuring Only
as Crystalline Excipients By Category
Other
Diluents
ExcipientsThat Can Lubricants
Be Either Binders
0 10 20 30 40 50
% of Excipients in Category
with > 1 Solid Form
7

8. Impact of Polymorphism and Transformation
Thermodynamics
• Mechanical Properties Polymorph Transition Polymorph Transition
• Hardness
• Tensile Strength
• Compactibility, Tabletability Liquid
• Surface Morphology /Chemistry
• Surface Energy
• Habit
• Thermodynamics
• MP Amorphous-Crystalline
• Heat Capacity Transition Hydrate Formation
• Free Energy
• Vapor Pressure
• Solubility
• Hygroscopicity
• Kinetics and Chemical Reactivity
• Dissolution
• Stability
8

9. Process Stresses
Unit Operation or Process Processing Stresses

Thermal* Pressure Mechanical Liquid Vapor
Impact Exposure Exposure
Crystallization/Precipitation   
Milling    
Granulation (Fluid Bed= )    
Compression (Tableting;
 
Roller Compaction)
Drying  
Powder Mixing/Blending  
Tablet Coating   
Handling/Transport   
Storage   
Spray Drying   
Hot Melt Extrusion  
*Thermal Stress defined as potential to exceed recognized suitable long-term storage condition
[York 1983. Int. J. Pharm. 14:1-28]

10. Break Down of Types of Transformation During Processing
Govindarajan, R.; Suryanarayanan, R. Processing-induced phase transformations and their implications on
pharmaceutical product quality. In Polymorphism; Hilfiker, R., Ed., 2006; 333-364.
.

11. Kinetic Resolution of Phase Composition
Subsequent
Wet Massing Phase Drying Phase
Storage
tGranulation > Amorph
ous
tSupersaturation
tDrying  tEMC
Transient
Meta- Stable
Hydrate stable Form I
Form
Meta
Stable tDrying < Stable
Form I Dissolution Form II
tConversion II --> I
tNucleation/Growth > tDrying > Stable
tGranulation tConversion II --> I Form I
Meta
Stable Stable
Stable Dissolution
Form I Form I
Form II
Hydrate
Exceed Dehydration tDrying  tEMC
Threshold Iso-
Hydrate morphic
Desolvate
Anhydrate
Form
Adapted from Morris et al. Adv. Drug Del. Rev. 48 (2001):91-114

12. Excipient Hydration Example: Arginine
Arginine
Moisture Sorption Isotherm @ 40 OC
25
20
% Weight Change
15
10 (@ 25 C)
Prototype Tablets Scale Up Batch 5
Adsorption
Desorption
1 day @ 25 °C/60% RH 0
white speckles/ 0 10 20 30 40 50 60 70 80 90 100
dimples % Relative Humidity
PXRD Comparison Anhydrate: P 21 Dihydrate: P 21 21 21
a = 9.75, b = 16.02, c = 5.58 a = 5.64, b = 11.85, c = 15.68
V = 863.8 V = 1047.6
"Pimples"
Anhydrate
Dihydrate
5 10 15 20 25 30 RIET_1_publ ARGIND11
2-Theta Data courtesy of D. Chen, BIPI 12

13. Mannitol Process Induced Transformation: Good or Bad?
Crystal Forms of Mannitol -form -form

Thermo Stability
ENATIO 97% RH or Water

 -form -form
Compressibility: >>
97% RH or Water
Compactibility:  > =
No transformation under mechanical stress
Crystalline Mannitol Formulations
Direct Compression Wet Granulation • -form undergoes water mediated
transformation

 • 6X increase in Surface Area
• Particle Size Reduction
  • Change in Hygroscopicity
• Increase in tabletability
Yoshinari, T.; Forbes, R. T.; York, P.; Kawashima, Y.
Int. J. Pharm. 2003, 258 (1-2), 121. 13

14. Calcium Phosphate Dihydrate and Anhydrous
CaHPO4 • 2H2O  / RH
CaHPO4 60 C Isothermal Dehydration
DCPD DCPA as a Function of %RH
- H2 O
H2O (liquid)
DCPD is ~ 21% Water by Wt.
DCPD
Tabletability
Tensile Strength
@ 32% RH Storage
DCPD
Hygroscopicity DCPA
DCPA Compression Pressure
Lot Variation in
DCPD Dehydration Kinetics
Kaushal, A. M.; Vangala, V. R.; Suryanarayanan, R. J. Pharm. Sci., 100 (4), 1456 (2011). 14

15. Dicalcium Phosphate: Impact of Dehydration
DP
Arora, K. K.; Tayade, N. G.; Suryanarayanan, R. Molecular Pharmaceutics 2011, 8 (3), 982-989.
Manufac.
Process
Variation
Temp/RH
Supplier
Stress Excipient
Solid
40 °C; Closed System Form in
CBZ-NMA
DF
Cocrystal DCPD  CBZ
Grade/
Phase
Particle
Purity
Size
- H2O
• Hydrolysis/Chemical Instability
• API hydration/Phase transform
• Disintegrant Deactivation
• Tablet Hardening
• Tg lowering of Amorphous
Dispersions 15

16. Secondary Interactions Related to Form Transformation
Qualitative Risk Assessment
Secondary Impacts
• Excipient moisture uptake ability can Excipient Transformation
affect API solid form transformation Risk Assessment
in processing
# of Potential Solid Forms
• Different Forms or Form composition
of the excipient affecting moisture =>
tabletting
• Differences in Excipient Form
solubility/dissolution rate may affect
API dissolution rate
• Form or presence of form impurities
may impact potential for Eutectic
Formation Dosage Form Processing Complexity and
Transformational Impact 16
• Physical stability of DF in the
presence of moisture may be altered

17. ICH Q6A Guidance:Polymorphism Decision Tree
Can
API polymorph
Polymorphs be No No further action
screen
formed ?
Yes
Characterize
What Forms Exist ?
Forms
(Characterization)
Does Drug Product Establish
1 performance testing provide
Yes
acceptance criteria
adequate control if polymorph for the relevant
content changes performance tests
No
Do the forms have
No further Test or Control of
Polymorph
No acceptance
different properties ? Monitor Polymorph
criterion for DS
form during
stability of DP
in DP
Yes
No
No need to set
Is drug product safety, Does a change occur
acceptance criteria
performance or efficacy which could affect safety No
for form change in
affected ? or efficacy ?
DP
Single Form Yes
Will Crystal Form Yes
Or Mixture ? be affected by DP
Set Criteria for
Polymorph content
Manufacture ? Establish
acceptance criteria
in DS consistent with
2 Safety and
Efficacy
3

18. QbD for Excipients: Solid Form Edition
Focus Area Control Point Critical Question Potential Impacts
Form Diversity Selection of What is the right Physical Chemical
Excipient Solid Form form for the API and Properties;
Process? Transformation
Input Form Control Variation in Solid Will material Extent of
Form of the variation affect Transformation in
excipient based on processing or process;
source , grade or product quality ? hygroscopicity/
supplier moisture balance
Output Form Control Process and its Does process impact Change in
variation impact excipient form or Interaction with DS
excipient phase functionality ? or formulation
composition
18

19. Where do we go from here ?
• Industry
• Know and understand raw materials
• Choose Wisely
• Be aware of changes that can occur as a result of processing
• Screen and investigate
• Academia
• Characterize complex interactions related to excipient performance and solid state
variation
• Tools to interrogate functional performance.
• Manufacturers
• Control, measure and inform
• Pharmacopeial Harmonization
• Continue development of Compendial Standards
• Common characterization methodology and guidance
Acknowledgements: Dabing Chen @ BIPI for the Arginine Data
19