Journal of Pharmaceutical Sciences 108 (2019) 485-493

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Journal of Pharmaceutical Sciences

journal homepage: www.jpharmsci.org

Pharmaceutics, Drug Delivery and Pharmaceutical Technology

Tablet Compression Force as a Process Analytical Technology (PAT):

100% Inspection and Control of Tablet Weight Uniformity
Leo Manley 1, *, Jon Hilden 1, Pablo Valero 2, Tim Kramer 3
1
Product and Analytical Development, Small Molecule Design and Development, Eli Lilly and Company, Indianapolis, Indiana 46285
2
Process, Control and Automation Engineering, Lilly de Caribe, Carolina 00987, Puerto Rico
3
Statistics, Discovery and Development, Eli Lilly and Company, Indianapolis, Indiana 46285

a r t i c l e i n f o a b s t r a c t

Article history: The modern rotary pharmaceutical tablet press is capable of accepting or rejecting individual tablets
Received 8 March 2018 based on the measured compression force of the tablet. Because during steady operation, each tablet is
Revised 16 May 2018 compressed to the same thickness, a larger compression force implies a heavier tablet. Tablets that are
Accepted 3 July 2018
too heavy likely contain more than the desired content of drug substance. The measured compression
Available online 6 September 2018
force thus becomes an important input to the overall control strategy, and variability in the compression
force from one tablet to the next corresponds directly with the uniformity of dosage units. This provides
Keywords:
tableting an extraordinary opportunity to use the instantaneous compression force signal as a process analytical
compression technology to make product collection decisions on every individual tablet. Only 1 question requires
unit operations investigation: how to set the main compression force limits to achieve the desired tablet weights? In this
solid dosage form
work, a small-scale characterization method and associated mathematical model are developed to
content uniformity
PAT answer this question.
© 2019 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Introduction a unique opportunity to use the main compression force reading as

The drug product control strategy must ensure tablets satisfy
the content uniformity and potency critical quality attributes. The
content uniformity requirements are defined by the harmonized
Uniformity of Dosage Units test.1 Sandell et al.2 recommend indi-
vidual tablet drug substance label claim limits of 85%-115% or ±15%
of target to ensure passing the harmonized Uniformity of Dosage
Units test a high percentage of the time. Tablet label claim is a
function of tablet weight and drug substance concentration.
Therefore, the ±15% range can be distributed among tablet weight
and drug substance concentration. However, the European Agency
requires batch release label claim averages be within ±5% of
nominal quantity,3 suggesting that tablet weight uniformity should
be at ±5% of target for a homogeneous blend.
The single tablet sorting feed forward control loop makes prod-
uct collection decisions on 100% of the core tablets based on main
compression force. This control loop works by comparing an indi-
vidual tablet's peak compression force value to predefined force
limits, accepting tablets within the limits and rejecting tablets
outside the limits via a multichannel discharge chute. This provides
* Correspondence to: Leo Manley (Telephone: 317-433-3069).
E-mail address: manley@lilly.com (L. Manley).
an indirect measure of tablet weight as part of a Process Analytical
Technology (PAT) (as defined by the Guidance for Industry PAT4)
based control strategy, which can be incorporated into Real Time
Release testing applications. Utilizing this feed forward control loop
and setting appropriate main compression force limits can be
advantageous for the drug product tableting control strategy, which
contributes to potency and content uniformity quality assurance.
The development of the appropriate force limits requires a
quantitative understanding of powder mechanics. Fortunately, a
significant number of authors have studied various applications of
powder mechanics. For example, Zinchuk et al.5 determined that
when compacted to the same solid fractions, real and simulated
ribbons exhibited similar compression behavior and equivalent
mechanical properties. Hilden et al.6,7 developed a simple yet
robust model to control the solid fraction of ribbons produced
during a roller compaction unit operation and determined that roll
force is the most dominant process parameter on ribbon solid
fraction. Mitra et al.8 showed a strong linear relationship (with a
negative slope) between the tablet tensile strength and granule
solid fraction. Tensile strength increased linearly with the apparent
deformation potential (difference between the tablet solid fraction
and initial granule solid fraction) for all tablet solid fractions. Dec
et al.9 determined that a finite element method offers the most
versatile model relating basic roller compaction process because it

https://doi.org/10.1016/j.xphs.2018.07.004
0022-3549/© 2019 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.
486 L. Manley et al. / Journal of Pharmaceutical Sciences 108 (2019) 485-493
Figure 1. Mechanistic model describing the relationship between tablet mass and
compression force for a fixed nominal “tip-to-tip” setting.
incorporates adequate information about powder behavior, ge-
ometry, and frictional conditions. Swaminathan et al.10,11 studied
the adhesive force between a punch face and the powder compact
and determined that the adhesive force increased as compact solid
fraction increased, the number of compacts produced in a row
increased, and concentration of lubricant in the blends decreased.
They also developed, validated, and implemented a modeling
methodology for predicting the shape and relative density fields in
the vicinity of debossed features on a tablet surface. Mitra et al.12,13
calibrated to the Drucker-Prager Cap model using monodispersed
microcrystalline cellulose dry granules to improve the under-
standing of how granule solid fraction impacts compaction
behavior. Aburub et al.14 examined the use of compaction ener-
getics as a tool to predict particle deformation mechanism. Almaya
et al.15 investigated the effect of excipient particle size on
compaction properties of brittle, plastic, and viscoelastic materials
with and without lubricants. Cunningham et al.16 and Sinka et al.17
modeled the experimental inputs related to the constitutive model
of the powder and the powder/tooling friction. Xiaorong et al.18
examined the solid fraction distribution in curved-faced tablets
with special reference to the die wall lubrication conditions.
Wu et al.19 investigated powder bed solid fraction variation with
applied pressure and calibrated the Drucker-Prager Cap model with
experimental measurements from which realistic powder proper-
ties are generated and fed into finite element analysis.
In most literature examples, powder mechanics studies have
involved “out of die” measurements of tablet properties such as
solid fraction. However, in this work, the “in die” values are critical.
In this application, the machine stiffness becomes important and
affects the relationship between the powder fill weight and the
compression force measured by the rotary tablet press. As a result,
it is necessary to consider both powder-mechanical properties as
well as equipment properties.
Mechanistic Modeling
Tablet compression force variations resulting from tablet
weight variations occur at a fixed nominal separation distance
Figure 2. Force versus tablet thickness curves indicating the machine stiffness and the
tablet compression profiles for tablets with different masses.
between the top and bottom rolls. The system can be mechanis-
tically modeled as illustrated in Figure 1. The model includes 2
parts: a spring, which represents the machine stiffness (elastic
response) of the tablet press and punches, and the tablet, which is
characterized by a nonlinear compression force versus displace-
ment curve. The model represents compression of a single tablet;
representative of a single station on a rotary tablet press for
example. On the left hand side, the nominal, steady-operation
condition is represented. Tablets of a nominal mass, m0, are
compressed to a nominal in-die thickness, t0, resulting in a nom-
inal compression force, F0. The force acting on the tablet is equal to
the force acting on the spring, resulting in some nominal level of
compression of the spring. If through some small normal variation
in the powder bulk density, a tablet is produced with a higher-
than-nominal mass, m1, a new force balance is established. The
resulting in-die tablet thickness will increase slightly to a new
value, t1, at the expense of further compression of the spring. As
the spring is compressed further, the compression force increases
to a new value, F1. The force on the tablet is still equal to the force
on the spring.
The model depicted by Figure 1 leads to several predictions. For
example, the tablet thickness, t1, will be smaller if the spring is
stiffer, as represented by a larger spring constant, k. Thus, in the
limit of an infinitely stiff spring, there will be no change in tablet
thickness, and the larger tablet mass will manifest as a higher tablet
solid fraction (lower porosity). The change in compression force in
this case will be maximal. In the limit of an infinitely compliant
spring, the change in tablet mass will manifest in an equal per-
centage change in the tablet volume. No change in force will result,
and the tablet thickness change will be maximal. For intermediate
spring constants, larger force variations will result from larger
thickness changes. Thus, tablets that are thick to begin with, will
produce larger force variations for a fixed percentage change in
tablet mass.
The relationship between tablet compression force and tablet
mass can be calculated from inputs of the machine stiffness (spring
constant), k, and from a measured tablet solid fraction versus
compression stress profile. The approach is illustrated in Figure 2.
Figure 2 shows expected tablet compression force versus tablet
thickness profiles for tablets of 3 different masses, m0, m1, and m2.
Superimposed is the linear elastic response representing the ma-
chine stiffness. The data point at the location (t0, F0) represents the
nominal condition as represented on the left hand side of Figure 1.
In this case, the linear machine stiffness is represented by the
equation:
 L. Manley et al. / Journal of Pharmaceutical Sciences 108 (2019) 485-493 487

Fortunately, the partial derivatives of the tablet compression

FM ¼ k,ðt  t0 Þ þ F0 (1) force response can be determined with knowledge of the in-die
Although the machine force described by Equation 1 is a func- tablet solid fraction (SF), as a function of the compression stress,
tion of only the tablet thickness, the tablet compression force is a s. The SF versus s response can be calculated from a simple
function of both tablet thickness and the tablet mass, FT(t,m). For a compression force versus tablet thickness plot by invoking the
fixed tablet mass, the tablet force versus thickness response can be definitions of these variables as follows.
approximated as: Tablet solid fraction can be calculated from the standard tablet
tooling dimensions presented on engineering drawings, along with


dFT knowledge of the tablet weight, thickness, and the formulation true
FT ¼ ,ðt  t0 Þ þ F0 (2) density as follows:
dt

where dFT/dt denotes the partial derivative of the tablet force m=r
function with respect to tablet thickness. If the tablet mass were to SF ¼ t  (9)
2VCup þ Adie t  2dCup
increase by a small amount, Dm, then a new force versus thickness
profile would be reached as described by the curve labeled m1, Where t is the tablet thickness, m is the tablet mass, rt is the
Figure 2. The tablet thickness would change in balance with the formulation true density, VCup is the cup volume of the tablet
machine response, and a new equilibrium would be established as tooling, Adie is the die-hole area, and dCup is the cup depth of the
indicated by point (t1, F1). The position of this new point can be tablet tooling. The tablet true density, rt, may be measured using
approximated for small changes in tablet mass, by establishing a helium pycnometry or calculated from the weight percentages and
linear approximation to the curve labeled m1 as follows: true densities of individual constituent powders as follows:



dFT dF WT%1 þ WT%2 þ …WT%n
FT ¼ ,ðt  t0 Þ þ F0 þ T ,Dm (3) rt ¼       (10)
dt dm WT%1
r1 þ WT%
r
2
þ … WT%
r
n
2 n
Note that Equation 3 describes a linear response that is parallel
to the line described by Equation 2 and shifted vertically upward to where WT%i and ri denote the weight percent and true density of
pass through point i. Thus, the change in slope from curve m0 to m1 constituent powder i, and n denotes the total number of powders.


Finally, the tablet compression stress, s, can be determined by
dt z0). Note also that
d dFT
is considered negligibly small here (i.e., dm
dividing the tablet main compression force, F, by the cross-sectional
point i represents the change in force that would occur in the limit area of the die as follows:
of an infinitely stiff spring. Since force equilibrium must be main-
tained within the system, FM () must equal FT (). Thus: F
s¼ (11)


 Adie
dFT dF
k,ðt  t0 Þ þ F0 ¼ ,ðt  t0 Þ þ F0 þ T ,Dm (4) With the above definitions, Equation 8 can now be further
dt dm
reduced. The slope of the force to tablet mass relationship can be
which can by simplified to arrive at: determined at any point on the SF versus s profile by invoking the
chain rule for derivatives:
dFT
Dt dt




¼  dm  ¼ (5) dFT dFT dSF ds dSF
Dm k dFT dm ¼ ¼ Adie (12)
dt dm dSF dm dSF dm

where Dt is defined as (t  to) and the approximation of the dif- where Equation 11 is used to replace F on the right hand side.
ferential element on the right hand side is valid for small changes in Invoking Equation 9 to perform the derivative, dSF/dm, on the right
tablet mass. A change in machine force can now be described as a hand side yields:
function of the change in tablet mass as follows:
!

dFT Adie ds Adie $SFo ds
dt ¼    ¼
DFM ¼ k, ,Dm (6) dm rt 2VCup þ Adie t  2dCup dSF mo dSF
dm
(13)
or
The final simplification on the right hand side can be obtained
dFT
dFM dt by again invoking Equation 9. The subscripts “o” denote values for
¼ k, ¼ k, dm  (7) the nominal condition (left hand side of Fig. 1). Similarly, the slope
dm dm k  dFT dt of the force to tablet thickness relationship in Equation 8 can also be
It is often desired to represent percentage changes in determined at any point on the profile by invoking the chain rule
compression force resulting from percentage changes in tablet for derivatives:
mass, in which case Equation 7 can be modified as follows:


dFT ds dSF
¼ Adie (14)
dFM=F m dFT dt dSF dt
¼ k, 0 , dm 
o
(8)
dm=m Fo k  dFT
0 dt which simplifies to:

Thus, the change in compression force resulting from a change !


dFT A2die ,rt ,SF2o ds
in tablet mass can be predicted with knowledge of k and of the ¼ (15)
partial derivatives of the tablet compression response.
dt mo dSF
488 L. Manley et al. / Journal of Pharmaceutical Sciences 108 (2019) 485-493

Table 1
Tooling and Unit Formula Properties Used in This Study

rt (g/cm3) 1.533
Adie (mm2) 43.53
VCup (mm3) 23.52
dCup (mm) 0.99

Substituting the partial derivatives in Equations 13 and 15 into

Equation 8 yields:

dFM=F ðAdie ,SFo ,k,mo Þ

o
¼  (16)
dm=m dSF ,k,mo ,Fo  A2die ,rt ,SF2o ,Fo
0 ds

This is the final result, predicting the percentage change in

compression force resulting from a percentage change in tablet mass
as a function of the nominal solid fraction, force, and tablet mass and
with knowledge of the slope of the SF versus s profile. The solution
has the expected features. For example, for a perfectly compliant
spring (k/0), the right hand side becomes zero, and the solution
predicts no change in force with a change in tablet mass. This makes
sense because the additional tablet mass results in a thicker tablet and
therefore more compression of the spring. Since the spring constant is
zero, there is no increase in force with further spring compression.
Since the force does not change, the tablet SF would not change either
in this case. In the limit of an infinitely stiff spring (k/∞), k is
eliminated from the right hand side and Equation 16 reduces to:

dFM=F

o SF ds
¼ (17)
dm=m s dSF Figure 3. Instron set up with tooling holder.
0

In this case, the change in force resulting from a change in tablet
mass is maximal and is a function of only the powder properties
(specifically, the steepness of the SF vs. s curve). This makes sense
because additional tablet mass results in no change of tablet
thickness. The additional mass must be accommodated entirely by
further densification of the tablet (i.e., increased tablet SF). In this
case, of a constant-volume tablet, the spring constant is irrelevant
and does not appear on the right hand side of Equation 17.
Methods and Materials
To test the predictive nature of Equation 16, tablets were com-
pressed on both an Instron and large-scale rotary presses at low,
nominal, and high tablet weights at a fixed punch tip-to-tip dis-
tance. The percentage change in compression force was compared
to the percentage change in tablet weight and evaluated in light of
the predictions provided by Equation 16.
Materials
The final blend material for both the small-scale material sparing
and commercial scale press studies were produced using a high shear
wet granulation manufacturing process with a lactose monohydrate/
microcrystalline cellulose based unit formula. The formulation true
density and tooling dimensions are provided in Table 1. Data from 8
different batches were analyzed to determine variability.
Tablet Compression on the Instron
The Instron method needs main compression force versus punch
tip-to-tip distance curves at multiple tablet weights to determine the
main compression force to core tablet weight relationship. Therefore,
an Instron (model # 5569 with a 50 kN load cell, traveling at a
displacement rate 50 mm/min with Lilly production tooling) was
used to execute this test. The target, lower, and upper individual tablet
weight values were selected before executing the study (175, 166 and
184 mg representing target, 95% and 105% of target, respectively).
Three individual core tablets were compressed at each weight.
Final blend material was manually weighed, loaded into the
device shown in Figure 3 and compressed into a tablet. The Instron
recorded both the force and punch displacement values during the
compression event. This process was repeated for each tablet.
Before executing the test, an Instron test profile was created to
compress each tablet to approximately þ40% of the target main
compression force to ensure the tablet press single sort upper limit
can be determined. The maximum force was restricted to be below
the maximum tooling force rating.
Tablet Compression on a Commercial Scale Rotary Tablet Press
All commercial-scale compression experiments were conducted
at a fixed punch “tip-to-tip” distance. Manual setups of the Fette
2090i and 3090i tablet presses were conducted to produce tablets
with a target tablet weight of 175 mg. Tablet weights were verified
with sampling of ten (10) tablets using a Checkmaster 4.1. The
resulting main compression force at target tablet weight was used
as the main compression force set point for the Force Control Loop
and as a baseline value to execute this study.
The tablet press force control loop automatically adjusts the die
fill depth to achieve a match between the actual main compression
force and its set point value. To execute the study, the main
compression force set point value was increased by intervals þ0.5 kN,
and the press was allowed to stabilize before collecting tablet sam-
ples for weight measurements, (n ¼ 10, using the Checkmaster). This
was repeated until the main compression force percent increase from
baseline was approximately þ40% to produce the increasing portion
of the force to weight curve. This process was repeated using 0.5 kN
increments from the baseline main compression force set point to
 L. Manley et al. / Journal of Pharmaceutical Sciences 108 (2019) 485-493 489

Figure 4. Raw force versus tip-to-tip distance profile.

produce the decreasing portion of the force to weight curve. At each
main compression force set point, the average tablet weight and
actual main compression force values were recorded. The percent
difference from the actual main compression force and the baseline
main compression force set point was calculated as well as the tablet
weight percent difference from actual to baseline at each increment.
Seven runs were completed on the Fette 2090i, and 2 were
completed on the Fette 3090i.
Results and Discussion
Instron Results
Nine tablets were compressed on the Instron consuming
approximately 2 g of final blend material. The compression force is
plotted against the tip-to-tip distance for all 9 tablets in Figure 4. As
each tablet was initially compressed (moving toward the left in the
figure), a smooth curve was generated. Upon changing direction, a
linear profile was obtained until a force of zero was reached at
which point the force remained zero as the upper punch was raised.
The linear portion represents the elastic expansion of both tablets
and punches/equipment.
The relevant compression portions of all 9 curves in Figure 4 are
overlaid in Figure 5. Figure 5 shows 3 groupings of curves. The
central grouping corresponds to tablet weights close to 100% of the
target (175 mg). The upper and lower groupings correspond to
tablets near 105% and 95% of the target, respectively. The separation
of the curves within each group resulted from small tablet weight
variations around the desired value. The horizontal dotted line in-
dicates the nominal compression force of 9500 N, corresponding to

Figure 5. Instron compression force versus tip-to-tip displacement curves.

490 L. Manley et al. / Journal of Pharmaceutical Sciences 108 (2019) 485-493

Figure 6. Main force to tablet weight relationship based on Instron results.

a nominal tip-to-tip distance of ~1.32 mm indicated by the vertical tablet press data also demonstrate a linear relationship between
dashed line. At this nominal tip-to-tip distance, the callouts indi- main compression force and tablet weight over the range of ±5% of
cate that a tablet weight variation of þ5% or 5% produces target tablet weight. Figure 7 also shows that the Instron results
approximately a þ25% or 27% force variation. Thus, at a fixed (solid red circles) align with the commercial scale results (all
punch tip-to-tip distance, tablet weight variations are amplified in noncircular markers). Specifically, the individual Instron points fall
the force signal by a factor of approximately 5. within the 95% confidence band for the individual press predictions
The actual tablet weights as a percent difference from target of as indicated by the light blue shaded area. This indicates that the
175 mg and the resulting Instron force values as a percent difference Instron method is representative of the commercial press method.
from the target force of 9500 N were calculated (Fig. 6). The rank In light of Equation 16, the alignment of data between the Instron
order of the tablet weights align with the resulting Instron and the commercial-scale rotary presses suggest that the machine
compression forces, such that the resulting Instron force increases as stiffness is similar in all 3 sets of equipment. This is the expected
tablet weight increases at a constant punch tip-to-tip distance. result if most of the machine compliance is accounted for in the
Figure 6 shows a linear relationship, with a slope of 5.35 between punches (which are the same for all 3 data sets).
main compression force and tablet weight for this unit formula and The individual batch slopes ranged from 4.56 to 5.42 for the 8
compression tools. It is recommended to repeat this exercise for batches in Figure 7. This suggests that the amplification factor
each dose strength to account for formulation and/or compression (slope) is relatively insensitive to equipment and material variation
punch size impacts. The figure also illustrates how individual tablet for a fixed unit formula. Once the most conservative amplification
force reject limits can be calculated using the force to weight linear factor is identified, the upper and lower force limits can be calcu-
relationship. For example, if the control strategy is to only accept lated and entered into the appropriate location of the tablet press
tablets within 95%-105% of the target tablet weight, then the indi-
vidual tablet force rejection limits can be set at ±5% * 5.35 ¼ ±26.8%
of the target main compression force. The resulting acceptable force
and weight region is represented by the green shaded area in
Figure 6. It is recommended to account for raw material and process
variability by assessing unit formulas and the manufacturing pro-
cesses that represent extreme conditions and implementing the
most conservative slope value (e.g., smallest slope value).
This control strategy reacts to the relative change in measured
force value from its set point when the tablet mass changes (e.g.,
when moving from m0 to m1, Fig. 2). Therefore, the percent dif-
ference in force from its set point is important and not the absolute
force value. This eliminates the impact of force measurement bias
since it is relatively constant throughout a batch and batch-to-
batch main compression force set point variability.

Commercial Scale Rotary Tablet Press Results

The data analysis performed on the Instron results was repeated Figure 7. Press and Instron main force % difference versus tablet weight % difference
on the Fette 2090i and 3090i results (Fig. 7). The commercial scale from baseline.
 L. Manley et al. / Journal of Pharmaceutical Sciences 108 (2019) 485-493 491

Figure 8. Indistinguishable SF versus s profiles of all 9 tablets.

control software (e.g., parameters 10 and 11 for the Fette single sort machine stiffness-corrected displacements, are shown in Figure 8.
control logic). The tablet press software will now collect only tab- The 9 curves in Figure 8 are so reproducible that they cannot be
lets that are within the predetermined force limits, which align visually distinguished. This is somewhat expected because all 9
with the desired acceptable tablet weight range. tests used the same material, and the solid fraction versus stress
profile is an intrinsic material property.
Direct use of the Mechanistic Model
Tablet Response Only
To evaluate the mechanistic models described by Equation 17 In this section, the predicted force variations with tablet mass
(for an infinitely rigid machine) and Equation 16 (for the full are predicted for the case of an infinitely rigid machine (i.e., an
model), it was necessary to estimate the machine stiffness for the infinite spring constant), according to Equation 17. In this case, the
Instron and determine the in-die tablet SF versus s response. The tablet thickness cannot change and any increase in tablet mass
linear portions of the curves in Figure 5 were used to estimate the must be accommodated by a corresponding increase in tablet solid
machine stiffness value for the Instron. Specifically, the slope of the fraction. The results are plotted in Figure 9 for all 9 curves shown in
linear release profile represents elastic expansion of both the tablet Figure 8. Figure 9 shows that again, the 9 curves are so similar that
and the equipment. The equipment-component of this relaxation is even after calculating the derivative in Equation 17, they cannot be
defined as the machine stiffness. The tablet-component of this
relaxation is expected to be negligibly small because the tablets are
very thin in comparison with the lengths of punches and the
crosshead (i.e., even a large percentage of elastic expansion for
tablets results in only a small vertical displacement of the equip-
ment). Thus, the equipment-component of the elastic rebound, or
“machine stiffness”, was estimated directly from the slopes of the
linear portions of the curves. Specifically, the average slope was
calculated to arrive at a machine stiffness value of 3.18  104 N/mm.
Thus, for example, under a load of 10,000 N, the machine will
elastically compress by 10,000 N/3.18  104 N/mm ¼ 0.314 mm. The
similar Instron and tablet press results in Figure 7 suggest that the
machine stiffness is similar for both sets of equipment despite
significant differences in geometry.
The compression curves in Figure 5 were converted to SF versus
s profiles. To estimate the in-die tablet thickness and calculate the
associated solid fraction under load, it was necessary to subtract the
equipment displacement from the total displacement at each point
in the profile. The equipment displacement was calculated as the
product of machine stiffness multiplied by the compression force at
each point in the profile. The in-die SF versus s profiles, based on Figure 9. Correlation between percent force change and percent mass change.
492 L. Manley et al. / Journal of Pharmaceutical Sciences 108 (2019) 485-493
Figure 10. The predicted percentage change in compression force resulting from a percentage change in tablet mass.
easily distinguished. The figure predicts an amplification factor of
approximately 12.5 at a compression stress of 218 MPa, which
corresponds to the nominal compression force of 9500 N (i.e., 218
MPa ¼ 9500 N/43.53 mm2). In other words, at a nominal
compression stress of 218 MPa, a 1% increase in tablet mass would
produce a 12.5% increase in the compression force at fixed tablet
volume. The amplification factor of 12.5 does not compare well to
the slope of 5.35 for the regression line in Figure 6. The large dif-
ference shows that the impact of machine stiffness cannot be
ignored. The data in Figure 9 also show that this amplification
factor increases with increasing compressive stress. This trend
makes sense because a larger compressive stress produces a denser
tablet, which can less easily accommodate additional tablet mass at
fixed volume. The curves in Figure 9 should accordingly approach a
nearly infinite value for a fully dense tablet (at very large
compression stresses).
Combined Machine Stiffness and Tablet Response
The impact of machine stiffness is incorporated in the model
described by Equation 16. The data in Table 1 and in Figure 8 were
used to perform the calculation on the right hand side of Equation
16. The results are plotted as a function of compression stress for all
9 tablets in Figure 10. Figure 10 shows an average value of
approximately 5.3 (green lines) at the target main compression
stress of 218 MPa (9500 N/43.53 mm2). This value is in excellent
agreement with the slope of 5.35 for the regressed line in Figure 6
and confirms that machine stiffness plays a critical role in the
correlation of force variability with tablet weight variability.
Figure 10 shows that the amplification factor decreases with
increasing compression stress. This makes sense because the
tablets are almost fully dense at the high-stress conditions. Thus,
any change in mass manifests as the same change in thickness and
therefore the same change in force. However, at higher nominal
forces, a fixed change in force corresponds to a lower percentage
of change. Stated another way, as the tablet becomes very dense,
the spring constant becomes small relative to the effective stiff-
ness of the tablet. As explained previously, in the limit of a zero
spring constant, the right hand side of Equation 16 vanishes and
the curves in Figure 10 approach zero. Figure 10 also shows 3
groupings of curves corresponding to tablets with different nom-
inal mass. The largest tablets (105% of nominal weight) thus pro-
duce a larger force change (for a given percentage weight change)
than the smaller tablets (95% of nominal weight). This makes
sense in light of the mechanistic model because the heavier tablets
are also thicker. Therefore, a fixed percentage mass change results
in a larger tablet thickness change and therefore a larger per-
centage force change.
Conclusions
The utility of monitoring tablet compression force as a surrogate
for tablet mass was explored on both a theoretical and experi-
mental basis, with excellent agreement between the two. Because
tablet compression forces can be monitored with 100% inspection
of tablets, the force signal provides an excellent PAT application to
accept and reject tablets that are out of the desired range with
regard to tablet mass and can be incorporated into real-time release
testing applications. This work shows that the amplification factor
(main compression force to tablet weight relationship) is similar on
both the Instron and commercial scales presses. In addition, this
work shows that the generation of the SF versus s profile for even a
single tablet on an Instron is sufficient to predict the relationship
between compression force and tablet weight on a rotary press,
provided that the machine stiffness between the 2 sets of equip-
ment is similar.
 L. Manley et al. / Journal of Pharmaceutical Sciences 108 (2019) 485-493 493

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