The development of tablet products is often faced with challenges of poor flowability, tabletability, and bad taste of active pharmaceutical ingredients (API). In contrast to empiricism, the development of successful tablet products requires the employment materials science and engineering from solid form selection to formulation design. In this talk, recent examples of successful development of challenging APIs based on crystal and particle engineering will be discussed to illustrate the usefulness of such an approach of tablet product development.

1. Crystal and Particle Engineering for
Expedited Development of
High Quality Tablet Products
Changquan Calvin Sun, Ph.D.
Nov. 9, 2017, Webinar
All rights reserved
sunx0053@umn.edu
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2. Outline
1. Introduction
2. Crystal and particle engineering strategies
3. Case study – Metformin ODT development
4. Conclusions
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3. • Stability
• Manufacturability
• Bioavailability
• Bioequivalency
• Pharmaceutical elegance
• Quality requirements
• Regulatory/GMP compliance
Criteria for Successful Tablets
Tablet Weight
Content Uniformity
Tablet Hardness
Tablet Friability
3
Flowability
Tabletability

4. A Typical Tablet Formulation
1. Drug(s)
2. Filler: Lactose, sucrose, mannitol, DiCal …
3. Binder: Microcrystalline cellulose …
4. Disintegrant: sodium croscarmellose, crospovidon …
5. Flow aid: fumed silica …
6. Colorant: orange, red …
7. Lubricant: magnesium stearate …
8. Coating: Aquadry ….
9. Other ingredients: surfactant, pH modifier, anti-aherent
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5. QbD based on Material Science Tetrahedron
Art Science
Fundamental understanding of materials and processes
Appropriate crystal and particle engineering
processing
structure
performance
properties
Quality-by-luck Quality-by-design
Sun, 2009, J. Pharm. Sci. 98:1671-1687
Materials Science
Engineering
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API Crystal
engineering
Particle
engineering
Process
engineering
Tablet manufacturability
= Tabletability + flowability + other properties

6. 6
Tabletability
(Bonding Area - Bonding Strength)
compression decompression
elastic
plastic
compression decompression
elastic
plastic
a b
c
d
Sun, 2009, J. Pharm. Sci. 98:1671-1687
1. Adequate plasticity is necessary for good tabletability (larger BA)!
2. Higher bonding Strength (BS) also favors good tabletability!

7. 0 100 200 300 400
0
1
2
Tensile
strength
(MPa)
Compactionpressure (MPa)
1
FormI
Crystal Engineering (Salt formation)
Perumalla et al., 2012, CrystEngComm, 14:2389-2390
Crystallized from concentrated HCl(aq.)
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Acetaminophen HCl
(monohydrate)

8. 8
Crystal Engineering
(cocrystallization)
Tabletability of the cocrystal is significantly better than both methyl gallate and caffeine.
0
1
2
3
4
5
0 50 100 150 200 250 300 350 400 450 500
Compaction pressure (MPa)
Tensile
strength
(MPa)
Caffeine-Methyl gallate cocrystal
Methyl gallate
Caffeine
Sun and Hou, 2008, Cryst. Growth Des., 8:1575-1579
Flat slip planes are clearly present in the cocrystal.
3D H-bond network, rigid lattice.

9. 9
Increasing BA by Coating
small bonding area
low tabletability
large bonding area
high tabletability
Chen et al, 2017, J. Control Rel., 262:222-231

10. 10
API Particle Engineering
(spray-drying)
0 100 200 300 400
0
2
4
6
8
Physical mixture with 1%~ 40%HPC
1%HPC
2.5%HPC
5%HPC
Tensile
strength
(MPa)
Compaction pressure(MPa)
10%HPC
Shi & Sun, 2011, Pharm. Res. 12:3248-3255
Spray-drying
(HPC/acetaminophen)

11. 11
Particle Engineering
(fluid bed coating)
Osei-Yeboah & Sun, 2015, J.Pharm. Sci. 104:2645–2648
0
1
2
3
4
5
6
7
Tablet
Tensile
Strength
(MPa)
B
C
D
E
F
A
A
B
C
D
E
Cellets
PVP:caffeine
Kollicoat®
PVP
silica
aging
Fluid bed coating

12. 12
Flowability
(Gravity vs. Adhesion)
K. Kendall, 1994, Science, 263:1720 - 1725
1. Larger size → better flow
2. Larger particle-particle separation → better flow

13. 13
Particle Engineering
(Nanocoating)
0
2
4
6
8
10
12
Uncoated
PH105
Physical blend Nanocoated
PH105
Uncoated
PH102
Flow
factor
(ff)
1. Little improvement in flowability for a physical mixture
2. Significant improvement in flowability when surface-coated with nano silica particles by comilling
Process is important!!
Chatteraj et al, J Pharm Sci, 2011, 100:4943-4952

14. Crystal Engineering (Hydrate formation)
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Citric acid
69.9% RH at 20 oC
a b
monohydrate
anhydrate
anhydrate monohydrate
Conditioned over night at 60% RH.
Sun, 2009, J. Pharm. Sci. 98:1744-1749

15. Expedited Dev. of Metformin ODT
Motivations
1. Developing a tablet product for patients with difficulty in swallowing
tablet or without access to water
2. Using direct compression
Challenges
1. Salty and bitter taste
2. High dose (250 mg and 500 mg)
3. Poor tabletability and flowability
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 A first-line prescription drug for treating type 2 diabetes
 HCl salt is used in commercial tablets

16. Crystal Engineering
(forming a salt with acesulfame)
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Met-Acs
Wang, et al., 2017, Int. J. Pharm. 532:435-443

17. Improved Taste
Met·Acs exhibited much better taste profile!
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Wang, et al., 2017, Int. J. Pharm. 532:435-443
1. Sweet 2. Slightly sweet 3. No taste 4. Slightly bitter 5. Bitter

18. Improved Tabletability
Better tabletability of Met-Acs is attributed to its lower hardness (larger BA)
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Wang, et al., 2017, Int. J. Pharm. 532:435-443

19. ODT Formulation
Ingredient % (w/w) Function
Met·Acs 60 drug
Avicel PH102 33 Dry binder
Croscarmellose
sodium
5 disintegrant
Fumed silica 1 Flow aid
Mg. St. 1 lubricant
Total 100
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Met·Acs exhibited poor flowability
Particle engineering (nano – silica coating) was applied

20. Manufacturability of Met·Acs ODT
formulation
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Wang, et al., 2017, Int. J. Pharm. 532:435-443

21. Identifying Compaction Force
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735 mg (250 mg of Metformin) tablets, 10 kN,
D.T. < 30 s & friability < 0.8%, acceptable taste
Wang, et al., 2017, Int. J. Pharm. 532:435-443
7.5 – 12.5 kN

22. Conclusions
• Materials science tetrahedron is a useful tool for product
development
• Tabletability can be modified through controlling BA and BS
• Nanocoating is effective in improving powder flowability
• Integrated crystal and particle engineering made possible
fast development of a metformin ODT by direct compression
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23. 23
Acknowledgements
Dr. Chenguang Wang
Dr. Reddy Perumalla
Dr. Limin Shi
Dr. Sayantan Chattoraj
Dr. Helen Hou
Dr. Frederick Osei-Yeboah
AAPS
Abbott Laboratories
BASF
Boehringer Ingelheim
Cima Labs
DFE Pharma
Eli Lilly
Merck
NSF - CPPR
Pfizer
PhRMA Foundation
Univ. of Minnesota
US FDA
https://www.pharmacy.umn.edu/departments/pharmaceutics/changquan-calvin-sun-lab
Sun Lab