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where u is the fraction of surface covered by a tightly bound, monomolecular

moisture layer, f is the fraction of surface covered by a multilayer of moisture, a is


the total amount of condensed moisture measured in molecular layers, q1 is the
heat of adsorption of water, qL is the normal heat of condensation of water
molecules, k is the Boltzmanns constant, T is the absolute temperature, Ms and Md
are the moisture contents of the sample during sorption and desorption,
respectively, RH and RHmax are relative humidity and maximum relative humidity,
respectively, rw is the density of water, Vm and Va are the volumes of the adsorbed
and absorbed moisture, respectively, and Wm is the dry weight of the powder. Using
a combination of iteration and multiple regression techniques, the experimental
data was fit to these equations using the following procedure: The value of an
exponential term, E was assumed and used to calculate u, f and a using Eqs. (4), (5)
and (7). Eqs. (8) and (9) were then re-written as:

With the experimental data for Ms and Md together with a multiple regression
technique, the values of A and B were calculated for each assumed value of E. The
experimental and calculated values of Ms and Md were then subjected to error
analysis and the unique values of E, A and B that resulted in the highest correlation
coefficient between the experimental and theoretical values of moisture content
were used for further analysis.

2.3. Storage of crospovidone Crospovidone samples were stored in open glass jars
kept inside sealed humidity chambers containing specific saturated salt solutions for
two weeks. Relative humidity (RH) conditions chosen were 11, 33, 53 and 75% RH
and maintained using saturated salt solutions of LiCl, MgCl6H2O, Mg(NO3)26H2O
and NaCl, respec- tively (Greenspan, 1977). The RH values in each chamber were
verified by measuring the water activities of the saturated salt solutions with a dew
point hygrometer (AquaLab 4TE Duo, Decagon Devices, USA). Three sets of
crospovidone samples in separate humidity chambers were prepared for each RH.
Equilib- rium water activities of crospovidone were measured using the same dew
point hygrometer. 2.4. Loss on drying After two weeks of storage, moisture content
of the crospo- vidone samples was determined by a loss on drying test method and
the dry weight of crospovidone was used for subsequent calculations. Samples of
about 1 g were accurately weighed and introduced into glass beakers. The beakers
were transferred into a vacuum oven (Model 273800, Hotpack, USA) pre-heated to
105 C and dried for 1 h. The oven was then vacuumed, heating was switched off
and samples were left under vacuum overnight. Weight loss was recorded after 24 h
and moisture content of samples were calculated according to Eq. (12).

2.5. Size characterization using optical microscopy Crospovidone samples were


passed through a 1.4 mm aperture size sieve (Endecotts, London, UK) with gentle
tapping onto glass slides. Using a 40X objective with an optical microscope (BX 61,
Olympus, Japan) connected to a video camera (DXC-390, Sony, Japan) and
computer, images were captured and analyzed with an image analysis system
(Image Pro Plus 6.3, Media Cybernetics, USA). A minimum of 625 randomly captured
particles for each sample were examined for their maximum diameters, defined as
the length of the longest line joining two outline points and passing through the
centroid of the particle. Particle median size (D50) and span, calculated according to
Eq. (13), were determined

2.6. Solution calorimetry The enthalpy of interaction between the equilibrated


crospo- vidone samples and water was measured using a solution calorimeter (Parr
6755, Parr Instrument Company, USA). The calorimeter was calibrated by dissolving
0.5 g tris (hydroxymethyl) aminomethane, (TRIS), in 100 g of 0.1 N HCl, and the net
corrected temperature rise (DTc-ref) was used as the reference for enthalpy
calculations. The dewar in calorimeter was first filled with 100 g of deionized water
and 0.5 g sample of crospovidone was loaded from a Teflon cell with rotation and
immersed into the liquid. The calorimeter was allowed to equilibrate and the
thermogram was obtained to determine DTc. 2.6.1. Enthalpy calculation The known
energy input (QE) of TRIS was calculated using the following equation:

where QE (calories) is the energy input, mref (g) is the weight of TRIS, and T(0.63R)
is the point on the thermogram where the temperature ( C) is 63% of its total rise.
Subsequently, energy equivalent of the calorimeter, e (calories/ C) was calculated
using the following equation:

where DTc-ref ( C) is the net corrected temperature rise from the interaction
between TRIS and 0.1 N HCl. The energy change, Q (calories), was further
calculated with the following equation: Q = (DTc) (e) (15) where DTc ( C) is the net
corrected temperature rise from sample-solvent interaction, while e (calories/ C) is
the equivalent energy. Finally, the change in enthalpy, also known as enthalpy of
immersion, DHT, where T is the temperature at the 0.63R point on the thermogram,
was calculated using the following equation:

2.7. Preparation of tablets DCP tablets with 0.5, 1, 1.5 or 2% crospovidone and 0.5%
MgSt were made. Well mixed samples of 400 mg mixed tablet feed were individually
weighed and compressed using 10 mm standard concave punches on a semi-
automated tablet press (NP-RD10A, Natoli Engineering Company, USA). Maximum
compression pressure was set at 62.4, 187.3 and 249.7 MPa. At least 30 tablets
were prepared for each set of designed variables (storage RH, concentration of
disintegrant and tablet compression pressure), and 15 tablets were evaluated
immediately after compression, while the balance tablets were stored in the pre-
equilibrated chambers corresponding to the storage RH of crospovidone for 24 h
before further evaluation. Replicates were prepared for each set of conditions.
Tablets containing only DCP were prepared to serve as control. 2.8. Evaluation of
tablets Thickness was determined by a thickness gauge (ID-C1012 EXBS, Mitutoyo,
Japan) from at least six randomly chosen tablets. Hardness was measured (TBF
1000, Copley Scientific, UK) using at least six tablets and results were averaged.
Disintegration tests (The United States Pharmacopeia method; DT2, Sotax,
Switzerland) were carried out at 37 2 C in purified water with at least six randomly
chosen tablets and results were averaged. 3. Results 3.1. Disintegrant properties
Size, size distribution, moisture content, water activity and enthalpy of immersion of
crospovidone stored at the four relative humidities are presented in Table 1. The
median particle size of crospovidone stored at 11, 33 and 53% RH were similar, but
a two- fold increase in median particle size accompanied by a slight increase in
span was observed for crospovidone stored at 75% RH, which suggests the
formation of agglomerates at high storage humidity. Measured water activities were
close to the storage humidity, implying that equilibrium between the samples and
the storage environment was achieved. There was a positive correla-tion (R2 =
0.987) between the calculated externally adsorbed moisture and enthalpy of
immersion, which indicated that the interaction between crospovidone and water
became less exo- thermic as more moisture was adsorbed by crospovidone. 3.2.
Moisture sorption and desorption isotherms Fig. 2a shows the sorption and
desorption isotherms of crospovidone and DCP. The sorption and desorption profiles
of crospovidone are very close, with minimal hysteresis observed between 0.1 and
0.6 aw. The J-shaped curves of the crospovidone isotherms suggest that they are
Type III isotherms (Brunauer et al., 1940). Unlike crospovidone, DCP did not show
any increase in moisture content with increasing water activity but contained a
fairly stable moisture content of approximately 1%. 3.2.1. GAB analysis The
apparent GAB monolayer coverage (Mm), and sorption constants (C and K) are
shown in Table 2. Fitting of the isotherms to the equation was successful (Fig. 2b)
and the predicted sorption and desorption values were in excellent correlation with
the experimental data (R2 = 0.999). The Mmvalue obtained in this study was in
close agreement with other studies (Malamataris et al., 1991; Rokar and Kmetec,
2005; Saripella et al., 2014b). The K value of 0.756 obtained in this study was
slightly lower than that found in other studies (Malamataris et al., 1991; Rokar and
Kmetec, 2005; Saripella et al., 2014b), while the C value of 4.82 obtained was
between those obtained by Malamataris et al. (1991) and Saripella et al. (2014b)
and much higher than the 1.61 reported by Rokar and Kmetec (2005). These
differences could be attributed to the different brands and grades of crospovidone
used in the studies. 3.2.2. Young and Nelson analysis The Young and Nelson model
also showed excellent fit with the experimental isotherms (Fig. 2c), with the
calculated E, A and B values of 0.2, 0.1132 and 0.05489, respectively, giving the
best correlation (R2 = 0.999). Following the fit of the Young and Nelson equations to
the sorption and desorption data, it was observed that the monolayer moisture
started to plateau at approximately 0.4 aw, while the condensed moisture increased
exponentially with increasing water activity. The bound moisture only accounted for
a small fraction of the total moisture content, which increased linearly with
increasing humidity, reaching a maximum of approximately 11% at 0.9 aw (Fig. 2d).
As a result of the exponential increase of condensed moisture, the increase in water
activity did not drastically reduce the proportion of externally adsorbed moisture
despite the plateau of the monolayer moisture (Table 3). Therefore, it can be
concluded that externally adsorbed moisture accounted for the bulk of the total
moisture content in crospovidone, with minimal bound moisture. Thus, much of the
moisture adsorbed is distributed loosely on the large surface area of crospovidone
particles. 3.3. Tablet properties 3.3.1. Disintegration time Regardless of storage
humidity, as the concentration of crospovidone in the tablet formulation increased,
disintegration time decreased after storage for 24 h. The change in disintegration
time with respect to crospovidone concentration was evaluated by comparing the
disintegration time between tablets containing crospovidone and tablets that
contain DCP only. When the tablets were compressed at 62.4 MPa, there was an
improvement in disintegration performance with a lowered storage humidity from
53 to 11% RH (Fig. 3). Even with a low concentration of 0.5% crospovidone stored at
11% RH in the tablets, disintegration time reduced by 22.8% compared to tablets
without disintegrant. The improvement in disintegration time became less
prominent as the storage humidity increased, with tablets containing crospovidone
stored at 53% RH showing a 13.7% increase in disintegration time instead. This
trend was consistently observed as the amount of crospovidone added to the
powder blend increased, with tablets containing crospovidone stored at 53% RH
eventually showing an improvement in disintegration time with 1.5% crospovidone
added. In the case of tablets compressed at 187.3 and 249.7 MPa, there was a
drastic improvement in disintegration time with the addition of crospovidone, as
tablets containing DCP only did not disintegrate within 15 min (data not shown).
3.3.2. Hardness Change in tablet hardness was assessed by measuring the
difference in hardness between tablets containing crospovidone and tablets
containing only DCP after post-compression storage of 24 h (Fig. 4). In general,
tablets containing crospovidone stored at 11% RH became harder, especially for
tablets compressed at 62.4 MPa. As crospovidone was reported to also be able to
act as a dry binder in addition to its disintegrant function, the increase in hardness
could be the result of crospovidone promoting stronger bond formation within the
tablet matrix. As the storage humidity of crospovidone increased to 33 and 53% RH,
the difference in hardness between tablets with and without crospovidone became
nearly indistinguishable. However, the use of crospovidone stored at 75% RH
resulted in tablets very soft when compressed at 62.4 MPa, while tablets
compressed at 187.3 and 249.7 MPa also showed a decrease in tablet hardness.
3.3.3. Thickness In general, the change in tablet thickness was within 2% compared
to tablets without crospovidone, with the exception of tablets containing
crospovidone stored at 75% RH (Fig. 5), where the increase in thickness was
proportional to the concentration of crospovidone added. This suggests the
occurrence of strain recovery of compaction induced deformation within the tablet.
3.4. Compression pressure and disintegration time As the concentration of
crospovidone in the tablets increased from 0.5 to 2%, a crossover trend in
disintegration time was observed as compression pressure was increased (Fig. 6).
Disinte-gration time of tablets containing 0.5% crospovidone predictably increased
with compression pressure, with the exception of crospovidone stored at 11% RH,
where no significant difference in disintegration time was found. In contrast, for
tablets containing 1, 1.5 or 2% crospovidone, disintegration times were shortened
for tablets prepared at higher compression pressures, with tablets compressed at
249.7 MPa showing a most drastic improvement in disintegration time. When the
tablets were compressed at 62.4 MPa, a gradual decrease in disintegration time was
observed with increased disintegrant concentration. However, it can be observed
that tablets compressed at 187.3 and 249.7 MPa showed a significant improvement
in disintegration time as concentration of crospovidone was increased from 0.5 to
1%, beyond which, only very small improvement in disintegration time was
observed. This suggested that if the concentration of crospovidone used is 1% or
more, the compression pressure used is a predominating variable that affects
disintegration time, as a higher compression pressure would result in faster
disintegration.

4. Discussion 4.1. Effect of crospovidone concentration and compression pressure


on disintegration time The crossover trend observed in disintegration time when
concentration of crospovidone was increased from 0.5 to 1% suggested that when
used at low levels, disintegration concentra-tion was a critical factor affecting tablet
disintegratability. While crospovidone is known as a tablet disintegrant, the
contribution of DCP in assisting the break-up of the tablet matrix should also be
recognized. As crospovidone has limited capacity for water uptake, the initiation of
the disintegration process is partially dependent on water uptake by DCP. Therefore,
longer disintegration time with an increase in compression pressure was expected,
as a higher compression pressure reduces the number of capillary networks in the
less porous tablets formed. At higher concentrations of crospovidone however, an
increase in compression pressure led to faster disintegrating tablets. This suggested
that when higher concentrations of crospovidone were used, tablets performance
was more sensitive to compression pressure (Di Martino et al., 2005). It has been
previously reported that the mechanism of disintegration action of crospovidone is
strain recovery of compaction induced deformation (Desai et al., 2012), where the
deformed disintegrant particles after compaction exhibited shape memory polymer
properties by regaining their original shape when wetted. Therefore, it can be
inferred that a higher compression force would translate into greater extent of
compaction induced deformation, which in turn results in greater force exerted on
the surrounding during the strain recovery process. Accordingly, shorter
disintegration times were observed for tablets compressed at 249.7 MPa, followed
by those com-pressed at 187.3 and 62.4 MPa. 4.2. Effect of humidity changes on
crospovidone performance At a low sorption level, the proportion of water molecules
interacting with crospovidone was high relative to water-water interaction, as most
of the moisture present was bound to the solid surface as part of the monolayer
moisture (Table 3). However, as the formation of monolayer moisture approached
saturation and the adsorbed moisture started to form multilayers, water-water
interaction such as hydrogen bonding predominated. This was consistent with the
enthalpy of immersion ranking, where the reaction between crospovidone and water
became less exothermic as the amount of adsorbed moisture increased. The
enthalpy of immersion is inversely related to amount of moisture present in the
sample, with a dry solid being the most exothermic when interacting with water
(Hollenbeck et al., 1978; Wurster et al., 1984). The opposing trend between
moisture content and enthalpy of immersion is therefore indicative of the behavior
of externally adsorbed moisture. As more moisture is adsorbed on the surface of a
solid, the enthalpy of immersion gradually decreases and approaches to almost
zero, indicating that moisture adsorbing behavior would eventually resemble that of
condensation. Wetting of the disintegrant particles plays an important role in
initiating disintegration, and externally adsorbed moisture could therefore pose
several negative consequences on the performance of crospovidone. Firstly, the
adsorbed moisture could lead to wetting of the disintegrant particles. An increase in
the amount of adsorbed moisture could have led to the premature initiation of strain
recovery of compacts during storage, which can have adverse consequences on
disintegrant performance. Besides, moisture was shown to exhibit plasticizing effect
on crospovidone (Saripella et al., 2014a). The solid-liquid hydrogen bonding led to
increased flexibility of the polymeric chains, which caused a reduction in glass
transition temperature (Leng et al., 2011; Yang et al., 2006; Yu et al., 2011).
Similarly, the plasticization of crospovidone by moisture had brought about the early
release of strain energy stored in compacted crospovidone particles. While
disintegration performance of crospovidone deteriorated with an increase in storage
humidity from 11 to 53% RH, this trend did not persist for crospovidone stored at
75% RH when used for the preparation of tablets. Several factors could have caused
this anomaly. The hardness of tablets containing crospovidone stored at 75% RH
dropped significantly after 24 h of storage. Visual inspection revealed considerable
physical surface deformations on the tablets by the presence of many small,
irregularly shaped protuberances (Fig. 7). This observation suggests that the post-
compaction strain recovery of the crospovidone particles had contributed to
considerable stress within the tablet matrix, especially by the surface particles,
resulting in the formation of microcracks that disrupted and weakened the
interparticulate molecular forces (Hersen-Delesalle et al., 2007). Condensed
moisture on the powder surface could also play a role in disturbing the
interparticulate interaction within the tablet matrix (Ahlneck and Alderborn, 1989).
The increase in median particle size also suggests the formation of crospovidone
agglomerates. When presented as agglomerates, the effect of strain recovery could
be cumulative and therefore augmented, which caused considerable loci of
disruptions to the intermolecular forces within the tablet. A weakened tablet matrix
coupled with a significant increase in tablet thickness would translate into an
enlargement of tablet pores, thereby promoting water permeability and uptake
during disintegration (Washburn, 1921). While crospovidone was shown to have
relatively poor water uptake upon wetting, DCP was found to attract water via
capillary action, hence the reduction in tablet porosity could have resulted in the
improvement in disintegrat- ability, but at the expense of tablet hardness. 5.
Conclusion Moisture sorption and desorption isotherms of crospovidone and DCP
were measured, and the isotherms of crospovidone were further devolved using the
GAB and Young and Nelson equations. The moisture content of DCP did not increase
or decrease during sorption and desorption, but crospovidone was shown to sorb
and desorb moisture in a J-shape Type III manner. Young and Nelson equations were
successfully applied to the experimental data to demonstrate that the bulk of the
moisture taken up by crospovidone was mostly located externally, with minimal
bound moisture. This was further verified by the decrease in enthalpy of immersion
with increasing storage humidity, which illustrated that as humidity was increased,
the reaction betweencrospovidone and water became less exothermic, thus
indicating that the surface solid-water interaction increasingly resembled that of
surface condensation. Crospovidone was also stored at four different relative
humidities and subsequently used to prepare tablets containing different
crospovidone concentrations and compressed at three compression pressures. High
relative humidities were found to be detrimental to the performance of
crospovidone. This is postulated to be a consequence of premature wetting of the
disintegrant by adsorbed moisture, which led to the initiation of strain recovery from
post compaction deformation. Besides, the plasticizing effect of moisture could have
resulted in the release of strain energy within the disintegrant particles. Tablets
containing crospovidone stored at 75% RH also demonstrated improved
disintegration performance, but the tablets were too soft to be handled and had
obvious defects on the tablet surface. It could be concluded that high humidity was
detrimental to the performance of crospovi- done as a consequence of high
moisture adsorption. In view of the negative consequences of adsorbed moisture on
crospovidone, the knowledge of crospovidone-water interaction could provide a
better understanding of crospovidone stored at different humidity conditions and its
consequence on tablet disintegration time, thickness and hardness.

Acknowledgements The authors would like to acknowledge the financial support


from GEA-NUS PPRL fund (N-148-000-008-001). Tze Ning Hiew is a recipient of the
National University of Singapore Graduate Research Scholarship.