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PII: S0022-3549(18)30185-0
DOI: 10.1016/j.xphs.2018.03.020
Reference: XPHS 1115
Please cite this article as: Persson AS, Ahmed H, Velaga S, Alderborn G, Powder compression
properties of paracetamol, paracetamol hydrochloride, paracetamol cocrystals and coformers, Journal of
Pharmaceutical Sciences (2018), doi: 10.1016/j.xphs.2018.03.020.
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Powder compression properties of paracetamol, paracetamol hydrochloride, paracetamol
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1
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Department of Pharmacy, Uppsala University, SE-751 23 Uppsala, Sweden
2
Pharmaceutical research, Department of Health Sciences, Luleå University of Technology,
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SE-971 87 Luleå, Sweden
E-mail: ann-sofie.persson@farmaci.uu.se
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The objective was to study the relationship between crystal structure, particle deformation
properties and tablet-forming ability for the monoclinic form of paracetamol (PRA), two
cocrystals and a salt crystal of PRA in addition to two coformers (oxalic acid and 4,4’-
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Analytical powder compression was used for determination of effective plasticity, as inferred
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from the Heckel yield pressure and the Frenning parameter, and the elastic deformation was
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The plasticity could not be linked to the crystal lattice structure as crystals containing zig-zag
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layers displayed similar plasticity as crystals containing slip planes. In addition, crystals
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containing slip-planes displayed both high and low plasticity.
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The mechanical properties could neither be linked to the tablet-forming ability as the tablet
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stiffness. Furthermore, the elastic deformation could not explain the tablet forming ability.
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paracetamol and its cocrystals and salt could be established. Thus, it was indicated that to
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1. Introduction
The mechanical properties of particles used in solid dosage forms strongly affect the
possibility to formulate a tablet with expected product profile, e.g. porosity, mechanical
strength and disintegration time. It is thus important to determine key mechanical properties
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of particles during tablet formulation development, such as their deformation properties, i.e.
plasticity and elasticity, and their fracture mechanics.1 Among these, the plasticity of particles
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is often considered fundamental for the development of the area of inter-particle bonds which
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affects the tablet-forming ability. In addition, the generation of fragments and new surfaces
due to fragmentation of brittle materials2 may also set up conditions for increased inter-
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particulate contact area and a higher tablet tensile strength, i.e. an improved bonding ability.
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Furthermore, the tablet tensile strength is affected by the bonding mechanism and thus the
inter-particle bonding strength.2 Due to the importance of particle plastic deformation, the
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crystallographic properties of particles controlling particle plasticity has been addressed in the
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literature as well as the question of how the crystal structure can be modified in order to
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improve plasticity and thus tablet-forming ability. A common reasoning seems to be that the
presence of parallel planes (commonly referred to as slip planes) in the crystal structure
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promotes plane movement during loading due to a relatively low energy barrier along such
planes and thus facilitates plastic flow.3 One approach proposed to facilitate formation of
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planar structures in the crystal lattice, and thus promote particle plasticity, is the use of
cocrystals.
a coformer.4 The tensile strength of tablets formed of cocrystals has been reported to both
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increase3,5 and decrease6 compared to the tablet tensile strength of the API. This change in
tablet-forming ability may be attributed to both altered plasticity and elasticity of the
cocrystals.
The analgesic drug paracetamol form I (PRA) is known to show poor tablet-forming ability,
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explained by the zig-zag shape of the crystal lattice structure.7,8 This crystal structure
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strength and capping. However, it is reported that the metastable polymorphic form of PRA
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deforms plastically7,8 and exhibits a reduced elastic recovery7 due to the presence of planar
structures in the crystal lattice. More on, it is also earlier reported by Ahmed et al.,10 that
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cocrystals and a salt of PRA showed improved tablet-forming ability compared to the PRA
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form I particles. This was explained in crystallographic terms by different slip planes with
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weaker inter-planar bonds in the cocrystals and the salt. In order to better understand the
causative factors behind the improved tablet-forming ability of the cocrystals and the salt
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compared to the PRA, the consecutive relationship between crystal structure, particle
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needs to be investigated. The objectives of this study were thus to analyze the compression
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properties of powders of PRA and two cocrystals and a salt of PRA as well as the coformers
and to address the question of the structure – property – performance relationships of the
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crystals. The studied cocrystals were formed from a 1:1 stoichiometric ratio of PRA and the
coformers α-oxalic acid anhydrate (OXA) and 4, 4'-bipyridine (BPY). Analytical powder
compression11 was used to analyze the mechanical properties of the powders in terms of
particle plasticity, as assessed by the Heckel yield pressure, and particle elasticity, as assessed
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2. Materials and methods
2.1. Materials
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powders were purchased from Sigma-Aldrich Chemie GmbH (Germany). These are
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henceforth referred to as PRA, OXA, and BPY. Cocrystals of PRA with OXA and BPY, and a
paracetamol hydrochloride monohydrate salt were prepared and characterized for the solid
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state properties as described previously.10 Briefly, cocrystals were produced by stoichiometric
slurrying of pure components in respective solvents while the salt was generated by simple
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acid-base reaction. These are hereafter denoted PRA-OXA, PRA-BPY, and PRA-HCl. The
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materials were dry sieved into three size fractions (<90 µm, 90-360 µm, >360 µm) using a set
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of precision sieves (VECO, Eerbeek, Holland) and a sieve shaker (Retsch KG, type RV, Haan,
Germany) operating at a relative agitation intensity of 40 for 10 minutes. The size fraction 90-
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360 µm was selected for further analysis due to its suitability to be used for direct
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compression. The materials were stored in a desiccator over a saturated MgCl2 (Sigma-
PRA and the cocrystals (~1 g of the size fraction larger than 360 µm) were milled for 35
minutes (including a 5 min pause period after 20 minutes) in a planetary ball mill (PM 100,
Retsch, Germany). The milling was done in a 12 cm3 stainless steel container with 50 steel
balls with a diameter of 5 mm. The milled cocrystals showed no alteration in solid state
properties (as inferred from and compared to earlier differential scanning calorimetry
analysis,10 data not shown). The milling of the PRA-HCl crystals altered their solid state
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properties, as inferred from both smaller and broader peaks in the thermogram, and the milled
2.2.1. Densities
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The apparent particle density (also referred to as the gas pycnometric density in the Ph. Eur.,
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(AccuPyc 1330, Micrometrics, USA). Each measurement was calculated from an average of
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ten repeated cycles. Determined particle densities are reported in Table 1.
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The poured (unsettled) bulk density ( , n=2) was measured by manually pouring 10 ml
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powder into a graduated measuring cylinder (11.1 mm diameter) and weighed on an analytical
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balance (Mettler Toledo, AG245, Switzerland). This diameter was selected to enable an
estimation of the in-die poured bulk density and hence enable powder bed height calculations
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of the powders in-die prior to compression.13 Determined bulk densities are reported in Table
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1.
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A materials testing machine (Zwick Z100, Zwick/Roell Zwick GmbH & Co. KG, Ulm,
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Germany) equipped with 11.3 mm diameter flat-faced punches was used for the powder
~33% relative humidity and at room temperature (~22 °C). In order to reduce the frictional
forces between powder and die wall, the die and the punch faces were lubricated with a 1%
w/w magnesium stearate (Kebo, Sweden) ethanol suspension and air dried prior to
compression. During compression the lower punch was stationary and the upper punch moved
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with a rate 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)
The elastic punch deformation was assessed from punch deformation curves obtained by
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pressing the upper and the lower punch together up to 500 MPa as described earlier.14 The
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punch deformation amounted to approximately 0.4 µm/MPa and was used for correction of
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2.2.3. Powder compression analysis
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The compression analysis during loading was performed according to the classification
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protocol suggested by Nordström et al.11 which is based on global compression equations
often used in powder compression analysis, i.e. the Kawakita equation15 and the Heckel
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equation.16 In addition, the analytically derived Frenning effective medium (EM) equation
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was used.17
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The Kawakita equation15 describes the relationship between engineering strain ( ) and
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pressure (
) as,
= = ,
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(1)
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where is the initial powder bed height calculated from and is the powder bed
height during compression. and are known as Kawakita parameters and resemble the
maximal engineering strain ( ) at infinite pressure and the pressure required to reach /2,
respectively. The parameters were calculated from the linear form of the Kawakita equation,
= + , (2)
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using linear regression in the pressure range 25-500 MPa ( >0.999). The product
during compression.13 An -index larger than 0.1 suggests extensive particle rearrangement
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The Heckel equation16 describes the change in powder bed porosity (!) with applied pressure
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(
) as,
"# $ = %
+ &' , (3)
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where ( and &' are the slope and the intercept of the linear region, respectively. 1/( is
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commonly referred to as the Heckel parameter and considered to represent the yield pressure
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(
+ ) of the powder material. The Heckel parameter was calculated by linear regression as
described earlier.18 The pressure range for regression analysis was selected by an Excel macro
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which identified a minimum derivative as the middle pressure and the first and second
pressure values were identified from a 25% increased derivative in both directions. This
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derivation was performed in a pressure interval between 0.5 to 500 MPa. For all
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The Frenning effective medium equation17 describes the relationship between pressure and in-
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−
= &- ./ ln 2 3 − ln 2 37, (4)
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or in linear form,
The parameter &- , referred to as the Frenning parameter, is the slope of the linear part of the
profile and is earlier proposed to be proportional to the yield stress of the particles18 and
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represents thus an indication of the particle plasticity. &- was determined by linear regression
in a similar manner as the Heckel parameter, however, the middle pressure value was obtained
from a maximum derivative and the first and the second pressure values from a 25% decrease.
Powder bed heights exceeding 10 mm were excluded in the analysis ( >0.998). was
calculated from the unsettled bulk density of each powder determined using the glass cylinder
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described above and the corresponding pressure
was thus set at 0 MPa. @A was
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calculated based on a compact with a porosity of zero.
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2.2.4. In-die elastic recovery
Calculations of the in-die elastic recovery (B@AC@D ) were performed from the complete
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decompression curves (n=2) according to Eq. 7,19,20
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B@AC@D = , (6)
E
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where is the powder bed height in-die during decompression and F is the height of the
powder bed at maximum load, i.e. 500 MPa. The elastic punch deformation during
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decompression was set equal to the punch deformation during compression and corrected for
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∗
in the calculations of as described in Sec. 2.2.2. The maximum elastic recovery (B@AC@D )
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was used as an indication of the total elastic recovery occurring after decompression in-die
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prior to ejection. The B@AC@D was determined from the last pressure recorded by the
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materials tester that was < 0.06 MPa for all materials except for PRA for which the last
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An elastic parameter or modulus, denoted BH , was calculated from the reciprocal of the slope
range of 100-400 MPa. The of the linear regression was > 0.989 and was regarded as
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2.3. Statistical analysis
Results are given as mean values and where applicable (i.e. in Tables) together with standard
followed by Tukey post hoc tests using the MINITAB®15 statistical software. A p-value <
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0.05 was considered as significant.
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3. Results and discussion
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3.1. Powder compression properties and particle plasticity
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In order to get a broad description of the compression properties of the powders their
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pressure-engineering strain relationships were derived (Fig. 1a) and analyzed according to an
of the cocrystals and the salt crystals had intermediate character compared to the starting
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materials i.e., PRA, BPY, and OXA. The pressure-engineering strain relationships were
transformed into linear relationships using the Kawakita equation (Fig. 1b) and the Kawakita
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the substances either decreased (PRA) or increased (BPY and OXA) when self-assembled
PRA. The initial part of the engineering strain-pressure profiles (Fig. 1a) displayed a rapid
increase in with the lowest gradient for OXA. This was reflected by the parameter,
which was higher for OXA (about 11 MPa) compared to the other substances (Table 2) which
showed a small spread in parameter ranging from 3 to 6 MPa. The product of and
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i.e., the -index (Table 2), was for OXA lower than 0.1, i.e. indicating a limited degree of
particle rearrangement during compression. OXA was thus classified as a Class II material.13
The other powders displayed values > 0.1 and were accordingly classified as Class I
materials displaying extensive particle rearrangement. Similar results have previously been
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For all materials, the Heckel yield pressure (
+ )22 was used as an indication of the particle
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plasticity. In general, the Heckel profiles (Fig. 2) were similar with respect to the overall
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curve shape for all powders except for OXA. All profiles displayed an initial bending that was
followed by a linear region during which plastic particle deformation was the dominating
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compression mechanism and thus used for calculation of
+ . Finally, a non-linear region at
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high compression pressure was obtained for all materials except OXA at which plastic particle
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deformation became limited and the compact started to deform elastically.23 Based on the
calculated
+ (Table 2) the materials were categorized according to Roberts and Rowe.22 Both
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the BPY and the PRA-BPY were categorized as soft materials as the
+ of BPY was not
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significantly lower than 40 MPa, which was the limit between soft and very soft materials.
low slope of the Heckel profile was obtained over an extended pressure range (Fig. 2). A large
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MPa. This may indicate that the particles fractured over a large pressure range or it may be
indicative of a strain hardening of the crystals during compression. Thus, OXA was classified
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In addition to the Heckel parameter, the Frenning &- parameter was used as an indication of
particle plasticity. The shapes of the EM profiles could as for the Heckel profiles be divided
into three regions, i.e an initial nonlinear, a linear, and finally a bending towards a plateau
(Fig. 3). The shape of the curves was expected with regard to the classification as Class I and
Class IIB materials.18 The derived &- parameters are reported in Table 2 and ranges between
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43.0 MPa for BPY and 1016.3 MPa for OXA. A good correlation between &- and
+ was
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obtained18 but the values of &- were about a 1.1 factor higher than
+ . The use of the EM
equation supports the classification according to the plasticity scale and the Heckel yield
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pressure is henceforth used to represent the material plasticity.
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In summary, the cocrystals showed different compression properties compared to the starting
materials, i.e. PRA and coformers. Also the salt crystals showed a change in compression
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properties compared to PRA. In terms of particle plasticity, cocrystals and salt crystals were
more plastic than PRA. The range in plasticity was however relatively low for PRA, PRA-
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HCl, PRA-OXA, PRA-BPY and three of four materials were classified as moderately hard
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and only one material (PRA-BPY) as soft, i.e. PRA-BPY was softer than PRA. In a
compilation of yield pressure values from the literature,1 a range of values from 5 MPa to
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nearly 1000 MPa have been reported. Hence, the differences in both &- and
+ reported here
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indicate a relatively limited change in plasticity while forming the salt crystals and the
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cocrystals of PRA.
a consistent sieve fraction of powder was used for all materials in this study. However, since a
broad sieve cut was used, a variation in particle size distribution between the materials may
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plasticity of the materials and their classification, milled powders of the materials were
prepared and studied. The yield pressures of the milled PRA, PRA-OXA and PRA-BPY
powders (Table 3) increased with an average factor of 1.3 and thus, the milled and the finer
particles seemed less plastic than the original particles. However, the relative ranking of the
materials based on their yield pressures as well as the plasticity classification of the materials
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was unaltered post milling (Table 3). Thus, this supports the classification of the materials as
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moderately hard (PRA and PRA-OXA) and soft (PRA-BPY).
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3.2. Tablet elastic recovery and particle elastic deformation
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A common means to derive a measure of the elasticity of a tablet is to calculate the ratio
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between the height of the powder bed in-die during maximal loading and the height of the
powder bed in-die when the powder bed is completely unloaded (e.g. Sun and Hou3 and Sun
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and Grant18), as described in Eq. (7). Such a value of elastic recovery has been referred to as
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the immediate axial recovery27 and are reported in Table 4 for the materials used in this study.
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The B@AC@D ranged from 4.1% for OXA to 9.6% for PRA (Table 4). The low elastic recovery
for OXA (Table 4) is consistent with other reports on the properties of fragmenting
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materials.27,28 In an earlier paper on the compaction of the same materials as used in this
study,10 PRA, PRA-OXA, and PRA-BPY gave tablets which showed lamination and capping
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while no such tendencies were reported for PRA-HCl, OXA, and BPY. The highest B@AC@D
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(Table 4) among the materials were obtained for PRA and PRA-PBY which may partly
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explain their capping propensity. However, the B@AC@D for PRA-OXA was significantly
lower than for BPY and equal to PRA-HCl, i.e. two materials which did not give tablets with
visible cracks or caps. Hence, other factors are also of importance for the capping propensity,
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The Young’s modulus is a measure of elastic deformation and is commonly determined from
bending, indentation or compression testing1 but rarely from the decompression phase.30
Bending and indentation tests are frequently done using compacts, often referred to as beams,
and give thus an indication of the elastic deformation of the compact. It is however argued
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that for a compact of zero porosity, the measured modulus may represent the elastic
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consistent porosity have also been used.31 In this paper, a parameter was calculated from the
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in-die decompression profile at which the compact recover by elastic strain.30,32 Such a
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better indication of the elastic deformation of the material in comparison to a single value of
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tablet elastic recovery, i.e. B@AC@D . The parameter (BH ) was calculated from a series of
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consecutive elastic recovery values (B@AC@D ) as a function of the reduction in upper punch
pressure during unloading,33 i.e. the slope of the relationship between B@AC@D and
−
.
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All materials showed during the initial part of the decompression phase a negative recovery
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particles under nearly constant loading. It is unclear if this is a plastic or an elastic time-
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deformation was most pronounced for OXA and its cocrystal PRA-OXA.
After the initial viscous stage, the B@AC@D increased nearly linearly over a considerable range
of pressures up to a
−
of about 450 MPa. Thereafter, a marked bending of the
relationship occurred followed by high rate of elastic recovery during the final stage of
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unloading. The final stage accounted for the majority of the elastic recovery of all materials as
the resistance towards elastic recovery of the tablet was low due to reduction of the upper
punch pressure.
The elastic modulus (BH ) was calculated for all materials in the pressure range 100-400 MPa
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and are reported in Table 4 together with some tablet porosity data from the unloading phase.
For the materials used in this study, the BH ranged from 8.48 GPa (BPY) to 14.6 GPa (OXA).
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In Table 4, porosities of tablets at some selected loading states of the decompression phase are
reported. The minimum recorded porosities were negative for all materials except for OXA.
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An accurate determination of the porosities during the transition between compression and
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decompression is difficult but negative porosities have been reported earlier.33 The negative
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values indicate that the materials were densified at the highest applied pressures due to an
calculations of BH (i.e. 100-400 MPa), the porosities of the tablets were generally low and
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close to zero porosity and the rates of elastic recovery were low in comparison to the rates of
recovery in the final recovery phase. It is thus proposed that in the decompression pressure
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range used for calculation of BH , the tablet elastic recovery was controlled by the elastic strain
of the crystals. This supports that the calculated values of BH represent indications of the
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elastic deformation of the crystals with the possible exception for OXA. At the final unloading
stage, the porosities increased quickly, giving significant increases in tablet porosities. This
suggests that during the final decompression stage and eventually also during ejection, pores
are formed in the compact which also may be associated with the breakage of inter-particulate
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Values of Young’s modulus of paracetamol have previously been reported to be approximately
10-11 GPa, derived from bending1 and decompression30 testing. The value obtained by beam
testing was derived by extrapolation of a series of moduli to zero beam porosity. The reported
moduli compare favorably to the estimated value of 11.33 GPa for PRA derived in this paper
(Table 4), further supporting that the calculated values of BH represents the elastic
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deformation of the crystals. For the salt, the BH and thus the elastic deformation was the same
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as for PRA while for the cocrystals, the moduli were similar but slightly lower. This indicates
that the cocrystals displayed a somewhat lower elastic deformation than PRA. In a
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compilation of Young’s moduli from the literature,1 a range of values from 3 GPa to 88 GPa
have been reported. Hence, the small differences in BH reported in this work indicate nearly
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the same elastic deformation for PRA, the salt and the cocrystals.
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relationships)
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As previously mentioned, it is commonly conjectured that the presence of slip planes within
the crystal lattice structure facilitates particle plastic deformation during loading. Slip planes
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can be identified by visual inspections of crystal structure and by crystal energy calculations.34
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The lattice structure of the crystals investigated in this work has been described in a preceding
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paper, hence for details regarding the crystal structure and potential slip planes the reader is
referred to Ahmed et al.10 In summary, no slip planes were identified in PRA and PRA-BPY
crystals while slip-planes were identified for OXA, BPY, PRA-OXA and PRA-HCl crystals.
Thus, there was no general relationship between the presence of slip planes and the effective
plasticity of the materials as assessed by the Heckel and the Frenning parameters, i.e.
materials with both high and low plasticity had slip planes in the crystal lattice structure. OXA
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exhibited a low plasticity despite the presence of slip planes in the crystal structure which may
be explained by the presence of weak inter-planar hydrogen bonds that prevent plane
slipping.34 In addition, based on the results presented by Bansal and co-workers34 it may be
conjectured that both the shape of the lattice structure and the presence of inter-planar
bonding influences the plasticity. The PRA-HCl and PRA powders which displayed
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intermediate plasticity have both zig-zag layers in the crystal structure. It seems thus that
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relative movement of crystal layers may be possible also in crystals of a zig-zag structure. For
PRA-HCl, the presence of water molecules in the crystal lattice may facilitate the relative
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movement of crystal layers and thus affects the deformation properties.35
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The mode and direction of force application influence the response of the crystals in terms of
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plastic deformation. Crystal hardness has often been determined by nano-indentation
powder compression, particles are stochastically oriented in the die and subjected to both
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axial and radial forces, approaching an isostatic loading condition. The net-effect may be that
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simple slip-plane movement is difficult or even prohibited due to a complex mode of force
It is thus concluded that a relationship between plastic deformation expressed during powder
compression and the presence of slip planes in a crystal is difficult to establish. The
and other approaches to identify potential slip planes may be needed, such as the use of
slip planes and plastic deformation of particles expressed during powder compression may not
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exist due to the complex loading situation during powder compression. The value of crystal
Regarding the elastic deformation, the two materials with the highest and lowest BH (OXA
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and BPY respectively) both had slip planes while materials showing intermediate BH (PRA
and PRA-BPY) had a zig-zag layered crystal lattice structure.10 As pointed out above, all
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materials could be described as of the same elastic deformation. Thus, there seemed to be no
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relationship between crystal structure and elastic deformation of the studied crystals.
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3.4. Relationships between particle deformation and tablet-forming ability (property-
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performance relationships)
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It has been reported10 that the cocrystals and the salt (PRA-BPY, PRA-OXA and PRA-HCl)
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used in this study could be compacted into tablets in contrast to the monoclinic form of PRA
(form I) which did not form coherent compacts. However, capping was reported for tablets of
EP
the cocrystals giving problems in determination of tablet tensile strength.10 In addition, the co-
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It is often assumed that the tablet-forming ability is related to the contact area available for
inter-particle bonding and the inter-particle bonding strength.2 It is further assumed that
particle plastic deformation is fundamental for the contact area development during
compaction. Thus, the contact area is typically larger for particles with high plasticity
compared to particles of low plasticity. In addition, an increased contact area may be observed
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after particle fracture. Both the cocrystals and the salt used in this study showed a slightly
increased plasticity compared to PRA as inferred from both the Heckel and the Frenning
plastic parameters (Table 2) which may contribute to the difference in tablet-forming ability.
In order to study the relationship between particle plasticity and tablet-forming ability for the
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crystals used in this study, the tensile strength of tablets formed at compaction pressures of ~
100 MPa and ~140 MPa (from Ahmed et al.10) was plotted as a function of
+ (Fig. 5). The
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main image of Fig. 5 displays the relationship between compaction pressure and
+ for all
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studied materials whereas the inserted image displays the relationship between PRA,
cocrystals and salt crystals. The compaction pressures of 100 MPa and 140 MPa were used in
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the comparison in order to have at least three independent measurements of tablet tensile
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strength also for the capping prone crystals. There was no general relationship between tensile
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strength and particle plasticity. For the powders forming tablets, i.e. the coformers, the
cocrystals and the salt, the tablet tensile strength tended to decrease with a decreased
+ which
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is opposite to an expected relationship. This is applicable also to the four materials identified
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to have slip-planes in their crystal structure (OXA, BPY, PRA-OXA and PRA-HCl). This was
further confirmed from a similar relationship between the tablet tensile strength and the
EP
plasticity.26 Thus, the variation in particle plastic deformation as expressed during powder
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compression between the materials is not the primary explanation for the variation in tablet-
forming ability.
The formation of pores during the final decompression stage, i.e. the stage where the tablet
porosities increased rapidly (Table 4), may induce breakage of inter-particle bonds in the
∗
compact. The B@AC@D was reported to be highest (7.8%) for PRA-BPY which may affect the
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∗
low tablet tensile strength (0.61 MPa) obtained for this powder. The B@AC@D was similar for
PRA-OXA (5.8%) and PRA-HCl (5.9%) and they gave tablets of similar tensile strength after
compaction at 100 MPa (1.18 MPa vs 1.17 MPa) but different tensile strength after
compaction at 140 MPa (1.30 MPa vs 1.64 MPa). Since the particle elastic deformation was
similar for all crystals studied, elastic deformation and tablet elastic recovery could not
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explain the different tablet-forming ability of the crystals.
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The findings reported in this study thus indicate that other factors than difference in particle
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plasticity and elastic deformation contribute to or are the main explanation for the earlier
reported differences in tablet-forming ability. This conclusion seems valid also for the
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improved tablet-forming ability of the cocrystals and the salt compared to PRA. Possible
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factors are particle fragmentation and particle surface energy, i.e. properties that may affect
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the inter-particle bonding strength rather than the inter-particle contact area.
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4. Conclusions
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In this work, the effective particle plasticity and elastic deformation of paracetamol (PRA)
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and two cocrystals (PRA-OXA and PRA-BPY) and a salt (PRA-HCl) of PRA in addition to
the coformers (OXA and BPY) were analyzed and related to the crystal structure and powder
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tablet-forming ability.
The studied crystals displayed similar effective particle plasticity and elastic deformation
irrespective of the presence of slip-planes or zig-zag layers in the crystal lattice structure.
However, the tablet-forming ability of the cocrystals and the salt was improved compared to
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the PRA although an obvious relationship between particle deformation properties and tablet
To conclude, the results in this paper show that crystal engineering can be used to modifiy the
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structure-property-performance relationship for a series of crystals is intricate and there is a
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need to improve our understanding of the importance of crystallographic features for the
deformation properties of crystals and the subsequent effect on their tablet-forming ability. In
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addition, other factors controlling the evolution in inter-particle bond strength during
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Table legends
Table 1: Particle and powder densities. Standard deviations are given in parentheses.
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and cocrystals. Standard deviations are given in parentheses.
∗
Table 4: Maximal in-die elastic recovery (B@AC@D ), elastic modulus (BH ) and compact
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porosity (!) calculated from decompression data (n=2). Standard deviations are given in
parentheses.
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Figure legends
Figure 1: Typical representations of the non-linear (a) and the linear (b) Kawakita
relationships for the powders.
Figure 2: Representative Heckel profiles for the studied powders in the complete pressure
range (a) and the initial pressure range (b).
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Figure 4: Typical plots of the in-die axial elastic recovery. Note that the pressure is
normalized with respect to maximum applied pressure (
−
).
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Figure 5: Correlation between tablet tensile strength for tablets compacted at ~100 MPa
(squares) and ~140 MPa (dots) (n ≥ 3, adapted from Ahmed et al.10) and yield pressure (
+ )
for the studied materials. The inserted image displays the relationship for PRA, cocrystals and
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salt crystals.
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Tables
Table 1: Particle and powder densities. Standard deviations are given in parentheses.
3 3
Substance a (g/cm ) b (g/cm )
PRA 1.287 (0.001) 0.26 (0.001)
PRA-OXA 1.481 (0.002) 0.31 (0.001)
PRA-BPY 1.260 (0.001) 0.34 (0.001)
PRA-HCl 1.420 (0.000) 0.43 (0.002)
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OXA 1.903 (0.001) 0.63 (0.002)
BPY 1.232 (0.003) 0.46 (0.000)
a
Apparent particle density (n=3), obtained from Ahmed et al.10
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b
Poured bulk density (n=2), obtained from Ahmed et al.10
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Table 2: Compression parameters and mechanical classification of the powders (standard
deviations are given in parentheses).
a
b c
d e
Substance (-) (MPa) (-) (MPa) (MPa) Classification
0.811 2.95 0.27 105.7 115.4
PRA (0.000) (0.01) (0.001) (0.6) (0.3) Moderately hard
0.804 3.39 0.24 85.4 93.3
PRA-OXA (0.000) (0.03) (0.002) (1.0) (5.7) Moderately hard
0.746 4.26 0.18 61.2 68.9
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PRA-BPY (0.000) (0.01) (0.001) (0.9) (1.2) Soft
0.714 5.98 0.12 91.0 104.5
PRA-HCl (0.000) (0.06) (0.001) (1.1) (7.4) Moderately hard
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0.643 11.43 0.06 898.0 1016.3
OXA (0.000) (0.11) (0.001) (3.6) (9.3) Hard
0.651 4.68 0.14 39.0 43.0
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BPY (0.000) (0.05) (0.001) (1.0) (1.0) Soft
a
Kawakita parameter (n=2).
b
Kawakita parameter (n=2).
c
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Rearrangement index (n=2).
d
Heckel yield pressure (n=2).
e
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Frenning effective medium parameter (n=2).
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Table 3: Yield pressure (
, ) and relative yield pressure (
, /
) for milled PRA
and cocrystals. Standard deviations are given in parentheses.
Substance
, (MPa)
, /
(-)
PRA 146.3 (18.8) 1.37
PRA-OXA 106.4 (1.4) 1.22
PRA-BPY 79.5 (1.3) 1.28
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∗
Table 4: Maximal in-die elastic recovery (
), elastic modulus ( ) and compact
porosity () calculated from decompression data (n=2). Standard deviations are given in
parentheses.
∗
a b c d
Substance (%) (GPa) (%) (%) (%) (%)
9.6 11.33 -4.1 -3.8 -1.1 5.2
PRA (0.0) (0.04) (0.01) (0.07) (0.05) (0.00)
5.8 10.51 -4.2 -3.8 -0.88 1.8
PRA-OXA (0.1) (0.03) (0.14) (0.12) (0.08) (0.18)
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7.8 9.59 -5.8 -5.3 -2.1 1.9
PRA-BPY (0.1) (0.02) (0.09) (0.03) (0.05) (0.02)
5.9 11.29 -3.0 -2.8 -0.06 2.9
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PRA-HCl (0.1) (0.01) (0.04) (0.02) (0.03) (0.01)
4.1 14.57 9.9 10 12 14
OXA (0.1) (0.14) (0.05) (0.05) (0.07) (0.00)
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7.2 8.48 -6.7 -6.1 -2.5 0.66
BPY (0.0) (0.00) (0.07) (0.04) (0.08) (0.08)
a
Minimum detected in-die compact porosity.
b
In-die compact porosity at
= 400 MPa corresponding to
−
= 100 MPa.
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c
In-die compact porosity at
= 100 MPa corresponding to
−
= 400 MPa.
d
In-die compact porosity at
≈ 0 MPa corresponding to
−
= 500 MPa i.e. when fully
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unloaded but prior to ejection.
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