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Drug Development and Industrial Pharmacy
ISSN: 0363-9045 (Print) 1520-5762 (Online) Journal homepage: http://www.tandfonline.com/loi/iddi20
Quality-by-design approach for development of

telmisartan potassium tablets
Ga-hui Oh, Jin-Hyun Park, Hye-Won Shin, Joo-Eun Kim & Young-Joon Park
To cite this article: Ga-hui Oh, Jin-Hyun Park, Hye-Won Shin, Joo-Eun Kim & Young-Joon
Park (2017): Quality-by-design approach for development of telmisartan potassium tablets, Drug
Development and Industrial Pharmacy, DOI: 10.1080/03639045.2017.1414233
To link to this article: https://doi.org/10.1080/03639045.2017.1414233
Accepted author version posted online: 18

Dec 2017.
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Download by: [Gothenburg University Library] Date: 19 December 2017, At: 03:54
Quality-by-design approach for development of
telmisartan potassium tablets
Ga-hui Oh, Jin-Hyun Park, Hye-Won Shin, Joo-Eun Kim†, and Young-Joon Park††
College of Pharmacy, Ajou University, Suwon, Korea

Downloaded by [Gothenburg University Library] at 03:54 19 December 2017
††
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Corresponding author: College of Pharmacy, Ajou University, Suwon City 443-749, Korea
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Phone: +82-31-219-3493, Fax: +82-31-219-3432, E-mail: parkyj64@gmail.com
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†
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Corresponding author: Yuhan R&D institute, Yongin City, Korea
Phone: +82-31-899-4052, Fax: +82-31-275-6145, E-mail: 77jooeun@naver.com

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Abstract
A quality-by-design approach was adopted to develop telmisartan potassium (TP) tablets, which
were bioequivalent with the commercially available Micardis® (telmisartan free base) tablets. The
dissolution pattern and impurity profile of TP tablets differed from those of Micardis® tablets
because telmisartan free base is poorly soluble in water. After identifying the quality target product
profile and critical quality attributes (CQAs), drug dissolution and impurities were predicted to be
risky CQAs. To determine the exact range and cause of risks, we used the risk assessment (RA) tools,
PHA and FMEA to determine the parameters affecting drug dissolution, impurities, and formulation.
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The range of the design space was optimized using the face-centered central composite design
among the design of experiment (DOE) methods. The binder, disintegrant, and kneading time in the
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wet granulation were identified as X values affecting Y values (disintegration, hardness, friability,
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dissolution, and impurities). After determining the design space with the desired Y values, the TP
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tablets were formulated and their dissolution pattern was compared with that of the reference tablet.
The selected TP tablet formulated using design space showed a similar dissolution to that of
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Micardis® tablets at pH 7.5. The QbD approach TP tablet was bioequivalent to Micardis® tablets in
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beagle dogs.
Keywords: Telmisartan potassium, Quality-by-Design, Design of Experiment, Risk Assessment,

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Design Space, Bioequivalence.

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Abbreviations
QbD : Quality by Design
TP : Telmisartan Potassium
QTPP : Quality Target Product Profiles
CQA : Critical Quality Attributes
RA : Risk Assessment
CMA : Critical Material Attributes
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CPP : Critical Process Parameters
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PHA : Preliminary Hazard Analysis
FMEA : Failure Mode and Effect Analysis us

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DoE : Design of Experiments
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CCD: Central Composite Design

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FCCCD: Face-centered Central Composite Design

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API : Active Pharmaceutical Ingredients

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RPN : Risk Priority Numbers (RPNs = P × S × D).

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P : Probability, D : Detectability, and S : Severity.
USP : United States Pharmacopeia

1. Introduction
Telmisartan, 4-[(2-n-propyl-4-methyl-6-(1-methylbenzimidazole-2-yl)-benzimidazole-
1yl)methyl]-biphenyl-2-carboxylic acid, is a selective angiotensin II type 1 receptor (AT1R) blocker,
which reduces blood pressure [1]. It was developed by Boehringer Ingelheim and launched in 1999
as Micardis®. Telmisartan free base has been mainly used in commercial products. Owing to its low
solubility in water (BCS class II), its oral bioavailability is poor [2]. The solubility of telmisartan
free base has been increased by the addition of sodium salt using sodium hydroxide (NaOH) and
meglumine as alkylating agents [3]. In contrast, telmisartan potassium (TP, a salt form) is highly
soluble, and thus, it exhibits a different dissolution pattern.
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Most drugs are either weak organic acids or bases and, therefore, can exist in different salt forms.
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Although the active pharmaceutical ingredient (API) is the same in all these salts, they could be
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considered as distinct chemical entities with their own chemical and biological profiles [4]. To
improve the general properties of APIs such as solubility and stability, their novel salts are often
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introduced. Numerous pharmaceutical technologies for enhancing the solubility of insoluble drugs
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use formulations such as amorphous forms (solid dispersions/cocrystals), polymeric micelles,
inclusion complexation, size reduction including nanonization [5], self-microemulsifying drug

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delivery systems (SMEDDS), surfactant/co-solvent systems [6], solid lipid nanoparticles
(SLN)/liposomes, pH-modified form, and salt forms [7]. However, one of the strategies for
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improving solubility and stability is the incorporation of different salt forms of an approved API into
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the marketed brand dosage form of a company, followed by bioequivalence assessment [4].
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To develop a bioequivalent formulation with the salt alternative of telmisartan free base, we used a
quality-by-design (QbD) approach [8], which involves building quality into products by design [9].
The QbD [10] approach ensures that the pharmaceutical development process is focused on
ultimately providing a scientific understanding of how process parameters affect product
performance. This knowledge enables the establishment of a design space, product, and process
specifications, as well as appropriate manufacturing controls that ensure the consistent achievement
of all necessary quality targets and product requirements [11]. Hence, QbD emphasizes the
systematic development of pharmaceutical products based on sound scientific principles and refers
to the achievement of predictable quality with desired, predetermined specifications [12].
The process and formulation can be understood by developing them based on the multivariate
analysis of designed experiments, historical data, or both that identify and characterize the critical-
to-quality process parameters as well as the root causes of variability [13]. Design of experiments
(DOE) is a useful tool for identifying and optimizing critical process parameters (CPPs)/critical
material attributes (CMAs) [14]. To optimize the process and formulation, statistical DOEs [15] are
used during the pharmaceutical product/process development [16]. In particular, response surface
methodologies, including statistical experimental designs such as central composite design and Box-
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Behnken design, have been commonly used [17, 18, 19].
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The aim of this study was to develop a novel alternative TP salt with bioequivalence to telmisartan
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free base using a QbD approach. After defining the quality target product profile (QTPP) and critical
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quality attributes (CQAs), drug dissolution and impurities in the process were predicted to be the
risky CQAs. To determine the exact range and cause of the risk, we used the risk assessment (RA)
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tool preliminary hazard analysis (PHA) [20] and failure mode effect analysis (FMEA) [21] to
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identify the parameters that affect drug dissolution, impurities, and formulation [22]. The range of
design space was optimized using the face-centered central composite design, which is one of the
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DoE methods [23]. Furthermore, the drug dissolution and bioavailability of the TP tablet were
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evaluated in beagle dogs and compared with those of Micardis® tablet(telmisartan free base).
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The tablets of this novel TP salt were significantly smaller than the marketed tablets, thereby
increasing patients’ compliance, especially in elderly patients with hypertension who face difficulties
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in swallowing.
2. Materials and methods
2.1 Materials
TP was provided by Hwail Pharmaceutical Co., Ltd. (Seoul, Korea). Magnesium oxide (MgO) was
purchased from Tomita Pharmaceutical Co., Ltd (Tokushima, Japan). Potassium chloride was
purchased from Samchun Chemical Co., Ltd. (Pyeongtaek-si, Korea). D-mannitol was purchased
from Merck & Co., Inc. (Kenilworth, NJ, USA). Microcrystalline cellulose and croscarmellose
sodium were purchased from JRS Pharma Co., Ltd. (Patterson, NY, USA). Crospovidone was
purchased from BASF Pharma Co., Ltd., (Rotherstraße, Berlin, Germany). Colloidal silicon dioxide
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was purchased from Evonic Health Care Co., Ltd., (Rellinghauser Straße, Essen, Germany).
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Magnesium stearate was provided by Merck KGaA (Frankfurter StraBe, Darmstadt, Germany). All
other chemicals were of reagent grade and obtained commercially.
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2.2 Defining QTPP
To determine the QTPP of the TP tablet, we specified the indication; dosage form, design, and
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strength; the route of administration, pharmacokinetics, shelf life, and primary packaging.
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Furthermore, these items were also justified in detail from the perspectives of pharmacists,
physicians, and patients. In addition, the research goals and risk of justification according to
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pharmacists, physicians, and patients were specified (Table 1).

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2.3 Determining CQAs

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To identify the CQAs of the TP tablet, the quality attributes such as physical characteristics,
appearance, identification, dissolution, impurities, weight variation, content uniformity, assay, and
residual solvents were specified. Furthermore, the acceptable values of the various items and the
CQAs were specified. The results of the CQA estimation are shown in green, yellow, and red colors
depending on the risk (Table 2). Thus, the CQA colors in the Table 2 were justified and evaluated
according to safety, efficacy, and quality specifications as the three major parameters of medicines.
The CQA targets are similar to the criteria specified in the certificate of analysis (CoA); however,
in contrast, the CQA list includes items to determine whether the QA is general or critical. Among
the various QAs, CQAs were identified by color, and the QA feasibility was described in terms of
safety, efficacy, and quality.
The “Justification” section in the CQA table is written as; content and content uniformity test may
affect safety and efficacy; currently, these process variables and excipients may affect the content
and content uniformity of the TP product. Therefore, content and content uniformity tests should be
performed using formulation studies and process development; thus, they were selected as CQAs.
However, the “Identification test” in the CQA table did not affect the formulation studies and
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process variables of the TP tablets because only the presence of the API was confirmed. Therefore, it
is not a CQA but only a general quality attribute.
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2.4 RA of CMAs and CPPs
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An RA was performed to select and evaluate the CMAs and CPPs that affect the CQAs. In this
study, PHA and FMEA were used as RA tools [24]. PHA consist of a table in which each item is
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indicated by a color: green, yellow, or red (low-, medium-, or high-risk, respectively). Green
indicates a broadly acceptable risk and no further investigation is needed while yellow indicates an
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acceptable risk level, which may require further investigation/justification to reduce the probability.
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Finally, red indicates an unacceptable risk that requires further investigation to reduce the risk.
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Among the various MAs, the functional groups of excipients and APIs that are considered to affect
CQAs are listed in the PHA and FMEA Tables. For the FMEA analysis, each failure mode was
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ranked using an estimated frequency of probability (P), the probability of failure undetected later in
the detectability (D), and severity (S). The P of detection and S are scored using a scale of 1–4. P is
defined as the frequency of a specific failure that can result in failure mode. It should refer to the P
of the cause, which is a specific failure mode for a particular effect/event.
The score based on the P of occurrence of failure is divided into unlikely (1), occasional (2),
repeated (3), and regular (4). The scores based on the likely S effect on a drug product with CQAs
were divided into minor (1), moderate (2), major (3), and extreme (4).The score based on the P of
failure of detection is divided into always detected (1), regularly detected (2), likely not detected (3),
and normally not detected (4). Failure risks were calculated using risk priority numbers (RPNs),
which are the product of P, S, and D (RPNs = P × S × D). The values of P, S, and D for each failure
mode in the case of the TP tablets were assigned based on previous experience and literature reviews,
and the RPNs were calculated.
A high RPN value for the concentration of disintegrant indicated that it could introduce a lag time
in dissolution. The potential cause could be a low disintegrant concentration with a high occurrence
value (P = 4), a low detectability value (D = 2), and an extreme severity value (S = 4); the calculated
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RPN for this failure mode was 32. Failure modes with RPNs ≥ 30 were set as criteria for
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considering the DoE as a possible failure.
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2.5 Preparation of TP tablets
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The TP tablets were prepared according to the formulation compositions shown in the range of
design space or preliminary studies using the wet granulation method with a high shear mixer. The
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TP tablets each comprised 91.1 mg TP, 30.0 mg magnesium oxide (MgO), 10.0 mg potassium
chloride, 151.9 mg microcrystalline cellulose (MCC), 20.0 mg D-mannitol, 20.0 mg croscarmellose

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sodium, 10.0 mg crospovidone, 10.0 mg colloidal silicon dioxide, and 7.0 mg magnesium stearate.
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TP, the API, and part of the colloidal silicon dioxide were mixed for 5 min at 15 rpm using a
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laboratory mixer. The obtained mixture, MgO, D-mannitol, crospovidone, and part of the MCC were
further mixed for 8 min at 15 rpm using a laboratory mixer, and then the obtained mixture was
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filtered through a 20-mesh screen. For the wet granulation process, an ethanol solution was added to
this mixture as a binding solution to yield wet granules, and the impeller and chopper speed (150 and
2,000 rpm, respectively) were maintained during the wet granulation process using a high shear
mixer for 5 min. Then, the granules were dried using a fluid bed dryer (Glatt GPCG1, Ramsey, NJ,
USA) at 55°C for 1.5 h until the water content was < 2.0%. The dried granules were passed through
a 0.065-inch screen processed using a Cone Mill instrument (Hosokawa micron Ltd., Cheshire, UK).
The milled granules were mixed with croscarmellose sodium, potassium chloride, part of the MCC,
and part of the colloidal silicon dioxide for 3 min and then finally blended with magnesium stearate.
TP tablets were prepared by compression using a rotary tablet machine to a targeted hardness and
mass weight of 11 kp and 350 mg, respectively, as indicated by the design space.
2.6 Evaluation of TP tablets
2.6.1 Hardness test
The hardness level of the TP tablets was assayed using the Model 8M bench top hardness tester
(Pharmatron, Aesch, Switzerland). The tablet was placed between the edges of the fixed and
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movable part of the instrument, and the hardness was measured in kiloponds.
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2.6.2 Friability
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The friability of the TP tablets was assayed using a FT 2 friability tester (Pharmatron model FT
2 friability tester, Aesch, Switzerland). Friability is the measure of tablet strength, and it was
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calculated as a percentage using the following formula:
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Friability (%) = [(w1 - w2)/w1] × 100,
where w1 and w2 are the weights of the tablets before and after the test.
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2.6.3 Disintegration test

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The disintegration rate of the TP tablets was assayed using a tablet disintegration tester
(Pharmatron model DisiTest 20 tablet disintegration tester, Aesch, Switzerland). The disintegration
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test was performed according to the US Pharmacopeia (USP) by placing six TP tablets into a tablet
disintegration tester.
2.6.4 In vitro dissolution of TP tablets
The dissolution test was performed using the USP XXXII dissolution apparatus II with 900 mL
of 20 mM potassium dihydrogen phosphate buffer at pH 7.5 ± 0.1 as the dissolution medium at 37 ±

0.5°C. The speed of the paddle was adjusted to 75 rpm. The TP and Micardis® tablets at an
equivalent dose of 80 mg telmisartan base were placed into a dissolution tester (Agilent dissolution
tester, Santa Clara, CA, USA). After 30 min or at predetermined intervals, 4 mL of the medium was
sampled and filtered through a membrane filter (0.45-μm). The concentration of telmisartan in the
filtrate was analyzed using ultraviolet (UV) spectrophotometer (Agilent 8453 UV/visible [Vis]
spectrophotometer, Santa Clara, CA, USA) at 296 nm. Then, the in vitro dissolution profiles of the
TP tablets and reference drug (Micardis®) were compared using the similarity factor (f2)
recommended for dissolution profile comparison in the Guidance for Industry of US Food and Drug
Administration (FDA).
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2.6.5 High-performance liquid chromatography (HPLC) analysis
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The content and impurity level of telmisartan were assayed using a high-performance liquid
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chromatography (HPLC) system equipped with a separation module and a UV/Vis detector (Agilent
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1200 series, Santa Clara, CA, USA). To assay telmisartan content, a Luna C18 column, (150 × 3.9
mm, 5 μm; Phenomenex Inc., Torrance, CA, USA) was used as the stationary phase. The mobile
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phase, composed of 20 mM potassium dihydrogen phosphate:methanol (4:6, v/v, pH 3.0 ± 0.05),
was filtered through a 0.22-μm membrane filter and degassed using an online degasser. The column
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temperature, detection wavelength, eluent flow rate, and injection volume were 40°C, 237 nm, 1.5
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mL/min, and 20 µL, respectively. Calibration samples were prepared by accurately weighing and
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dissolving 32.0 mg telmisartan to obtain a stock solution, which was subsequently diluted to
concentrations of 32.0–320 μg/mL. The calibration curve was rectilinear with a correlation
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coefficient of 0.999, whereas the standard deviation (SD) of the accuracy and precision was < 2%.
To assay telmisartan impurity levels, a Zorbax SB C18 column (50 × 4.6 mm, 3.5 μm; Agilent
Inc.) was used as the stationary phase. Mobile phases A and B were composed of 18 mM ammonium
dihydrogen phosphate (pH 3.0 ± 0.1):methanol in the ratios of 4:6 and 2:8 (v/v), respectively. The
following gradient program was followed: 0% B (0–12 min), 0–20% B (12–13 min), 20–90% B (13–
15 min), 90% B (15–25 min), and 90–0% B (25–30 min). The column temperature, detection
wavelength, eluent flow rate, and injection volume were 35°C, 298 nm, 1.2 mL/min, and 10 µL,
respectively.
2.7 Development of the design space
The Minitab® software (version 18; Minitab Inc., State College PA, USA) was used for
performing the DoE. Three input (X) values were selected [two types of CMAs (binding solution
and a disintegrant) and one type of CPP (granulation time) through the PHA/FMEA of RA]. The
levels were tested at a narrow range in the knowledge space based on the preliminary studies.
The DoE was set in the range of 40 to 100 mL binding solution, 2 to 6% disintegrant agent, and 3
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to 7 min of wet granulation (kneading) time. Thus, the output (Y) value was selected as the most
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important variable to optimize the disintegrant, hardness, friability, drug dissolution, and impurities
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as a factor affected by the three X values.
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A face-centered center composite design(FCCCD) was used for the DoE to optimize the CQAs
according to the selected CPPs and CMAs. The experimental plan of 20 experimental runs (23 + [2 x
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3] + 6) was obtained and performed randomly. The values of the predetermined dependent variables
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were obtained and statistically analyzed. The main, interaction, and quadratic effects of the factors
related to the properties of the TP tablets were evaluated and the effect of each independent variable
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on the dependent variables was investigated. Variables with p-values < 0.05 were considered
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statistically significant. Each factor was tested at three different levels, and six center points were
included. The Minitab® software was used for the design, analysis, and plotting of the various three-
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dimensional (3D) and contour plots. With the models developed and validated, the design space was
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finally set through all individual acceptance regions for each CMA and CPP.
2.8 Bioequivalence in beagle dogs
Ten Canis familiaris (beagle dogs) were randomly divided into two groups, and the reference
drug (Micardis®) and TP tablets were orally administered under fasting conditions using a two-
period single-dose crossover design. There was a 1-week drug washout period between each dosing.
After oral drug administration, blood samples (3.0 mL) were collected from the jugular vein at 0,
0.25, 0.5, 1, 2, 4, 6, 8, 12, 24, 36, 48, and 72 h. The blood samples were immediately centrifuged at
3,000 rpm for 10 min, and the plasma was stored at -70°C until the analysis. The plasma
concentration of telmisartan in beagle dogs administering the reference drug (Micardis®) or the TP
tablets was analyzed using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The
Waters® Micromass® Quattro Premier XE Tandem quadrupole mass spectrometer (Quattro Premier
XE, Waters, Milford, MA, USA), interfaced with an ultraperformance LC (UPLC, Alliance HT
2795, Waters, Milford, MA, USA), and equipped with a Unison UK-C18 column (75 mm × 2.0 mm
internal diameter, 3 μm, Imtakt, Ringoes, NJ, USA) was used.

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The stock solution of telmisartan was prepared by adjust the concentration of 200 μg/mL in
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methanol, which was subsequently diluted with the blank serum to a concentration range of 10, 30,
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50, 100, 500, 1000, 5,000, and 20,000 ng/mL as a plasma standard. The standard solutions and test
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solutions were prepared by adding 10 μL of the internal standard solution (50 μg/mL of telmisartan-
d7 in 50% methanol) to 50 uL of each standard plasma and test plasma. After adding 1000 μL of
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acetonitrile, centrifuging for 10 minutes at 3,000 rpm for 1 minute with vortexing, 2 μL of
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supernatant was added to LC-MS/MS. A 2 μL sample was separated chromatographically using
isocratic conditions for the mobile phase (A:B, 35:65, v/v). The mobile phase A was 0.1% formic
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acid in 10 mM ammonium formate in distilled water and mobile phase B was 99.99% acetonitrile.
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The flow rate was set at 0.35 mL/min. The calibration curve was drawn with the telmisartan peak
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area ratio to the peak area ratio of the internal standard (of telmisartan-d7) obtained. We have
performed assay validation with specificity, linearity, accuracy and precision. The calibration curve
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was rectilinear with a correlation coefficient of 0.99849 to 0.99937 while the SD of the accuracy and
precision was < 2%.
Statistical analysis
Pharmacokinetic parameters, including total area under the plasma concentration-time curve from
time zero to infinity (AUC0–∞), half-life (t1/2), maximum plasma drug concentration (Cmax), and time
to reach Cmax (Tmax) were calculated using the WinNonlin® software (Pharsight Co., Cary, NC, USA)
of Crystal Genomics Pharmaceutical Co., Ltd.

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3. Results and Discussion
3.1 Defining QTPP
QTPP is a summary of the quality characteristics or attributes of a drug product that need to be
achieved to ensure its safety and efficacy [25]. It forms the basis for product development design.
As shown in Table 1, the indication; dosage form, design, and strength; the route of administration,
pharmacokinetics, shelf life, and primary packaging were specified. All items except the route of
administration, indication, and residual solvents showed risky justification as QTTP elements
between the TP and reference tablets. This indicates that the requirements for pharmaceutical
equivalence with Micardis® as a reference drug were an approximately similar or the same dosage
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form, design, and strength; the route of administration; pharmacokinetics; shelf life; and primary
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packaging according to pharmacists, physicians, and patients' perspectives. However, the QTPP may
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be updated or revised at various stages of development as new information is obtained during the
process [25].
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3.2 Determining CQAs
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As shown in Table 2, the quality attributes of the TP tablet such as physical attributes, appearance,
identification, dissolution, impurities, weight variation, content uniformity, assay, and residual
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solvents were specified. This indicated that the requirements for pharmaceutical equivalence
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between Micardis® as a reference drug and the TP tablets were approximately or the same quality of
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attributes: physical characteristics, appearance, identification, dissolution, impurities, weight
variation, content uniformity, assay, and residual solvents with respect to safety, efficacy, and
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quality. However, dissolution and impurities were deemed the CQAs of the TP tablet.
Failure to meet the dissolution specification would affect the bioavailability and efficacy while
both formulation and process variables affect the dissolution profile. This CQA was investigated
throughout the formulation and process development in the quality RA and design space.
Degradation products can affect safety and must be controlled based on compendia/International
Council for Harmonisation ICH requirements or reference product characterization to limit patient
exposure[8]. Formulation and process variables may affect degradation products. Therefore, the
degradation products were evaluated during product and process development in the quality RA and
design space[23].
3.3 Quality RA of CMAs and CPPs affecting CQAs
The PHA and FMEA were performed based on previous experience and preliminary
experiments[22]. CMA has a critical effect on the CQA among several MAs. CPP refers to the
critical effect of CQAs among several PPs. The PHA and FMEA of the MAs were included in the
analysis and RPNs were calculated for each parameter (Table 3). The PHA and FMEA of PPs were
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included in the analysis and RPNs were calculated for each parameter (Table 4).
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In the group of core-related factors, wet granulation agents (ethanol as a binding solution) and
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superdisintegrants (croscarmellose sodium and crospovidone) were estimated. Table 3 shows the
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selection of CMAs from several MAs using PHA and FMEA. The risk factors that must be
addressed in the DoE selected by the RPN calculation were identified as “binding solution” and
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“disintegrant.” Table 4 also shows the results of the screening of CPPs among several PPs using
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PHA and FMEA. The risk factor that must be addressed in the DoE selected by the RPN calculation
was confirmed as the “time of the granulation” (the kneading time).

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3.4 Development of design space
The binding solution, disintegrant agent, and granule kneading time, which are the critical factors
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influencing CQAs were selected as CMAs and CPPs at the risk assessment stage. The experimental
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runs with independent variables and corresponding responses for the 20 formulations tested are
presented in Table 5. We used a three-factor, three-level face-centered composite design, which
consisted of replicated center points and a set of points lying at the midpoints of each edge of a
multidimensional cube that defined the area of interest. The center composite design method is a
reactive surface design method that can estimate the first and second terms effectively and model the
curvature of the response variables by adding the experimental points to the previous factor
design[19]. The face-centered composite design is the central composite design which, unlike a
general centered composite design, has all the axis points on but not outside the face in a rectangular
parallelepiped. As shown in Table 5, the number of total experiments conducted was 23 + (2 × 3) + 6
= 20 because it occurred at the face and vertex of the rectangular parallelepiped.
For optimized modeling of the DoE, the response surface design analysis using the regression
equation and the ANOVA was optimized by selecting only the significant factors. Finally, we
determined whether the model was adequate using a lack of fit test. The P-value was > 0.05 and, so,
we could not reject the null hypothesis for lack of conformity. Therefore, the DoE modeling was
optimized, and then the results could be interpreted using a program such as a Pareto chart and
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residual plots for each of the five reaction values (Y 1–5 values) in Figure 1.
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As shown in the factorial plots of Figure 2, the results could be interpreted based on whether or not
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the binding solution, disintegrant agent, and granulation kneading time affected the disintegration
(Y1), hardness (Y2), friability (Y3), drug dissolution at 30 min (Y4), and impurities after 3 months
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(Y5). In addition, the graph of the 2D contour plots and the 3D response surface plots (Figure 2)
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demonstrated how the binder, disintegration, and granulation time affected each reaction Y value.
In the contour plot and main effect plot of hardness (Y2), we observed that the hardness increased
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with increasing amounts of binding solution, but the amount of disintegrant agent had little effect on
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hardness. However, the contour plot and main effect plot of disintegration (Y1) showed that the
disintegration rate depended more on the specific disintegrant concentration (rate) than it did on the
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amount of binding solution. The contour plot and main effect plot of drug dissolution (Y4) showed
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that the specific disintegrant concentration (rate), the amount of binding solution, and kneading time
affected the dissolution rate. In addition, contour plots for impurities (Y5) showed that degradation
products depended on the amount of disintegrant and binding solution, rather than on the time of
granulation.
Figure 3 shows the optimum design value of the actual operating space by superimposing the
contour plots shown in Figure 2. By overlaying the contour maps from each response on top of each
other, RSM was used to identify the ideal window of operability design space per proven acceptable
range and edges of failure with regard to individual goals.
For the design space, the range for contour plots of disintegrant was set up such that the tablet
disintegration was not more than 10 min. The range of the contour plots of hardness was set at 10.0–
11.5 kp. The range of the contour plots of friability was set up such that the minimum friability was
not more than 0.15%. The range of the contour plots of disintegrant was set such that the maximum
dissolution after 30 min was not less than 90%. The range of the contour plots of impurities was set
such that the minimum impurities after 3 months was not less than 0.15%.
The knowledge space area, which was derived from the preliminary studies of the disintegrant
t
agent (X2), was in the range of 2% to 6%. However, the range of disintegrant that satisfied the target
ip
values of the five individual reaction values was 3.0–4.5%, but it is different from the actual usage
cr
range. Therefore, it is possible to set the control space area to 3.0–4.0% because the values need to
remain at this level in terms of dissolution and impurities.

us
The knowledge space area, which was derived from the preliminary studies of the binding solution
an
(X1), was in the range of 40–100 mL. However, the range of binding solution that satisfied the target
M
values of the five individual reaction values was 57.0–75.0 mL, but it was different from the actual
range. Therefore, the control space area should be between 60.0 and 70.0 mL considering the
ed
dissolution and impurities.

pt
The knowledge space area, which was derived from the preliminary studies of the kneading time
(X3), was in the range of 3.0–7.0 min. However, the range of kneading time that satisfied the target
ce
values of the five individual reaction values was in the range of 3.5 to 6.0 min, but it differed from
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the actual usage range. Therefore, the control space area must be between 4.0 and 5.5 min,
considering the dissolution and impurities.
3.5 In vitro dissolution of TP tablets
After preparing the final formulation in the range of the design space, the drug dissolution test was
performed on the TP and the commercial Micardis® reference tablets. Figure 4 shows the drug
release profiles of the TP and Micardis® reference tablets were similar. The dissolution rate of the
TP and Micardis® reference tablets in the pH 7.5 medium was 28.4 ± 4.26 and 26.7 ± 2.39, 61.0 ±
5.31 and 56.1 ± 2.50, 82.9 ± 4.96 and 76.9 ± 2.5, 100.1 ± 0.49 and 97.5 ±0.57, and 100.7 ± 0.42 and
98.1 ± 0.40 at 5, 10, 15, 30, 45 min, respectively. Furthermore, the similarity of the results of the in
vitro dissolution tests was confirmed by the f2 value [4], with 50 < f2 < 100 indicating the similar
dissolution pattern of the two products. The f2 of the TP and Micardis® reference tablets was 69.6 in
the pH 7.5 medium in the standard and test methods based on the USP monograph. Thus, the TP
tablets and Micardis® reference drugs showed a similar correlation of dissolution profiles in the pH
t
ip
7.5 medium of the standard and test methods in the USP monograph. Furthermore, the results of the
cr
in vitro dissolution tests in the pH 7.5 medium of the standard and test methods indicated that both
us
the TP tablets and Micardis® reference drugs completely dissolved within 30 min by up to 70%.
an
Therefore, the TP tablets had a comparable dissolution with the Micardis® reference drug.
M
3.7 Bioequivalence in beagles

ed
The in vivo pharmacokinetic properties of TP after oral administration in beagle dogs were
pt
evaluated. The TP concentrations assessed from the plasma concentration-time profiles of Micardis®
ce
and the TP tablets at a dose of 8.0 mg/kg are presented in Table 6 and Figure 5. After oral
Ac
administration of various drug formulations to beagles, the AUC of the TP and Micardis® tablets
(20,838.2 ± 7,044.3 and 21,285.1 ± 8,340.3 ng·h−1·mL−1, respectively) were not significantly
different (P > 0.05), which indicates that they had similar absorption and circulation times in the
blood. The 90% confidence interval (CI, 0.9071–1.0814) of the geometric least square mean ratios of
the AUC was 0.9790 of the point estimate, which was within 0.80–1.25 of the bioequivalence
criteria for telmisartan.
The Cmax values of the TP and Micardis® tablets (7,925.2 ± 1,662.0 and 8,315.5 ± 1,675.9
ng/mL, respectively) were not significantly different (P > 0.05), which indicates that they had similar
absorption rates in the blood. Furthermore, the 90% CI (0.8598–1.0976) of the Cmax was 0.9531 of
the point estimate, which was within the 0.80–1.25 range of the bioequivalence criteria of
telmisartan. These results indicate that the TP and Micardis® tablets have similar absorption rates
t
following oral administration.
ip
Table 6 shows that the 90% CI of the geometric mean ratios (test/reference drug) of the C max was not
cr
within the acceptable range in the in vivo experiment in beagles. Therefore, the preclinical study
us
demonstrated that the reference and test product were bioequivalent, indicating that the test drug
an
could be a suitable alternative for the commercial product (Micardis®).
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4. Conclusion
ed
We developed TP tablet that was bioequivalent to the commercial Micardis® tablet using a QbD
pt
approach. Telmisartan free base, which is indicated for the treatment of hypertension has a different
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dissolution pattern from that of TP because it is poorly soluble in water.

Ac
After listing the QTPP and CQA, rapid drug dissolution was predicted as a risky CQA. To
determine the exact range and cause of risk according to the CMAs and CPPs, we used PHA and
FMEA to determine the parameters that affect drug dissolution and formulation. The range of the
design space was optimized using the face-centered central composite design among the available
DoE methods. The binding solution, disintegrant agent, and granule manufacturing time in the wet
granulation methods were identified as X values affecting Y values (disintegration time, hardness,
friability, drug dissolution at 30 min, and impurities after 3 months). The design space of the desired
hardness, degree of grinding, elution, impurities, and disintegration time was determined, the tablets
were prepared, and then the dissolution patterns of the TP and reference tablets were compared.
The selected TP tablets comprised telmisartan potassium, magnesium oxide, potassium chloride,
microcrystalline cellulose, D-mannitol, croscarmellose sodium, crospovidone, colloidal silicon
dioxide, and magnesium stearate. The TP tablets were manufactured using wet granulation because
t
of the dissolution properties. The TP tablet selected through the design space showed a similar
ip
dissolution rate to that of the Micardis® tablet at pH 1.2. Finally, the TP tablets were bioequivalent to
cr
the Micardis® tablets in beagles. Thus, the TP tablet appears to be a promising candidate
formulation. us
an
Moreover, the TP tablet of novel alternative salt was significantly smaller than the Micardis® tablet
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of telmisartan free base. Therefore, it may improve patients’ compliance, especially in elderly
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patients with hypertension, who have trouble in swallowing.

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Acknowledgement
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This work was supported by the Technological Innovation R&D Program (C0400223) funded by the
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Small and Medium Business Administration (SMBA, Korea).

REFERENCES
1. Pitt B, Konstam MA. Overview of angiotensin II-receptor antagonists. The American journal
of cardiology. 1998;82(10):S47-S49.
2. Sekar V, Chellan VR. Immediate release tablets of telmisartan using superdisintegrant-
formulation, evaluation and stability studies. Chemical and Pharmaceutical Bulletin.
2008;56(4):575-577.
3. Tran PHL, Tran HTT, Lee B-J. Modulation of microenvironmental pH and crystallinity of
ionizable telmisartan using alkalizers in solid dispersions for controlled release. Journal of
Controlled Release. 2008;129(1):59-65.
4. Cho KH, Choi H-G. Development of novel bepotastine salicylate salt bioequivalent to the
commercial bepotastine besilate in beagle dogs. Drug development and industrial pharmacy.
2013;39(6):901-908.
5. Kim J-e, Park Y-J. Paclitaxel-loaded hyaluronan solid nanoemulsions for enhanced treatment
efficacy in ovarian cancer. International journal of nanomedicine. 2017;12:645.
6. Kim J-E, Park Y-J. High paclitaxel-loaded and tumor cell-targeting hyaluronan-coated
nanoemulsions. Colloids and Surfaces B: Biointerfaces. 2017;150:362-372.
7. Kalepu S, Nekkanti V. Insoluble drug delivery strategies: review of recent advances and
t
ip
business prospects. Acta Pharmaceutica Sinica B. 2015;5(5):442-453.
8. Guideline IHT. Pharmaceutical development. Q8 (2R) As revised in August. 2009.
9. Visser JC, Dohmen WM, Hinrichs WL, et al. Quality by design approach for optimizing the
cr
formulation and physical properties of extemporaneously prepared orodispersible films.
International journal of pharmaceutics. 2015;485(1):70-76.
10.
11.
services. Simon and Schuster; 1992.
us
Juran JM. Juran on quality by design: the new steps for planning quality into goods and
Rathore AS, Winkle H. Quality by design for biopharmaceuticals. Nature biotechnology.

an
2009;27(1):26-34.
12. McKenzie P, Kiang S, Tom J, et al. Can pharmaceutical process development become high
tech? AIChE Journal. 2006;52(12):3990-3994.
M
13. Rahman Z, Zidan AS, Habib MJ, et al. Understanding the quality of protein loaded PLGA
nanoparticles variability by Plackett–Burman design. International journal of pharmaceutics.
2010;389(1):186-194.
14. Salazar J, Heinzerling O, Müller RH, et al. Process optimization of a novel production
ed
method for nanosuspensions using design of experiments (DoE). International journal of

pharmaceutics. 2011;420(2):395-403.
15. Wu H, White M, Khan MA. Quality-by-Design (QbD): An integrated process analytical
pt
technology (PAT) approach for a dynamic pharmaceutical co-precipitation process

characterization and process design space development. International journal of
ce
pharmaceutics. 2011;405(1):63-78.
16. Lawrence XY. Pharmaceutical quality by design: product and process development,
understanding, and control. Pharmaceutical research. 2008;25(4):781-791.
Ac
17. Zidan AS, Sammour OA, Hammad MA, et al. Quality by design: Understanding the
formulation variables of a cyclosporine A self-nanoemulsified drug delivery systems by
Box–Behnken design and desirability function. International journal of pharmaceutics.
2007;332(1):55-63.
18. Lee Y-L, Kim M-S, Park M-Y, et al. Quality by design: understanding the formulation
variables and optimization of metformin hydrochloride 750 mg sustained release tablet by
Box–Behnken design. Journal of Pharmaceutical Investigation. 2012;42(4):213-220.
19. Park S-J, Choo G-H, Hwang S-J, et al. Quality by design: screening of critical variables and
formulation optimization of Eudragit E nanoparticles containing dutasteride. Archives of
pharmacal research. 2013;36(5):593-601.
20. Rausand M. Preliminary hazard analysis. Norwegian University of Science and Technology.
2005.
21. Stamatis DH. Failure mode and effect analysis: FMEA from theory to execution. ASQ
Quality Press; 2003.
22. Guideline IHT. Quality risk management. Q9, Current step. 2005;4:408.
23. Hakemeyer C, McKnight N, John RS, et al. Process characterization and design space
definition. Biologicals. 2016;44(5):306-318.
24. Kaljević O, Djuriš J, Djurić Z, et al. Application of failure mode and effects analysis in
quality by design approach for formulation of carvedilol compression coated tablets. Journal
of Drug Delivery Science and Technology. 2016;32:56-63.
25. Rathore AS. Roadmap for implementation of quality by design (QbD) for biotechnology
products. Trends in biotechnology. 2009;27(9):546-553.
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Table 1. Quality target product profile (QTPP)
t
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us
an
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TP, telmisartan potassium; USP, United States Pharmacopoeia; RSD, relative standard deviation; CI,
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confidence interval; PK, pharmacokinetics; AUC0–t, area under the plasma concentration-time curve
pt
from time 0 to t; AUC0–, area under the plasma concentration-time curve from time 0 extrapolated to
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infinity; Cmax, maximum plasma concentration; API, active pharmaceutical ingredient; NMT, not
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more than; NLT, not less than; green color, low risk; yellow color, medium risk; red color, high risk
Table 2. Critical quality attributes (CQAs)
t
ip
cr
us
an
QA, quality attribute; TP, telmisartan potassium; USP, United States Pharmacopoeia; RSD, relative
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standard deviation; NMT, not more than; NLT, not less than; green color, low risk; yellow color,
medium risk; red color, high risk

ed
pt
ce
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Table 3. (A) Qualitative preliminary hazard analysis (PHA) and (B) quantitative failure mode
effects analysis (FMEA) of material attributes (MAs)

t
ip
cr
us
an
M
TP, telmisartan potassium; CQA, critical quality attribute; CMA, critical material attribute; QTPP,
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quality target product profile; PSD, particle size distribution; RPN, risk priority number.
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Each failure mode in FMEA was ranked for estimated probability/frequency of occurrence (P), the
ce
probability that the failure would remain undetected later in the process (D), and severity (S) on a
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scale of 1–4
Table 4. (A) Qualitative preliminary hazard analysis (PHA) and (B) quantitative failure mode
effects analysis (FMEA) of processing parameters (PPs)

t
ip
cr
us
an
M
ed
CQA, critical quality attribute; CPP, critical process parameter; QTPP, quality target product
profile; RPN, risk priority number.

pt
Each failure mode in FMEA was ranked for estimated probability/frequency of occurrence (P), the
ce
probability that the failure would remain undetected later in the process (D), and severity (S) on a
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scale of 1–4
Table 5. Critical material attributes (CMA) and critical process parameters (CPP) affecting
critical quality attributes (CQAs)
CMA CPP CQA
X1 Y4 Y5
X2 Y1
Binding X3 Y2 Drug Impurities
Disintegrant Disintegrati Y3
Run solution Granulation Hardness dissolution (%) after
concentratio on time Friability (%)
volume time (min) (kp) after 30 min three months
n (%) (min)
(mL) (%)
1 40 2 3 10 7.20 0.22 95 ± 1.2 0.029
2 100 2 3 15 12.60 0.08 73 ± 3.3 0.065
3 40 6 3 6 7.05 0.23 98 ± 2.1 0.151
4 100 6 3 9 11.55 0.09 81 ± 2.2 0.320
5 40 2 7 12 8.40 0.17 80 ± 0.4 0.038

t
6 100 2 7 18 14.55 0.05 69 ± 5.2 0.089
ip
7 40 6 7 7 8.85 0.18 87 ± 0.8 0.153
8 100 6 7 10 14.10 0.05 77 ± 2.2 0.339
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9 70 4 5 5 7.95 0.22 97 ± 1.4 0.080
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10 70 4 5 12 13.05 0.06 79 ± 2.7 0.190
11 70 2 5 15 12.15 0.09 88 ± 3.5 0.046
12 70 6 5 9 10.20 0.13 97 ± 2.4 0.238

an
13 70 4 3 7 9.60 0.15 86 ± 4.3 0.135
14 70 4 7 10 12.45 0.09 94 ± 4.2 0.143

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15 70 4 5 8 11.70 0.11 94 ± 2.2 0.139
16 70 4 5 7 11.40 0.11 96 ± 1.1 0.138

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17 70 4 5 8 10.65 0.12 96 ± 1.2 0.135
18 70 4 5 8 11.40 0.11 95 ± 1.7 0.135
19 70 4 5 9 10.80 0.12 93 ± 1.4 0.136

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20 70 4 5 9 11.25 0.10 97 ± 1.2 0.139

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Table 6. Pharmacokinetic parameters of telmisartan after oral administration as Micardis®
and TP tablets (80 mg) in beagle dogs
Micardis® tablet TP tablet1)

Pharmacokinetic Point
90% CI
parameters estimate
Mean ± SD*
Tmax (h)** 0.75 ± 0.21 0.85 ± 0.3 - -
Cmax (ng/mL) 8,315.5 ± 1,675.9 7,925.2 ± 1,662.0 0.9531 0.8598–1.0976
AUC(last) (ng∙h-1∙mL-1) 21,285.1 ± 8,340.3 20,838.2 ± 7,044.3 0.9790 0.9071–1.0814
AUC(inf) (ng∙h-1∙mL-1) 21,644.2 ± 8,861.4 21,024.2 ± 7,210.6 0.9713 0.9204–1.1302

t
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T1/2 (h) 13.9 ± 7.4 11.4 ± 5.7 - -
Data are presented as mean ± SD (n = 12).
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1
p < 0.05 compared with TP tablet group; CI, confidence interval; Tmax, time to reach
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maximum plasma concentration; Cmax, maximum plasma concentration; AUClast, area
under the plasma concentration-time curve at the last time point; AUC0–, AUC
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extrapolated to infinity; T1/2, half-life
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Drug Development and Industrial Pharmacy

ISSN: 0363-9045 (Print) 1520-5762 (Online) Journal homepage: http://www.tandfonline.com/loi/iddi20

Quality-by-design approach for development of

To link to this article: https://doi.org/10.1080/03639045.2017.1414233

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College of Pharmacy, Ajou University, Suwon, Korea

Phone: +82-31-899-4052, Fax: +82-31-275-6145, E-mail: 77jooeun@naver.com

Keywords: Telmisartan potassium, Quality-by-Design, Design of Experiment, Risk Assessment,

Design Space, Bioequivalence.

QbD : Quality by Design

QTPP : Quality Target Product Profiles

CQA : Critical Quality Attributes

CMA : Critical Material Attributes

FMEA : Failure Mode and Effect Analysis us

CCD: Central Composite Design

FCCCD: Face-centered Central Composite Design

API : Active Pharmaceutical Ingredients

RPN : Risk Priority Numbers (RPNs = P × S × D).

P : Probability, D : Detectability, and S : Severity.

USP : United States Pharmacopeia

1yl)methyl]-biphenyl-2-carboxylic acid, is a selective angiotensin II type 1 receptor (AT1R) blocker,

soluble, and thus, it exhibits a different dissolution pattern.

use formulations such as amorphous forms (solid dispersions/cocrystals), polymeric micelles,

inclusion complexation, size reduction including nanonization [5], self-microemulsifying drug

delivery systems (SMEDDS), surfactant/co-solvent systems [6], solid lipid nanoparticles

ultimately providing a scientific understanding of how process parameters affect product

to the achievement of predictable quality with desired, predetermined specifications [12].

other chemicals were of reagent grade and obtained commercially.

pharmacists, physicians, and patients were specified (Table 1).

2.3 Determining CQAs

safety, efficacy, and quality.

is not a CQA but only a general quality attribute.

of the cause, which is a specific failure mode for a particular effect/event.

and the RPNs were calculated.

chloride, 151.9 mg microcrystalline cellulose (MCC), 20.0 mg D-mannitol, 20.0 mg croscarmellose

2.6 Evaluation of TP tablets

2.6.1 Hardness test

Friability (%) = [(w1 - w2)/w1] × 100,

2.6.3 Disintegration test

2.6.4 In vitro dissolution of TP tablets

of 20 mM potassium dihydrogen phosphate buffer at pH 7.5 ± 0.1 as the dissolution medium at 37 ±

phase, composed of 20 mM potassium dihydrogen phosphate:methanol (4:6, v/v, pH 3.0 ± 0.05),

2.7 Development of the design space

2.8 Bioequivalence in beagle dogs

internal diameter, 3 μm, Imtakt, Ringoes, NJ, USA) was used.

supernatant was added to LC-MS/MS. A 2 μL sample was separated chromatographically using

precision was < 2%.

of Crystal Genomics Pharmaceutical Co., Ltd.

attributes: physical characteristics, appearance, identification, dissolution, impurities, weight

3.3 Quality RA of CMAs and CPPs affecting CQAs

was confirmed as the “time of the granulation” (the kneading time).

3.4 Development of design space

presented in Table 5. We used a three-factor, three-level face-centered composite design, which

parallelepiped. As shown in Table 5, the number of total experiments conducted was 23 + (2 × 3) + 6

= 20 because it occurred at the face and vertex of the rectangular parallelepiped.

range and edges of failure with regard to individual goals.

remain at this level in terms of dissolution and impurities.

dissolution and impurities.

considering the dissolution and impurities.

3.5 In vitro dissolution of TP tablets