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Research Article
Physiologically Based Dissolution Testing in a Drug Development Process—a
Case Study of a Successful Application in a Bioequivalence Study of Trazodone
ER Formulations Under Fed Conditions
Dorota Danielak,
1,6
Bartłomiej Milanowski,
2
Krzysztof Wentowski,
3
Maria Nogowska,
3
MichałKątny,
3
Piotr Rogowski,
3
Łukasz Konwicki,
3
Ewa Puk,
3
Jarosław Pieczuro,
3
Marek Bawiec,
4
Grzegorz Garbacz,
5
and Janina Lulek
2
Received 26 November 2019; accepted 13 March 2020
Abstract. Development of generic extended-release (ER) formulations is challenging.
Especially under fed conditions, the risk of failure in bioequivalence trials is high because of
long gastric residence times and susceptibility to food effects. We describe the development
of a generic trazodone ER formulation that was aided with a biorelevant dissolution
evaluation. Trazodone hydrochloride 300-mg monolithic matrix tablets were dissolved both
in USP and EMA compliant conditions and in the StressTest device that simulated both
physicochemical and mechanical conditions of the gastrointestinal passage. The final
formulation was tested against the originator, Trittico XR 300 mg, in a randomized cross-
over bioequivalence trial with 44 healthy volunteers, in agreement with EMA guidelines.
Initially developed formulations dissolved trazodone similarly to the originator under
standard conditions (f
2
factor above 50), but their dissolution kinetics differed significantly
in the biorelevant tests. The formulation was optimized by the addition of low-viscosity
hypromellose and mannitol. The final formulation was approved for the bioequivalence trial.
Calculated C
max
were 1.92 ± 0.77 and 1.92 ± 0.63 [μg/mL], AUC
0-t
were 27.46 ± 8.39 and
29.96 ± 9.09 [μg∙h/mL], and AUC
0-∞
were 28.22 ± 8.91 and 30.82 ± 9.41 [μg∙h/mL] for the
originator and test formulations, respectively. The 90% confidence intervals of all primary
pharmacokinetic parameters fell within the 80–125% range. In summary, biorelevant
dissolution tests supported successful development of a generic trazodone ER formulation
pharmaceutically equivalent with the originator under fed conditions. Employment of
biorelevant dissolution tests may decrease the risk of failure in bioequivalence trials of ER
formulations.
KEY WORDS: Trazodone; Generic; Bioequivalence; Extended release; Biorelevant dissolution.
INTRODUCTION
The global pharmaceutical market requires high-quality
generic drugs. Solely in the USA, approximately 90% of
prescribed drugs are generic; at the same time, they account for
less than a quarter of total expenses on prescription drugs (1). In
2018, savings from generic drug prescription amounted to 292.6
billion dollars in the USA alone (2). Pharmaceutical companies
are required to prove bioequivalence of the manufactured generic
drug with a brand name product unless the regulatory agency
approves biowaiver. This process is time- and cost-consuming.
Therefore, the sponsor of the study should make all the efforts to
develop a formulation that will ensure the success of the
pharmacokinetic bioequivalence trial. Drug pharmacokinetics
differs both within and between subjects due to physiological
conditions such as sex, age, or genetic polymorphisms of enzymes
involved in the metabolism of xenobiotics. Therefore, variability of
Electronic supplementary material The online version of this article
(https://doi.org/10.1208/s12249-020-01662-8) contains supplementary
material, which is available to authorized users.
1
Department of Physical Pharmacy and Pharmacokinetics, Faculty of
Pharmacy, Poznan University of Medical Sciences, 6 Święcickiego st,
60-781, Poznań, Poland.
2
Department of Pharmaceutical Technology, Faculty of Pharmacy,
Poznan University of Medical Sciences, 6 Grunwaldzka st, 60-780,
Poznań, Poland.
3
Biofarm Sp. z o.o, 13 Wałbrzyska st, 60-198, Poznań, Poland.
4
Institute of Computer Engineering, Control and Robotics, Wroclaw
University of Technology, 27 Wybrzeże Wyspańskiego st, 50-370,
Wrocław, Poland.
5
Physiolution GmbH, Walther-Rathenau Strasse 49a, 17489,
Greifswald, Germany.
6
To whom correspondence should be addressed. (e–mail:
danielak@ump.edu.pl)
AAPS PharmSciTech (2020) 21:161
DOI: 10.1208/s12249-020-01662-8
1530-9932/20/0000-0001/0 #2020 The Author(s)
drug dissolution should be as low as possible. Also, drug release
from generic formulation should resemble the brand name
product as closely as possible under fasted and fed conditions, if
applicable. It is even more critical in modified (MR) and extended-
release (ER) formulations. As the ER forms are designed to
release the active ingredient over prolonged time, they are prone
to food effects (3). Koziolek et al.(3) distinguished three categories
of food effects relevant for MR and ER dosage forms: (i) drug-
related factors including partition coefficient, stability in different
pH values, or absorption rate; (ii) formulation-related factors
comprising dose, size, excipients, and drug release profiles; and (iii)
physiology-related factors including gastrointestinal motility, spe-
cificpHprofile, gastric emptying, or food composition and caloric
content. Novel test methods allow the in vitro evaluation of drug
dissolution profiles under physiologically relevant conditions.
They allow the use of media simulating the composition of fluids
in human gastrointestinal tract, such as simulated gastric fluid
(SGF)orsimulatedintestinalfluid (SIF) (4). Additionally, devices
such as Dissolution Stress Test (5)oraFedStomachModel(6)can
effectively simulate shear stresses generated by peristaltics during
gastrointestinal passage. As shown in the SmartPill® studies, these
contractions generate pressure up to 500 mbar, especially in the
antro-pyloric region during gastric emptying (7).
Since the drug delivery of ER products is often
dependent on their geometry, the simulation of mechanical
stresses in dissolution tests, such as simulated motility forces
or dynamic events of transport, can effectively point dissim-
ilarities between ER formulations under biorelevant condi-
tions (8). Different susceptibility of formulations to
mechanical stress in vivo can cause irregular drug release
and increase pharmacokinetic variability (9,10). Therefore,
advanced dissolution stress devices can aid the successful
development of high-quality generic drugs.
In this paper, we demonstrate the development of a
generic trazodone ER formulation. Trazodone is a weak base.
This Biopharmaceutics Classification System (BCS) Class II
drug is sparingly soluble in water, and its experimentally
evaluated logP is 2.9 (11). It is also pH sensitive with a pK
a
of
about 6.74 (12). Trazodone is most commonly used as a salt of
hydrochloric acid.
The novelty of the study is an intensive use of bio-
predictive, physiology-mimicking dissolution tests during the
formulation development process, leading to a successful
bioequivalence trial under fed conditions. Until now, the
usefulness of the StressTest device was used for the develop-
ment of novel, pressure-sensitive dosage forms (13) or for an
explanation of observed fluctuations in the pharmacokinetics
of drugs administered as ER formulations (10). Therefore,
the paper presents a new application of the device for
bioequivalent generic drug development.
MATERIALS AND METHODS
Reagents
Trazodone Formulations
Generic trazodone hydrochloride ER tablets (Trazodon
XR 300 mg), containing 300 mg of the active ingredient
(equivalent to 273.2 mg of trazodone), were manufactured by
a direct compression method. The dissolution profiles of the
active substance were tested along with the brand name
product—Trittico XR 300 mg (Aziende Chimiche Riunite
Angelini Francesco A.C.R.A.F. S.p.A.). Six batches, labeled
A to F, were tested in biorelevant conditions. The qualitative
composition of each analyzed batch is available in Table I.
The amount of the active ingredient—trazodone—did not
exceed 35% of total tablet mass.
Dissolution Media
In the development process, both standard and
biorelevant media were used. Standard media included
0.1 M hydrochloric acid with 2.92 g/L sodium chloride
(pH 01.2) and 50 mM phosphate buffer pH 06.0. Biorelevant
media were 50 mM phosphate buffer at pH ranging from 4.5
down to 1.8 (with the addition of HCl), and 50 mM phosphate
buffer pH 06.5 with FaSSIF (Fasted State Simulated Intesti-
nal Fluid)/FeSSIF (Fed State Simulated Intestinal Fluid)/
FaSSGF (Fasted State Simulated Gastric Fluid) powder
(Biorelevant.com Ltd., London, UK) in a concentration
corresponding to a fed state. All of the reagents were of
analytical grade.
Dissolution Tests
Each tablet batch was preliminarily tested in a standard
dissolution media. Then, it was investigated further in
biorelevant conditions resembling fed state. In all biorelevant
tests, the dissolution profiles of trazodone from generic
formulations were compared with the originator. If the
dissolution profile differed significantly from the originator,
reformulation and further characterization were performed.
The batch with the dissolution profile most comparable with
the brand name product was qualified for use in the clinical
bioequivalence trial.
Standard Dissolution Tests
Standard dissolution tests were performed in a conven-
tional USP dissolution apparatus 2 (Agilent VK7025 and
Agilent 708 DS) with a constant paddle rotation at 150 rpm,
according to “Guideline on quality of oral modified release
products”issued by European Medicines Agency (EMA)
(14). The tablets were placed in USP compliant Japanese
basket sinkers. The conditions used for dissolution studies
were based on a Trazodone once daily patent documentation,
No. US7829120B2 (12). Initially, the dissolution medium was
0.1 M hydrochloric acid with 2.92 g/L sodium chloride (pH 0
1.2). After 1 h, the medium was exchanged to a 50-mM
phosphate buffer pH 06.0. Dissolution profiles were deter-
mined for 24 h. Collected samples were assayed with a high-
performance liquid chromatography method, validated ac-
cording to “Validation of Analytical Procedures: Text and
Methodology”guidelines developed by the ICH (15). The
chromatographic separation was performed on an XBridge
C18 column 3.5 μm, 75 × 4.6 mm (Waters, MA, USA), using
acetonitrile and trifluoroacetic acid (0.2%) (35:65; v/v) as a
mobile phase, at the isocratic flow rate of 1.2 mL/min. The
total run time was 2 min, the injection volume was 5.0 μL, and
the detection (UV-Vis) wavelength was set at 246 nm. The
column temperature was maintained at 25°C. Additionally, an
161 Page 2 of 11 Danielak et al. (2020) 21:161
f
2
similarity factor was calculated, according to the EMA
guideline (16). The f
2
values greater than 50 ensured the
equivalence of both test and originator products in standard
dissolution studies.
Biorelevant Dissolution Tests
Stress Test Device. The dissolution stress test device was
first introduced by G. Garbacz and W. Wetschies (9). The
core principle of the StressTest device is to simulate the
mechanical agitation of physiological intensity that acts on a
solid dosage form during the GI transit as well as the
physicochemical conditions in the subsequent sections of the
GI. A detailed description of the device is given elsewhere
(5).
Test Setup Parameters. Dissolution tests were designed
to simulate the fed intake conditions of the bioequivalence
trial. First, the medium was 1100 mL 50 mM phosphate buffer
at pH 4.5. The pH of the medium was gradually decreased to
1.8 by addition of 5 M hydrochloric acid; then, after 5 h the
pH was adjusted to pH 6.5 by the addition of 40% sodium
hydroxide, and 40 mL of a FaSSIF/FeSSIF/FaSSGF concen-
trate solution in a 50 mM phosphate buffer concentrate was
added (77.9 g of the powder in a 50 mM phosphate buffer,
filled up to a final volume of 240 mL, stirred until dissolved,
and allowed to settle for at least 1 h before addition to the
media). The final concentration of the FaSSIF/FeSSIF/
FaSSGF in the simulated intestinal fluid was 11.2 g/L,
corresponding to the fed state. The media change pattern
was aligned with the simulation of the mechanical aspects of
the GI tract. The stress program was set up. Figure 1presents
stress as well as the media type and change pattern used in
the present biorelevant dissolution studies.
Determination of Trazodone in Biorelevant Media. The
amount of the drug dissolved was determined every 10 min
using online closed-loop UV-Vis spectroscopy. The samples
were filtered through a PES (polysulfone) filter with a pore
size of 1 μm (Sartorious, Göttingen, Germany) and analyzed
in a flow-through mode. Flow-through quartz cuvettes of a 5-
mm path length (Hellma, Müllheim, Germany) were used
with an Agilent 8543 spectrophotometric system (Agilent,
Santa Clara, USA) with the photometers set to a differential
mode at two wavelengths of λ0313 nm for trazodone signal
and λ0450 nm for the background, respectively.
Bioequivalence Study
The bioequivalence study was a single-center, single-
dose, open-label (laboratory blinded), randomized, four-
period, four-way cross-over study, according to the “Guide-
line on the pharmacokinetic and clinical evaluation of
modified release dosage forms”(EMA/CPMP/EWP/280/96
Corr1) (17). The protocol of the study was approved by the
Independent Ethics Committee at the Regional Chamber of
Physicians in Warsaw, and by the Office for Registration of
Medicinal Products, Medical Devices and Biocidal Products
in Poland. The trial was registered in the EU Clinical Trial
Register under the number 2018-000598-57.
Sustained and predictable release of the drug from the
ER dosage is more challenging in fed conditions than in a
fasted state, both in dissolution studies and in the proper
setup of the clinical study protocol. Therefore, in this paper,
we will present the results of the bioequivalence trial
performed under fed conditions only.
Study Group
The minimum sample size needed to adequately assess
the bioequivalence of two trazodone formulations was
calculated as suggested by Diletti et al.(18). Based on the
reported clinical studies NCT00839072 (19)and
NCT01121900 (20), the C
max
of trazodone after administra-
tion of 300 mg trazodone hydrochloride varies intra-
individually by approximately 29%. Assuming the power of
the test at 80% and significance level α00.05, the bioequiv-
alence assessment required at least 38 subjects.
The study included forty-four healthy subjects of both
sexes. The characteristics of the study group are presented in
Table II. Each subject signed an Informed Consent Form.
Before and during the study, the subjects had to refrain from
the use of other drugs, products containing nicotine, alcohol,
caffeine, or grapefruit juice. Each subject had the right to
withdraw from the study. The participation of a subject might
have been discontinued for reasons including adverse events
and study protocol deviation.
Table I. Composition of Developed Formulations Tested in Biorelevant Dissolution Tests. For All of the Ingredients Besides Trazodone
Hydrochloride, the Values Are Presented as Mass Percentages of the Total Mass of the Tablet
Ingredient A B C D E F
Trazodone hydrochloride (mg) 300
Hypromellose 100,000 (%) 16–19 21–24 21–24 5–10 5–10 5–10
Hypromellose 4000 (%) –––5–10 5–10 5–10
Microcrystalline cellulose (%) 20–25 20–25 15–20 23–32 20–26 20–26
Silicified microcrystalline cellulose (%) 20–25 15–20 15–20 16–19 16–19 16–19
Mannitol (%) ––3–8–3–63–6
Talc (% 1–2
Magnesium stearate (%) 1–2
Polyvinyl coating Yes Yes Yes No No Yes
161 Page 3 of 11Dissolution Tests in Generic Drug Development (2020) 21:161
Protocol
A single dose of the test product (Trazodon XR 300 mg)
or the brand name product (Trittico XR 300 mg), both
containing 300 mg trazodone hydrochloride, was adminis-
tered by the oral route. The administration was within 30 min
after the start of a standardized high-fat meal, with 250 mL of
still, room temperature water. No other fluid intake was
allowed from 2 h before until 1-h post-dosing. Additionally,
fluids were administered as follows: 250 mL of fluid with
breakfast, 150 mL of still water at 1, 2, and 3 h post-
administration, 200 mL fluid with meals at 4 and 12 h post-
administration, and 100 mL at 5, 6, 7, 8, 9, 10, and 11 h post-
administration. Standardized lunch and supper were served at
about 4 and 12 h after drug administration.
From each subject 4 mL of full blood was collected
before drug administration (time “0”), and at 1, 2, 3, 4, 5, 6, 8,
9, 10, 11, 12, 13, 14, 15, 16, 20, 24, 28, 32, 36, 42, 48, and 72 h
after the intake of the drug. The blood samples were taken
before the intake of fluids. Full blood was collected through
heparinized capillaries into a vacuum blood collection system.
Immediately after collection, the samples were centrifuged,
and the plasma was transferred into separate tubes, stored in
dry ice, and shipped into the laboratory for trazodone
determination. Any deviations from the sampling protocol
were noted, and the actual sampling times were reported for
further analysis.
Determination of Trazodone Concentrations and
Pharmacokinetic Parameter Calculations
Plasma samples were shipped in dry ice to an external,
certified laboratory for the determination of trazodone. The
drug concentrations were determined with a high-
performance liquid chromatography mass spectrometry
method (LC-MS), in a multiple reaction monitoring mode
(MRM). The method was validated according to the EMA
guidelines in terms of selectivity, accuracy, and precision (21).
The lower limit of trazodone quantitation was 10 ng/mL.
The pharmacokinetic evaluation was planned in agree-
ment with the guideline CPMP/EWP/QWP/1401/98 Rev.
1/Corr** (16) and EMA/CPMP/EWP/280/96 Corr1 (17).
Following pharmacokinetic parameters were considered for
bioequivalence evaluation: area under the time-concentration
curve from time 0 to 72 h (AUC
0-t
), area under time-
concentration curve extrapolated to infinity (AUC
0-∞
), and
maximum concentration obtained directly from the measured
concentrations (C
max
). Additional secondary parameters
included time to C
max
(T
max
) and plasma half-life (T
1/2
) that
was calculated from 0.693/K
el
,whereK
el
represents the
elimination rate constant determined through a linear regres-
sion. Of note, only the actual sampling times were used. The
parameters were calculated by the linear-log trapezoidal rule
in Phoenix WinNonlin software, build 8.1.0.3530 (Certara
USA, Princeton, NJ, USA).
Bioequivalence after a single dose of trazodone 300 mg
under fed conditions was established upon a ratio of test and
reference product parameters. Before the analysis, the
parameters were log-transformed. The 90% confidence
interval for the ratio should be contained within 80.00–
125.00%. The pharmacokinetic parameters were analyzed
with ANOVA test, with factors for sequence, subject within
sequence, period, and treatment. Also, the Schuirmann’s two
one-sided parametric T tests were calculated with the null
hypothesis of bioinequivalence at the 5% (α00.05) level of
significance.
RESULTS
Standard Dissolution Tests
The release profiles of trazodone from tested formula-
tions are presented in Fig. 2. All of the tablets release the
active substance steadily over 24 h. Most of the formulations
released less than 30% of trazodone within the first hour, no
less than 70% after 12 h, and at least 80% after 24 h from the
beginning of the dissolution study. The originator released
trazodone slower than any of the tested formulations. Batches
A, B, and C resembled most the release profile of the
Fig. 1. Setup of the program for biorelevant dissolution tests
Table II. Characteristics of the Study Group. Data Are Presented as
Means ± Standard Deviations
Parameter Female (n011) Male (n033)
Age (years) 39.3 ± 11.4 33.4 ± 9.3
Weight (kg) 66.0 ± 7.4 74.5 ± 8.3
Body mass index (kg/m
2
) 23.8 ± 2.8 23.4 ± 2.1
161 Page 4 of 11 Danielak et al. (2020) 21:161
originator. In contrast, batches D, and E released the active
ingredient at a noticeably faster rate. This observation also
holds for the final batch F that was the model for the clinical
batch. The calculated f
2
factors were as follows: batch A 0
51.4, batch B 072.3, batch C 069.0, batch D 032.9, batch E 0
33.8, batch F 044.3.
Dissolution Tests in Biorelevant Conditions
First developed batches—A, B, and C—resembled the
trazodone release profile of the originator during the first 5 h
(Fig. 3). However, the drug release changed noticeably after
the introduction of 300 mbar stress mimicking the gastric
emptying and transition from gastric to intestinal media. The
mechanical stress affected the dissolution of the originator
more than all of the tested batches. Susceptibility of the
originator to the events of the mechanical stress of
biorelevant fortitude caused a faster release of trazodone
and the complete dissolution of tablet matrices. At the same
time, the generic matrices resisted biorelevant mechanical
agitation and were deformed only slightly. Therefore, further
reformulation was required.
Batches D and E were more similar to the brand name
product. The final batch F, that was approved for use in the
clinical trial, was developed upon batch E. The only
difference between batches E and F was a polyvinyl coating
that did not influence the release of trazodone from the
tablets, as shown in Fig. 3. Batch D was not chosen for further
studies because of distinctly different dissolution characteris-
tics under fasted conditions. However, the characterization of
drug release under fasted conditions is outside of the scope of
this paper.
Clinical Bioequivalence Trial
Thirty-nine subjects completed the study. As stated
above, the trial required a minimum of 38 participants to
assess bioequivalence with a sufficient power. Table III
presents the calculated pharmacokinetic parameters for both
formulations. Both primary and secondary parameters of the
test formulation (Trazodon XR 300 mg) resembled those
calculated for the brand name product (Trittico XR 300 mg).
Pharmacokinetic profiles of both formulations were similar
(Fig. 4). Individual pharmacokinetic profiles are available in
the Online Supplementary Data file (Supplement 1). The
intra-subject variability for AUC
0-t
, AUC
0-∞
, and C
max
was
11.56%, 10.74%, and 22.18%, respectively. The inter-subject
variability for AUC
0-t
,AUC
0-∞
,andC
max
was 27.80%,
28.83%, and 28.11%, respectively.
ANOVA test showed that the sequence and period
effects were negligible for all primary parameters. One of
the statistically significant factors was a joint subject and
sequence effect. These parameters affected all three primary
parameters (p< 0.0001). Also, the type of formulation (test
product or the brand name product) influenced the exposure
to trazodone, expressed as AUC
0-t
, and AUC
0-∞
(p00.0014
and p00.0005, respectively). For C
max
this effect was not
statistically important (p00.5955).
The results of the bioequivalence assessment presented
in Table IV show that the test product fulfilled the criteria for
bioequivalence with the brand name product under fed
conditions.
DISCUSSION
In the present study, we demonstrate how the use of
biorelevant methods, i.e., the biorelevant stress test device,
supported the development of a generic ER trazodone
formulation. The test protocols were utilized to predict the
drug delivery behavior of the tested formulations. In this
context, the performed study served as a proof-of-concept for
the predictive power of the StressTest device. As a result, the
developed formulation fulfilled the bioequivalence criteria
under fed conditions.
The successful formulation of a generic ER dosage form
is a complex and challenging process. In general, if the
originator and generic formulations are similar, they should
also have similar dissolution characteristics under every
condition tested. However, the formulation can be considered
as equivalent only if the bioequivalence trial is passed under
the same test conditions (fasted and/or fed) as the originator.
It becomes challenging if the exposure to the drug differs
significantly between fasted and fed states. This phenomenon
is observed for trazodone. Karhu et al.(22) showed that
pharmacokinetics of a once-daily Trazodone Contramid
300 mg formulation differed significantly between fasted and
fed conditions. The AUC between these two states was
similar. However, after a high-fat meal, the C
max
of trazodone
was 86% higher compared with fasted conditions. The C
max
values falling outside 80–125% confidence intervals show that
two products are not equivalent.
Consequently, the fed conditions can be considered as
more difficult with respect to the development of generics.
Therefore, the present paper aims at the description of the
product performance under fed conditions. The strict criteria
for primary pharmacokinetic parameters obtained in the
bioequivalence trial result in setting up requirements for the
pharmaceutical development and characterization of oral
medicines in the preclinical stage. Such characterization,
especially when performed with biorelevant methodology,
may reduce the risk of failure and accelerate the development
process.
Adequate reflection of luminal conditions requires more
than the compendial media. Food ingredients such as lipids,
proteins and their digestion products act as natural surfac-
tants affecting both the solubility of the active pharmaceutical
ingredient (API), as well as hydration and erosion processes
of MR matrices (7). These components are also present in
biorelevant media, such as simulated gastric fluid, fed state
simulated intestinal fluid, fasted state simulated intestinal
fluid, milk, and nutritional drink. Therefore, these media
should be used to predict the disintegration of ER matrices
(23,24). The type of food also affects the tablet erosion
process. In fed conditions the tablets disintegrate slower in
comparison with the fasting state, and thus drug dissolution in
the stomach is delayed (25,26). For this reason, we adjusted
the study protocol to reflect the physico-chemical properties
of gastrointestinal fluids more accurately than conventional
dissolution media. The media composition and pH profiles
and transit times used in the present study were set according
to Koziolek et al.(27,28).
161 Page 5 of 11Dissolution Tests in Generic Drug Development (2020) 21:161
The drug delivery behavior of monolithic hydrogel
matrix tablets, such as ones developed in this study, may be
remarkably affected by the mechanical and hydrodynamical
agitation. Motility forces produce such stress during the
physiologic events of transport such as gastric emptying, and
ileocaecal and colonic passage (29). In some cases, mechan-
ical agitation results in deformation, fast erosion of the tablets
matrices, and an increase in the drug delivery rate or even
dose dumping (29,30). Such agitation may be more pro-
nounced under fed conditions due to increased motoric
activity and passage times through the highly active proximal
parts of gastrointestinal tract. Thus, in the present study, we
used a test program with differing patterns intended for the
simulation of the fed state (Fig. 1). The arrangement of the
stress program was derived from the in vivo studies per-
formed using telemetric capsules (7,27,31). For the fed state,
moderate 200-mbar intragastric stress events were pro-
grammed within the first 2–4 h, followed by the major gastric
emptying stress (300 mbar) at 5 h. Then, after the transition
to ‘intestinal’conditions, regular stress of 110 and 200 mbar
was introduced. In summary, the fed conditions proposed in
our study (Fig. 1)reflect these in vivo findings according to
both composition, residence times, and stress patterns.
All of the tested tablets were monolithic hydrophilic
matrix systems. First batches (A–C) consisted mainly of high-
viscosity hydroxypropyl methylcellulose (hypromellose,
HPMC). In the dissolution study performed according to
USP, they released the drug steadily, reaching almost 95% of
the dose labeled within 24 h. Subsequent batches, D and E,
were characterized by a noticeably faster drug release than
batches A–C. In these two batches, the amount of
Hypromellose 100000 was decreased to less than 10% of the
total tablet mass, and a low viscosity Hypromellose 4000 was
introduced; also, batch E included a small amount of
mannitol. Final batch F, which differed from batch E only
by a presence of polyvinyl coating, had a comparable
dissolution profile. Increased release of the drug was also
achieved by increasing the amount of microcrystalline cellu-
lose. Properties of hypromellose may explain observed
dissolution performance. Of note, all of the batches tested in
the USP apparatus had different dissolution kinetics as
compared with the originator, Trittico XR 300 mg. As
revealed later in the test under biorelevant conditions, the
batches with the dissolution profiles that were most similar to
the originator performed worse, especially after the transition
to media simulating intestinal fluids.
As shown by Conti et al.(32,33), high-viscosity polymers
release the drug through a diffusion-controlled mechanism, as
expressed by Fick’s law, while low viscosity gelling agents
promote erosion of the swollen polymer. Poorly water-soluble
drugs, such as trazodone under the simulated intestinal
conditions, are mostly released through the latter mechanism
(34). Additionally, high molecular viscosity polymers may
decrease the drug release rate (35). Other properties of
hypromellose, such as a higher percentage of
hydroxypropoxy groups or particle size, may increase the
dissolution rates (36,37). Other excipients used for the
preparation of the batches include microcrystalline cellulose
and silicified microcrystalline cellulose. They show good
binding properties, are compatible with a broad range of
drugs, and are physiologically inert; silicified microcrystalline
cellulose also has an increased surface area and improved
flow characteristics (38,39). Lastly, mannitol can also increase
drug release due to the faster uptake of water (40). All of
these excipients contributed to an improved dissolution of
trazodone from the test tablets.
Fig. 2. Trittico XR 300 mg and Trazodon XR 300 mg dissolution profiles obtained in standard dissolution tests,
according to USP. Data are presented as means (n04 for Trittico XR 300 mg, A–D, n02 for E–F) with standard
deviations as whiskers
161 Page 6 of 11 Danielak et al. (2020) 21:161
Interestingly, the dissolution profile of the originator was
characterized by an increased release of the active ingredient
after transition to intestinal media (Fig. 3). None of the
generic products exhibited such a behavior. Trazodone is a
weak base with a pK
a
06.74, and it is most commonly used as
trazodone hydrochloride. This salt is sparingly soluble in
water, but its solubility increases with an increased acidity of
the media (41). Thus, in the upper gastrointestinal tract,
where pH is below trazodone pK
a
, it dissolves well. Owing to
the high volume, weak buffering capacity of the dissolution
Fig. 3. Dissolution profiles of trazodone from tested Trazodon XR 300 mg batches (A–F) versus Trittico XR 300 mg
obtained under simulated fed conditions. Data are presented as means (n06) with standard deviations as whiskers
Table III. The pharmacokinetic parameters calculated from the results obtained in the bioequivalence study under fed conditions for the brand
name product (Trittico XR 300 mg) and the test product (Trazodon XR 300 mg) (n= 39). The data are presented as means ± standard deviations
Parameter C
max
[μg/mL] AUC
0-t
[μg∙h/mL] AUC
0-∞
[μg∙h/mL] T
max
[h] T
1/2
[h]
Trittico XR 300 mg 1.92 ± 0.77 27.46 ± 8.39 28.22 ± 8.91 7.46 ± 2.29 9.71 ± 2.75
Trazodon XR 300 mg 1.92 ± 0.63 29.96 ± 9.09 30.82 ± 9.41 7.69 ± 2.07 9.52 ± 3.72
AUC
0-∞
- area under the time-concentration curve extrapolated to infinity, AUC
0-t
- area under the time-concentration curve between time 0 to
72 hours, C
max
- maximum concentration, T
1/2
- plasma half-life, T
max
–time to maximum concentration
161 Page 7 of 11Dissolution Tests in Generic Drug Development (2020) 21:161
media, and presence of natural surfactants, the solubility of
trazodone is far below the equilibrium solubility. Solubility of
trazodone hydrochloride in the simulated intestinal media
estimated during the course of our experiment (0.15 mg/mL,
data not shown) was much lower than in pure water (18 mg/
mL, (41)). Therefore, the higher release of trazodone from
Trittico XR 300 mg may result from an extensive stress
corresponding to the gastric emptying and it is not an artifact
related to the solubility of trazodone. In the case of solubility
issues, similar tendencies would also be observed for the
generic batches. It underlines a potential advantage of the
Stress Test device to discriminate between stress-susceptible
and robust extended release dosage forms. In contrast with
products developed in the present study, the originator
product relies on granulated cross-linked high-amylose starch
(Contramide®), mixed with hypromellose, anhydrous colloi-
dal silica, and sodium stearyl fumarate (42). Contramide
swells and forms a rubbery gel, similarly to hypromellose
(43), but at the same time it is prone to degradation and
erosion caused by α-amylase (44). Also, the addition of
hypromellose may greatly affect dissolution from cross-linked
amylose-based tablets and cause different pharmacokinetic
profiles under fasted and fed conditions, as shown by
Lenaerts et al.(45). The composition of Trittico XR 300 mg
may therefore explain observed differences in the trazodone
bioavailability under fasted and fed conditions and underlines
the importance of biorelevant conditions for a thorough
examination of dissolution profiles during product develop-
ment and release of the clinical batches.
The study concluded with a successful clinical bioequiv-
alence trial under fed conditions. A statistically significant
subject-sequence effect can be explained by a relatively high
intra-subject variability in the studied population. The type of
formulation (the brand name product vs. tested product) was
shown to be significant for AUC
0-t
and AUC
0-∞
in the latin-
square ANOVA. However, all of the primary pharmacoki-
netic parameters fell within the assumed confidence intervals.
Therefore, the formulation effect may be considered as
negligible, and the two formulations may be concluded as
bioequivalent under fed conditions. Besides the development
of a formulation with an optimal release profile, the design of
the study also contributed to the success in the clinical trial.
According to the protocol, not only meals but also fluid
intake were tightly scheduled. In the proposed regimen all
subjects received a specific liquid volume every hour after
administration. A recently established consortium in Under-
standing Gastrointestinal Absorption-related Processes
(UNGAP) investigated the food-drug interactions that may
influence the absorption of orally administered drugs (46).
According to their state-of-art review, the volume of fluids
present in the lumen is one of these factors. First, it influences
the concentration-driven passive uptake of the drug and
saturable membrane transporters, and second, it exerts an
effect on formulation transit times. Another fact is that a
standard breakfast is a high-fat energy-rich meal with a high
fraction of solids. In stomach it creates a layered, heteroge-
neous mass that contains layers of solids, fats and fluids (16).
Water, a drink of choice in clinical bioequivalence trials, does
not mix well with gastric contents rich in fats. Instead, it
rapidly follows a so-called stomach road, also known as
Magenstrasse, and is emptied from the stomach. In case of ER
formulations, this may cause even life-threatening conse-
quences due to dose dumping. Also, ad libitum intake of
water during a controlled clinical trial with ER formulations
can lead to a “double peak”phenomenon and contribute to
the pharmacokinetic variability (47).
Another aspect is tablet residence time and location in
the stomach. If a tablet is taken under fed conditions, it may
remain in a fundus region of the stomach; this part of the
stomach is poorly mixed and acts as storage (48). If the gastric
emptying is delayed, the drug is released slowly and
accumulates in the proximal stomach (48). Then, after the
gastric emptying, it appears in plasma after a long lag phase
and at high concentrations. In consequence it may cause
erratic pharmacokinetic profiles and ultimately a failure of
the bioequivalence trial. Proposed frequent drinking schedule
aimed to reduce the risk of drug accumulation in the fundus
and significantly contributed to the success of the trial.
Fig. 4. Pharmacokinetic profiles of Trittico XR 300 mg (originator product) versus Trazodon XR 300 mg (test product).
Data are presented as means with standard deviations as whiskers (n039)
161 Page 8 of 11 Danielak et al. (2020) 21:161
As shown in this study, the development of a pharma-
ceutically equivalent ER dosage form with a BCS II class
active ingredient is a complex process. Simple, compendial
methods may not be adequate to ascertain the success in an
expensive bioequivalence trial. Also, the use of solely
biorelevant media may not be sufficient. In the present study,
tested and reference products differed most significantly after
the introduction of physiologically relevant stress. Therefore,
we confirmed that for monolithic ER formulations the
gastrointestinal stress could be an essential element of dosage
development. It should be pointed out that all the literature
data available so far, describing the usability of the StressTest
device, concern only its use for prediction of the dissolution
behavior of ER/MR products under fasted conditions.
Consequently, the present manuscript represents an original
work that describes for the first time the application of the
StressTest device and test protocols capable of predicting the
in vivo drug delivery behavior under the fed state. The
obtained results are supported by the outcome of the clinical
trial being a part of the study.
CONCLUSIONS
In summary, the present study shows that a preclinical
development of ER formulations may be aided by advanced
dissolution studies that take into account not only the
composition of luminal fluids and respective residence times
but also timing and fortitude of the physiological mechanical
stress that occurs during the gastrointestinal passage.
FUNDING INFORMATION
This publication was developed as a result of industrial
research and development work carried out as part of the
project “Implementation of innovative methods for assessing
the release and absorption of drugs in the gastrointestinal
tract”No. RPWP.01.02.00-30-0021/16, co-financed by the
Marshal’sOffice of the Wielkopolska Region within the
Wielkopolska Regional Operational Programme for 2014-
2020 with the support of the European Regional Develop-
ment Fund. D. Danielak is supported in part by the European
Union’s Horizon 2020 research and innovation program
under the Marie Skłodowska-Curie grant agreement No
778051 “ORBIS - Open Research Biopharmaceutical Intern-
ships Support”and the Ministry of Science and Higher
Education of Poland fund for supporting internationally co-
financed projects in 2018 to 2022 (agreement No 3899/H2020/
2018/2). This article reflects the authors’view only.
COMPLIANCE WITH ETHICAL STANDARDS
Disclaimer Neither the Research Executive Agency nor the Polish
Ministry of Science and Higher Education may be held responsible
for the use which may be made of the information contained
therein.
Conflict of Interest The authors declare no conflict of interest.
Ethics Statement The protocol of the study was approved by the
Independent Ethics Committee at the Regional Chamber of Physi-
cians in Warsaw, and by the Office for Registration of Medicinal
Products, Medical Devices and Biocidal Products in Poland.
Open Access This article is licensed under a Creative
Commons Attribution 4.0 International License, which per-
mits use, sharing, adaptation, distribution and reproduction in
any medium or format, as long as you give appropriate credit
to the original author(s) and the source, provide a link to the
Creative Commons licence, and indicate if changes were
made. The images or other third party material in this article
are included in the article's Creative Commons licence, unless
indicated otherwise in a credit line to the material. If material
is not included in the article's Creative Commons licence and
your intended use is not permitted by statutory regulation or
exceeds the permitted use, you will need to obtain permission
directly from the copyright holder. To view a copy of this
licence, visit http://creativecommons.org/licenses/by/4.0/.
PUBLISHER’S NOTE
Springer Nature remains neutral with regard to jurisdic-
tional claims in published maps and institutional affiliations.
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