Cocrystallization is a promising approach in improving the physicochemical properties of drugs/APIs. But to develop a suitable formulation mechanical properties should also be considered and cocrystallization technique has demonstrated improvement in the mechanical properties of poorly compressible drugs.

1. Impact of Molecular and Thermodynamic
Properties on Compaction Behavior of Cocrystal
Project Proposal
GE-611
Mannat Sehra
17PTFM2699
M.Pharm (Semester II)
Department of Pharmaceutical Technology (Formulation)
National Institute of Pharmaceutical Education and Research, SAS Nagar, Mohali

2. Flow of Presentation
01
02
03
04
05
06
Objective and Specific aims
Research Envisaged
Introduction and Background
Proposed Methodology
Work Plan
Timeline

3. Introduction
and
Background

4. 1
1
Tablets are one of the most common dosage
forms due to the patient compliance and ease
of use
2
The mechanical properties of a material
includes strength, hardness, plasticity,
elasticity, brittleness and ductility.
3
These properties of the APIs affect the
processability of tablets by influencing
common unit operations such as milling,
mixing and compression.
Importance of mechanical
properties
Latif, S.; et al.2018 Drug. Dev. Ind. Pharm, 1-10
Seo, J.-W.;et al. 2017,Pharm. Dev. Technol , 1-10.

5. 2
The BABS model can be used to understand the factors that influence powder tabletability and also helps in
guiding formulation and process development. The complex tableting behavior can be explained by studying
the interplay of bonding area and bonding strength.
Tablet
tensile
strength
Inter-particulate bonding area
• Slip planes
Inter-particulate bonding
strength
• Crystal packing density
• Heat of fusion
• Melting temperature
Bonding Area-Bonding Strength (BABS) model
Sun, C. C. 2011,J. Adhes. Sci. Technol, 25, (4-5), 483-499.

6. COCRYSTALS
Crystalline materials composed of two or
more different molecules, one of which is
the API, in a defined stoichiometric ratio
within the same crystal lattice that are
associated by nonionic and noncovalent
bonds.
Impact of Molecular & Thermodynamic Properties on Compaction Behavior of Cocrystal
UDFA, Guidance for industry-Regulatory classification of
pharmaceutical cocrystals assessed on April 15,2018

7. 4
Any chemical or physical
properties that are a function
of the supramolecular
structure can be potentially
modified by cocrystal
formation
Importance of cocrystals in modulation of
mechanical properties
Cocrystallization is an innovative technique that has
been found to improve the mechanical properties of
the APIs exhibiting poor compaction
Cocrystallization results in structural variations in
the molecular packing of the crystals and thereby,
can alter the deformation behavior of the material
Enhancement in tabletability is linked to the higher
plasticity of cocrystals
Larger bonding area between particles is developed
in tablets which favors the formation of stronger
tablets
1
2
3
4
Chattoraj, S.;et al.2014. Cryst. Growth. Des, 14, (8), 3864-3874.
Chattoraj, S.;et al.2010. CrystEngComm, 12, (8), 2466-2472.

8. Sr.
No.
Cocrystal system Impact on mechanical
property
Correlation with crystallographic feature Conclusion of the study
1 Caffeine:methyl gallate
cocrystal
Reduction in elastic recovery
and high tabletability
Presence of slip planes and high heat of
fusion than caffeine
Tabletability of cocrystal
was better than caffeine
due to presence of slip
planes
2 Paracetamol (PCA) with
oxalic acid (PCA-OXA),
theophylline (PCA-THP),
naphthalene (PCA2-NAP) and
phenazine (PC-PHE2)
Improved plasticity and
tabletability in all the
cocrystals in order
Presence of layered structure and weak
inter layer interactions
PCA-THP exhibited higher
tensile strength and
structurally similar to PCA
form II
3 Carbamazepine:nicotinamide
cocrystal
Compacts with higher tensile
strength were obtained
Low true density of cocrystal Inverse correlation between
compactibility and true
density was found
4 Carbamazepine:saccharin
cocrystal
Improved compaction and
plastic deformation at lower
compression pressure
Melting temperature of cocrystal is higher
and true density is higher than
carbamazepine
Higher melting point could
be the reason of higher
interparticulate bonding
strength and higher true
density resulted in higher
compactibility
5 Caffeine:oxalic acid cocrystal No change in mechanical
property
Absence of hydrogen bonded flat layers,
needle shaped cocrystals
High elastic recovery, low
plasticity due to absence of
sliding planes and poor
bonding strength 5
Literature studies
Contd…

9. Concept of Material-Science Tetrahedron(MST)
6
Performance is determined by properties of the
material that are in turn determined by its structure
The understanding of structure–property
relationship is at the heart of material science and
engineering
Once the relationship is clear, material properties
can be modified by changing structure of the matter
through engineering approaches
Sun, C. C. 2009,J. Pharm. Sci, 98, (5), 1671-1687.

10. 7
Mechanical properties
of salts and polymorphs
Polymorph and salts having higher true density,
resists densification under the applied compaction
pressure and exhibits higher yield pressure and
poor compressibility. Higher true density enables
greater inter molecular contacts during compaction,
resulting into higher interparticulate bonding
strength.
Khomane, K. S.;et al. 2012, J. Pharm. Sci, 101, (7), 2408-2416.

11. Compaction behavior of pharmaceutical polymorphs (without slip plane system)
Polymorphic
system
Polymorph
True Density
(g/cm3)
Compressibility Compactibility Tabletability
Clopidogrel
Bisulphate (CLP)
I Higher (1.50) Lower Higher Higher
II Lower (1.47) Higher Lower Lower
Ranitidine
Hydrochloride
(RAN)
I Higher (1.36) Lower Higher Higher
II Lower (1.32) Higher Lower Lower
Indomethacin
(IMC)
α Higher (1.43) Lower Higher Higher
γ Lower (1.38) Higher Lower Lower
Carbamazepine
I Lower (1.24) Higher Lower Lower
III Higher (1.34) Lower Higher Higher
Sulfathiazol
I Lower (1.5) Higher Lower Lower
III Higher (1.57) Lower Higher Higher
Metoprolol
tartrate
I Lower Higher Lower Lower
II Higher Lower Higher Higher
Contd…

12. 9
Compaction behavior of pharmaceutical polymorphs (with slip plane system)
Polymorphic
system
Polymorph
Slip
Planes
True Density
(g/cm3)
Compressibility Compactibility Tabletability
Febuxostat
polymorphs
Q Y Higher (1.31) Higher Higher Higher
H1 N Lower (1.24) Lower Lower Lower
Clarithromycin
Polymorphs
I Y Lower (1.17) Higher Lower Higher
II N Higher (1.18) Lower Higher Lower
Paracetamol
Polymorphs
I N Lower (1.29) Lower Lower Lower
II Y Higher (1.35) Higher Higher Higher
Contd…

13. 10
Active pharmaceutical
ingredients
Heat of fusion (J/g) Melting points (C) True density (g/mL)
Tensile strength at
zero porosity, σ0 (MPa)
Clarithromycin 81.9 228.1 1.18 2.50
Paracetamol 105.3 165.3 1.29 14.55
Ranitidine Hydrochloride 62.7 133.7 1.37 19.90
Mebendazole 120.1 288.3 1.40 22.16
Aspirin 93.2 144.1 1.43 25.02
Indomethacin 92.5 154.7 1.43 26.21
Diclofenac 101.0 284.0 1.47 28.48
Clopidogrel Bisulphate 80.7 181.2 1.51 33.89
Aceclofenac 322.8 157.1 1.62 45.35
Sulfamethoxazole 153.4 171.9 1.69 53.38
y = 98.298x - 114.228
R² = 0.993
0
20
40
60
1 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8
σ0(MPa)
True density (g/cm3)
True density can be used as a
‘descriptor’ of interparticulate bonding
strength of the pharmaceutical
materials
Low density materials may pose a
problem during development
Contd…
Crystal packing density governs interparticulate bonding strength

14. Research
Envisaged

15. 11
Molecular properties
Thermodynamic properties• Slip planes
• True density
• Melting temperature
• Heat of fusion
Research envisaged
In case of polymorphs and salts
Higher true density
Low compressibility but higher
compactibility
This relationship may
hold true in case of
cocrystals also

16. Objective
and
Specific Aims

17. 12
Objective
To investigate the impact of
molecular (slip planes and true
density) and thermodynamic (heat
of fusion and melting temperature)
properties on compaction behavior
of cocrystals
Impact of Molecular & Thermodynamic Properties on Compaction Behavior of Cocrystal

18. Aim 1
Molecular modelling to identify
slip plane system
Aim 2
Selection of cocrystal systems
Aim 3
Genelation of cocrystals
Aim 4
Characterization of cocrystals
to confirm their solid form and
purity
13
Specific aims

19. 14
Aim 5
Characterization of bulk level
and particle level properties
Aim 6
Compressibility-tabletability-
compactibility (CTC) profiling
of drug and cocrystal
Aim 7
Generation of single crystal for
nanoindentation study
Aim 8
Correlating CTC with heat of
fusion, melting temperature
and true density
Specific aims

20. Work Plan

21. Work plan
• The tablet tensile strength depends upon the molecular
(slip planes and true density) and thermodynamic (heat of
fusion and melting temperature) properties
• There are evidences in case of salts and polymorphic
systems that the compaction is affected by slip planes
and true density of the molecule
• This relationship may hold true in case of cocrystals
system
Hypothesis
• The tablet tensile strength depends upon the molecular
(slip planes and true density) and thermodynamic (heat of
fusion and melting temperature) properties
• There are evidences in case of salts and polymorphic
systems that the compaction is affected by slip planes
and true density of the molecule
• This relationship may hold true in case of cocrystals
system
Hypothesis
• Two reported cocrystals with slip planes and two reported
cocrystals without slip planes
• Availability of crystallographic information file (.CIF)
Selection of cocrystals
• Differential scanning calorimetry
• Powder x-ray diffraction
• Optical and polarized state microscopy
Characterization of cocrystals to
confirm their purity and solid form
Compressibility – porosity vs. compaction pressure
Tabletability – tensile strength vs. compaction pressure
Compactibility – tensile strength vs. porosity
Calculation of tensile strength
2𝐹
Compressibility-tabletability-
compactibility (CTC) profiling
• To investigate the impact of molecular (slip planes and
true density) and thermodynamic (heat of fusion and
melting temperature) properties on compaction behaviour
of cocrystals.
ObjectiveObjective • Particle size distribution and specific surface area should be
similar
• Scanning electron microscopy
• Density (bulk, tapped and true density)
• porosity
Particle level and bulk level
characterization
Impact of Molecular & Thermodynamic Properties on Compaction Behavior of Cocrystal
15

22. Proposed
Methodology

23. Proposed methodology
01
05
02
04
06
Selection of cocrystals
system
Characterization of
cocrystal
CTC profiling
Analyzing the impact of molecular
and thermodynamic properties on
compaction behavior
of cocrystals
Generation of
cocrystal
Particle and bulk level
characterization
Nanoindentation
03
05
07
04
Impact of Molecular & Thermodynamic Properties on Compaction Behavior of Cocrystal
16

24. Selection of cocrystals
• Two reported cocrystals with slip planes
and two reported cocrystals without slip
planes
• Availability of crystallographic information
file (.CIF)
Generation of cocrystals
Cocrystals will be prepared as per the method
reported in literature
Impact of Molecular & Thermodynamic Properties on Compaction Behavior of Cocrystal
Contd…
17

25. Differential Scanning
Calorimetry (DSC)
To analyze thermal
behavior of cocrystals
Optical and Polarized
Microscopy
To determine particle
size distribution and
crystal habit
Powder X-ray
Diffraction (PXRD)
To confirm generation of
cocrystal and its purity
18
Impact of Molecular & Thermodynamic Properties on Compaction Behavior of Cocrystal
Contd…Characterization of Cocrystals

26. 19
Scanning electron microscopy
To determine surface morphology as well as crystal
habit
Particle and bulk level
characterization
Specific surface area
To determine the actual surface area available for
contact points
Density
True density will be calculated using the helium
pycnometer
Porosity
Porosity is required to determine the
compressibility and compactibility of the powder
Impact of Molecular & Thermodynamic Properties on Compaction Behavior of Cocrystal
Contd…

27. 20
COMPACTIBILITY COMPRESSIBILITYTABLETABILITY
Tensile strength vs. porosity
Porosity vs. compaction
pressure
Tensile strength vs.
compaction pressure
CTC Profiling
Tensile strength Porosity
σ =
2𝐹
𝜋𝑑𝑡
ε = 1 -
𝜌 𝑐
𝜌 𝑡
Impact of Molecular & Thermodynamic Properties on Compaction Behavior of Cocrystal
Contd…

28. 21
Nanoindentation
Nanoindentation gives the measurement of hardness and
elastic modulus at particle level
Single crystal will be generated for nanoindentation study
Impact of Molecular & Thermodynamic Properties on Compaction Behavior of Cocrystal
Contd…

29. 22
Analysing the impact of molecular and thermodynamic properties on compaction
behaviour of cocrystals
Compaction
True density
Melting
temperature
Heat of fusion Slip planes
Contd…

30. 23
Year 2018 2019
Month July Aug Sept Oct Nov Dec Jan Feb Mar Apr May June
Literature survey
Molecular modelling to identify slip
plane system
Generation of cocrystals
Characterization of cocrsyats to
confirm purity and solid form
Particle level and bulk level
characterization
CTC profiling
Nanoindentation
Correlating the molecular (slip planes
and true density) and thermodynamic
(heat of fusion and melting
temperature) properties with CTC
profiling
Thesis writing
Timeline
Impact of Molecular & Thermodynamic Properties on Compaction Behavior of Cocrystal

31. THANK YOU

32. Caffeine Salicylic acid Dipicolinic acid 3-Chloro-4-
nirobenzoic acid
Methyl gallate Oxalic acid
Caffeine-oxalic acid cocrystal