AAPS PharmSciTech ( # 2017)

DOI: 10.1208/s12249-017-0870-6

Research Article

Investigation of Dissolution Behavior HPMC/Eudragit®/Magnesium

Aluminometasilicate Oral Matrices Based on NMR Solid-State Spectroscopy
and Dynamic Characteristics of Gel Layer

M. Naiserová,1 K. Kubová,1,5 J. Vysloužil,1 S. Pavloková,1 D. Vetchý,1 M. Urbanová,2 J. Brus,2

J. Vysloužil,3 and P. Kulich4

Received 7 July 2017; accepted 24 August 2017

Abstract. Burst drug release is often considered a negative phenomenon resulting in

unexpected toxicity or tissue irritation. Optimal release of a highly soluble active pharmaceutical
ingredient (API) from hypromellose (HPMC) matrices is technologically impossible; therefore, a
combination of polymers is required for burst effect reduction. Promising variant could be seen in
combination of HPMC and insoluble Eudragits® as water dispersions. These can be applied only
on API/insoluble filler mixture as over-wetting prevention. The main hurdle is a limited water
absorption capacity (WAC) of filler. Therefore, the object of this study was to investigate the
dissolution behavior of levetiracetam from HPMC/Eudragit®NE matrices using magnesium
aluminometasilicate (Neusilin® US2) as filler with excellent WAC. Part of this study was also to
assess influence of thermal treatment on quality parameters of matrices. The use of Neusilin®
allowed the application of Eudragit® dispersion to API/Neusilin® mixture in one step during
high-shear wet granulation. HPMC was added extragranularly. Obtained matrices were
investigated for qualitative characteristics, NMR solid-state spectroscopy (ssNMR), gel layer
dynamic parameters, SEM, and principal component analysis (PCA). Decrease in burst effect
(max. of 33.6%) and dissolution rate, increase in fitting to zero-order kinetics, and paradoxical
reduction in gel layer thickness were observed with rising Eudragit® NE concentration. The
explanation was done by ssNMR, which clearly showed a significant reduction of the API particle
size (150–500 nm) in granules as effect of surfactant present in dispersion in dependence on
Eudragit®NE amount. This change in API particle size resulted in a significantly larger interface
between these two entities. Based on ANOVA and PCA, thermal treatment was not revealed as
a useful procedure for this system.
KEY WORDS: matrix tablets; HPMC; Eudragit® NE30D; Neusilin® US2; gel layer; Levetiracetam;
Burst effect; thermal treatment; multivariate data analysis.

INTRODUCTION independence, and high water swellability, which contribute

Hypromellose (HPMC) is the most commonly and
successfully used material for oral hydrophilic matrix tablets
(1) with controlled drug release (2–4). It has some excellent
characteristics including non-toxicity, enzyme resistance, pH
1
Department of Pharmaceutics, Faculty of Pharmacy, University of
Veterinary and Pharmaceutical Sciences Brno, Palackého tř. 1,
61242, Brno, Czech Republic.
2
Institute of Macromolecular Chemistry, Academy of Sciences of the
Czech Republic, Prague 1, Czech Republic.
3
Department of Biochemistry, Faculty of Science, Masaryk Univer-
sity, Brno, Czech Republic.
4
Department of Chemistry and Toxicology, Veterinary Research
Institute, Brno, Czech Republic.
5
To whom correspondence should be addressed. (e-mail:
kubovak@vfu.cz)
to obtaining a desirable drug-release profile (4).
Generally, HPMC matrices exhibit an extended burst
effect (no steady-state, high-rate drug release, at the begin-
ning of contact with an aqueous medium), especially when a
water-soluble active pharmaceutical ingredient (API) is
incorporated (5–7). The drug burst release can be caused by
numerous reasons such as a desorption of the drug molecules
entrapped on the gel surface or a poor drug distribution
within the hydrogel network during formation. Drying,
storage, heterogeneous nature of polymer network, or
percolation-limited diffusion of entrapped materials are also
reasons as to why the drug burst release can be caused (8). In
most cases, burst drug release is considered a negative
phenomenon resulting in unexpected toxicity or a tissue
irritation in the human body (9).
The burst effect continues to be a challenge in the
development of successful controlled release formulations,

1530-9932/17/0000-0001/0 # 2017 American Association of Pharmaceutical Scientists


especially in hydrogel-based systems, where the needless drug
loss during the burst release usually accounts for a significant
percentage of the total drug released (10). Several different
and usually expensive methods have been applied to avoid
the burst effect, i.e., surface coating of tablets, surface
extraction, and creation of devices with non-uniform drug
distributions (10).
An optimal release of a water-soluble drug from the
HPMC single polymer matrix is technologically impossible;
therefore, a combination of different kinds of polymers is
required for the burst effect adjustment (11). Moreover, the
thermal treatment of tablets above the glass transition which
alters the drug release profile could be used for some types of
polymers (12,13).
From this point of view, a promising variant for burst
effect (BE) reduction could be seen in combination with
HPMC and widely used insoluble Eudragit® polymers
(Eudragit® NE (14), NM (15), RL, and RS (16)). Reddy
et al. published a significant burst release reduction of freely
soluble nicorandil by granulation of the HPMC K4M/drug
mixture (4:1) with ethanolic solutions of Eudragits® RL-100
(10%) and RS-100 (4 and 8%). The initial release during the
first 2 h significantly decreased when Eudragit® RL (10%)
was used (19.7 vs. 32.6% in reference); lower BE reduction
was achieved for Eudragit® RS (27.4 vs. 30.8% for reference)
(17). Therefore, the desired effect of Eudragit® polymers was
confirmed.
The current trend gives a priority to the Eudragits®
application in forms of environmentally friendly water
dispersions (polymer content is 30% for all, for NM also
40%) (18). In scientific literature, only experimental works
describing their application in non-HPMC systems have been
published. To reduce the burst effect Eudragit® NE 30D (5,
10, 15, and 20% (w/w)) was added in a one-step granulation
process to a mixture of slightly water-soluble drug theophyl-
line, microcrystalline cellulose (Avicel® PH 102), and lactose
monohydrate (19). Similarly, direct hand granulation of
slightly soluble diclofenac sodium (DS) with Eudragit® NE
40D (mass ratio of DS:Eudragit® was 6:1 or 3:1) brought
prolonged drug dissolution profiles from compressed matrices
without burst release (20).
The application of water dispersions directly on the
particles of API during the wet granulation seems to be a very
effective tool for this purpose. The effect could be attributed
to a creation of discontinuous polymeric layer on the particles
decreasing the surface area for burst release of incorporated
drug (21). With respect to the solubility of the drug,
Eudragit® water dispersions cannot be applied directly on a
very soluble material, due to the risk of huge over-wetting
and creation of strongly sticking mass unsuitable for another
use (22). For this reason, it is necessary to apply Eudragit®
dispersions on a mixture of a very soluble drug and an
insoluble filler.
In our previous study, a burst effect reduction of very
soluble drug levetiracetam from HPMC K4M matrices was
partly achieved when 30% water dispersions of Eudragits®
(NE, NM, RL, RS) was used as a granulation liquid for a
drug/microcrystalline cellulose (MCC PH 101) mixture (2:1)
in a high-shear mixer. The amount of water dispersion used in
granulation was strongly limited by the MCC water
Naiserová et al.
absorption capacity (specific surface area (SSA) about
1.18 m2/g (23)), which allowed an application only at a
1:0.38 ratio (drug + MCC:Eudragit® water dispersion),
resulting in a maximum 33.7% decrease of burst effect (24).
Nevertheless, several excipients with extremely large
SSA and significantly higher liquid adsorption capacity are
available at the market which could overcome this hurdle.
Magnesium aluminometasilicates (Neusilin®) could be a
potential good alternative to MCC for this matrix tablet
design. The combination of HPMC/Eudragit®/Neusilin® has
not been published in scientific literature yet.
The object of this experimental study was to prepare and
explore the dissolution behavior of the HPMC/Eudragit® NE
matrices using magnesium aluminometasilicate as an
insoluble filler with an excellent water absorption capacity
based on NMR solid-state spectroscopy and dynamic param-
eters of the gel layer using multivariate data analysis. The
integral part of this study was also to assess the influence of
thermal treatment on quality parameters dealing with these
types of matrices.
MATERIALS AND METHODS
Materials
Levetiracetam (Zentiva k.s., Prague, Czech Republic)
was selected as a highly soluble model API with an aqueous
solubility at 20 °C in 104 g/100 ml (25) and particle size of
101.7 ± 23.7 μm (optical microscope evaluation, n = 200).
Magnesium aluminometasilicate (Neusilin ® US2, Fuji
Chemical Industries Co., Ltd., Toyoma, Japan) was used as
the insoluble filler. Hypromellose-HPMC K4M (Methocel®
K4M, Dow Chemicals, Midland, USA) was used as a
polymeric carrier. The matrix tablets contained the different
amounts of insoluble filler microcrystalline cellulose (MCC)
(type Avicel® PH 102, FMC Biopolymers, Rockland, USA).
Eudragit® NE 30D (kindly donated by Evonik Röhm GmbH,
Darmstadt, Germany) was added in the form of 30% water
dispersion as the wetting liquid for the granulation.
Magnesium stearate (Peter Greven, Bad Műnstereifel,
Germany) and colloidal silicon dioxide (Degussa, Vicenza,
Italy) were used to improve the flow properties.
Methods
Preparation and Evaluation of Granules
The granules from the API, Neusilin® US2, and 30%
aqueous dispersion of Eudragit® NE were prepared (Table I)
in a high-shear mixer (ROTOLAB, Zanchetta, S. Salvatore
Montecarlo, Italy). The instrument settings were as follows:
impeller pause time, 0 s; impeller working time, 300 s; cycle
time, 300 s; and impeller speed, 1200 rpm. For homogeniza-
tion, API and Neusilin® US2 were mixed together for 30 s;
then Eudragit® NE 30D was manually added for another 60 s.
Finally, the mixture was granulated for 210 s. The wet mass
was then passed through a 1.25-mm mesh sieve, and the
granules were dried for 24 h at 25 °C in a cabinet dryer. After
drying, the granules were passed through the sieve again. The
granulation of samples was always performed in one step.
HPMC/Eudragit®/magnesium aluminometasilicate oral matrices

Table I. Composition of Samples for Granulation Process and was implemented in column Venusil XBP C18 (150 × 4.6 mm;
Numbers of Granulation Steps particle size 3 μm). The mobile phase contained 68%
phosphoric acid and 0.2 and 32% methanol. In total, the
Sample API (g) Neusilin® Eudragit® NE analysis took 5 min and the chromatograms were detected at
US2 (g) 220 nm. The mobile phase flow rate was 1.0 ml min−1, column
30% WD (g) Solid (g)
temperature 27 °C, and injection volume was 20 μl. To
NE5 NEU50 100.0 50.0 55.7 16.7 confirm the stability of API in tablets, the evaluation of
NE7.5 NEU50 100.0 50.0 83.7 25.1 content was repeated again after 12 months (condition 25 °C,
NE5 NEU100 100.0 100.0 55.7 16.7 60% of relative humidity).
NE7.5 NEU100 100.0 100.0 83.7 25.1
NE10 NEU100 100.0 100.0 111.3 33.4 Solid-State NMR Spectroscopy of Granules and Tablets
WD water dispersion
Solid-state NMR spectra of granules and the final tablets
were measured at 11.7 T using a Bruker Avance III HD 500
The final granules were divided into two parts; one of WB NMR spectrometer in 4-mm ZrO2 rotors. The 13C cross-
these was thermally treated at 70 °C for 24 h (TTG) and the polarization (CP) magic angle spinning (MAS) NMR spectra
second part was not. Due to the melting point of levetirac- were measured at a spinning frequency of 11 kHz, a B1(13C)
etam 170.19 °C (26), the curing temperature did not affect its field nutation frequency of 62.5 kHz, a contact time of 1 ms,
stability. According to the literature source, the solid state of and with a repetition delay ranging from 7 to 30 s, depending
API is considered very stable under various extreme condi- on the expected relaxation time. The 13C-detected T1(1H)
tions (27). relaxation times were measured using a saturation-recovery
experiment in which the initial train of 1H saturation pulses
was followed by a variable delay (0.01–15 s). The intensity of
Matrix Tablets Preparation and Evaluation the 1H spin-locking field in frequency units was 80 kHz.
Glycine was used as an external standard to calibrate the 13C
Extragranular excipients were gradually added in the NMR chemical shift scales (176.03 ppm), respectively.
following order: HPMC, MCC PH 102, magnesium stearate
(2.5%), and colloidal silicon dioxide (0.5%) to both non-
treated and treated granules. The excipients were then Multivariate Data Analysis
homogenized by a 3-axial homogenizer Turbula (T2C WAB,
Basel, Switzerland; 10 min). Prior to tablet preparation, the The first step carried out was the standardization of data
final mixtures were evaluated according to the Ph. Eur. 9 for and how it transformed the variables into comparable scales.
Hausner ratio (HR; SVM 102, Erweka, Heusenstamm, In order to compare the reference samples, with and without
Germany). Eudragit®, with regard to important characteristics and the
Matrix tablets (sets of non-treated tablets (NTT) and variability among samples based on the concentration of
TTG) of the same weight (343 mg) with a theoretical drug Eudragit®, the amount of NEU entering the granulation, and
content of 100 mg were compressed using convex punches of the technology used, respectively, an analysis was performed
10 mm diameter (excentric tablet press Korsch EK 0, Korsch by implementing the principal component analysis (PCA).
Pressen, Berlin, Germany). A half amount of NTT tablets For exploring the influence of thermal treatment on chosen
was thermally treated at 70 °C for 24 h to obtain the set of variables, an analysis of variance (ANOVA) was used. The
thermally treated tablets (TT) set. The composition of the data analysis was performed by means of software R, version
matrix tablets and applied procedures are shown in Table II. 3.2.2 (28).
References were prepared using direct compression. Tablets
were compressed to a maximum hardness. All tablets were Determining the Dissolution Profiles, Similarity Factor
tested according to Ph. Eur. 9 for weight uniformity, hardness, Analysis, and Kinetic Analysis of the Dissolution Data
and friability. A YL 9100 high-performance liquid chromato-
graph (Young Lin Instrument) was used to determine The dissolution profiles of the samples were determined
levetiracetam content (n = 10). Chromatographic separation by a 12-h dissolution test with SOTAX AT 7 On-Line System

Table II. Composition of Matrix Tablets

Sample Drug (mg) Neusilin® US2 (mg) Eudragit® NE (mg) HPMC K4Mex (mg) MCC PH 102ex (mg)

R1 NEU 50d 100.0 50.0 – 66.7 116.7

R2 NEU 100d 100.0 100.0 – 66.7 66.7
NE5 NEU50 100.0 50.0 16.7 66.7 100.0
NE7.5 NEU50 100.0 50.0 25.1 66.7 91.6
NE5 NEU100 100.0 100.0 16.7 66.7 50.0
NE7.5 NEU100 100.0 100.0 25.1 66.7 41.6
NE10 NEU100 100.0 100.0 33.4 66.7 33.3

Each sample contains 0.5% of Aerosil® 200 ex and 2.5% of magnesium stearate ex for better flowability and compression feasibility
ex extragranular excipients, d direct compression

(Donau Lab, Zurich, Switzerland) while using the paddle
method at 50 rpm in 900 ml of a phosphate buffer (pH 6.0,
Ph. Eur. 9) at 37 °C. Sampling was carried out with the
following time periods: 30 min, 60 min, and then each 1 h.
These were analyzed for the released drug using high-
performance liquid chromatography according to the afore-
mentioned conditions. The mean value of API release (n = 6)
and the standard deviation (SD) were calculated.
In order to compare the levetiracetam dissolution
profiles, similarity factors f2 were calculated. The factors
were determined between the samples to examine the effect
of different parameters on dissolution characteristics. Then
the data were analyzed by equation for similarity factors f2
(29). The mechanism and kinetics of drug release from matrix
systems were studied correlating obtained dissolution data
with the following equations: zero-order equation, first-order
equation, square root-time kinetics (Higuchi model),
Korsmeyer-Peppas equation, Hixson-Crowell model, and the
Baker-Lonsdale model (30–34).
Dynamic Characteristics of the Gel Layer
The gel layer thickness of swelling matrices and pene-
tration force, depicted by work performed as a function of
time, were measured every hour under the same conditions as
the dissolution test in a separated apparatus using a Texture
Analyzer CT 3 (Brookfield, Great Britain) for 6 h. The test
consisted of each tablet being placed into a holder made of
polyvinylchloride (PVC) which covered the tablet, and the
polymer could swell in one direction only (35).
After being pulled out of the dissolution vessel, the tablet
in PVC mold was placed in the center of the testing platform.
A cylinder/rod probe TA39 (2 mm in diameter and 30 mm in
depth) was used to determine these parameters. The probe
was moved towards the sample at a speed of 0.5 mm/s. The
measurement of the penetration depth and work performed
was started when the trigger load of 5 g was achieved (which
corresponded to the contact of the probe with the edge of the
gel layer). The measurement was terminated when the trigger
load of 250 g was registered (corresponding to contact of the
probe with a border between the hydrated gel layer and non-
hydrated polymer in the core of the matrix). Then the probe
was withdrawn automatically out of the gel layer at the speed
of 10 mm/s (36). The obtained data were analyzed at a rate of
200 points/s by software Texture Expert (Brookfield, Great
Britain). The mean value of three samples and a SD for both
parameters were calculated for each individual time point.
Characterization of the Gel Layer by Scanning Electron
Microscopy
The characterization of the gel layer formed on the
surface shape and morphology of the matrix tablets were
examined with a scanning electron microscope Hitachi
SU8010 (Hitachi High-Technologies, Tokyo, Japan). The
matrix tablets were allowed to swell in a dissolution medium
under the conditions of the dissolution test. A special PVC
tablet-shaped container was used to restrict tablet swelling
just to one direction, towards the top surface of the tablet.
After the first and sixth hours, the tablets were removed from
the vessels, transversely cut into two parts and immediately
Naiserová et al.
lyophilized. Freeze drying was carried out in the freeze dryer
Alpha 1–2 LDplus (Christ, Osterode, Germany) at a temper-
ature of − 50 °C and 1030 mbar pressure using a rotary
vacuum pump (Vacuubrand RZ 2.5, Wertheim, Germany).
The drying time was 20 h. The structure and the magnitude of
the gel layer were observed.
RESULTS AND DISCUSSION
Preparation and Evaluation of Granules and the Matrix
Tablets
With respect to the solubility of the API, Eudragit® NE
water dispersion (NE30D) was not applied directly on a very
soluble levetiracetam (L or API) due to the risk of over-
wetting (22). The granules were prepared by the application
of NE30D in a mixture of API and filler Neusilin® US2
(NEU) as can be seen in Table I. Compared with the same
formulation with MCC PH101 as the filler, NEU allowed a
decrease in a number of granulation steps and an increase in
the amount of NE30D applied on the drug/filler mixture (37)
due to the significantly higher specific surface area (SSA) of
300 m2/g, hydrophilicity, and water adsorption capacity of
3.1 ml/g (38). The flow characteristics of final mixtures varied
from fair to passable. The HR of samples NEU50 and
NEU100 reached values from 1.28 to 1.32 and 1.25 to 1.29,
respectively (Table III). The thermal treatment of granules
had no effect on this parameter. The samples with higher
NEU/MCC PH 102 ratio exhibited slightly better flow
properties due to a regular shape of the NEU particles
(38,39). However, no improvement of flow properties was
noticed with increasing NE30D at the same NEU concentra-
tion. It is a well-known fact that the higher proportion of a
binder used for the granulation process leads to an enlarge-
ment of granule particle diameter resulting in better flow
behavior (40). This statement was not confirmed in our study
probably due to the higher water adsorption capacity of
NEU, which eliminated the differences in the amount of
added wetting agent.
The results of mass and content uniformity, content after
12 months, hardness, and friability of prepared matrix tablets
are provided in Table III. Each tested parameter complied
with Ph. Eur. 9 limits. The maximum change in the content of
samples after 12 months at 2.54% confirmed the API stability
in HPMC/Eudragit®/magnesium aluminometasilicate system.
Tablet hardness was recognized as excellent (all > 124.4 N)
and was found to be significantly higher for the NEU100
samples (compared with the NEU50 samples), which is in
accordance with literature sources describing NEU as an
excipient providing hard tablets at low compression force,
and in addition, it improves the impact of other fillers and
binders on mechanical properties of tablets (41). From the
PCA analysis (explained later), a significant increase in
hardness after addition of Eudragit® for samples NEU100
with a maximum for 7.5% concentration (compare
R2NEU100–170.7 N, NE7.5/NEU100–305.3–332.0 N) can be
clearly seen. This effect could be explained by the
improvement of bonding among particles (42). The effect of
thermal treatment was the most noticeable in samples
prepared from thermally treated granules (the highest
hardness: sample TTG NE7.5/NEU100–332.0 N and TTG
HPMC/Eudragit®/magnesium aluminometasilicate oral matrices

Table III. Flow Properties of Final Mixtures and Characteristics of Matrix Tablets

Sample Set HR Flow F (%) Hardness Average drug content Average weight
evaluation (N) ± SD (%) ± SD, after 12 months (%) (mg) ± SD

R1 NEU50 1.29 Passable 0.21 154.7 ± 3.70 95.84 ± 2.75, + 2.54 350.2 ± 0.0024
R2 NEU100 1.25 Fair 0.20 170.7 ± 9.50 93.96 ± 1.25, + 0.86 351.6 ± 0.0035
NE5NEU50 NTT 1.32 Passable 0.09 124.4 ± 9.00 92.80 ± 1.91, + 2.12 344.5 ± 0.0033
TTG 1.29 Passable 0.10 217.5 ± 5.40 98.43 ± 7.21, + 1.31 349.4 ± 0.0017
TT 1.32 Passable 0.12 129.3 ± 9.60 96.51 ± 0.94, − 0.79 343.9 ± 0.0045
NE7.5 NEU50 NTT 1.28 Passable 0.03 150.0 ± 5.20 102.04 ± 2.93, + 2.09 348.0 ± 0.0022
TTG 1.29 Passable 0.16 199.9 ± 4.80 104.32 ± 1.19, − 1.44 349.5 ± 0.0014
TT 1.28 Passable 0.08 159.4 ± 5.30 97.06 ± 0.19, + 2.19 349.2 ± 0.0015
NE5 NEU100 NTT 1.26 Passable 0.05 179.8 ± 4.20 98.24 ± 2.51, + 2.36 351.1 ± 0.0030
TTG 1.26 Passable 0.10 245.6 ± 7.70 106.11 ± 7.50, − 0.69 348.4 ± 0.0022
TT 1.26 Passable 0.06 195.5 ± 3.80 100.13 ± 1.54, + 2.51 349.4 ± 0.0016
NE7.5 NEU100 NTT 1.26 Passable 0.09 305.3 ± 7.30 108.52 ± 1.29, − 0.58 350.1 ± 0.0021
TTG 1.26 Passable 0.11 332.0 ± 4.40 108.80 ± 4.15, − 1.15 350.7 ± 0.0026
TT 1.26 Passable 0.04 305.3 ± 6.60 108.13 ± 3.01, − 0.78 349.6 ± 0.0013
NE10 NEU100 NTT 1.29 Passable 0.10 228.5 ± 6.10 105.38 ± 2.19, − 0.89 349.8 ± 0.0015
TTG 1.29 Passable 0.02 317.8 ± 4.30 102.33 ± 2.10, − 1.52 347.3 ± 0.0021
TT 1.29 Passable 0.03 221.7 ± 7.20 106.36 ± 2.68, − 1.11 348.2 ± 0.0020

HR Hausner ratio (SDmax 0.01), F flowability

NE10/NEU100–317.8 N). Significantly higher hardness of
these samples could also be explained by polymeric redistri-
bution due to the increased mobility of the polymer chains
after exceeding the glass transition temperature (43). There-
fore, it is perceived that such an effect would have been more
intensive probably before the addition of extragranular
excipients. Furthermore, the friability of tablets (0.02–
0.21%) was reduced by the addition of Eudragit® NE
probably due to its more plastic character ensuring higher
mechanical resistance (42).
1
H–1H spin diffusion, a fast magnetization transfer over large
distances taking place during the relaxation periods, induces
equilibration of 1H magnetization behavior of different spins.
The rate of this equilibration then reflects the extent of phase
separation. To approximately quantify the extent that APIs
were mixed at, with the polymer matrix, we estimated the
maximum diffuse path length using the relaxation times. The
maximum diffusive path length (L) obtained with the spin
diffusion in three dimensions over time T1(1H) is as follows
(47–50):

1=2
NMR Solid-State Spectroscopy of the Granules and Tablets L ¼ 6D T 1 1 H ð1Þ

For explanation of the behavior of matrix systems, the

selected samples were investigated by NMR solid-state
spectroscopy (ssNMR). Changes in physical state and size of
domains of levetiracetam in the presence of Eudragit® NE
were probed as the structural transformations Bcrystalline
phase^–Bamorphous phase,^ as well as the reduced size of
crystallites or other domains have generally a substantial
influence on the samples behavior. The 13C CP/MAS NMR
spectra (Fig. 1) provide a comparison of neat substances
(levetiracetam and Eudragit®, Scheme 1), prepared by NTT
granules and tablets. The signal assignment was performed on
the basis of the previous NMR studies and our experience.
Structural changes of levetiracetam upon the formation of
granules with Eudragit® were not observed in the 13C CP/
MAS NMR spectra, and the active compound therefore
remains in the same crystalline state, regardless of the amount
of Eudragit® added.
However, the 13C-detected 1H spin-lattice relaxation
experiments (T1(1 H)) revealed considerable differences in
1
H spin-lattice relaxation times of levetiracetam molecules.
On the basis of the results obtained for the different
experiments in the solid state, it was possible to conclude
that T1(1H) could be used to obtain information on crystal
sizes in the scale from 1 to 500 nm (44–46). In this case, the
where D is the spin-diffusion coefficient, typically 0.8 nm2/ms
for organic solids (51). In analogy with structural descriptions
of polymeric composites and blends, we focused on analyzing
the 1H–1H spin diffusion in order to obtain a more detailed
insight into the distribution of levetiracetam in matrix
systems. In our case, the T1(1H) relaxation times of neat
levetiracetam and API in reference tablet (R2NEU100) is
relatively long ca. 32–35 s. The obtained T1(1H) relaxation
times of the API in the prepared granulates were
considerably shorter being ca. 24 s in the NTT NE5/
NEU100 system and even 5 s in the NTT NE10/NEU100
system. The reduction of relaxation times detected in the
N T T N E 1 0 / N E U 1 0 0 s y s t e m r e fle c t s e ffic i e n t 1 H
magnetization transfer (spin diffusion) from the rapidly
relaxing Eudragit polymer matrix with T1(1H) = 2 s to the
levetiracetam crystallites which are shown to be in close
contact (52).
By applying the above-introduced relation (x), the
maximum diffusive path length (L) was calculated
L = 150 nm. This indicates that size of domains of
levetiracetam in the NTT NE10/NEU 100 system was not
smaller than ca. 150 nm. It can be concluded that API
(average particle size, 101.7 ± 23.7 μm) was dissolved in

Fig. 1. 13C CP/MAS NMR spectra of the neat leviteracetam (a), NTT NE10/NEU 100 (b), NTT NE10/NEU 100 _tab (c), NTT NE5/NEU100
(d), NTT NE5/NEU 100_tab (e), R2 NEU 100 (f), and Eudragit® (g)
NE30D during granulation and recrystallized to significantly
smaller particles during the drying process. Formation of
smaller particles was probably ensured by presence of non-
ionic surfactant nonoxynol 100 (53–57) in NE30D (1.5%).
Particle size of API was reduced with increasing the amount
of NE30D containing in total a higher surfactant
concentration.
Multivariate Data Analysis
The created PCA model represented the main data
structure and was intended for comparing the reference
samples with samples with Eudragit® and between each
other based on fundamentally important mechanical
properties (such as hardness) and release characteristics
(dissolution profile (burst effect), time required for a 50%
drug release (T50%), drug release mechanism, and kinetics).
Also, the gel layer characteristics (such as thickness and
penetration force) describe the variability associated with the
amount of Eudragit® and NEU entering the granulation and
thermal treatment. To reduce the number of variables,
parameters from the set of dissolution data and the gel layer
characteristics for all measured time periods were selected on
the basis of correlation structure in the data (from the group
Naiserová et al.
of highly correlated variables only one was kept in the
model).
Graphical representations of PCA were created with a
loading plot (Fig. 2a), which displays the projection of
variables in ordination space, and a score plot (Fig. 2b),
which shows the projection of objects in ordination space. It is
seen that in the score plot, closely spaced samples have
similar properties while samples far apart differ from each
other. Original variables are displayed as arrows in the new
space of the first two principal components. The lengths of
the arrows are directly proportional to the explained vari-
ability; the angle between any two arrows indicates the
amount of correlation. An extremely small angle implies high
positive correlation between variables while arrows pointing
in opposite directions are negatively correlated, whereas a
lack of correlation is represented by a right angle (58).
Dissolution Study, Drug Release Kinetics, and Mechanism
The main aim of this study was to adjust the dissolution
profile of very soluble drug levetiracetam from
HPMC/Eudragit® NE/NEU matrices towards zero-order
kinetics and decrease the burst effect by applying a water
dispersion of insoluble Eudragit® to drug/NEU (2:1, 1:1)
HPMC/Eudragit®/magnesium aluminometasilicate oral matrices

Fig. 2. PCA loadings and scores plot: a PCA loading plot; variables included in the model—tablet hardness; amount of
released drug in dissolution time 30min—burst effect; time required for a 50% drug release—T50%; thickness of the gel layer
for time point 60 min; penetration force for the time point 240 min; determination coefficient for zero-order kinetics R2 (ZO)
and exponent n for the Korsmeyer-Peppas kinetic model (KPM). b PCA scores plot; objects included in the
model—samples with a different amount of Eudragit® (differentiated by colors); amount of Neusilin® US2 entering the
granulation (triangles vs. circles); thermal treatment (NTT, TTG, TT)

mixture during the granulation and by subsequent thermal
treatment. The dissolution characteristics and the fittings of
API release data to different kinetic equations can be seen in
Tables IV and V, respectively.
The score plot (Fig. 2) clearly shows the similarity
between the reference samples. Similarity in dissolution
behavior for reference samples (f2 73.70) was also confirmed
by the similarity factor analysis. According to PCA, reference
sample R1NEU50 exhibited similar properties to samples
with a minimum different composition NE5/NEU50 and the
similarity factor f2 verified this finding (NE5/NEU50 NTT,
TG, and TT compared with R1NEU50—83.39, 78.86, and
79.35, respectively). Likewise, the reference sample
R2NEU100 had a relatively close position to samples NE5/
NEU100 (NE5/NEU100 NTT, TG, and TT compared with
NEU100—72.99, 54.28, and 56.52, respectively). On the other
hand, the reference samples were very well separated from
samples with higher amount of Eudragit® (7.5 and 10.0%),
confirming their dissimilarity. This finding was also confirmed
by the similarity factor analysis especially for the NE100

Table IV. Dissolution Profiles of Levetiracetam Samples

Amount of drug released (%) in time (min)

Sample Set 30 60 120 180 240 300 360 420 480 540 600 660 720 SDmax

R1 NEU50 27.6 39.3 55.8 66.8 75.4 82.3 87.5 92.0 95.4 98.0 99.9 101.4 102.5 1.14
R2 NEU100 28.9 42.0 59.1 70.8 79.3 85.7 90.5 94.4 97.4 99.7 101.2 102.4 103.3 1.98
NE5 NEU50 NTT 26.6 37.9 53.9 65.1 72.9 79.9 85.6 90.0 92.9 95.0 96.4 97.5 98.4 1.59
TTG 25.9 37.2 53.1 64.3 72.3 79.7 85.6 90.0 93.1 95.2 96.6 97.6 98.3 1.08
TT 26.9 38.9 55.9 68.6 78.7 86.7 92.7 97.0 99.5 100.0 100.0 101.8 103.8 2.74
NE7.5 NEU50 NTT 23.6 34.5 50.0 61.9 71.4 78.9 84.7 88.7 91.1 91.5 91.5 93.2 95.2 3.69
TTG 22.1 32.5 47.0 58.2 67.2 74.6 80.5 84.9 88.5 91.5 93.7 95.5 96.8 2.00
TT 21.8 31.9 46.5 58.5 67.8 75.7 81.9 86.6 90.5 93.6 96.1 98.1 99.4 3.99
NE5 NEU100 NTT 28.7 41.6 57.3 67.2 74.4 80.6 85.6 89.9 93.5 97.0 99.7 102.1 103.9 1.91
TTG 23.3 33.4 46.5 55.9 63.2 69.4 74.7 79.9 83.4 86.3 88.6 90.3 91.5 3.70
TT 26.6 37.7 52.9 62.5 69.6 75.9 81.0 85.2 89.0 92.4 95.3 97.9 99.9 1.17
NE7.5 NEU100 NTT 22.7 32.6 45.8 55.5 63.4 69.9 76.4 81.8 86.4 90.0 93.0 95.3 96.9 4.00
TTG 22.5 32.1 45.0 54.8 62.6 68.7 74.6 79.4 84.2 87.0 90.2 92.8 95.3 0.89
TT 20.1 29.7 41.9 51.0 58.4 64.4 70.0 74.6 79.2 82.0 85.1 87.7 90.1 2.50
NE10 NEU100 NTT 19.2 28.1 40.9 50.6 58.5 64.7 70.0 74.7 79.0 82.7 85.8 88.2 90.2 3.92
TTG 21.8 31.7 45.7 55.7 62.6 67.2 72.2 77.1 81.3 84.6 87.4 89.5 91.0 3.72
TT 20.1 29.1 41.3 50.3 57.8 63.8 68.6 72.9 76.8 80.2 82.9 85.0 86.7 3.42
 Naiserová et al.

Table V. Mathematical Modeling and Drug Release Kinetics from Matrices

Model Higuchi Korsmeyer-Peppas Zero order First order Hixson-Crowell Baker-Lonsdale

Sample Set R2 R2 n R2 R2 R2 R2

R1 NEU50 0.9618 0.9999 0.5079 0.8155 0.7462 0.9312 0.9905

R2 NEU100 0.9449 0.9993 0.5156 0.7861 0.7184 0.9466 0.9794
NE5 NEU50 NTT 0.9547 1.0000 0.5082 0.8076 0.7378 0.9864 0.9927
TTG 0.9557 0.9999 0.5175 0.8132 0.7390 0.9854 0.9909
TT 0.9346 0.9999 0.5266 0.7906 0.7114 0.9848 0.9848
NE7.5 NEU50 NTT 0.9367 0.9999 0.5399 0.8684 0.7130 0.9383 0.9596
TTG 0.9739 0.9999 0.5392 0.8547 0.7631 0.9919 0.9983
TT 0.9767 0.9999 0.5510 0.8648 0.7681 0.9980 0.9963
NE5 NEU100 NTT 0.9750 0.9983 0.4988 0.8246 0.7665 0.9798 0.9884
TTG 0.9808 0.9992 0.4892 0.8534 0.7835 0.9824 0.9967
TT 0.9815 0.9999 0.4964 0.8432 0.7811 0.9730 0.9859
NE7.5 NEU100 NTT 0.9904 0.9996 0.4998 0.8835 0.8063 0.9990 0.9937
TTG 0.9908 0.9998 0.4967 0.8808 0.8050 0.9968 0.9956
TT 0.9914 0.9986 0.5119 0.8865 0.8007 0.9914 0.9984
NE10 NEU100 NTT 0.9907 0.9998 0.5380 0.8909 0.7960 0.9913 0.9983
TTG 0.9837 0.9997 0.5249 0.8818 0.7791 0.9859 0.9988
TT 0.9879 0.9996 0.5080 0.8764 0.7938 0.9827 0.9990

samples (NE7.5/NEU100 NTT, TG, and TT compared with
R2NEU100—43.96, 42.78, and 38.01, respectively, and NE7.5/
NEU100 NTT, TG, and TT compared with R2NEU100—37.46,
42.54, and 37.32, respectively). Therefore, it is generally shown
that no impact of the thermal treatment, which may be an
effective tool in extended drug release due to the decrease of the
matrix porosity (16,59), on the PCA-observed parameters was
revealed in the scores plot (whereas at first glance, the random
distribution of samples with different treatments are shown).
Thus, statistical testing by means of ANOVAwas carried out, for
a level of significance of α = 0.05. P values for all parameters
were much higher than 0.05, which confirmed statistical
insignificance of thermal treatment. Therefore, it was excluded
from following discussion. These findings are in contrast with
our previous study in which MCC PH 101 was used as the
insoluble filler in similar design of the matrices (24).

Fig. 3. Cross-section of the gel layers of lyophilized matrices visualized by the SEM technique after 6 h of the
dissolution test (pH 6.0): a R1NE50, b R2NE100, c NTT NE5/NEU50,and d NTT NE5/NEU100
HPMC/Eudragit®/magnesium aluminometasilicate oral matrices
Fig. 4. Gel layer thickness of the matrices during: a samples NE50, SDmax 0.77 mm; b samples NE100, SDmax 0.63 mm and
penetration force through the gel layer; c samples NE50, SDmax 0.38 N; and d samples NE100, SDmax 0.39 N
The value of the burst effect ranged between 21.8 and 26.9%
for samples with NEU50 and 19.2 and 28.7% for NEU100
samples, respectively. In comparison with the burst effect of the
reference samples R1NEU50 (27.6%) and R2NEU100 (28.9%),
these values represented a 2.5–6.2% decrease in this parameter
for the NE5/NEU50 samples, 14.5–21.0% for the NE7.5/NEU50
samples, 0.69–19.3% decrease for the NE5/NEU100 samples,
21.5–30.4% for the NE7.5/NEU100 samples, and 24.6–33.56% for
the 10% samples. When reviewing the results of PCA (arrow
burst effect), it could be concluded that the burst effect decreased
with increasing Eudragit® concentration. Resources show that the
explanation for lower burst effect could pertain to the non-uniform
covering of the of the API particle surface by a thin layer of
insoluble Eudragit® during the granulation, leading to a decrease
in surface area for API release (21). Another literature source
explains it simply as a result of limited penetration of dissolution
medium into the matrix system due to insoluble character of
Eudragit® (16). While conducting this study, we will base our
reasoning in compliance with ssNMR spectroscopy results. The
reduction of burst effect was caused by creating a large interface
between API and Eudragit® NE film due to the API particle size
reduction in the dependence on the added amount of NE30D.
The rest of Eudragit® NE film inside the selected NTT
tablets after 6 h of the dissolution test are shown in Fig. 3c, d
compared with a, b (without Eudragit®). Probably, a brittle film of
Eudragit® NE created throughout the whole matrix was broken
by the high compaction forces during tableting (43,60).
As expected from the PCA model, it is evident that the
extent of the burst effect was negatively correlated with T50%
(almost overlaps with the arrow R2 for zero order (ZO)). Thus, the
time necessary for release of 50% of API was prolonged with
higher Eudragit® concentration in the matrix. After excluding one
of the highly correlated variables (determination coefficient for
zero-order kinetics or T50%) from the analysis, the PCA model
remained almost unchanged. According to the PCA analysis, the
amount of NEU entering the granulation affected neither the
burst effect nor the T50%. The extent of the burst effect was not
correlated with hardness of tablet; therefore, the statement that
increasing tablet hardness decreases porosity, water uptake, and
consequently drug release was not confirmed (57,61).
Release Kinetics and Mechanism. Zero-order kinetics expressed
through the determination coefficient R2 was revealed as
another parameter negatively correlating with the extent of
burst effect. All values for R2 (ZO) can be seen in Table V. If
their value is compared with the reference samples (R2 0.816 for
R1NEU50 and R2 0.786 for R2NEU100), an increase in this
parameter and an adjustment towards zero-order kinetics was
observed for all samples with Eudragit® (R2 0.825–891) except
set NE5/NEU50 (0.791–813). The maximum R2 0.891 was
achieved for the sample with the highest Eudragit ®
concentration NTT NE10/NEU100. The dissolution data
showed excellent agreement with the Korsmeyer-Peppas model
(R2 > 0.999); therefore, the exponent n could be used to

Fig. 5. Surface gel layers of the lyophilized matrices visualized by the SEM technique during the dissolution test
(pH 6.0) in different time intervals: a NTT NE10/NEU100 after 1 h, b R2NE100 after 1 h, c NTT NE10/NEU100
after 6 h, and d NTT NE5/NEU100 after 6 h
estimate the API release mechanism. Exponent n values for all
samples (n = 0.49–0.54) indicated the so-called anomalous
transport (62), concluding that the predominant diffusion and a
minor erosion process probably participated. This finding
corresponds with literature sources saying that water-soluble
drugs are primarily released by diffusion of dissolved drug
molecules through hydrated gel layer from HPMC matrix tablets
(63). Moreover, predominant diffusion was supported also by a
high value of R2 for the Baker-Lonsdale model (R2 > 0.96). On
the contrary, participation of erosion was proved by a high value
of R2 for the Hixson-Crowell model (R2 > 0.97) for dissolution
data of samples with Eudragit®. Rising release exponent n
(Korsmeyer-Peppas model) indicated an increasing role of
erosion in API liberation from a matrix. From the PCA analysis,
it can be observed that the highest release exponent n was in the
samples with the highest ratio Eudragit®/NEU (ratio 0.15 for
NE7.5/NEU50; n = 0.54–0.55, vs. ratio 0.05 for NE5/NEU100;
n = 0.45–0.50). The creation of granules from higher-ratio
Eudragit®NE/NEU probably led to a significant disruption in
consistency of HPMC gel layer and therefore resulting in its
higher tendency to erosion (64).
Dynamic Characteristics of the Gel Layer
For this experimental work, the gel layer thickness and
penetration force (Fig. 4) were measured to observe the dynamic
behavior of the gel layer. Gel layer thickness and its consistency at
the beginning of the dissolution test are considered the key
Naiserová et al.
parameters influencing the burst effect for swelling controlled
systems (65). At 30 min, both references exhibited the thickest gel
layers but with the smallest rigidity in comparison with the
Eudragit®-loaded samples. It can be concluded that the highest
burst effect of these samples is associated with these obtained
results (66). PCA (arrow, thickness 60 min) and scanning electron
microscopy (SEM) clearly confirmed this conclusion. On SEM
images, a significantly thinner gel layer can be recognized for
NTT NE10/NEU100 (Fig. 5a) in comparison with reference (Fig.
5b) after 1 h of the dissolution test. Gel layer appearance of the
selected samples NTT NE10/NEU100 and NTT NE5/NEU100
after 6 h is shown in Fig. 5c, d. This behavior could be described as
a dynamics paradox of HPMC gel layer because other studies
with HPMC matrices described the exact opposite (6). Higher
amounts of NEU slightly reduced the swelling of samples
probably due to a more massive transport of the dissolution
medium into the Neusilin® particles (38). Based on PCA, the
penetration force of the gel layer at the time of 240 min of the
dissolution test (arrow force) decreased with an increase in matrix
erosion expressed as exponent n (KP) and tablet hardness. The
fluctuating course of penetration force in time was probably
caused by the presence of an erosion process which was
responsible for some step changes in the internal structure of
the gel layer.
CONCLUSION
Applying Eudragit ® NE water dispersion as a
granulation liquid to the drug/Neusilin® US2 mixture in a
HPMC/Eudragit®/magnesium aluminometasilicate oral matrices
high-shear mixer in preparation of HPMC matrix tablets is
recognized as an effective tool for a significant decrease in
burst release of highly soluble APIs. Using Neusilin® US2
with large adsorption capacity allowed applying water
dispersion of Eudragit® to the drug in one step. Based on
ANOVA and PCA, thermal treatment was not revealed as a
useful procedure for this system. Decrease in burst effect and
dissolution rate, increase in fitting to zero-order kinetics, and
paradoxical reduction in the HPMC gel layer thickness was
observed after the addition of Eudragit ® NE. The
explanation for this behavior was done by ssNMR
spectroscopy which clearly showed the significant reduction
of particle size of levetiracetam (150–500 nm) in granules in
dependence on the amount of Eudragit® NE and creation of
significantly larger interface between these two entities.
ACKNOWLEDGMENTS
This experimental work was realized by support from
IGA VFU, Brno Czech Republic (project 311/2017/FaF).
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