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LICENTIATE T H E S I S
Department of Health ScienceDivision of Medical Science (Pharmacy)
Relationship Between Crystal Structure and Mechanical Properties in Cocrystals and
Salts of Paracetamol
Hamzah Ahmed
ISSN 1402-1757ISBN 978-91-7583-196-1 (print)ISBN 978-91-7583-197-8 (pdf)
Luleå University of Technology 2014
Ham
zah Ahm
ed Relationship B
etween C
rystal Structure and Mechanical Properties in C
ocrystals and Salts of Paracetamol
ISSN: 1402-1757 ISBN 978-91-7583-XXX-X Se i listan och fyll i siffror där kryssen är
Relationship Between Crystal Structure and Mechanical Properties
in Cocrystals and Salts of Paracetamol
Licentiate thesis
By
Hamzah Ahmed
Division of Medical Science (Pharmacy)
Department of Health Science
Luleå University of Technology
December 2014
Printed by Luleå University of Technology, Graphic Production 2014
ISSN 1402-1757 ISBN 978-91-7583-196-1 (print)ISBN 978-91-7583-197-8 (pdf)
Luleå 2014
www.ltu.se
To my family and
To the protectors of human dignity in the city of Kobanê in Rojava and in Bashur.
1
Abstract
Oral tablets are convenient and widely administered drug dosage forms. The mechanical
properties of a drug substance such as plasticity, ability to cohere into compacts and
friction/adhesion are important in the development of a tablet formulation. Crystal engineering
is an interesting and viable tool for improving or optimizing these technical properties of a drug
substance. The creation of alternative polymorphic forms, cocrystals, salts or hydrates of a drug
substance can result in structural variations in the molecular packing of the crystals and,
thereby, can alter the deformation behavior of the materials. Knowledge of the relationships
between crystal modifications and the technical properties in multicomponent systems is
limited, but represents a possibility to predict mechanical properties based on crystal structure
that facilitates engineering particles for the optimal processing performance. The overall
objective of this thesis is thus to gain better understanding of the relationships between the
crystal structure features and the mechanical properties of cocrystals and salts.
Paracetamol form I, its cocrystals with oxalic acid and 4,4-bipyridine, and its
hydrochloride salt were selected as model systems in the study. The materials were scaled-up
using rational crystallization methods and the physical purity was confirmed. The relevant
properties of these powders were determined. Tablets were then made at applied pressures of
50-250 MPa under controlled conditions. The tabletability and compactability of the powders
were determined. The compression mechanics of the powders were then investigated according
to a material classification protocol. Slip planes were identified by visually observing the
crystal structures and based on the attachment energies calculated using different force fields in
the materials studio.
The tensile strengths of the powders increased with increasing pressure and the
tabletability decreased in the order oxalic acid > paracetamol- hydrochloride salt ≈
paracetamol- oxalic acid > 4,4-bipyridine > paracetamol- 4,4-bipyridine. The tensile strength
of the tablets decreased exponentially with increasing porosity, with some exceptions. In
general, the cocrystals and the salt displayed intermediate compression characteristics as
compared to the reference substances. The elastic recovery of the cocrystal and salt forms of
paracetamol was not markedly different from that of paracetamol.
It was found that slip plane prediction based on the attachment energies was not
reliable. While it was possible to explain the improved tableting properties of powders based on
the crystal features (i.e. the presence of slip planes and flat layers), no clear relationship was
2
found with yield pressure. This may be attributed to possible brittle material characteristics and
the surface energies of the crystals, which need to be further studied.
Thus, cocrystallization and salt formation introduced structural features that were
responsible for changes in the compaction and compression properties of drug substances. In
future work, we intend to extend these studies to provide a clear picture of structure-mechanical
property relationships in organic molecular crystals over multiple length scales; molecules to
crystals to bulk powder.
Key words
Crystal engineering, solid forms, cocrystals, salts, tableting, crystal structure, mechanical
properties, compression analysis
3
Appended papers
I. Insight on the correlation between mechanical properties and crystal structure of
cocrystals and salt of paracetamol
Hamzah Ahmed, Manishkumar R. Shimpi, Göran Alderborn and Sitaram Velaga
(Manuscript)
II. Effect of cocrystallization and salt formation on the mechanical properties of
paracetamol analyzed by powder compression
Hamzah Ahmed, Göran Alderborn, Sitaram Velaga and Ann-Sofie Persson
(Manuscript)
4
Table of Contents
1. Introduction .............................................................................................................................. 7
2. Overall Objective and Aims ................................................................................................... 10
3. Materials and Methods ........................................................................................................... 11
3.1 Materials ........................................................................................................................... 11
3.2 Scale-up of Cocrystals and Salts of Paracetamol ............................................................. 11
3.2.1 Preparation of paracetamol-oxalic acid cocrystal (PRA-OXA) ................................ 11
3.2.2 Preparation of paracetamol-4,4-bipyridine cocrystal (PRA-BPY) ........................... 11
3.2.3 Preparation of paracetamol-hydrochloride monohydrate salt (PRA-HCL) ............... 11
3.3 Physical Purity Assessment of Scaled-up Materials ......................................................... 11
3.3.1 Differential scanning calorimetry (DSC) ................................................................... 11
3.3.2 Powder X-ray diffraction (PXRD)............................................................................. 12
3.4 Dry Sieving of Powders .................................................................................................... 12
3.5 Powder Characterization ................................................................................................... 12
3.5.1 Powder density measurements ................................................................................... 12
3.5.2 Scanning electron microscopy (SEM) ....................................................................... 13
3.6 Characterization of Tableting Behaviour .......................................................................... 13
3.6.1 Tabletability ............................................................................................................... 13
3.6.2 Characterization of tablets ......................................................................................... 14
3.6.3 Measurement of tensile strength/hardness ................................................................. 14
3.6.4 Tablet porosity ........................................................................................................... 14
3.7 Powder Compression ........................................................................................................ 14
3.8 Compression Analysis Using Powder Compression Models ........................................... 15
3.8.1 The Kawakita equation .............................................................................................. 15
3.8.2 The Shapiro general compression equation ............................................................... 16
3.8.3 The Heckel equation .................................................................................................. 16
3.8.4 The Frenning effective medium equation .................................................................. 16
3.9 In-die Elastic Recovery .................................................................................................... 17
3.10 Molecular Modeling ....................................................................................................... 17
4. Results and Discussion ........................................................................................................... 19
4.1 Scale-up and Purity Evaluation of Different Solid Forms ................................................ 19
4.2 Powder Characterization ................................................................................................... 20
4.3 Compaction Behaviour of Powders .................................................................................. 22
4.4 Compression Behaviour of Powders ................................................................................ 24
4.5 In-die Elastic Recovery .................................................................................................... 28
4.6 Crystal Structure Visualization and Analysis.................................................................... 29
5. Conclusions ............................................................................................................................ 33
6. Future Perspectives ................................................................................................................. 34
7. Acknowledgements ................................................................................................................. 35
8. References .............................................................................................................................. 36
5
Abbreviations and symbols
Effective medium parameter
A Heckel compression parameter
ab Product of Kawakita parameters
API Active Pharmaceutical Ingredient
BPY 4, 4'-Bipyridine
Kawakita compression parameter
Engineering strain
CIF Crystallographic Information File
CSD Cambridge Structural Database
DSC Differential Scanning Calorimetry
dt Tablet diameter
Young’s modulus
E Powder bed porosity
Eatt Attachment energy
The in-die elastic recovery
E0 Initial powder bed porosity
EM Effective Medium
ER Elastic recovery
tF Force
FDA Food and Drug Administration
f Shapiro compression parameter
GPa Giga Pascal
Powder bed height during compression
Initial powder bed height
Initial height
Height at zero porosity
Height of the powder bed at maximum load
ht Tablet height
Height during decompression
IP Intellectual property
k Heckel compression parameter
mm Millimeter
6
MPa Mega Pascal
N Newton
n Number of experiments
OXA Oxalic Acid
P Applied compression pressure
Start pressure
PRA Paracetamol
PRA- BPY Cocrystal of Paracetamol with 4, 4'-Bipyridine
PRA- HCl Salt of Paracetamol with Hydrochloride monohydrate form
PRA- OXA Cocrystal of Paracetamol with Oxalic Acid
Py Yield pressure
RH Relative Humidity
s Second
SEM Scanning Electron Microscopy
PXRD Powder X-Ray Diffraction
Elastic punch deformation
µm Micrometer
ρapp Apparent particle density
ρbulk Poured powder bulk density
ρcal Calculated crystal density
ρtap Tapped powder bulk density
t Tablet tensile strength
7
1. Introduction
Oral tablets are popular solid dosage forms because of ease of administration, potential for
accurate dosage and self-medication, associated avoidance of injection pain, and improved
patient compliance. Understanding the mechanical properties of a drug substance, such as
plasticity, ability to cohere into compacts and friction/adhesion, is very important in the
development of a tablet formulation. An active pharmaceutical ingredient (API) can exist in
amorphous or crystalline forms. The crystalline solid forms can be classified into polymorphs,
hydrates, salts, cocrystals, etc. Polymorphs are single-component systems with different crystal
packing patterns or conformations. In contrast, hydrates, cocrystals and salts are
multicomponent systems that contain guest molecules in the crystal lattice. Different solid
forms of an API can display significantly different physical, chemical, thermal, spectroscopic
and mechanical properties, which can consequently affect the formulation, manufacturing, and
performance of the product (1).
1.1 Cocrystals
Crystal engineering, a method of designing solids through the manipulation of the crystal
structure, is an effective tool for tailoring the physicochemical and technical properties of
pharmaceutical solids (2). Of the different solid forms mentioned above, cocrystals have been
extensively studied for diverse applications in pharmaceutics, including improving the
solubility of poorly soluble drugs and modifying the technical properties of an API. The United
States Food and Drug Administration (FDA) defines pharmaceutical cocrystals as crystalline
materials composed of two or more molecules within the same crystal lattice (3). Another
generally accepted definition defines cocrystals as crystalline materials that comprise an API
and one or more cocrystal formers (coformers), which are solids at room temperature (4). In the
cocrystal lattice, an API and the coformer(s) are bound together by several interactions,
including hydrogen bonding, pi-stacking, and Van der Waals forces (5).
Cocrystals can also offer benefits in terms of intellectual property (IP) protection
and extending the life cycle of an old API (6). In recent years, increasing numbers of patent
applications for cocrystals indicate that pharmaceutical companies appear to be developing
drug formulations containing cocrystals (7).
8
1.2 Salts
Salt formation is an acid-base reaction between the API and an acidic or basic counter ion. This
strategy has been widely implemented in pharmaceutical development to rectify undesirable
properties of APIs (8). Salts are formed through ionic interactions whilst cocrystals rely on
directional hydrogen bonds in their crystal structures. The location of the proton between the
acid and the base distinguishes a cocrystal from a salt; the proton is shared in cocrystals and
transferred in salts.
1.3 Mechanical Properties
It is important to properly understand these mechanical properties and material deformation
phenomena in the context of powder compaction as well as material processing by milling (9).
Materials under an applied stress can undergo deformation involving elasticity, plasticity,
viscoelasticity, brittle fracture or fragmentation, or a combination of these, depending on the
nature of the applied stress and the crystal structure (10). If the deformation of a material is
reversible, it is called an elastic material. The elastic deformation is proportional to the applied
stress, as explained by the reversible stretching of intermolecular bonds (11). On the other
hand, plastic deformation refers to permanent, irreversible changes in the molecular structure
(12). Viscoelasticity is the combination of these phenomena, as exhibited by pharmaceutical
materials in reality (13). Finally, if the strain exceeds the stress created in the material,
fragmentation occurs (14). Elastic recovery predominates during the decompression stage of
the compression process for pharmaceutical materials (15, 16). The decompression stage may
be divided into two phases (17). The first, immediate axial elastic recovery, occurs during the
initial decompression phase. The second phase is viscoelastic recovery, which can occur over a
prolonged period of time both in-die and out-of-die. Extensive axial elastic recovery typically
causes tablets to cap, thus indicating that the material has poor compressibility properties. The
material compression properties have been modeled by Heckel, Kawakita, Shapiro and
Frenning. Recently, a protocol for classifying materials based on these compression models has
been developed (18).
Changes to the crystal structures/packing and interaction energy of a material can
cause differences in its mechanical properties. A few studies focusing on single-component
systems have investigated the relationships between the compaction properties and the
plasticity of the crystal structure of a material (19). However, studies on the relationships
between crystal structure and mechanical properties are scarce in multicomponent
9
pharmaceutical solids like cocrystals or salts (20). Thus, this thesis aims to improve
understanding of structure-property relationships in multicomponent systems.
1.4 Paracetamol and its Cocrystals and Salt
Paracetamol can exist in three polymorphic forms: form I (monoclinic), form II (orthorhombic)
and form III; of these, form I is thermodynamically stable. It is well known that form I (the
commercial form) exhibits poor tableting properties due to lack of slip planes in the crystal
structure (21). Many cocrystals and salt forms of paracetamol have been prepared with the aim
of improving its physical and mechanical properties (22, 23). The model systems we selected
for this work include paracetamol (form I; PRA), two of its cocrystals [1:1 cocrystals of
paracetamol with oxalic acid (PRA-OXA) and paracetamol with 4, 4'-bipyridine (PRA-BPY)],
and its hydrochloride salt (monohydrate form; PRA-HCl). PRA-OXA and PRA-BPY were
selected because of their significant differences from PRA in crystal packing and hydrogen
bonding patterns. PRA-HCl undergoes ionic interactions that result in different packing of
molecules and ions in the crystal structure.
10
2. Overall Objective and Aims
The overall objective of the thesis is to improve understanding of the relationships between the
crystal structure features and the mechanical properties of pharmaceutical solids with particular
focus on multicomponent systems such as cocrystals and salts. Thereby, we intend to provide
insights and tools for predicting the mechanical properties of pharmaceutical solids based on
their crystal structures. The specific aims of this part of the work include:
To experimentally investigate the mechanical properties of different solid forms;
To identify slip planes through visualization of the crystal structures and calculation of
attachment energies (Eatt) using molecular modeling software;
To apply the models of Heckel, Kawakita, Shapiro, and Frenning to compression
analysis and to evaluate the compression properties.
11
3. Materials and Methods
3.1 MATERIALS
Paracetamol (form I, monoclinic form), α-oxalic acid and 4,4-bipyridine were purchased from
Sigma-Aldrich (Germany). Hydrochloric acid (37%) was purchased from Merck KGaA
(Germany). Solvents used were GC grade and were purchased from Sigma Chemical Company
(St. Louis, MO). Chemicals and solvents were used as received.
3.2 SCALE-UP OF COCRYSTALS AND SALTS OF PARACETAMOL
3.2.1 Preparation of paracetamol-oxalic acid cocrystal (PRA-OXA)
A 50 mL glass vial was charged with 30.2 g (0.2 mmol) of paracetamol, and 18 g (0.2
mmol) of oxalic acid. About 10 mL of ethyl acetate was added to form a slurry. The
reaction was left to stir for a total of 48 hours, at which time the solids present were
isolated by vacuum filtration and air dried at room temperature.
3.2.2 Preparation of paracetamol-4,4-bipyridine cocrystal (PRA-BPY)
A 50 mL glass vial was charged with 30.2 g (0.2 mmol) of paracetamol, and 31.2 g (0.2
mmol) of 4,4-bipyridine. 10 mL of acetonitrile was added to form a slurry. The reaction
was left to stir for a total of 18 hours, at which time the solids present were isolated by
vacuum filtration and air dried at room temperature.
3.2.3 Preparation of paracetamol-hydrochloride monohydrate salt (PRA-HCL)
A 250 mL conical flask charged with 30.2 g (0.2 mmol) of paracetamol in conc. HCl
(150 mL) was left at room temperature with constant stirring for 12 hours. The solids
present were isolated by vacuum filtration and air dried for 12 hours at 40 °C in an oven.
3.3 PHYSICAL PURITY ASSESSMENT OF SCALED-UP MATERIALS
3.3.1 Differential scanning calorimetry (DSC)
The DSC profiles of the solid samples were generated over a range of 30–200 °C using a TA
Q1000 DSC instrument with a refrigerated cooling unit. The temperature was calibrated using
an indium metal standard at the respective heating rate. Samples (3–5 mg) were crimped into
12
non-hermetic aluminum pans and scanned at a heating rate of 10 °C/min under a continuously
purged dry nitrogen atmosphere (flow rate 50 mL/min) using a similar empty pan as reference.
The data were collected in triplicate for each sample and analyzed using TA Universal Analysis
software.
3.3.2 Powder X-ray diffraction (PXRD)
PXRD patterns for the samples were collected using an Empyrean X-ray diffractometer
(PANalytical, The Netherlands) equipped with a PIXel3D detector and a monochromatic Cu Kα
radiation X-ray tube (1.54056). The tube voltage and amperage were set at 45 kV and 40 mA,
respectively. Samples were placed onto a metal sample holder and flattened. The instrument
was calibrated using a silicon reference standard. Each sample was scanned over a 2θ range of
5o to 40
o, increasing at a step size of 0.02
o. The data were processed using HighScore Plus
software (PANalytical, The Netherlands).
3.4 DRY SIEVING OF POWDERS
Size fractions (<90 µm, 90-360 µm, >360 µm) of all the materials were prepared by dry sieving
through a series of sieves (Precision sieve, Eerbeek-Holland) mounted on a mechanical sieve
shaker (Retsch KG, Germany) that were vibrated for 10 minutes at an intensity of 40. The size
fraction 90-360 µm was chosen for subsequent study. The sieved powders were stored in a
desiccator over a saturated MgCl2 (Sigma-Aldrich, Steinberg, Germany) solution for at least
one week at ̴ 33% relative humidity and room temperature ( ̴ 22 °C) before other powder
characterizations. The salt solution was prepared according to Nyqvist (24).
3.5 POWDER CHARACTERIZATION
3.5.1 Powder density measurements
The apparent (ρapp), tapped (ρtapped) and poured bulk (ρbulk) densities of the dry sieved raw
material and its solid forms (size fractions 90-360 µm) were also determined.
The apparent particle densities, which are sometimes also called the true particle densities, of
substances were measured using helium pycnometry (AccuPyc 1330, Micromeritics, USA).
The equipment was calibrated before use and three analyses were performed for each
substance. Ten repeated cycles were measured for each analysis and an average value was
obtained.
13
The tapped bulk densities were measured using tap density testing equipment (PharmaTest, PT-
TD, Germany). First, the substance was poured carefully via a funnel into a 50 mL graduated
glass cylinder. Then the sample was weighed on an analytical balance (Sartorius, PT610,
Germany). The glass cylinder was then mounted on the equipment and tapped up to 1000 taps.
The volume of the substance was then determined visually; three experiments were carried out
and the tapped bulk densities were calculated.
The poured bulk densities of the dry sieved substances (size fractions 90-360 µm)
were also determined. The substance was poured carefully, using a funnel to avoid any shaking,
into a 10 ml graduated glass cylinder with a diameter of 11.1 mm. The sample was then
weighed on a balance (Mettler Toledo, AG245, Switzerland). The volume of the substance was
determined visually; two experiments were conducted and the poured bulk densities were
calculated.
3.5.2 Scanning electron microscopy (SEM)
Scanning electron microscopy was used to examine the particle shape and size of the sieved
fractions of particles of PRA powder, PRA-OXA, PRA-BPY, OXA and BPY. The powders
were carefully sprinkled onto the double-sided adhesive carbon tape which was then stuck onto
the metal sample holder and gold sputtered under vacuum. SEM examinations were performed
on a LEO 1530 (Gemini, Leo, UK). A Merlin SEM (Zeiss, Germany) was used for examining
morphology of PRA-HCl. An accelerating voltage of 4 KV, a current of 1.2 nA and a working
distance of 8.5 mm were used. The samples were coated with a thin film of tungsten (ca 3 nm).
3.6 CHARACTERIZATION OF TABLETING BEHAVIOUR
3.6.1 Tabletability
Five tablets (an amount of 340-570 mg) were produced from each of the sieved materials
except PRA at an applied pressure of 50-250 MPa under ambient conditions at ̴ 22 °C and ̴
33% relative humidity. Before the experiments were carried out, the die, upper punch and lower
punch were lubricated with a thin layer of magnesium stearate. A single-punch tablet press
machine (Korsch EK0, Berlin, Germany) was used to produce the tablets. The distance between
the lower punch and the upper punch was constant (3 mm) and the machine was equipped with
11.3 diameter flat-faced punches.
14
3.6.2 Characterization of tablets
After compression, the tablets were stored in a humidity-controlled room at 33% relative
humidity and room temperature (̴ 22 °C) for 48 hours. Then the tablets were weighed on an
analytical balance (Mettler Toledo, AG245, Switzerland). The height ( th ) and diameter ( td )
were measured in micrometers (Mitutoyo, Japan).
3.6.3 Measurement of tensile strength/hardness
The force ( tF ) required to break the tablets was determined with a tablet testing machine
(Pharma Test, type PT B311E, Germany) and in a diametric tablet hardness tester (Holland
C50, UK) at a constant speed of 1 mm/min (used only for 5 tablets of OXA at a pressure of 250
MPa). The tablet tensile strength ( t ) was computed using Fell and Newton's equation
(equation 1) (25):
tt
tt
dh
F
2 [Equation 1]
where Ft is the force needed to crush the tablets, ht is the tablet height and dt is the tablet
diameter.
3.6.4 Tablet porosity
The tablet porosity was obtained from the tablet density ( tablet ) and the apparent powder
density ( app ) using equation 2 (26). The tablet density ( tablet ) was calculated from tablet
weight and volume.
app
tablet
1 [Equation 2]
3.7 POWDER COMPRESSION
A materials testing machine (Zwick Z100, Zwick/Roell Zwick GmbH & Co. KG, Ulm,
Germany) equipped with 11.3 mm diameter flat-faced punches was used for the compressions.
The powder was compressed in a humidity-controlled room at ~33% relative humidity and at
room temperature (~22 °C). Before the compressions, to reduce the frictional forces, the die
and punches were lubricated with a 1% w/w magnesium stearate (Kebo, Sweden) suspension in
ethanol and air dried. During compression, the lower punch was stationary and the upper punch
15
moved with a speed of 10 mm/min up to an applied pressure of 500 MPa. Approximately 400
mg of each substance was weighed on an analytical balance (Mettler Toledo, AG245,
Switzerland) and poured manually into the die. Two analyses were performed for each
substance. Samples were taken at increasing forces (every 5 N), times (every 0.01 s), and
distances (every 0.1 mm).
The elastic punch deformation ( ) was assessed from punch deformation curves
obtained by pressing the upper and lower punches together at up to 500 MPa, as described
earlier (27). The punch deformation curves were fitted to the equation where the exponential term describes the initial curvature at low pressures. The parameters ,
, and were determined from the fit and used to correct the powder bed height during
compression and decompression. The punch deformation amounted to approximately 0.4
µm/MPa.
3.8 COMPRESSION ANALYSIS USING POWDER COMPRESSION MODELS
Compression analysis during loading was carried out according to the classification protocol
suggested by Nordström et al. (18). This is based on equations commonly encountered in
powder compression analysis, including the Kawakita equation [17], the Shapiro general
compression equation (28), and the Heckel equation (29). In addition, the novel analytically
derived Frenning effective medium (EM) equation was used (30). The equations were used as
described below.
3.8.1 The Kawakita equation
The Kawakita equation (31) describes the relationship between engineering strain ( ) and
pressure ( ) as:
, [Equation 3]
where is the height of the initial powder bed, calculated from the poured bulk density, and
is the height of the powder bed during compression. and are known as the Kawakita
parameters and represent the maximal engineering strain and the pressure required to reach
, respectively. The parameters were calculated from the linear form of the equation,
, [Equation 4]
using linear regression in the pressure range 25-500 MPa ( >0.999). The product has
recently been shown to have the potential to indicate the extent of particle rearrangement
16
during compression (32). An index larger than 0.1 suggests extensive particle
rearrangement and classifies the powder as a Class I material (18).
3.8.2 The Shapiro general compression equation
The Shapiro general compression equation (28),
, [Equation 5]
was applied to determine the ductile (Class IIA) and brittle (Class IIB) material properties of
Class II materials, i.e. powders exhibiting limited particle rearrangement (33). This equation
describes the relationship between the porosity of the powder bed during loading ( ) and the
pressure. is the initial powder bed porosity and and are constants. The Shapiro
parameter was calculated using the least-square method in the pressure range 0.1-50 MPa using
a relative criterion of ≤ 0.00001.
3.8.3 The Heckel equation
The Heckel equation (29) describes the change in powder bed porosity ( ) with applied
pressure as,
, [Equation 6]
where and are the slope and intercept of the linear region, respectively. is commonly
referred to as the Heckel number and is considered to represent the yield pressure of the powder
material. The Heckel number was calculated by linear regression as described earlier (34). The
pressure range for the regression analysis was selected by an Excel macro identifying a
minimum derivative as the first value and a 25% increased derivative as the second value for
each compression. This derivation used a pressure interval between 0.5 and 500 MPa. For all
compressions, the regression analysis was >0.999.
3.8.4 The Frenning effective medium equation
The Frenning EM equation (30), which is also related to the material yield pressure (34),
describes the relationship between the pressure and the height of the powder bed ( ) during
compression as,
, [Equation 7]
17
or in linear form,
. [Equation 8]
The equation considers the start pressure ( ), the initial height ( ) and the
height at zero porosity ( ). The latter was calculated from the material weight and the
apparent particle density. is a product of and . was determined by linear regression in a
similar manner to that used for the Heckel number except that the first value was obtained from
a maximum derivative and the second value from a minimum derivative (25% deviation).
Powder bed heights exceeding 10 mm were excluded from the analysis ( >0.998).
3.9 IN-DIE ELASTIC RECOVERY
Calculations of the in-die elastic recovery ( ) were performed from the complete
decompression curves (n=2) according to Eq. 9 (35, 36),
, [Equation 9]
where is the height during decompression and is the height of the powder bed
at maximum load. The elastic punch deformation during decompression was assumed to be
equal to the deformation during compression and was corrected for in the calculations of
.
The elastic Young’s modulus was calculated from the reciprocal of the slope of the relationship
between and the normalized pressure ( ) in the range 100-400 MPa (
0.989).
3.10 MOLECULAR MODELING
The crystal structure data files for PRA (monoclinic form), PRA-OXA, PRA-BPY, PRA-HCL,
OXA, and BPY were acquired from the Cambridge Structural Database (ConQuest 1.15, CSD,
UK) with CSD crystal IDs HXACAN01, LUJTAM, MUPQAP, 835705, OXALAC03 and
HIQWEJ02, respectively. Diamond software (37) was used to visualize the molecular packing,
crystal lattice, hydrogen bonding pattern, and slip planes and to generate simulated PXRD
patterns. These simulated X-ray patterns were used as a reference for identification and
experimental evaluation of the solid phase.
The Materials Studio 7.0 (Accelrys, Inc.) was used to calculate the attachment
energies (Eatt) of the different solid forms of paracetamol. The CIFs of the respective solid
forms were imported into the software and bond angles and distances were set to ideal values.
18
In the next step, the geometry of the crystal structures was optimized using the Forcite module
with COMPASS II force fields (with the Qeq charging scheme) without changing the symmetry
and unit cell parameters. The geometrically optimized structures were utilized to calculate the
attachment energies using the growth morphology module as implemented in the Materials
Studio. COMPASS II and Dreiding force fields (both with Qeq charging schemes) were
implemented to yield the list of attachment energies (in Kcal/mol) for the different faces (38,
39).
19
4. Results and Discussion
4.1 SCALE-UP AND PURITY EVALUATION OF DIFFERENT SOLID FORMS
Solution crystallization methods such as reaction crystallization and slurry conversion have
been successfully employed in the large-scale preparation of cocrystals (40). These methods
rely on creating a thermodynamic driving force towards the formation of cocrystals, i.e.
controlled supersaturation with respect to cocrystals (41-44). Phase solubility or ternary phase
diagrams, constructed from the empirical solubility data of the components, have been used to
identify the operating regions for successful preparation of cocrystals (45). The knowledge of
these phase diagrams and regions of thermodynamic stability for cocrystals and their
components have been applied in the scale up of PRA-OXA and PRA-BPY cocrystals. The
region of cocrystal formation (i.e. the region where cocrystals are the thermodynamically
favoured phase) was accessed by selecting a solvent in which the solubilities of PRA and OXA
or BPY were similar. Slurry conversion experiments based on the stoichiometric ratios of the
components in the respective solvents led to the formation of PRA-OXA and PRA-BPY
cocrystals. About 100g of the cocrystals were produced. The PRA-HCL salt was obtained from
an acid-base reaction as monohydrate. The physical purity of the cocrystals and the salt was
confirmed by DSC and PXRD (Figure 1). DSC thermograms of the bulk cocrystals and the salt
showed distinct melting points for the pure phases, confirming the absence of traces of starting
materials (Figure 1a). Furthermore, the PXRD patterns of the bulk cocrystals and the salt were
distinct and compared well with the simulated PXRD patterns. These results confirmed the
purity of the bulk cocrystals and the salt (Figure 1b).
20
(a) (b)
Figure 1. (a) PXRD patterns for paracetamol (form I) and its cocrystals and salt. The
experimental simulated patterns generated from CIF of the cocrystals and the salt (shown in the
same color) are overlaid for comparison. PXRD patterns for OXA and BPY are not shown. (b)
DSC thermograms for PRA, PRA-OXA, PRA-BPY, PRA-HCl, OXA and BPY.
4.2 POWDER CHARACTERIZATION
SEM micrographs of the sieved materials are shown in figure 2. PRA particles are plate-like
while the remaining powders are block-shaped with varying degrees of aggregation. The
primary particles of the sieved materials were visibly smaller than the intended size fraction of
90-360 µm. The apparent particle densities ( app), tapped bulk densities ( tapped) and poured
bulk densities ( bulk) of all substances are summarized in Table 1. The apparent particle
densities of all the starting materials were between 1.232 and 1.903 g/cm3; the tapped bulk
densities were between 0.580 and 0.824 g/cm3. The poured bulk densities for the sieved
fraction 90-360 µm were between 0.255 and 0.627 g/cm3 for all the substances. No clear trends
in the densities of PRA and its cocrystals were found, although the apparent densities of the
cocrystals/salt were between those of the pure components. The apparent densities of the
powders were in reasonable agreement with the theoretical densities of the materials (Table1).
21
(a) (b)
(c) (d)
(e) (f)
Figure 2. Scanning electron micrographs of (a) PRA, (b) PRA-OXA, (c) PRA-BPY, (d) PRA-
HCl, (e) OXA and (f) BPY. Scale bar is different in different images.
22
Table 1. Powder densities of the studied substances (standard deviations are in parentheses).
a
Apparent particle density (n=3).
b Poured bulk density (n=2).
c Tapped bulk density (n=3).
d Calculated crystal density from crystal structure.
In general, particle size, particle shape, surface area and porosity influence the density of
powders (46). In a previous study in which the particles did not fracture, larger particles
showed lower surface area for bonding (47). This in turn led to lower tensile strength at the
same compaction pressure.
4.3 COMPACTION BEHAVIOUR OF POWDERS
The tabletability of a powder is its capacity to be transformed into a tablet of specified strength
under the effect of compaction pressure (48). The tabletability of a substance can be
represented by a plot of tensile strength versus compaction pressure. It was not possible to
make tablets of thermodynamically stable form of PRA at any pressure. In fact, many studies
have reported that this problem (high capping tendency) is related to the stiff nature and
relatively high elastic deformation properties of the material (49). A change in the crystal habit
or crystal structure improves the tableting properties of paracetamol (49, 50). The tabletability
profiles of the cocrystals (PRA-OXA and PRA-BPY), the salt (PRA-HCl) and the coformers
(OXA and BPY) are shown in Figure 3.
Substance
ρappa
(g/cm3
)
ρbulkb
(g/cm3
)
ρtapc
(g/cm3
)
ρcald
(g/cm3
)
PRA
1.297
(0.001)
0.255
(0.001)
0.599
(0.013)
1.293
PRA-OXA
1.481
(0.002)
0.307
(0.001)
0.610
(0.007)
1.507
PRA-BPY
1.260
(0.001)
0.344
(0.001)
0.580
(0.009)
1.306
PRA-HCL
1.420
(0.000)
0.426
(0.002)
0.633
(0.001)
1.426
OXA
1.903
(0.001)
0.627
(0.002)
0.824
(0.007)
1.913
BPY
1.232
(0.003)
0.461
(0.000)
0.733
(0.001)
1.256
23
(a) (b)
Figure 3. Tabletability (a) and compactability (b) curves for cocrystals of PRA-OXA, PRA-
BPY, PRA-HCl, OXA and BPY. The error bars show standard deviations.
The tabletability of the substances decreased in the following the order: OXA > PRA-HCl ≈
PRA-OXA > BPY > PRY-BPY (Figure 3a). With the exception of PRA-BPY, the powders
showed increased tensile strength with increasing pressure. The cocrystals and salt powders
displayed significantly better tableting properties than PRA. These results are in line with those
reported earlier (22, 23). However, a desirable tensile strength of >2 MPa was exhibited only
by OXA, although the values for PRA-OXA and PRA-HCl were >1.8 MPa. Improved
tabletability of a drug substance as a result of cocrystallization and salt formation has been
reported earlier (51). Although cocrystals of PRA-OXA and PRA-BPY showed considerably
better tableting properties than PRA, there was a tendency for varying degrees of random
capping, fragmentation and lamination. This capping tendency was also observed to be greater
at higher pressures in these powders. The common signs of overcompaction are a detrimental
effect of compaction pressure on tablet mechanical strength and severe lamination (51). In
contrast, no capping, fragmentation or lamination were detected for PRA-HCl, OXA or BPY.
Compactability is the ability of a powdered material to be transformed into strong
tablets during densification (48). The compactability curves (i.e. porosity vs tensile strength)
for the cocrystals, salt and coformers are shown in figure 3b. Tablet tensile strength decreases
exponentially with increasing porosity and the tensile strength at zero porosity is often used to
rank the tableting performance of powders (52). Most of the powders couldn’t be compacted
into intact tablets under ca 15% porosity. Interestingly, PRA-BPY and BPY showed very small
changes in porosity with increasing tensile strength. OXA formed an excellent tablet with a
porosity >25% at a tensile strength of 5MPa.
The powder compaction behaviour of pharmaceutical materials is dependent on
the relative predominance of the elastic and plastic components. The extent and strength of
24
interparticulate bonding, resulting from particle rearrangement and deformation, determine the
tablet formation and its mechanical strength. Thus, plastic materials tend to form larger
interparticulate bonding areas under compaction, resulting in tablets with good mechanical
strength (53). Modification of the crystal structure to promote the formation of larger
interparticulate bonding areas and plasticity has been proposed as a strategy to improve the
tensile strength of materials (54). The improved tableting properties can be attributed to the
changes in crystal structure. In depth analysis of the crystal structures is presented in a later
section, providing important insights into the reasons for these improvements.
4.4 COMPRESSION BEHAVIOUR OF POWDERS
Compressibility is the ability of a material to undergo a reduction in volume as a result of an
applied pressure (48). According to the classification protocol (18), the powders were first
classified by analyzing their pressure-strain relationship (Figure 4a). In general, the cocrystals
and the salt displayed pressure-strain profiles of intermediate character as compared to the
reference substances (i.e., paracetamol, bipyridine, and oxalic acid). The strain was highest for
PRA and lowest for BPY and OXA. However, the appearance of the two latter profiles differed,
as discussed below. The Kawakita parameters and were derived from the linear
relationship (Figure 4b) to generate an estimation of the compressibility properties of the
powders.
(a) (b)
Figure 4. Typical representations of the non-linear (a) and linear (b) Kawakita relationships for
the substances.
The powders were ranked in the following order in terms of the parameter reflecting the
compressibility (from high to low) at infinite pressure: PRA > PRA-OXA > PRA-BPY > PRA-
HCl > BPY > OXA (Table 2). Hence, the compressibility of the reference substances either
decreased (PRA) or increased (BPY and OXA) when self-assembled into cocrystals. In
25
addition, the compressibility of the PRA-HCl salt was decreased. The initial parts of the strain-
pressure profiles (Figure 4a) displayed a rapid increase in strain at low pressures for all
powders expect OXA. This was confirmed from the parameter that was much higher for
this substance than for the others (Table 2), suggesting that these decreased in volume more
rapidly. The product of and (i.e., the index; Table 2) was <0.1 for OXA, indicating a
limited degree of particle rearrangement during compression and OXA was hence classified as
a Class II material (32). The other substances displayed values > 0.1 and were classified as
Class I materials displaying extensive particle rearrangement. Similar results have previously
been reported for PRA (55).
Table 2. Compression parameters and mechanical classification of the powders (standard
deviations are given in parentheses).
Substance
a
(-)
b
(MPa)
c
(-)
d
(-)
e
(MPa)
f
(MPa) Klass
PRA
0.811
(0.000)
2.95
(0.01)
0.27
(0.001)
107.1
(0.6)
116.8
(0.3) I
PRA-OXA
0.803
(0.000)
3.39
(0.03)
0.24
(0.002)
87.0
(1.1)
91.7
(1.3) I
PRA-BPY
0.746
(0.000)
4.26
(0.01)
0.17
(0.001)
62.0
(0.8)
68.2
(0.9) I
PRA-HCl
0.713
(0.000)
5.98
(0.06)
0.12
(0.001)
91.6
(1.0)
99.0
(1.3) I
OXA
0.643
(0.000)
11.44
(0.11)
0.06
(0.001)
0.13
(0.00)
914.5
(5.4)
1039.1
(9.4) IIB
BPY
0.651
(0.000)
4.68
(0.05)
0.14
(0.001)
39.7
(0.8)
43.7
(0.9) I
a Kawakita parameter (n=2),
b Kawakita parameter (n=2),
c Rearrangement index (n=2),
d Shapiro parameter (n=2),
e Heckel yield pressure (n=2),
f Effective medium parameter (n=2).
The Class II substance was then classified with respect to the Shapiro parameter, which
considers the initial slope of the compressibility profile. For OXA, exceeded the limit of 0.1
(Table 2), thereby categorizing the material as a Class IIB material (i.e., a material with brittle
characteristics). The parameter was not calculated for the other powders because of their
propensity for extensive rearrangement. However, they might still be brittle; for example,
paracetamol is known for its fragmenting properties (56).
26
The hardness of the substances was then categorized with regard to the Heckel
yield pressure parameter ( ) to provide estimations of the particle plasticity (56). In general,
the complete Heckel profiles (Figure 5) were similar with respect to curve shape for all
substances except OXA. The initial slope of these curves corresponded to the extent of particle
rearrangement or fragmentation at low applied pressures (35). This was followed by a linear
region signifying the plastic particle deformation, which was subsequently used to determine
.
(a) (b)
Figure 5. Representative Heckel profiles for the substances in (a) the complete pressure range
and (b) the initial pressure range.
The non-linear region at high compression pressure is initiated when plastic particle
deformation becomes limited and elastic deformation instead becomes apparent (35). Elastic
deformation was not evident for OXA; the linear region continued throughout the investigated
pressure range. Based on the calculated (Table 2), BPY and PRA-BPY were categorized as
soft materials. The BPY was not significantly (p > 0.05) lower than 40 MPa, which was the
point of change from very soft to soft, and this material was thus categorized as soft. PRA-
OXA, PRA-HCl, and PRA had values between 80 and 200 MPa and were thereby denoted
moderately hard materials. The unrealistically high of OXA is indicative of a problem of the
Excel macro in identifying a linear region of the Heckel profile and it cannot be used as an
estimation of the particle plasticity. This suggests that the material continuously fractures
during compression and may also show strain hardening during compression; it can thus only
be described as a hard, brittle material.
Finally, the compression analysis was performed with the Frenning EM equation
from which the parameter was determined. As for the Heckel curves, the shapes of the EM
27
profiles could be divided into three regions: an initial nonlinear region, a linear region, and a
plateau (Figure 6a).
(a) (b)
Figure 6. Typical effective medium plots for all substances (a) and plots of the in-die axial
elastic recovery (b). Note that the pressure was normalized with respect to the maximum
applied pressure.
The shapes of the curves were expected with regard to the classification of the substances into
Class I and Class IIB materials (34). The parameters were ranked (from low to high) in the
same order as the values: BPY < PRA-BPY < PRA-OXA < PRA-HCl < PRA < OXA (Table
2). Additionally, the similar magnitudes of and supports their strong correlation, as
inferred from an earlier study (34). Interestingly, the parameter is a factor of 1.1 higher than
, independent of the substance. Moreover, no plastic properties for OXA were seen, due to
the very high , with the EM equation supporting the hypothesis that OXA is a hard, brittle
material.
In summary, the mechanics of PRA and co-formers were altered when they self-
assembled into cocrystals or as a salt. In general, intermediate characteristics with respect to the
parent compounds was obtained for the cocrystals and the salt in terms of the maximal
engineering strain and yield pressure, as inferred from both the Heckel and effective medium
relationships, with the exception of OXA. Moreover, was not solely correlated with the
crystal lattice structures. Flat slip planes were observed for PRA-OXA and PRA-HCl, whereas
zig-zag layers were observed for PRA-BPY (Table 4). Because of the relatively similar
plasticity properties of the substances, factors such as the brittleness and surface energies need
to be further investigated in order to accurately correlate the crystal lattices with the mechanical
properties.
28
4.5 IN-DIE ELASTIC RECOVERY
The relationship in equation 9 has been used previously to assess the elastic recovery when the
powder bed was completely unloaded (see e.g. (35, 57)); it is also known as the immediate
axial recovery (58). In this work, this equation was applied to the total unloading stage (i.e., to
all detectable pressures from the upper punch during decompression). The relationship between
the axial elastic recovery and the normalized pressure can be seen in Figure 6b. All materials
displayed a tendency for time-dependent viscous behaviour (i.e., the negative recovery evident
during the initial unloading). The origin (i.e., plastic or elastic) remains unclear; thus, we chose
to designate this behaviour as solely viscous. The degree of viscosity was greatest for OXA and
slightly lower for its co-crystal PRA-OXA. Hence, it appears that the fragmenting propensity of
OXA causes increased viscosity post-compression compared to plastic materials.
Table 3. The in-die elastic recovery ( ) and the Young’s modulus ( ) calculated from
decompression data (n=2). Standard deviations are given in parentheses.
Substance (%) a (GPa)
PRA 9.6 (0.0) 11.35 (0.04)
PRA-OXA 5.8 (0.1) 10.53 (0.03)
PRA-BPY 7.7 (0.1) 9.60 (0.02)
PRA-HCl 5.9 (0.1) 11.30 (0.01)
OXA 4.1 (0.1) 14.60 (0.14)
BPY 7.2 (0.0) 8.49 (0.00)
After the initial viscous stage, the axial elastic recovery increased linearly, followed by a
nonlinear region that reached a plateau during the last stage of decompression. The plateau was
reached rapidly, accounting for most of the elastic recovery in the materials. The complete axial
elastic recovery ranged from 4.1% for the fragmenting OXA to 9.6% for the elastic PRA (Table
3). Although PRA displayed the largest complete elastic recovery, its recovery during
decompression was lower than that of BPY and PRA-BPY (Figure 6b). It can be hypothesized
that the linear region corresponds to the immediate axial recovery while the nonlinear region
corresponds to the time-dependent viscoelastic recovery. Hence, BPY and PRA-BPY displayed
a higher degree of immediate axial recovery and PRA displayed a higher degree of viscoelastic
recovery. The recovery was smallest for OXA (Table 3), which is consistent with other findings
for fragmenting materials (58, 59). Additionally, this may be connected to the viscous
behaviour described above. Visual inspection indicated that capping occurred to a high degree
29
for PRA (both tablets) and to a lower degree for PRA-OXA (one of two tablets). According to
the (Table 3), this correlates well for PRA, which displayed the highest axial elastic
recovery. However, the axial elastic recovery for PRA-OXA was significantly lower than for
either BPY or PRA-BPY, which did not display any capping tendencies. Hence, other factors,
such as the degree of mechanical anisotropy often encountered from uniaxially compressed
tablets, could have affected the capping propensity (60).
The Young’s modulus is commonly determined from bending, indentation or
compression testing (61) but rarely from the decompression phase (15). However, in this work,
a parameter calculated from the in-die recovery profiles (i.e. the predominantly elastic
decompression phase (15, 16)) was denoted as Young’s modulus. These calculated
decompression Young’s moduli for the materials are given in Table 3. Values for Young's
modulus for paracetamol have previously been reported to be approximately 10-11 GPa from
both bending (61) and decompression testing (15). This compares favourably with the
estimated value of 11.35 GPa derived in this work (Table 3). The investigated substances were
ranked (as conjectured from ANOVA and post hoc tests, p < 0.05) in the following order with
respect to elastic deformation resistance (high to low): OXA > PRA = PRA-HCl > PRA-OXA >
PRA-BPY > BPY. However, both the elastic recoveries and the Young’s moduli were relatively
similar for the cocrystals and the salt compared to PRA. Young’s moduli reported in the
literature for various pharmaceutical substances vary widely (61). Hence, the small differences
reported in this work should be interpreted with caution. These small differences suggest that
the elastic stiffness values for the cocrystals and the salt were smaller than that for PRA. This
indicates that the propensity of these substances for elastic deformation increased. However, the
overall influence of this on the tablet-forming ability remains uncertain.
4.6 CRYSTAL STRUCTURE VISUALIZATION AND ANALYSIS
Crystal engineering has been extensively investigated in recent years for innovative
pharmaceutical applications to enhance solubility and stability and to improve mechanical
properties (13, 62-64). An understanding of crystals at the molecular level is important for
explaining the mechanical properties of powders. The presence of slip planes in the crystal
lattice allows easier slip under applied compaction pressures, resulting in plastic deformation
and increased interparticulate bonding of the powder (65, 66). In this work, we aim to achieve
insights into the molecular origins of the improved plasticity and tabletability of cocrystals and
salt powders.
30
Table 4. Slip planes and attachment energies of PRA, PRA-OXA, PRA-BPY, PRA-HCl, OXA
and BPY. The Miller indices of the predicted slip planes are bolded where results from Eatt
calculation and visualization match.
Name Crystal ID
Visual
Slip
Plane
Slip plane by Eatt
Comments
COMPASS II Dreiding
PRA HXACAN01
NO
SLIP
PLANE
110
020
001
110
001
200
Zig-zag layers
PRA-OXA LUJTAM 104
002
011
104
002
100
10-2
Flat layers
PRA-BPY MUPQAP
NO
SLIP
PLANE
020
100
110
020
110
110
Zig-zag layers
PRA-HCL 835705 100
200
020
011
10-2
020
11-1
011
Flat layers
OXA OXALAC03 100
200
200
020
111
200
111
201
Layers
BPY HIQWEJ02 110
220
100
110
010
100
010
001
Flat layers
Slip planes in the crystal systems were identified by visualization and attachment energy
calculation using COMPASS II and the Dreidling force field. The predicted slip planes are
tabulated in Table 4. As can be seen, two force fields of attachment energy calculation are in
good agreement in identifying slip planes. However, the overall success rate between
visualization and computation methods was only 50 %. Previous studies have also indicated the
invalidity of the direct attachment energy method in identifying slip or cleavage planes in
organic crystals (13, 19, 67). Although some deviations in explaining the mechanical properties
of materials have been reported, visualization methods are generally found to be more accurate
than the attachment energy methods (68).
No slip system was identified in the crystal structure paracetamol from I.
Furthermore, a zig-zag layered arrangement of paracetamol molecules was interlocked and held
strongly by hydrogen bonds, which explains the poor tableting properties (Figure 7a). In the
OXA crystal lattice, hydrogen-bonded catamers of oxalic acid molecules were held together by
hydrogen bonds to form layers parallel to the (200) and (100) planes (Figure 7e). This possibly
explains the extremely good tabletability of OXA. However, Bansal and coworkers reported
poor plastic deformation behaviour for OXA and explained this by the weak hydrogen bonding
31
interactions across the slip planes (69). PRA-OXA cocrystals exhibited a flat, layered structure
composed of PRA and OXA molecules. In the layers, PRA molecules were hydrogen-bonded to
four neighbouring OXA molecules through heteromeric interactions along the (104) plane, as
shown in Figure 7b. This could be the reason for the improved tableting behaviour of PRA-
OXA. In contrast, slip planes and interlocked layers were not found in PRA-BPY. Both the
tabletability and compactability of the powders decreased in the order: BPY > PRA-BPY >>
PRA, in line with the structural differences. BPY has flat and hydrogen-bonded layers with
relatively smooth surfaces (Figure 7f).
In the PRA-HCl crystal lattice, PRA molecules interacted with water molecules
and chloride ions through O-H…
O and O-H…
Cl hydrogen bonds, forming a flat layered network
that was parallel to the (100) plain (Figure 7d). In the intestine, water and chloride ions stabilize
the three-dimensional layered structure and this could facilitate easier slipping under pressure
(Figure 7d). Thus, the presence of water and chloride ions along the (200) planes could be
responsible for the enhanced compression properties and tabletability of PRA-HCl. Sun and
coworkers also demonstrated that water of crystallization could improve the mechanical
properties by facilitating the formation of slip planes (70). Thus, within the studied
multicomponent systems, flat layered structures have better mechanical properties. However, it
is difficult to explain the compressibility of the materials based on the crystal structures,
probably because other mechanisms play key roles.
32
Figure 7. Crystal lattices of different paracetamol solid forms with slip planes identified by
visualization (left side) or predicted using COMPASS II and Dreiding force fields (right side).
(a and g) PRA, (b and h) PRA-OXA, (c and i) PRA-BPY, (d and j) PRA-HCL, (e and k)
OXA, and (f and l) BPY. See Table 4 for the planes indicated here.
a g
h b
c i
d j
e k
f l
33
5. Conclusions
In paper I, we systematically studied the mechanical properties of powders to shed light on the
connections with their structural features. It was found that the tableting properties of
paracetamol form I were dramatically improved by forming cocrystals or the salt. The changes
in crystal packing features were reflected in the differences in the tabletability and
compactability of the studied materials. The presence of slip planes and flat layers in the
cocrystals and the salt were possibly behind the improved powder tableting performance. Thus,
this paper demonstrates the potential of crystal engineering to improve the mechanical
properties of pharmaceutical solids.
In paper II, we found that the mechanics of the paracetamol and coformers were
generally altered in the cocrystal and salt forms. The plasticity as represented by yield pressure
decreased for the cocrystals and salt as compared to paracetamol, which is inconsistent with
order of tensile strength of tablets in pater I. Accordingly, the change in yield pressure could
not be explained by the changes in the crystal structures of the salts and cocrystals. Moreover,
the elastic properties of the cocrystals and the salt were moderately altered as compared to
paracetamol. The Young’s modulus values indicated reduced elastic stiffness and, thus, a
somewhat increased propensity of the substances for elastic deformation. Hence, it was found
that the elastic and plastic properties assessed from powder compression analysis cannot be
directly correlated with the crystal lattice structure of the cocrystals and the salt and that the
influence of additional parameters such as brittleness and surface energies needs to be
investigated.
34
6. Future Perspectives
Successful tablet manufacturing depends on the mechanical properties of the materials. Plastic
materials often result in an increased interparticulate bonding area, and thus produce tablets
with good mechanical properties. The plastic deformation of the materials is attributed to
crystallographic features such as crystal packing and a slip plane system in the crystal lattice.
Thus, it is possible to predict the mechanical properties of the materials and the resulting tablet
performance from the crystal structure. The benefits of this predictive science are apparent, as it
facilitates the rapid development of robust, scalable formulations in a material-sparing manner.
Furthermore, an understanding of the structure-property relationships of engineering materials
provides important insights about desired properties.
In this part of the research work, we have investigated the bulk powder mechanical
properties (tabletability, compactability and compressibility) of paracetamol and how these are
related to the crystal structures. The overall objective of the follow-up research work is to
provide a clear picture of the structure-mechanical property relationships in organic molecular
crystals over a wide scale from molecules to crystals to bulk powders and, thereby, to develop
an approach for predicting the mechanical properties of multicomponent systems. The specific
objectives are:
To computationally calculate mechanical properties like Young’s modulus and identify
intermolecular interactions, slip planes (i.e. weakest inter-planar interactions) and d-
spacing etc. in a larger dataset of multicomponent systems;
To determine various mechanical properties, including surface roughness, hardness,
elastic modulus, yield strength, and brittleness index, for selected cocrystals and salt
crystals and their compacts using nanoindentation;
To correlate the experimentally and computationally measured mechanical properties of
cocrystals and salts, from crystals to bulk level, with their crystallographic features.
35
7. Acknowledgements
I would like to convey my great gratitude to my supervisor Professor Sitaram Velaga, who has
inspired and afforded me the opportunity to carry out this work and given me the help and
support when I need it.
My sincere thankfulness and appreciation are conveyed to my co-supervisor Professor Göran
Alderborn, who has given me the chance to perform a part of my research at the department of
Pharmacy, Uppsala University. I especially appreciate that you have created a work
environment where I felt like a member belonging to your group.
I am thankful to my co-author Dr. Manish who always shared his knowledge about
crystallography with me and kind cooperation during laboratory works. Many thanks to Amani
and Dr. Parameswara for your kindness support and help. I also want to thank all at Medical
Sciences division for being curious about my work and hospitality during my stays at Luleå.
My thanks also to Mai Lindström, head of Health Sciences department for her support and
help.
Stort tack till alla i galenikgruppen på farmaciavdelningen vid Uppsala universitet, speciellt
medförfattaren Dr. Ann-Sofie, Dr. Lucia, Dr. Josefina, Dr. Johan, Samaneh, Henrik, Joel och
alla andra för välbemötande samt för all hjälp och stöd som jag har fått från er under den tiden
som jag har varit hos er.
Pirr ji dil ez supasîya dayk û babên xwe û xuşk (Gulê û Dilberê û Rêjînê) û birayên xwe (Şivan
û Nêçîrvan) û mal û zarokên wan dikem bo hemî rengên harîkarîyê. Supasîyeka taybet bo
birayê min Şivan bo hemî ew palpiştî û xizmet û mandîbona te pêşkêşkirî bo me. Supas bo her
birader û xuşk û dûst û mirov û kes û karên me yên bi her corekê alîkarî bo me encam dabît.
Herwesa supasîyeka bê payan bo berêz Saeed Sulaiman Bendî û xêzan wî Jîyanê û hemî zarok
û xuşk û birayên wî bo hemî rengên alîkarî û piştgîrî û piştevanîyê. Çi cara nahête ji bîrkirin!
Gelek supas bo dayka Saeedî, ji bo lavayên (duaên) wê bo me!
Finally, I am very grateful to my lovely wife Kharija and my beloved children Viar and Nivar,
who has always stood by me and I appreciate everything you have done for me.
36
8. References
1. Sheth AR, Grant DJW. Relationship between the structure and properties of pharmaceutical
crystals. Kona. 2005;(23):36-48.
2. Almarsson Ö, Zaworotko MJ. Crystal engineering of the composition of pharmaceutical
phases. do pharmaceutical co-crystals represent a new path to improved medicines? Chemical
communications. 2004;(17):1889-96.
3. FDA, Guidance for industry: Regulatory classification of pharmaceutical co-crystals. CDER.
2013.
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