International Journal of Pharmaceutics 587 (2020) 119719

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International Journal of Pharmaceutics

journal homepage: www.elsevier.com/locate/ijpharm

Investigation of tablet disintegration pathways by the combined use of T

magnetic resonance imaging, texture analysis and static light scattering
Jakub Dvořáka,b, Jan Tomasa,b, Denisa Lizoňováa,b, Marek Schöngutb, Ondřej Dammerb,
⁎
Tomáš Pekárekb, Josef Beránekb, František Štěpáneka,
a
University of Chemistry and Technology Prague, Technická 5, 166 28 Prague 6, Czech Republic
b
Zentiva, k.s., U Kabelovny 130, 102 00 Prague 10, Czech Republic

A R T I C LE I N FO A B S T R A C T

Keywords: Efficient tablet disintegration is a pre-requisite for fast and complete drug dissolution from immediate release
Particle size distribution formulations. While the overall tablet disintegration time is a routinely measured quality attribute of pharma-
Dissolution ceutical products, little attention is usually paid to the analysis of disintegration fragments and the cascade of
Disintegration elementary steps that lead to their formation. In this work, we investigate the disintegration pathways of directly
Wetting
compressed tablets by a unique combination of three methods: (i) magnetic resonance imaging (MRI), to gain
Direct compression
insight into structural changes of tablets during disintegration; (ii) texture analysis, to measure the disintegration
kinetics; and (iii) static light scattering, to characterise the size distribution of disintegration fragments. By
systematically varying the tablet composition (50–90% of ibuprofen as a model active ingredient, 0–4% of
croscarmellose sodium disintegrant, 6–50% of lactose monohydrate filler), a relationship between the tablet
formulation, the size distribution of the disintegration fragments and the dissolution rate of the active ingredient
has been established. To interpret the experimental observations, we analyse the disintegration fragments by
Raman mapping and relate their composition and structure to the micro-scale arrangement of individual for-
mulation components inside the tablet.

1. Introduction
Tablets represent the most common pharmaceutical dosage form. In
the case immediate relase tablets, the dissolution of the Active
Pharmaceutical Ingredient (API) is typically preceeded by tablet dis-
integration – the process in which the tablet breaks up into smaller
fragments, granules or primary particle clusters after contact with the
dissolution medium (Quodbach and Kleinebudde, 2016). The ability of
a tablet to disintegrate depends both on its composition (the amount of
API and excipients, their hydrophilic/hydrophobic character, com-
pressibility and solubility) and the manufacturing process (wet granu-
lation, roller compaction, direct compression). Specific excipients –
disintegrants – are typically added to the formulation in order to help
the disintegration process through a combination of wicking properties
that enhance the rate of dissolution medium penetration into the tablet,
and swelling or shape recovery properties to create internal stresses that
break the tablet apart once hydrated (Desai et al., 2016).
The overall tablet disintegration time is a routinely measured pro-
duct quality attribute in the pharmaceutical industry, and standardised
pharmacopoeia methods and commercial instruments are available for
this purpose (Donauer and Löbenberg, 2007). However, the final dis-
integration time does not reveal the disintegration mechanism or the
properties of the disintegration fragments. Therefore, efforts have been
made to employ more sophisticated methods for the investigation of
phenomena that occur at various stages of the disintegration process as
recently reviewed in (Markl and Zeitler, 2017). For example, Magnetic
Resonance Imaging (MRI) has been used for investigating liquid pene-
tration into tablets containing bromhexin hydrochloride (Kwieciński
et al., 2002) or for comparing the efficiency of different disintegrants
such as croscarmellose, crospovidone, sodium starch glycolate and
plyacryline potassium (Quodbach et al., 2014). X-ray micro computed
tomography has been used for observing the disintegration of or-
odispersible tablets in a flow-through cell and correlation with in vivo
data (Otsuka et al., 2012). Susceptometry has been used for the mea-
surement of disintegration of effervescent tablets (Corá et al., 2008).
The use of spectroscopic imaging methods (e.g. Raman, FTIR, NIR or
THz pulse imaging) for the investigation of spatial distribution of in-
dividual components in the tablet and the surrounding medium in the
context of tablet dissolution has been reviewed in (Ewing and Kazarian,
2018). Approaches based on texture analysis (TA) were used to

⁎
Corresponding author.
E-mail address: Frantisek.Stepanek@vscht.cz (F. Štěpánek).

https://doi.org/10.1016/j.ijpharm.2020.119719
Received 7 January 2019; Received in revised form 27 July 2020; Accepted 28 July 2020
Available online 31 July 2020
0378-5173/ © 2020 Elsevier B.V. All rights reserved.
J. Dvořák, et al. International Journal of Pharmaceutics 587 (2020) 119719

characterise the mechanical properties of tablets and their changes

during disintegration. In reference (Szakonyi and Zelkó, 2013) the ta-
blet disintegration time was determined by pressing the tablet against a
perforated barrier in the presence of the dissolution medium and re-
cording the force required to do so. In reference (Tomas et al., 2018),
the penetration of a needle probe into a disintegrating tablet was used
for probing early stage disintegration phenomena. After tablet break-up
into smaller fragments or granules, their particle size distribution (PSD)
can be characterised by digital image analysis (Rajkumar et al., 2016)
or light scattering (Smrčka et al., 2016) methods. Despite the wealth of
methods described in the literature, it is relatively rare to find studies
that use a combination of approaches along with a systematic variation
of tablet composition.
From the micro-scale point of view, the purpose of tablet disin-
tegration is to facilitate drug release by exposing the API particles to the
dissolution medium. In the theoretical limit of complete tablet disin-
tegration into individual primary particles, the drug release rate would
be controlled by the surface dissolution kinetics of the API (Hsu and Lin,
1991; Usunoff, 1990). In reality, the extent of API surface exposure may
not be 100% and the dissolution rate can be also limited by diffusion
through the internal structure of the tablet disintegration fragments
(Kašpar et al., 2013). Hence, we hypothesise that there must exist some
critical size of the disintegration fragments at which the rate-limiting
step changes from external to internal mass transfer. The knowledge of
this critical fragment size would be important for making rational tablet
formulation decisions, i.e. for choosing the appropriate amount of dis-
integrant. A similar problem is known in mineral processing as the
Mineral Liberation Analysis (Fandrich et al., 2007). In that case, it is
necessary to make a decision on how finely should a mined rock be
milled in order to expose the embedded grains of a valuable mineral in
order to maximise its recovery in a leaching process (Miller et al.,
2003). Breaking down the mined rock into smaller fragments than the
critical size would no longer improve the mineral recovery, and the
energy invested into the milling step would be wasted. Similarly, dis-
integrating a pharmaceutical tablet into smaller fragments than the
critical size would no longer improve drug release rate. Although, the
drug dissolution and mineral leaching processes occur due to different
physico-chemical principles, the analogy between these two processes
lies in the relationship between the size of fragments and the degree of
exposure of the valuable component to the dissolution medium.
Thus, the aim of the present work is to establish a relationship be-
tween the tablet composition, the size distribution of the disintegration
fragments and the rate of drug release. We use a model formulation
containing 50–90% (w/w) of ibuprofen as a model API, 0–4% (w/w) of
croscarmellose sodium as a disintegrant and lactose monohydrate as a
filler. We deploy a combination of analytical methods (MRI, texture
analysis, laser diffraction, Raman spectroscopic mapping) to compre-
hensively characterise the disintegration process and the properties of
the disintegration fragments. To interpret the experimental observa-
tions, we relate the disintegration process to the micro-scale arrange-
ment of formulation components inside the tablet and their interaction. Fig. 1. SEM micrographs of primary particles used in this work: a) ibuprofen, b)
lactose monohydrate, c) croscarmellose sodium.
2. Materials and methods
Netherlands). The SEM micrographs of the tablet components are
2.1. Tablet formulation
shown in Fig. 1 and their particle size distributions are summarised in
Fig. 2. Lactose had a bi-modal size distribution with a d50 of 43 µm.
Tablets were prepared by direct compression at a compaction force
Ibuprofen crystals were elongated, cuboid-shaped with a d50 of 130 µm.
of 20 kN using a single-punch hydraulic press (Carver 4350). The flat-
Croscarmellose particles had a worm-like shape, with a d50 of 36 µm.
faced cylindrical tablets had a diameter of 13 mm and a mass of
The pore size distribution and total porosity of the tablets were mea-
500 mg. Tablet batches with a systematically varying composition were
sured by mercury intrusion porosimetry (AutoPore IV 9500, Micro-
prepared. There were 25 compositions in total: 50%, 60%, 70%, 80%
meritics) and helium pycnometry (Pycnometer 1305, Micromeritrics),
and 90% (w/w) of ibuprofen (Hubei Biocause Pharmaceuticals Co. Ltd.,
respectively. The porosity and pore size distribution of three tablets
China) as the active ingredient, containing either 0%, 0.5%, 1%, 2% or
taken from the opposite ends of the composition space are shown in
4% (w/w) of croscarmellose sodium (Ac-Di-Sol, FMC Health and
Fig. 3.
Nutrition) as a disintegrant; the remainder to 100% (w/w) in each case
was lactose monohydrate mesh 200 (Friesland Foods Domo,

2
J. Dvořák, et al. International Journal of Pharmaceutics 587 (2020) 119719

10 2.3. Tablet disintegration monitoring by texture analysis

9 Ibuprofen
LaĐtose The weakening of inter-particle bonds within the tablet after contact
8
CrosĐarmeůůose with the dissolution medium was monitored by texture analysis using a
7 stress relaxation method described in detail in our recent work (Tomas
6 et al., 2018). In brief, the tablet was placed in a crystallisation dish
q3 [%]

5 positioned on the base table of a precise force–displacement apparatus

(CT3 Texture Analyser, Brookfield Engineering). A needle probe (TA9,
4
Brookfield Engineering) was pushed against the tablet surface until a
3 trigger load of 1.0 N was reached, at which point the probe position was
2 fixed. The dissolution medium (10 mM PBS at pH 7.4) was then poured
1 into the crystallisation dish to fully submerge the tablet and the re-
sistance force acting on the probe was recorded as function of time. The
0
tests were done in triplicate, at room temperature.
1 10 100 1000
WĂƌƟĐůe size [ʅm] 2.4. Particle size and composition analysis
Fig. 2. Particle size distribution of the API and excipients used in this work.
The tablet disintegration fragments were obtained by placing the
tablet in 15 mL of PBS saturated with ibuprofen and lactose. The tablet
0.14
was allowed to fully disintegrate at room temperature without stirring,
dV/dlogR Pore Volume (mL/g)

0.12 50% IBU, 4% CC

which typically required 15–30 min depending on the tablet composi-
tion. The reason for using a dissolution medium saturated by ibuprofen
0.1 90% IBU, 4% CC and lactose was to suppress the dissolution of these components, and
50% IBU, 0% CC
therefore to “freeze” the size distribution of the disintegration frag-
0.08
ments as well as the refractive index of the dissolution medium for the
duration of the static light scattering measurement. To measure the size
0.06
distribution, a sample of the suspension was transferred by a pipette to
0.04 the fraction measurement cell of the static light scattering instrument
(Horiba Partica LA-950 S2), containing 10 mL of PBS saturated with
0.02 ibuprofen and lactose and enriched with 0.1 wt% sodium dodecyl sul-
phate to prevent particle floating or re-aggregation. The particle size
0
0.001 0.01 0.1 1 10 100 distribution (PSD) was evaluated by the Fraunhofer kernel. Three ta-
Pore RadiuƐ (ʅm) blets were analysed for each composition and each sample was mea-
sured 3 times. The final PSD curve for each tablet composition was
Fig. 3. Pore size distribution of three limiting cases of tablet composition as
obtained by averaging.
indicated. The total porosity was 8.01% (50% IBU, 0% CC), 8.12% (50% IBU,
4% CC) and 6.74% (90% IBU, 4% CC). To obtain information about the composition and microstructure of
the disintegration fragments, confocal Raman microscopy maps were
collected on the Raman spectrometer InVia Reflex (Renishaw, UK; laser
2.2. Magnetic resonance imaging line 532 nm). Each spectrum was accumulated for 0.1 s and the spatial
step was set to 5 µm in each direction. The total scanned area was
The Magnetic Resonance Imaging (MRI) 1 T desktop system Icon adjusted according to the analysed disintegration fragment and the final
(Bruker BioSpin, Germany) was used for non-invasive observation of depth was 100 µm. The Direct Classical Least Squares (DCLS) method
the tablet behaviour during disintegration. The parameters used for was used for the maps evaluation. The measured spectra were com-
MRI are summarised in Table 1. The tablet was placed to a custom pared with references and assigned to individual components using
dissolution cell (Gajdošová et al., 2016) filled with 10 mL of the dis- false colors (red = ibuprofen, green = lactose).
solution medium (10 mM PBS at pH 7.4), inserted into the imaging coil
of the MRI instrument and scanned using the localiser scan to locate the 2.5. Dissolution tests
tablet and adjust the field of view, followed by a Flash scan to obtain
the final image. The time of the scan was approximately 5 min since the The release rate of ibuprofen from the tablets of all 25 compositions
first contact of the tablet with the dissolution medium. The temperature was obtained by standard dissolution tests. To ensure sink conditions,
was kept at 25 °C. the dissolution medium was 10 mM phosphate buffered saline (PBS) at
pH 7.4, in which ibuprofen is well soluble. Each tablet was placed in
900 mL of continuously stirred dissolution medium (magnetic stirrer at
Table 1 600 rpm) in a 1000 mL cylindrical flat-bottom glass vessel. These
Parameters used for magnetic resonance imaging. conditions were set to ensure that the tablet would not come into
Measurement Protocol Flash physical contact with the stirrer and that the disintegration fragments
are well dispersed in the volume of the dissolution medium and
Flip Angle 45° therefore the measured rate of drug release is a true reflection of the
Time 3 min 12 s
sum of diffusion fluxes from all disintegration fragments. The dissolu-
Echo Time 10 ms
Repetition Time 150 ms tion tests were done at room temperature to ensure consistency with the
Matrix size 128 × 128 pixels MRI and texture analysis measurements. Samples were taken at 0, 1, 2,
Field of View 18 mm × 18 mm 5, 10, 15, 30, 45 and 60 min; 500 µL of the medium per each time point
Slice Thickness 1 mm was collected by a syringe equipped with a filter (pore size 200 nm) and
Interslice Distance 1.25 mm
the concentration was evaluated by High-Performance Liquid
Number of Averages 10
Spatial resolution of pixel 0.141 mm × 0.141 mm × 1.0 mm Chromatography (HPLC) with UV detection (Agilent 1260 Infinity),
using C18 column (75 mm, 4.6 mm, 5 μm) and a mobile phase

3
J. Dvořák, et al. International Journal of Pharmaceutics 587 (2020) 119719

Fig. 4. MRI cross-sections of tablets with varying croscarmellose (CC) and ibuprofen (IBU) content as indicated. The field of view is 18 mm × 18 mm in all cases. The
colour scale represents relative water content in each pixel. All MRI scans correspond to 5 min after first contact with the dissolution medium.

Fig. 5. Comparison of disintegration rate measured by texture analysis for tablets with varying croscarmellose (CC) and ibuprofen (IBU) content as indicated. The
curves were averaged from three experiments for each tablet composition.

4
J. Dvořák, et al. International Journal of Pharmaceutics 587 (2020) 119719

0.50% 50 % IBU 0.50% 60 % IBU

10 1% 10 1%
2% 2%
4% 4%

q3 [%]
q3 [%]
CaůĐuůated CaůĐuůated
5 5

0 0
1 10 100 1000 1 10 100 1000
ParƟĐůe size [ʅm] ParƟĐůe size [ʅm]
a) b)

0.50% 0.50%
10 70 % IBU 10 80 % IBU
1% 1%
2% 2%
4% 4%

q3 [%]
q3 [%]

CaůĐuůated CaůĐuůated
5 5

0 0
1 10 100 1000 1 10 100 1000
ParƟĐůe size [ʅm] ParƟĐůe size [ʅm]
c) d)

0.50% 90 % IBU 50% 4 % CC

1% 10 60%
10 2% 70%
4% 80%
CaůĐuůated
q3 [%]
q3 [%]

90%

5 5

0 0
1 10 100 1000 1 10 100 1000
e) ParƟĐůe size [ʅm] f) ParƟĐůe size [ʅm]
Fig. 6. Particle size distributions of tablet disintegration fragments for varying disintegrant (CC) and ibuprofen (IBU) content as indicated. Cases (a)–(e) are grouped
by ibuprofen content, case (f) is grouped by the disintegrant content. Each PSD curve was obtained by averaging from 9 measurements (three different tablets, each
measured three times). To avoid clutter, standard deviations are shown only in the 90% ibuprofen case. For 0.5% of disintegrant, the tablets containing 70%, 80%
and 90% of ibuprofen did not disintegrate sufficiently to enable PSD measurement. The calculated PSD curves (dashed line) represent the theoretical limit of
complete disintegration into primary particles, and were obtained as a weighted average from the pure component PSD curves shown in Fig. 2.

Table 2 consisting of acetonitrile (60%) and 0.01 M ammonium phosphate

Median particle size (d50) evaluated from the particle size distribution analysis buffer (pH 2.5), with the mobile phase flow rate of 1 mL/min. The
of tablet disintegration fragments. Cases indicated by N/A did not disintegrate dissolution tests were done in triplicate.
sufficiently to be reproducibly measurable by light scattering.
50% IBU 60% IBU 70% IBU 80% IBU 90% IBU 3. Results and discussion

4% CC 169.6 µm 168.5 µm 202.1 µm 229.0 µm 229.0 µm

3.1. Effect of tablet composition on disintegration rate
2% CC 244.8 µm 294.6 µm 295.7 µm 362.7 µm 377.6 µm
1% CC 323.5 µm 359.5 µm 536.5 µm 604.4 µm 817.0 µm
0.5% CC 448.5 µm 590.0 µm N/A N/A N/A The physical state of tablets containing 50% to 90% (w/w) of ibu-
0% CC N/A N/A N/A N/A N/A profen and 0% to 2% (w/w) of croscarmellose after 5 min immersion in
the dissolution medium is shown in Fig. 4. Owing to the fact that lactose

5
J. Dvořák, et al.
Fig. 7. Schematic illustration of tablet microstructure during disintegration. a) Local crack initiation due to the swelling of a single disintegrant particle. b) Fracture
network for low disintegrant content, giving rise to a small number of large fragments. c) Fracture network for high disintegrant content, giving rise to a larger
number of smaller fragments. When the fragment size is below a critical limit, all its constituent particles have a direct contact with the dissolution medium.
is hydrophilic while ibuprofen is hydrophobic, the rate of dissolution
medium penetration into the tablet can be expected to depend on the
ibuprofen content (Luginbühl and Leuenberger, 1994). In the case of
90% ibuprofen (far right column in Fig. 4), the MRI scans clearly show
the progress of disintegration from the outside of the tablet, with a
central core of the tablet still intact at 5 min. In this case, the rate of
dissolution medium penetration into the tablet structure is limited by
the high proportion of the hydrophobic API. As was shown recently
using directly compressed ibuprofen-lactose tablets without disin-
tegrant (Tomas et al., 2018), the tensile strength of the tablets strongly
depends on the ibuprofen:lactose ratio, which determines the relative
proportion of lactose-lactose, lactose-ibuprofen, and ibuprofen-ibu-
profen interparticle bonds in the tablet. Hence, the minimum amount of
disintegrant needed for breaking up the tablet can also be expected to
depend on the ibuprofen content. There exists a critical threshold of
disintegrant content, above which the tablet disintegrates readily (i.e.
1% w/w (around 0.75% v/v) of croscarmellose for most compositions),
but below which it either does not disintegrate at all (e.g. in the case
80% w/w ibuprofen, 0.5% w/w croscarmellose), or disintegrates only
partially by delamination (e.g. in the case 70% w/w ibuprofen, 0.5% w/
w croscarmellose). These two disintegration patterns (called spitting
and laminating) were recently reported also for microcrystalline cel-
lulose based tablets (Yin et al., 2018), in which case they could be
explained by the spatial distribution of micro-cavities within the tablet.
The kinetics of disintegration can be captured quantitatively by
texture analysis measurements, summarised in Fig. 5 for the same
ibuprofen-disintegrant combinations as shown in Fig. 4. The boundary
between no disintegration, partial and full disintegration can again be
distinguished, similarly as in the case of the MRI scans. In the absence
of disintegration (0% of disintegrant for all ibuprofen ratios, and 0.5%
(w/w) of disintegrant for 80% (w/w) and 90% (w/w) of ibuprofen), the
6
International Journal of Pharmaceutics 587 (2020) 119719
force acting against the needle probe is essentially constant in time,
barring a small drop just after the addition of the dissolution medium at
t = 1 min. In the intermediate cases (e.g. 70% (w/w) ibuprofen, 0.5%
(w/w) disintegrant), the force acting on the probe fluctuates due to
individual tablet fragments becoming loose and pushing against the
probe as they break off from the tablet. Finally, in the cases where a full
disintegration occurs (e.g. 2% (w/w) of disintegrant for all ibuprofen
ratios), the force relaxation curves are smoother and their slope can be
taken as a measure of the disintegration rate (Fig. 5). Even in these
cases, the recording of force against time shows minor fluctuations;
however, the frequency of the elementary disintegration events is
higher and the amplitude of the force fluctuations is lower. As will be
discussed in the following section, this is due to the decreasing size and
increasing number of the individual disintegration fragments that de-
tach from the tablet.
3.2. Analysis of disintegration fragments
As could be seen qualitatively in the MRI scans (Fig. 4), the tablet
composition determines not only the disintegration rate, but also the
size of the disintegration fragments. To measure the size distribution
quantitatively, static light scattering experiments were carried out as
described in Section 2.4. The PSD’s of the disintegration fragments are
summarised in Fig. 6 and Table 2. There is a clear trend of decreasing
particle size with increasing disintegrant content in the tablet, regard-
less of the ibuprofen/lactose ratio. For directly compressed tablets in
the theoretical limit of complete disintegration, the PSD of the disin-
tegration fragments should correspond to that of the primary particles
from which the tablet was compressed. Therefore, the theoretical par-
ticle size distribution calculated as a weighted average from the PSD’s
of the pure components (shown in Fig. 2) has been added to each set of
J. Dvořák, et al.
Fig. 8. a) Optical microscopy image of a typical tablet fragment recovered from
the disintegration experiment. The scale bar represents 100 µm. b), c) Confocal
Raman microscopy maps showing the spatial distribution of ibuprofen (red) and
lactose (green) within the tablet disintegration fragment. The box dimensions
are X = 60 µm, Y = 72 µm, Z = 45 µm in case b) and X = 95 µm, Y = 65 µm,
Z = 95 µm in case c).
PSD curves in Fig. 6a)–e) for reference. We can observe that with in-
creasing disintegrant content, the PSD’s are converging towards the
theoretical curves, but never quite reach them. Clearly, the highest
investigated disintegrant content of 4% (w/w) was still not high enough
to fully reconstitute the tablet into the original primary particles.
7
International Journal of Pharmaceutics 587 (2020) 119719
Conceptually, the relationship between the disintegrant content and
the particle size distribution of the disintegration fragments can be
represented as shown in Fig. 7. When the dissolution medium reaches
a disintegrant particle and the local stress due to its swelling or shape
recovery exceeds the local tensile strength of the tablet, a fracture can
be initiated (Fig. 7a). If the distance between individual disintegrant
particles is small enough to enable the formation of a macroscopically
percolating fracture network, the tablet will disintegrate (Fig. 7b). The
size distribution of the disintegration fragments will then depend on the
spatial distribution and orientation of the fracture planes, which in turn
depends on the number and the spatial distribution of the disintegrant
particles (Fig. 7c). Note that the scheme shown in Fig. 7 is conceptual
and not necessarily implying that the tablet disintegration occurs by
brittle fracture in all cases, as different binding forces may be at play
depending on the exact tablet formulation and the mechanical prop-
erties of the specific API and excipient used.
Returning to the experimental data, it is interesting to note that for
the highest disintegrant content of 4%(w/w), the PSD curves of the
tablet fragments are almost independent on the ibuprofen/lactose ratio
(Fig. 6f). The PSD curves are tri-modal, due to the fact that the lactose
PSD itself is bi-modal (Fig. 2) and the ibuprofen particle size (main
mode at approx. 200 µm) is sufficiently higher than the upper mode of
lactose so that all three modes can be individually distinguished in the
PSD of the mixture. Interestingly, we can see in Fig. 6f that while the
relative proportion of the upper lactose mode (just below 100 µm)
decreases with increasing ibuprofen ratio in the tablet in accordance
with theoretical expectation, this is not the case for the lower mode of
the fine lactose particles positioned around 10 µm. According to the
theoretical curves (e.g. Fig. 6a), at low ibuprofen content this peak
should be much more prominent than it is in the experiment, and also
the ibuprofen mode should be less pronounced. One reason for this
behaviour could be that the lower-mode lactose particles are smaller
than the disintegrant particles (cf. Fig. 2) and so it is not sterically
possible for the disintegrant particles to push all these fine lactose
particles apart. However, this would not explain the ibuprofen peak.
To understand the experimental observations, it is important to
consider that the Young’s modulus of lactose monohydrate is approx.
24 GPa, while that of ibuprofen is only 5 GPa (Byrn et al., 2017). During
tablet compression, small lactose particles (which are abundant on a
number-distribution basis) could be pushed into the surface of the
larger but softer ibuprofen crystals. The increased inter-particle contact
area is a prerequisite for various types of bonding (e.g. van der Waals)
which are ultimately responsible for keeping the tablet disintegration
fragments together. To verify this hypothesis, the recovered disin-
tegration fragments, corresponding in size to the upper mode of the tri-
modal size distribution, were subjected to a detailed analysis by con-
focal Raman microscopy (Fig. 8). The structure of the analysed frag-
ments was found to generally consist of a central ibuprofen crystal,
partially surrounded by an irregular layer of lactose. Additionally, the
disintegration fragments were observed under hot-stage microscopy
(Fig. 9). Using the fact that the melting point of lactose (approx.
203–211 °C) is higher than either the melting point (76 °C) or the
boiling point (146 °C) of ibuprofen, the melting and disappearance of
the individual components could provide further insight into the com-
position and structure of the disintegration fragments. The presence of
ibuprofen in the disintegration fragments was manifested by the oc-
currence of a pool of liquid phase above the melting point of ibuprofen,
followed by its evaporation (Fig. 9). The residual cluster of fine crystals,
which is visible in Fig. 9 at 146 °C, was stable until the melting point of
lactose above 200 °C, providing further evidence that the tablet disin-
tegration fragments contain both large ibuprofen crystals and fine lac-
tose particles.
3.3. Effect of disintegration on drug release
The ultimate purpose of tablet disintegration is to facilitate drug
J. Dvořák, et al.
Fig. 9. Hot-stage microscopy analysis of tablet disintegration fragments, showing the removal of ibuprofen (meting point 76 °C, boiling point 157 °C), followed by the
melting and decomposition of lactose (melting point 203–211 °C). The scale bar represents 100 µm.
release; hence, the dissolution tests of all 25 compositions were carried
out as described in Section 2.5 and summarised in Fig. 10. The general
trends are in accordance with the MRI observations and PSD analysis
discussed previously. For tablets that do not disintegrate (0% croscar-
mellose for all cases and 0.5% of croscarmellose for 80% and 90% of
ibuprofen) the dissolution rate was very slow, governed by the surface
erosion of the whole tablets. Once the disintegrant content exceeded the
minimum value needed for tablet break-up to occur (e.g. 0.5% (w/w) of
croscarmellose for 50% (w/w) to 70% (w/w) ibuprofen, or 1% (w/w) of
croscarmellose for 80% (w/w) and 90% (w/w) ibuprofen), the dis-
solution rate was significantly higher due to the increased surface area,
and kept increasing with increasing disintegrant content. While this
trend is consistent with the decreasing particle size discussed above, it
is interesting to observe that in the most readily disintegrating tablets
(e.g. 50% (w/w) and 60% (w/w) of ibuprofen, shown in Fig. 10a and
10b, respectively), an asymptotic dissolution curve seems to have been
reached even though the asymptotic particle size has not (Fig. 6a and
6b, respectively). It seems that there exists a critical particle size of the
disintegration fragments below which there are little or no additional
benefits in terms of dissolution rate enhancement in this case.
The critical fragment can be conceptualised as a cluster of primary
particles in which the surface dissolution of the API is not limited by the
presence of other API particles that would create a locally saturated
solution inside the cluster (Fig. 11). The overall dissolution rate of API
from the cluster is controlled by its mass flux across the diffusion
boundary layer. In the specific case of ibuprofen as the API and lactose
as the excipient, the presence of lactose particles attached to the ibu-
profen surface (cf. Fig. 8) is not limiting since lactose is a well-soluble
component. However, when the disintegration fragments contain sev-
eral API particles, as would be the case e.g. for the 90% (w/w) ibu-
profen tablets, the effective surface area from which the API can dis-
solve is reduced.
The relationship between the size of disintegration fragments (d50)
and the dissolution half-time (t50) for all tablet compositions where
some disintegration took place is summarised in Fig. 12. Statistically,
the data points can be categorised into two groups where a linear re-
lationship between particle size and dissolution time is satisfied with a
high correlation coefficient. One group is formed by data points origi-
nating from tablets containing 90% (w/w) of ibuprofen, and the second
8
International Journal of Pharmaceutics 587 (2020) 119719
one is formed by data points from all remaining compositions. The
linear relationship between the particle size and the dissolution time of
course has its limits – the smallest particle size theoretically achievable
by tablet disintegration is determined by the size distribution of the
primary particles (cf. Section 3.2) and the shortest theoretically possible
dissolution time is limited by the intrinsic dissolution kinetics of the API
under the hydrodynamic conditions of the dissolution test. As is evi-
denced by the increasing density of data points in the bottom-left part
of the data series in Fig. 12, these theoretical limits appear to be ap-
proached in this region. In the case of high ibuprofen content (90% w/
w), the longer dissolution half-times could be the consequence of a
delay in the dissolution medium penetration into the tablet core. From
the texture analysis data (Fig. 5), it takes approx. 6 min for the dis-
solution medium to fully penetrate into a tablet containing 90% (w/w)
ibuprofen and 2% (w/w) crosscarmelose. Hence, the dissolution of
ibuprofen particles that were in the middle of the tablet begins later
than those positioned at the tablet periphery (see also the residual dry
tablet core after 5 min, seen in the MRI images in Fig. 4), and conse-
quently the dissolution half-time of the tablet is higher even though the
size distribution of the disintegration fragments is comparable to that
obtained from tablets containing 80% (w/w) and less ibuprofen.
4. Conclusions
The particle size distribution (PSD) of disintegration fragments has
been quantitatively related to the tablet composition (API and disin-
tegrant content), and shown to directly influence the dissolution rate of
the API. It has been shown that with increasing disintegrant content,
the PSD of the disintegration fragments approaches that of the original
primary particles; however, in the specific case of ibuprofen and lactose
model formulations considered in this work, the size distribution of the
primary particles could be re-constituted only partially due to the bi-
modal nature of lactose PSD and a relatively large difference in the
hardness of ibuprofen and lactose. This meant that even for high dis-
integrant content, some fine lactose particles remained physically at-
tached to the surface of larger ibuprofen crystals. Due to good aqueous
solubility of lactose, this had no negative impact on the dissolution rate
of the API, but it provides a potential means of modifying the surface
(wettability) and dissolution properties API crystals by a suitably
J. Dvořák, et al. International Journal of Pharmaceutics 587 (2020) 119719

100% 100%

Ibuprofen release [%]

Ibuprofen release [%]

80% 80%
0%
60% 0.50% 60%
1%
40% 2% 40%
4%
20% 20%

0% 0%
0 20 40 60 0 20 40 60
Time [min] Time[min]
a) b)

100% 100%
Ibuprofen release [%]

Ibuprofen release [%]

80% 80%

60% 60%

40% 40%

20% 20%

0% 0%
0 20 40 60 0 20 40 60
c) Time[min] d) Time[min]

100%
Ibuprofen release [%]

80%

60%

40%

20%

0%
0 20 40 60
Time[min]
e)
Fig. 10. Dissolution curves for tablets with varying disintegrant levels, ranging from 0% to 4% as indicated in the legend. The ibuprofen content was 50% (a), 60%
(b), 70% (c), 80% (d), and 90% (e). The data points are mean values, the error bars represent standard deviations (N = 3). Dissolution conditions: PBS pH 7.4,
900 mL, 600 rpm, 25 °C.

chosen excipient in a similar way as in the hybridization (dry coating) Visualization, Writing - original draft, Writing - review & editing. Jan
process, without the high-energy mixing. The present was concerned Tomas: Methodology, Investigation, Data curation, Visualization,
only with directly compressed tablets; the next step of our research will Writing - original draft. Denisa Lizoňová: Methodology, Investigation,
deal with the effect of additional processing steps (dry or wet granu- Visualization, Writing - original draft. Marek Schöngut: Investigation,
lation) and the effect of intra- and extra-granular addition of disin- Data curation, Formal analysis. Ondřej Dammer: Data curation,
tegrant on the disintegration pathways. Supervision, Formal analysis. Tomáš Pekárek: Investigation, Data
curation, Visualization. Josef Beránek: Data curation, Supervision,
Formal analysis. František Štěpánek: Conceptualization,
CRediT authorship contribution statement
Methodology, Funding acquisition, Supervision, Writing - review &
Jakub Dvořák: Methodology, Investigation, Data curation, editing.

9
J. Dvořák, et al. International Journal of Pharmaceutics 587 (2020) 119719

Fig. 11. Schematic illustration of tablet disin-

tegration fragments with a different effect on API
dissolution. a) The API particle surface is topo-
logically equivalent to the hydrodynamic
boundary layer surrounding the fragment. b)
Multiple API particles are arranged to form
a topologically closed region in which a stagnant
layer of saturated solution can exist, reducing
the effective dissolution area.

45 Influence of compression forces on tablets disintegration by AC biosusceptometry.

Eur. J. Pharm. Biopharm. 69, 372–379.
40 0,50% Desai, P.M., Liew, C.V., Heng, P.W.S., 2016. Review of disintegrants and the disintegra-
1% tion phenomena. J. Pharm. Sci. 105, 2545–2555.
35 2% Donauer, N., Löbenberg, R., 2007. A mini review of scientific and pharmacopeial re-
quirements for the disintegration test. Int. J. Pharm. 345, 2–8.
30 4% Ewing, A.V., Kazarian, S.G., 2018. Recent advances in the applications of vibrational
spectroscopic imaging and mapping to pharmaceutical formulations. Spectrochim.
t50 [min]

25 Acta A 197, 10–29.

20
15
10
5
0 Kwieciński, S., Weychert, M., Jasiński, A., Kulinowski, P., Wawer, I., Sieradzki, E., 2002.
0 200 400 600 800 1000
d50 [ʅm]
Fig. 12. Correlation between the dissolution half-time t50 and the median
particle size of disintegration fragments d50 for all tablet combinations in-
vestigated in this work. The legend refers to the disintegrant content. The data
points are mean values, the x- and y-error bars represent standard deviations
(N = 3 for dissolution time, N = 9 for particle size). The three apparent outlier
points with a higher dissolution time are for 90% ibuprofen (R2 = 0.998); the
remaining data points are for all other compositions (R2 = 0.966).
Declaration of Competing Interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influ-
ence the work reported in this paper.
Acknowledgments
Financial support from the Specific university research MSMT No.
21-SVV/2019 is gratefully acknowledged. F.S. would like to acknowl-
edge support by the Czech Science Foundation (GAČR project no. 19-
26127X). We would like to thank Zentiva, k.s., for supporting this work.
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