Pharmaceutical Development and Technology

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Developing a quality by design approach to model

tablet dissolution testing: an industrial case study

Ketsia Yekpe, Nicolas Abatzoglou, Bernard Bataille, Ryan Gosselin, Tahmer

Sharkawi, Jean-Sébastien Simard & Antoine Cournoyer

To cite this article: Ketsia Yekpe, Nicolas Abatzoglou, Bernard Bataille, Ryan Gosselin, Tahmer
Sharkawi, Jean-Sébastien Simard & Antoine Cournoyer (2017): Developing a quality by design
approach to model tablet dissolution testing: an industrial case study, Pharmaceutical Development
and Technology, DOI: 10.1080/10837450.2017.1392566

To link to this article: http://dx.doi.org/10.1080/10837450.2017.1392566

Published online: 02 Nov 2017.

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 PHARMACEUTICAL DEVELOPMENT AND TECHNOLOGY, 2017
https://doi.org/10.1080/10837450.2017.1392566

RESEARCH ARTICLE

Developing a quality by design approach to model tablet dissolution testing: an

industrial case study
Ketsia Yekpea,b, Nicolas Abatzogloua, Bernard Batailleb, Ryan Gosselina, Tahmer Sharkawib,
Jean-S
ebastien Simarda,c and Antoine Cournoyera,c
a
Pfizer Industrial Research Chair on Process Analytical Technology in Pharmaceutical Engineering, Department of Chemical & Biotechnological
Engineering, Universit
e de Sherbrooke, Sherbrooke, Quebec, Canada; bFaculty of Pharmacy, University of Montpellier I, Montpellier, France;
c
Process Analytical Science Group, Pfizer, Saint-Laurent, Quebec, Canada

ABSTRACT ARTICLE HISTORY

This study applied the concept of Quality by Design (QbD) to tablet dissolution. Its goal was to propose a Received 4 May 2017
Downloaded by [Gothenburg University Library] at 02:52 03 November 2017

quality control strategy to model dissolution testing of solid oral dose products according to International Revised 10 October 2017
Conference on Harmonization guidelines. The methodology involved the following three steps: (1) a risk Accepted 10 October 2017
analysis to identify the material- and process-related parameters impacting the critical quality attributes of
dissolution testing, (2) an experimental design to evaluate the influence of design factors (attributes and KEYWORDS
parameters selected by risk analysis) on dissolution testing, and (3) an investigation of the relationship Dissolution testing; quality
between design factors and dissolution profiles. Results show that (a) in the case studied, the two parame- by design; design of
ters impacting dissolution kinetics are active pharmaceutical ingredient particle size distributions and tab- experiments; risk
let hardness and (b) these two parameters could be monitored with PAT tools to predict dissolution assessment; dissolution
profiles. Moreover, based on the results obtained, modeling dissolution is possible. The practicality and modeling; ICH Q8 guideline
effectiveness of the QbD approach were demonstrated through this industrial case study. Implementing
such an approach systematically in industrial pharmaceutical production would reduce the need for tablet
dissolution testing.

1. Introduction
The concept of Quality by Design (QbD) was first introduced in
1992 by Dr Joseph M. Juran (Juran 1992). The US Food and
Drug Administration (FDA) encourages risk-based approaches
and the adoption of QbD principles within pharmaceutical indus-
try (Yu et al. 2014). QbD proposes that quality should be built
into initial product design rather than assessed at the end of tab-
let manufacture (ICH Q8, R2 2009). Furthermore, the goal of QbD
is to ensure finished product quality, improve tablet manufactur-
ing and curtail product costs. Thus, with the QbD initiative, rou-
tine quality control testing, such as dissolution testing (DT)
performed after tablet manufacturing, could be discontinued if
influential parameters are controlled (Rathore et al. 2009).
DT aims at verifying active pharmaceutical ingredient (API) dis-
solution in simulated gastrointestinal fluid (Dressman and Kramer
2005; Le Hir et al. 2009). Such pharmaceutical control testing has
now been applied for more than 30 years and is recognized as a
gold standard for in vivo dissolution correlation (Buri 1983;
Juenemann et al. 2011). Moreover, this control test is routinely
employed by the pharmaceutical industry and regulatory agencies
to improve monitoring of batch-to-batch reproducibility in manu-
facturing processes (Dressman and Kramer 2005). However, the
test consumes much time, material, equipment, and human
resources. The present work evaluates the possibility of modeling
DT for solid oral dosage products based on QbD principles and
proposes a novel approach to ensure conformity with ICH
guidelines.
There has been a growing interest in the use of QbD tools for
understanding and prediction of drug release from tablets.
Hernandez et al. (2016) used NIR to predict in real time dissol-
ution of tablet exposed to different levels mechanical strength.
Yekpe et al. (2015) demonstrated that dissolution can be pre-
dicted based on disintegrant distribution with NIR Chemical
Imaging Technology. Basalious et al. (2011) applied QbD for
pharmaceutical development of felodipine solid mixture contain-
ing hydrophilic carriers and/or polymeric surfactants, for easier
development of controlled-release tablets of felodipine. Dumarey
et al. (2015) studied the influence of granule and compression
variability introduced by a design of experiments on the entire
dissolution profile with a multivariate tool. Cui et al. (2012) used a
single time point to study and predict the drug release as a func-
tion of API physical properties.
Ultimately, if influential parameters are identified and con-
trolled a priori, efficient applications of QbD principles and risk-
assessment tools could reduce and perhaps eliminate the need
for tests such as “tablet DT” (ICH Q8, R2 2009; ICH Q9 2011a, ICH
Q10 2011b). Such evolution would be highly beneficial to the
pharmaceutical industry in terms of process understanding, envir-
onmental impacts, and time to market.
The following methodology was adopted: after identifying
drug product dissolution as a Critical Quality Attribute (CQA),
quality risk assessment ascertained potentially critical material and
process parameters that may impact dissolution. Experiments
were designed to further identify crucial process parameters and
elucidate their impact on product dissolution profiles.

CONTACT Nicolas Abatzoglou Nicolas.Abatzoglou@USherbrooke.ca Department of Chemical & Biotechnological Engineering, Universit
e de Sherbrooke, 2500
boul. Universit
e, Sherbrooke, Quebec, J1K2R1, Canada
ß 2017 Informa UK Limited, trading as Taylor & Francis Group
 2 K. YEKPE ET AL.
2. Experimental methods
2.1. Risk assessment
Risk assessment is a valuable science-based process in quality risk
management that can help identify which material attributes and
process parameters could potentially have an effect on product
CQAs (ICH Q8, R2 2009; ICH Q9 2011a). A comprehensive risk
assessment was undertaken to identify process parameters whose
variability may influence DT of conventional, immediate-release
tablets containing ibuprofen, a Biopharmaceutical Classification
System (BCS) Class II API. Well-recognized risk assessment tools –
Fishbone diagram and failure mode effects analysis – were used
to classify process parameters and then quantify the associated
degree of risk. Since DT is influenced by numerous variables, these
steps were instrumental in identifying the critical DT parameters.
Before carrying out a Design of Experiments (DoE), the parame-
ters that were initially thought to influence DT have been classi-
fied in five categories:
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1. Tablet manufacturing and design of the drug product.
2. The properties of the materials (excipients) used to manufac-
ture the final drug product.
3. The properties of the drug product API: ibuprofen.
4. The type/role of the excipients used in the drug product.
5. The conditions under which the dissolution test is run.
Based on the above parameter classification, a Fishbone dia-
gram was developed (Figure 1).
Failure Mode and Effects Analysis (FMEA) was then applied to
identify the critical parameters that impact dissolution testing. The
latter are used to build a DoE and establish a control strategy for
the product under study. Each parameter presented in the
Fishbone diagram was ranked based on its Occurrence (O), its
Impact (I), and its Detectability (D). A Risk Priority Number (RPN)
was the calculated according to: RPN ¼ (O)  (I)  (D).
RPN was used to separate critical parameters from less critical
ones for the present system. Parameters that are characterized by
the highest RPN values were considered critical. These parameters
would strongly impact DT and would have to be first tested using
an appropriate DoE.
Figure 1. Fishbone Diagram of the factors thought to influence product CQAs.
According to the FMEA, parameters that impact dissolution
testing most are presented in Table 1 along with a justification of
each RPN value.
1. Tablet compression
2. Coating
3. Particle size of API
4. Ibuprofen properties (ibuprofen physical–chemical properties
and quantity)
5. Storage humidity
The first three parameters were expected to have the most
important impact on tablet dissolution. Before carrying out a com-
plete DoE, a preliminary study was performed on the other two
parameters (ibuprofen properties and humidity) to determine their
impact on dissolution.
Wet granulation is a step of the product manufacturing and
could eventually have an impact on dissolution. Moreover, it
should be noted that the product under study was already devel-
oped and properly validated using standard pharmaceutical
guidelines. Thus, the wet granulation process of the product
under study is robust.
Moreover, the wet granulation process of the product under
study was systematically controlled by means of:
1. LOD measurement for measuring powder wetness;
2. Powder yield, which is measured after granulation. The pow-
der yield is also an indicator of powder’s wetness. An
adequately granulated powder will result in a powder yield
within specifications.
Thus, thanks to these several stage gates, the risk of wet
granulation is mitigated.
2.1.1. Ibuprofen properties
The hypothesis that tablet dissolution can be influenced by the
physical properties and quantity of ibuprofen was tested in this
study. Ibuprofen bought from three different suppliers was eval-
uated: suppliers A, B, and C. Three properties – reported as factors
in this study – were chosen: particles size distribution (more spe-
cifically mean particle diameter), particle shape, and crystal form.
 PHARMACEUTICAL DEVELOPMENT AND TECHNOLOGY 3

Table 1. Failure Mode and Effects Analysis (FMEA) of parameters impacting the
dissolution tests – quantifying their Occurrence (O), Impact (I), and Detectability
(D).
Parameters I O D RPN Comments
Tablet 5 2 1 10 Tablets with inadequate hardness
compression will present unacceptable dis-
integration/dissolution profiles.
While its impact is important,
its presence is easily detect-
able and corrected by adjust-
ing compression setting.
Coating 5 2 1 10 Tablet coating is critical and
could have a very high impact
on dissolution profiles.
Inhomogeneous and/or under-
coated tablets can often easily
be detected.
API particle size 5 1 2 10 Particle size has a very important Figure 2. Ibuprofen PSD obtained from three suppliers: A – blue, B – red, and
impact on dissolution testing C – green.
as stated by the
Noyes–Whitney equation.
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Ibuprofen physical– 5 1 2 10 Ibuprofen Physical–Chemical
chemical properties Properties have a significant
effect on dissolution. As this
study is for an existing prod-
uct, these parameters are not
included into the DoE.
Ibuprofen 5 2 1 10 Drug concentration has an
concentration important impact on dissol-
ution testing as stated by the
Noyes–Whitney equation.
However, the ability to detect
a problem of drug concentra-
tion is easily to detect during
routine QC assay testing.
Storage humidity 5 2 1 10 Storage Humidity has a signifi-
cant effect on physical and
chemical properties of exci-
pients and API contained in
tablet. Thus, storage Humidity
could impact API dissolution.
In the following sections, ibuprofen powders from supplier A, B, C
will be referred to accordingly.
be rejected which indicates that the average particle sizes for the
three powders are statistically equal.
Factor 3: crystal identification. The third factor of this initial ibu-
profen study was crystal identification with X-Ray Diffraction
(XRD). The purpose of this part of this article was to determine if
the crystalline structure of the three ibuprofen powders is the
same. As ibuprofen structure is crystalline, it was expected to
obtain sharp narrow diffraction peaks for the three powders.
The crystal identification was realized with an X’pert Pro MRD
diffractometer from PANanalytical. The results are presented in
Figure 4. Peak position and intensity for the three ibuprofen pow-
ders were compared using the internal library of the apparatus;
the comparison shows that the three powders are identical.
However, peak intensity for the three powders presents slight dif-
ference for some peak positions. This difference is explained by a
phenomenon called preferred orientation, defined as the non-ran-
dom distribution of the crystallites within a sample, and is the
likely cause of intensity variations in XRD powder diffractograms.
Thus, no polymorph of ibuprofen and no amorphous phase have
been found on XRD spectra; consequently, the crystalline structure
of the three ibuprofen samples is the same.

Factor 1: particle size distribution. Particle size (PS) and particle
size distribution (PSD) are important variables in pharmaceutical
industry. Indeed, API and excipients PSD can affect final formula-
tion (dissolution, appearance, and stability). Ibuprofen A, B, and C
PS were measured via a light scattering method using a
Mastersizer 2000, Malvern instrument. The results are presented in
Figure 2. They illustrate that the volumetric PS of all three pow-
ders is unimodal, similar in shape with a relatively low proportion
of fines (mean particle size below 10 microns).
Factor 2: particle shape. The shape and surface morphology of
the particles were examined with a FEG-SEM S-4700, Hitachi
instrument. The micrograph of the three powders (Figure 3) indi-
cates that particles for the three suppliers have similar shapes.
Moreover, the typical range of PS is confirmed: a wide range of
mean particle sizes (from 12 to 188 microns) can be seen for all
three powders. Eight images were acquired for each of the three
powders. For each image, 10 particles were measured: ibuprofen
A, B and C present average particle sizes of 88.1(12.3), 82.4(8.7),
and 83.4(18.5) mm, respectively (values in parenthesis represent
standard deviation). An ANOVA was done to test the null hypoth-
esis that the average particle sizes for the three powders are stat-
istically equal. With a p values of 0.68, the null hypothesis cannot
Factor 4: Ibuprofen concentration. According to the FMEA, the
impact of API concentration on dissolution testing is high (Smith
2015). It was decided to test tablets containing 90, 100, and 110%
of ibuprofen claim in the tablets. Batches of 90 and 110% ibupro-
fen have the same formulation as regular ibuprofen tablets, but
excipient percentage within each formulation was modified in
order to reach either 90 or 110% of API claim. Dissolution profiles
of 90% and 100% ibuprofen as well as those of 110 and 100%
ibuprofen were compared in order to estimate if the dissolution
profiles of the two formulated batches are similar.
The dissolution testing was performed on six tablets of each
batch, using USP apparatus 2 (Distek Inc., North Brunswick, NJ) in
900 ml of dissolution media (phosphate buffer at pH 7.2) at
37 ± 0.5  C with UV detector as required in USP at 221 nm. Section
2.5 contains technical details concerning the dissolution test.
Each dissolution profile was compared with dissolution profiles
of 100% API Tablets. For all three cases, dissolution profiles show
that more than 85% of the drug is dissolved within 15 min, which
indicates that the products dissolve rapidly. Indeed, in 6 min more
than 85% of ibuprofen is dissolved for all three batches.
Coefficients of variation for the three batches were not more than
1% between 10 and 60 min indicating good data repeatability.
USP dissolution testing specifications require that at least 85% of
 4 K. YEKPE ET AL.
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Figure 3. SEM images obtained from 3 ibuprofen suppliers.
Figure 4. XRD spectra for ibuprofen A, B, and C.
the labeled API amount should be dissolved within 60 min at pH
7.2.
Low coefficient of variation implies that API concentration does
not impact dissolution. As a consequence, all batches met USP
specification.
2.1.2. Stability study
According to ICH Q1 stability testing provides evidence on “how
the quality of a drug substance or drug product varies over time
under the influence of a variety of environmental factors such as
temperature, humidity, and light ( … )” (ICH Q1A (R2) 2003).
In order to evaluate the impact of humidity on dissolution, ibu-
profen tablet stability data of five batches were analyzed and
compared to ibuprofen tablets dissolution testing USP specifica-
tions. Stability storage conditions for these tablets are 25  C and
60% relative humidity.
Figure 5 shows stability results for dissolution testing to stor-
age conditions 25  C/60%. The USP specifications for dissolution
testing results are: Q (amount of dissolved API) should not be
lower than 85% in 60 min. Specifications are met: the dissolution
percentage for all tested batches is above this limit. Moreover, no
trend is observed for the results over 36 months of storage. Based
on one-way ANOVA, as p values is higher than the significance
level (p values ¼0.521), all means at 60 min are equal at a signifi-
cance level of 0.05. Thus, these results prove that these stability
conditions have no influence on ibuprofen dissolution.
 PHARMACEUTICAL DEVELOPMENT AND TECHNOLOGY 5

Table 3. List of samples.

Hardness Coating weight
Group Batch (% of the nominal) (% of the nominal) API PS
1 1 100 86 Nominal
2 100 86 Nominal
3 100 86 Nominal
4 70 75 Nominal
5 70 100 Nominal
6 140 75 Nominal
7 140 100 Nominal
2 8 70 75 Reduced
9 70 100 Reduced
10 100 86 Reduced
11 100 86 Reduced
12 140 75 Reduced
13 140 100 Reduced
Figure 5. Stability dissolution testing data of ibuprofen tablets at 25  C and 60%
RH.

Table 2. Factors and levels of the DoE.

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Tablet Hardness Coating weight

(% of the nominal) (% of the nominal) API PS (lm)
Low level 70% 75% 90
Central Point 100% 86% N/A
High level 140% 100% 0.40-190
Comments:
Nominal PS is 0.40–190 lm
Reduced PS is 90 lm

2.1.3. Conclusion on preliminary study

This preliminary study showed that:
 The ibuprofen from different suppliers exhibited the same
physical properties (based on suppliers A, B, and C).
Consequently, it is expected they do not affect ibuprofen
tablet dissolution results;
 Ibuprofen concentration (90 and 110% API) has no influ-
ence on ibuprofen tablet dissolution results;
 Storage humidity (conditions: 25  C/60%) has no influence
on ibuprofen tablet dissolution results.
2.2. Design of experiments
The risk assessment identified API PS, tablet hardness and coating
thickness as parameters that may significantly affect the dissol-
ution of the product under investigation. To evaluate the effects
of these variables, a DoE was carried out. As the study must be as
representative as possible of current manufacturing processes, we
selected factor levels mirroring specifications for API particle size
(PS), tablet hardness, and tablet coating thickness (or tablet coat-
ing weight).
The experimental design space consisted of 13 experiments
(two factors at three levels and one factor at two levels). The fac-
tors at three levels were: tablet hardness (70, 100, and 140% of
the nominal value) and tablet coating weight (75, 86, and 100%
w/w of the nominal value) and the factor at two levels was API
mean particle size (0.40–190 lm and lower than or equal to
90 lm). Our experiments were designed to evaluate the effects of
these three factors on responses, i.e. ibuprofen dissolution percen-
tages over time.
Coating percentage of 100% represents the nominal coating
according to the manufacturing instructions. The nominal value is
the current coating value validated for this product. This value
was selected as the high level in the DoE since it would not likely
be possible to add additional coating solution as per manufactur-
ing instructions. Thus, variables for coating percentage level for
Figure 6. Dissolution profiles of all 13 batches at medium pH 6.4, 6.8, and 7.2.
Red line represents USP dissolution specifications.
the DoE are 75 and 100% with an intermediate point at 86%.
Coating percentage of 75, 86, and 100% indicate that batches
were coated respectively with 75, 86, and 100% of actual coating
solution quantity resulting in different coating thicknesses.
More over a lower coating thickness would affect the product
appearance as the coating would appear not homogeneous; such
a defect would be easily detected by In-Process Checks.
Experimental design and analysis were conducted with Design
Expert version 8.0.6 (Stat-ease Inc., Minneapolis, MN). Table 2 sum-
marizes the adopted DoE. As the ibuprofen used in this study is
ionic and its solubility depends on pH, we performed the DoE at
different pH levels.
2.3. Tablet manufacture
Small amounts of ibuprofen powder were withdrawn from com-
mercial batches after wet granulation, drying, sieving, and final
blending steps to produce the samples belonging to Group 1
(Table 3). Tablet compression and coating steps were carried out
after the final blending step.
To produce Group 2 samples containing smaller API particles,
the API commercial powder: 0.40–190 lm (“Nominal” in Table 3)
was separated with a mesh sieve in order to obtain API particles
sizes lower than or equal to 90 lm (“Reduced” in Table 3). After
mixing the API with other formulation ingredients, wet granula-
tion, drying, and sieving steps were carried out. After the sieving
step, the powder was compressed at the typical tablet hardness
 6 K. YEKPE ET AL.
of commercial product family. The tablets obtained after this step
have been coated.
2.4. Tablet properties
Tablet properties (weight uniformity, length, thickness, and hard-
ness) were measured in randomly selected tablets from each
batch. Five (5) tablets were tested for weight uniformity, length,
thickness, and hardness. Tablet weight uniformity was established
by AT460 Delta Range electronic balance (Mettler Toledo,
Columbus, OH). Length and thickness were quantified with a CD-
6" CX digital caliper (Mitutoyo, Aurora, IL). Hardness was analyzed
with a Type HT500 tablet hardness tester (Key International, Inc.,
New-York, NY). Relative standard deviation (RSD) values were cal-
culated for each batch.
2.5. DT of manufactured tablets
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Dissolution studies were performed using a Distek 2100 A USP dis-
solution apparatus 2 (Distek Inc., North Brunswick, NJ). Six tablets
from each batch were placed separately, each in 900 ml of dissol-
ution medium (potassium phosphate buffer at pH 6.4, 6.8, or 7.2:
0.05 M). Temperature was fixed at 37.0 ± 0.5  C and paddle stirring
was set at 50 rpm. Samples were analyzed by a continuous flow
system attached to an Agilent 8453 UV/VIS spectrophotometer
(Agilent Technologies, Inc., Wilmington, NC). Wavelength was set
as recommended by the USP monograph on API, which is 221 nm.
Absorbance was monitored every 2 min over a 60 min period
(totalizing of 30 times points). Data were acquired by Chemstation
software (Agilent Technologies, Inc., Wilmington, NJ). Values were
compared against a calibration curve, and percentages of dis-
solved drug were plotted for time profiles. According to USP, spe-
cification results must be higher than or equal to 85% of API
dissolution at 60 min (FDA 1997). Dissolution percentages over
time served as response variables for DoE analysis (13 DoE runs at
three different pH values).
2.6. Statistical analysis
Three variables were studied: API PS (A), tablet hardness (B), and
coating weight (C). Analysis Of Variance (ANOVA) was used to
understand relationships between variables (i.e. A, B, and C) and
dissolution percentages over test time.
3. Results and discussion
3.1. Tablet properties
Mean RSD values for all batches were 0.77, 0.16, 0.07, and 6.96%
for tablet weight uniformity, thickness, length, and hardness,
respectively. Thus, the results varied insignificantly for all tablet
properties studied, confirming good process reproducibility.
3.2. Dissolution profile in medium pH study
As described earlier, DoE established how design factors – API PS,
tablet hardness, and coating weight – affected responses (API dis-
solution percentage over time with test medium pH). Figure 6
shows the dissolution profiles of all 13 DoE runs at three different
pH values. Dissolution at each time point represented an average
of six tablets. For each time point, the dissolution RSD was less
than 5% and, therefore, for clarity, the error bars are not shown in
Figure 6. It can be observed that dissolution varied with pH
values.
Table 4. Dissolution models under study.
Model Equation
Zero-order (Costa and Sousa Lobo 2001) %disso ¼ kt (1)
First-order (Polli et al. 1997) %disso ¼ 1  ekt (2)
Higuchi (1963) %disso ¼ kt1=2 (3)
Korsmeyer–Peppas (Korsmeyer et al. 1983) %disso ¼ ktn (4)
3
Hixson–Crowell (Hixson and Crowell 1931) %disso ¼ ð1  ktÞ b (5)
Weibull (Dokoumetzidis et al. 2006) %disso ¼ 1  ðe ðatÞ
) (6)
Figure 7. Coefficients of determination (R2) of kinetic models in all 13 batches at
pH 6.4, 6.8, and 7.2.
USP dissolution testing specifications require that at least 85%
of the labeled API amount should be dissolved within 60 min at
pH 7.2 (the red threshold limit bar in Figure 6 represents USP
specifications). Every tested tablet, from every batch, met USP
specifications. Thus, despite different medium pH values and
changes in tablet properties, USP specifications were still met
within 60 min. As indicated in Figure 6, dissolution results for
batches tested at pH 7.2 were slightly above 100%. The observed
drug level variability was expected and acceptable. It may be a
reflection of DT variability (i.e. systematic errors) or analytical
artifacts.
3.3. Impact of dissolution medium pH on API release kinetics
API release kinetics were studied. The data were compared
through the applicability of models available in the literature:
zero-order, first-order, Higuchi, Korsmeyer–Peppas, Hixson–Crowell,
and Weibull equations. These models are considered as the most
relevant and commonly used for dissolution time profiles and are
presented in Table 4 (Costa and Sousa Lobo 2001). Figure 7
presents average R2 values for the 13 batches at the pH 6.4, 6.8,
and 7.2 for all kinetics models.
The Weibull and first order models give the highest R2 values;
thus, they were chosen for further study. In order to select the
most appropriate prediction model, the values of a and b parame-
ters of Weibull model and the constant k of the first-order equa-
tion were studied. Table 5 presents the means and standard
deviations associated with these values for the 13 lots to pH 6.4,
6.8, and 7.2. It shows that the standard deviations of a and b
parameters are very high for the pH 7.2 tests. Statistical analysis
using the Student t-test (a ¼ 0.05) indicates that the parameter k
of the first order model is highly significant in all cases, while the
parameters a and b of the Weibull model at pH 7.2 are not.
Moreover, the Weibull equation overfits individual profiles.
Consequently, the use of the first order model is considered more
appropriate. The computed k values for this model applied to all
 PHARMACEUTICAL DEVELOPMENT AND TECHNOLOGY 7

Table 5. Means and standard deviations associated with k, a, and b values for the 13 lots to pH 6.4. 6.8, and 7.2.
k Constant (1st order) a Parameter (Weibull) b Parameter (Weibull)
1 1
pH value Average (min ) Standard-deviation (min ) Average (min) Standard-deviation (min) Average (adimensional) Standard-deviation (adimensional)
6.4 0.13 0.03 1.33 0.27 0.30 0.05
6.8 0.22 0.05 0.78 0.13 0.20 0.04
7.2 0.40 0.12 16.58 34.88 1.51 0.95

Table 6. Significant models in ANOVA with a ¼ 0.05.

pH 6.4 pH 6.8 pH 7.2
Between 6–12 min No Yes Yes
Between 14–60 min No No No

Table 7. ANOVA at pH 6.8 and 7.2.

pH 6.8 pH 7.2
Source F value Probability (p-value) F value Probability (p-value)
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Model 6.84 0.0251 6.54 0.0276

A 33.14 0.0022 35.90 0.0019
B 7.54 0.0405 7.20 0.0437
C 0.26 0.6326 0.35 0.5801
AB 0.044 0.8418 0.70 0.4410
AC 2.73 0.1597 0.20 0.6765
BC 3.10 0.1387 0.013 0.9142
Figure 8. First-order dissolution rate constant (k) values for all 13 batches at pH ABC 1.08 0.3466 1.39 0.2909
6.4, 6.8, and 7.2. Lack of fit 0.35 0.7329 1.30 0.3920

batches are presented in Figure 8. It is shown that, as expected,

that k values vary with batch and increase with pH. As expected,
drug release performance is improved in more alkaline media.
Table 8. Selected limits for this modified control strategy.
Factors Tablet hardness Coating weight API PS
3.4. Statistical analysis
limit (% of the nominal) (% of the nominal) (lm)
Design factor effects on dissolution were studied quantitatively by Low threshold value 70% 75% 90
ANOVA. According to Table 6, with 13 runs, ANOVA indicates that High threshold value 140% 100% 0.40–190
models were significant for dissolution results with testing time
between 6 and 12 min at pH 6.8 and 7.2. Between 14 and 60 min,
none of the models and none of the effects were proven signifi- Y ¼ ð100:31 6 0:49Þ–ð2:28 6 0:38ÞAPI PS þ ð1:30 6 0:48Þ
cant (p < 0.05). Indeed, API particle size, tablet hardness, and coat- (8)
Tablet Hardness for pH 7:2
ing weight showed no significant effects on DT at 60 min.
At the end of steady state of the dissolution process, no critical
process variables impacted the dissolution results. This suggests Good correlations were obtained between observed and predicted
that these variables do not contribute to API dissolution anymore. values, as indicated by the high R2 values with both models: 0.905
At 10 min, modeling is possible only at pH 6.8 and 7.2. ANOVA is and 0.902 for pH 6.8 and 7.2, respectively.
presented in Table 7 for pH 6.8 and 7.2, respectively. Based on
the ANOVA results, two main effects were significant at pH 6.8 3.5. Discussion
and 7.2 (p < 0.05): API PS and tablet hardness.
These variables have a greater impact on API dissolution at an Risk analysis is an important step in QbD strategy application. For
earlier dissolution time than at the end of the dissolution process. this reason, in the first part of our study, risk analysis was per-
This phenomenon can be explained by the fact that dissolution is formed and three factors were identified as potential impact fac-
dependent on disintegration, which is mostly influenced by tablet tors. They included API PS, tablet hardness, and coating weight.
hardness. DoE involves relatively few runs (13 runs) and can estimate the
Thus, at earlier time points, tablets are still disintegrating and significance of main effects with high efficiency and accuracy. As
API particles are being released from them. The rate of API dissol- mentioned, at USP specifications of 60 min, no parameters were
ution, therefore, depends on API PS. Moreover, during the dissol- found to statistically affect dissolution results of the tablets, under
ution process, a visual inspection proved that coating was the ranges studied.
systematically removed in less than 1 min from tablets of all Two factors proved to be statistically significant, namely, API
batches, confirming qualitatively that this parameter has no sig- PS and tablet hardness. Of these factors, low API PS had a positive
nificant impact on dissolution results. effect on DT at earlier time points, emphasizing that small API par-
The final equations in terms of coded factors were determined. ticle size enhanced dissolution performance because of increased
The statistical models were: surface/volume ratio (Noyes and Whitney 1897).
First order models successfully described the dissolution rate,
Y ¼ ð86:95 6 0:49Þð2:82 6 0:49ÞAPI PS þ ð1:71 6 0:62Þ but further validation is required to evaluate their general predict-
(7)
Tablet Hardness for pH 6:7 ive capability.
 8 K. YEKPE ET AL.
Regarding ICH Q8/Q9/Q10 (R2) which explains the role of mod-
els in QbD (ICH Q8/Q9/Q10 (R2) 2011c), the models presented in
this article are categorized as high-impact models.
An interesting finding is that the last tested factor, coating
weight, had no effect on drug dissolution. This can be explained
by the fact that the tablets under study were film-coated and
principally composed of very soluble excipients that dissolved rap-
idly upon wetting, thus not interfering in tablet disintegration or
API dissolution.
According to QbD principles, a specific method is required to
specify the design space (ICH Q8, R2 2009). Design space gener-
ation begins with CQA identification, risk assessment, DoE, model
building, and design space visualization (Yu 2008; Little, 2013).
According to ICH Q8 (R2), a design space can be described in
terms of ranges of material attributes and process parameters, or
through more complex mathematical relationships (ICH Q8, R2
2009).
Thus, the relationship between the process inputs (material
Downloaded by [Gothenburg University Library] at 02:52 03 November 2017
attributes and process parameters) and the critical quality attrib-
utes can be described thanks to the design space. Inside the
design space, product quality is assured.
The design space is proposed by the applicant and is subject
to regulatory assessment and approval. Therefore, in order to be
approved, the model underlying the design space requires fulfill-
ing specifications.
The design space is this article can be explained mathematic-
ally through the equation describing relationships between quality
attributes and process parameters and/or Material Attributes:
Y(Dissolution percentage at a specific time) ¼ F(API PS and tablet
hardness).
Moreover, according to the results of the current study, the
edge of failure of the design space is beyond the selected limits
for this modified control strategy. The selected limits for this
modified control strategy are presented in Table 8.
Thus, the edge of failure of the design space was beyond the
limits selected. As stated in ICH Q8, R2 and confirmed in
“Questions and Answers on Design Space Verification” published
on 24 October 2013 (FDA and EMEA 2013), the determination or
demonstration of edge of failure is not an essential part of the
definition of design space; the edge of failure of this design space
was found to be outside the selected parameters studied.
Moreover, our study proves that the examined manufacturing pro-
cess was robust.
For the formulation under study, which has a relatively simple
dissolution behavior, the first order model worked satisfactorily.
However, more complex formulation where drug release depends
on amount of other ingredients like controlled-release polymers
and pH modifiers might be determined by other models (Costa
and Sousa Lobo 2001). In this case, the advantages and disadvan-
tages of model dependent and model independent methods
should be examined to predict dissolution. Once the ability to
predict dissolution with a model is well demonstrated, meeting
the remaining requirement for implantation in pharmaceutical
control quality strategy like method validation based on current
pharmaceutical guidelines will be necessary.
4. Conclusion
QbD tools made it possible to identify critical parameters, trans-
late them to attributes that the drug product should possess, and
establish how critical process parameters can be varied to consist-
ently produce drugs with desired characteristics. QbD principles
and tools presented in ICH Q8, ICH Q9, and ICH Q10 guidelines
were considered in the current case study to explore relationships
between formulation and manufacturing process variables and
BCS Class II API DT to improve our fundamental knowledge of dis-
solution testing (DT).
Risk analysis, identification of critical formulation/process varia-
bles, understanding the effects of these critical variables and inter-
actions on key product quality attributes are essential steps to
achieve enhanced product and process awareness and offer
opportunities to develop control strategies while ensuring final
product quality. Indeed, as DT results at 60 min were all similar, it
was not possible to model dissolution with operating conditions
specified by USP. Preliminary results have shown that modeling at
DT time of 10 min can be performed allowing us to understand
and predict DT. In these situations, opportunities exist to develop
more flexible regulatory approaches, for example, to facilitate real-
time quality control, leading to reduction of end-product release
testing.
This case study exemplified the application of QbD principles
and tools to drug product and process development. It demon-
strated that DoE effects/response surface analysis represents a
powerful tool to investigate the effects of selected factors (API PS,
tablet hardness, and coating weight) on response–dissolution per-
centages, showing product and process robustness. The following
points comprise the main new information brought forward by
our study:
 The two parameters impacting dissolution kinetics at
10 min are API PS and tablet hardness. They can easily be
controlled during and after the manufacturing process
with standard equipment such as an online laser-granul-
ometer and hardness tester, this information is highly use-
ful for formulation improvement.
 Models can be used to predict DT if appropriate validation
was to be performed.
 This QbD approach demonstrates product and process
robustness.
The QbD concept can completely eliminate the need of dissol-
ution testing or eventually either decreases required dissolution
testing time as the finale dissolution percentage can be predicted
knowing the first minute dissolution percentage the first minutes’
dissolution percentage. Thus, dissolution test can be reduced, or
even eliminated, if confirmed by a validation procedure.
In conclusion, the methodology presented in this article (FMEA,
DoE, and Design space definition) could be replicated and per-
formed in other dosage forms like controlled release tablets, emul-
sions, suspensions, etc.
Disclosure statement
The author declares that she has no relevant or material financial
interests that relate to the research described in this paper.
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