Drug Development and Industrial Pharmacy

ISSN: 0363-9045 (Print) 1520-5762 (Online) Journal homepage: [Link]

Evaluation about wettability, water absorption or

swelling of excipients through various methods
and the correlation between these parameters
and tablet disintegration

Baixue Yang, Chen Wei, Yang Yang, Qifang Wang & Sanming Li

To cite this article: Baixue Yang, Chen Wei, Yang Yang, Qifang Wang & Sanming Li (2018):
Evaluation about wettability, water absorption or swelling of excipients through various methods
and the correlation between these parameters and tablet disintegration, Drug Development and
Industrial Pharmacy, DOI: 10.1080/03639045.2018.1453519

To link to this article: [Link]

Accepted author version posted online: 20

Mar 2018.

Submit your article to this journal

View related articles

View Crossmark data

Full Terms & Conditions of access and use can be found at

[Link]
 Evaluation about wettability, water absorption or swelling of excipients through

various methods and the correlation between these parameters and tablet

disintegration

Baixue Yang,Chen Wei,Yang Yang,Qifang Wang,Sanming Li*

School of Pharmacy, Shenyang Pharmaceutical University, Benxi, Liaoning,PR China

*Corresponding author: Prof. Sanming Li, School of Pharmacy, Shenyang

t
ip
Pharmaceutical University, Huatuo Road 26, Benxi, Liaoning 117004, PR China. Tel:
+86-024-43520581 E-mail address: li_sanming@[Link]

cr
Abstract
us
an
Objective: To evaluate parameters about wettability, water absorption or swelling of
M

excipients in forms of powders or dosage through various methods systematically

ed

and explore its correlation with tablet disintegration.

Materials and methods: The water penetration and swelling of powders with
pt

different proportions of excipients including microcrystalline cellulose (MCC),

ce

mannitol, low-substituted hydroxypropyl cellulose (L-HPC), crospolyvinylpyrrolidone

Ac

(PVPP), carboxymethyl starch sodium (CMS-Na), croscarmellose sodium (CCMC-Na)

and magnesium stearate (MgSt) were determined by Washburn capillary rise. Both

contact angle of water on the excipient compacts and surface swelling volume were

measured by sessile drop technique. Moreover, the test about water absorption and

swelling of compacts was fulfilled by a modified method. Eventually, the

disintegration of tablets with or without loratadine was performed according to the

method described in USP.

Results and discussion: These parameters were successfully identified by the

methods above, which proved that excipient wettability or swelling properties varied

with the structure of excipients. For example, MgSt could improve the water uptake,

while impeded tablet swelling. Furthermore, in the present study it is verified that

tablet disintegration was closely related to these parameters, especially wetting rate

t
ip
and initial water absorption rate. The higher wetting rate of water on tablet or initial

cr
water absorption rate, the faster swelling it be, resulting in the shorter tablet

disintegration time.
us
Conclusion: The methods utilized in the present study were feasible and effective.
an
The disintegration of tablets did relate to these parameters, especially wetting rate
M

and initial water absorption rate.

ed

Keywords: Wettability; Water absorption; Swell; Excipient; Tablet disintegration

pt
ce
Ac
Introduction

Tablets break into fragments rapidly in the oral cavity or gastrointestinal fluid, which

is known as tablet disintegration1, 2. This process is the prerequisite of drug

dissolution. A faster tablet disintegration will generate a better drug release and

absorption, thus improving drug bioavailability3. Therefore, the tablet disintegration

time can be used to predict the drug dissolution sometimes4. Besides, it is also a

powerful tool to select the optimal prescription when a wide variety of excipients

t
ip
and active pharmaceutical ingredient (API) were used, normally which is effective but

cr
complex, time-consuming and high-cost considering the expensiveness of API. In

us
general, tablet disintegration starts only when tablet contact with water or other

aqueous medium5-7, which is likely to associate with the wettability, water

an
penetration and swelling of excipients8-10, especially disintegrant in powders or
M

dosage forms. An elegant work from Yoshinori Onuki et al showed that disintegrant
ed

content had an influence on the disintegration actions by investigating

physicochemical properties of 11 different disintegrant powders, including wetting

pt

time, water absorption ratio and swelling property11. Mohammad Chaheen et al

ce

studied the swelling force of disintegrant by using self-made device12. The

Ac

determination of these properties is often utilized to assess the applicable possibility

of single excipient as a potential disintegrant in tablets13 or their influnence on tablet

disintegration and drug dissolution. Nonetheless, in spite of disintegrant, the

formulation of excipients also includes filler, binder, lubricant, flavoring agent and so

on. These properties will also be affected by the addition of other functional
excipients in some extent, which might improve or hinder tablet disintegration. For

instance, the hydrophobicity of magnesium stearate lowered tablet surface

wettability14, leading to the longer tablet disintegration time and the lower drug

rlease rate. In addition, the systematic investigation about the influence of different

kinds of excipients on these properties that were measured by common methods has

not been conducted until now. Hence, this work aims at evaluating parameters about

wettability, water absorption or swelling of excipients in powders or dosage forms

t
ip
through various methods that will be described in the following section

cr
systematically and exploring the correlation between these parameters and tablet

us
disintegration. Meanwhile, a modified water absorption and swelling (WAS) test is

designed to evaluate the water uptake and swelling of compacts, which not only will
an
be beneficial to the quality assessment of new disintegrant but also can be used as
M

an effective screening tool during the formulation and evaluation of tablets.

ed

Washburn capillary rise (WCR)15, 16

has been widely employed to measure

relative contact angle of porous powders and thus evaluate the surface wettability of
pt

powders. The relationship between the squared height of the penetrating liquid in a
ce

packed cylindrical tube and penetrating time satisfies the Washburn’s equation.
Ac

Martim Victor Hammes et al17 studied the effect of water activity and gaseous phase

relative humidity on the wettability of microcrystalline cellulose by WCR. However,

the application of this method is limited owing to the lack of porous excipients or the

high viscosity of excipients. The sessile drop technique (SDT)18 is another option to

acquire the wettability of excipients via measuring the compact absolute contact
angle, which is not suitable for porous materials because their porous inside allow

water to penetrate easily so that water has penetrated into tablet completely before

images are captured. Patrick Hooper et al designed a new modified wetting test to

simulate the oral condition and record the wetting time of orally disintegrating

tablets19, 20. Water absorption ratio would be calculated and the results indicated

that the wetting time was related to the disintegration time of orally disintegrating

tablets, but not traditional tablets.

t
ip
Generally, water uptake of disintegrant powders was measured with the

cr
apparatus21. The graduated pipette full of liquid and a funnel that was closely

us
covered with filter paper were connected through a rubber tubing. Then a certain

quality of disintegrant powders was weighed and placed on the surface of the filter
an
paper. The amount of water uptake into powder beds was recorded at suitable time
M

intervals. By using this method13, Chengyu Wang evaluated the water absorption of
ed

nanocrystalline cellulose and concluded that nanocrystalline cellulose had a great

potential as a disintegrant in tablets. The test operation was simple but

pt

time-consuming. In addition, both the wetting time and water absorption ratio were
ce

obtained when powders were replaced by tablets22. What’s more, the kinetics of
Ac

water penetration into tablets could be studied with a tensiometer23, while the

swelling process could not be monitored.

In this work, these parameters were systematically measured by WCR, SDT and

modified WAS test. Microcrystalline cellulose, a purified and partially depolymerized

cellulose, is always considered as filler or binder24 with direct compression method.

When the above methods were employed, MCC with the high interparticle porosity

was chosen as the reference substrate owing to its good capillary action25. Loratadine

is an antihistaminic drug and belongs to the Class Ⅱ of the Biopharmaceutics

Classification System (BCS) on account of its low solubility and high permeability26.

When the oral tablets were taken by patients, this drug in salt form existed in acid

medium, which increased its solubility in the stomach27. In the present work, it was

selected as the model drug. In the end, the disintegration of tablets with or without

t
ip
loratadine was carried out in water, which would contribute to verify the correlation

cr
between these parameters and tablet disintegration.

Materials and methods

Materials
us
an
Microcrystalline cellulose (MCC) as the filler was supplied by Tianjin Guangfu Fine
M

Chemical Research Institute (Tianjin, China). Mannitol obtained from Beijing Fengli
ed

Jingqiu Commerce co., Ltd. (Beijing, China) was used as excipient and flavoring agent.

Crospolyvinylpyrrolidone (PVPP, Kollidon CL) was purchased from BASF AG

pt

(Ludwigshafen, Germany). Low-substituted hydroxypropyl cellulose (L-HPC) was

ce

provided by Sunshere Pharmaceutical Excipient co., Ltd. (Anhui, China).

Ac

Carboxymethyl starch sodium (CMS-Na) was a gift from Huzhou Zhanwang Pharmacy

co., Ltd. (Zhejiang, China). Croscarmellose sodium (CCMC-Na) was obtained from Eli

Lilly and Company (Shanghai, China). PVPP, L-HPC, CMS-Na and CCMC-Na were all

used as superdisintegrants. Magnesium stearate (MgSt) was purchased from Tianjin

Chemical reagent co., Ltd. (Tianjin, China) and used as lubricant and glidant.
Rhodamine B was supplied by Tianjin Bodi chemical co., Ltd. (Tianjin, China).

Loratadine provided by Nanjing Zhuo Pu Biotechnology co., Ltd. (Nanjing, China) was

selected as model drug. In the capillary rise test, 97% pure n-hexane was used as the

completely wetting liquid. Redistilled water was produced by our laboratory.

Preparation of tablets

All the pharmaceutical powders were sieved with 100-mesh screen. The formulation

composition of powder or tablet batches investigated in the present study were

t
ip
tabulated in Table 1. Loratadine or excipients were accurately weighed and manually

cr
mixed in a resealed bag for 10 min. 0.200 ± 0.005 g tablet with (From T1 to T4) or

us
without (From C9 to C12) loratadine was prepared respectively using a single-punch

tablet press (Type: TDP-5, Deke Machine co., Ltd. (Zhejiang, China)) with 7-mm die.
an
After compression, all tablets were stored in a desiccator with silica gel prior to use.
M

Mechanical properties of tablets

ed

The thickness of each tablet (n = 6) was measured using a vernier caliper (602,

Haliang co., Ltd. (Heilongjiang, China)). The measurement about tablet hardness was
pt

performed with a YD-1 tablet hardness tester (Tianjin, China). Their tensile strength
ce

Ts was calculated by the Eq. (1):

Ac

𝑇s = 2𝐹/(106 𝜋𝐷𝐿) (1)

where F is the tablet hardness (N), D is the tablet diameter (m) and L stands for the

tablet thickness (m).

The friability of tablets was estimated using a FT-2000AE friability tester (Tianjin,

China) according to the USP. The weight of forty undusted tablets was greater than
6.5 g. After 100 revolutions in 4 min, tablets were blew gently with an ear washing

bulb to remove excess powder and weighted again. The calculated percentage loss of

their initial mass should be less than 1%.

Characteristics of powders

Evaluation of water penetration and swelling of powders by WCR

Washburn capillary rise (WCR) is the phenomenon that the referred liquid is

permeated into the pores of a packed powder bed proactively owing to the

t
ip
capillarity28. The squared height of the liquid that penetrates the powder bed is

cr
proportional to the wetting time, which satisfy the Washburn Equation 29. The

(Δ𝑚)2 = 𝐶𝑟𝜎𝑐𝑜𝑠𝜃⁄2𝜂 × 𝑡
us
equation is derived properly and modified to be expressed as the Eq. (2):

(2)
an
where Δm is the mass of liquid penetrating the bed in time t, r the effective capillary
M

radius, σ the surface tension of liquid, and η the liquid viscosity. θ is the relative
ed

contact angle and C the capillary factor that can be measured with a completely

wetting liquid for the powder. Due to the fact that several excipients exhibited weak
pt

wicking when they contacted with water, MCC was used as a substrate to investigate
ce

the water penetration and swelling of various disintegrants indirectly.

Ac

The capillary rise apparatus was modified on the basis of the method reported 30.

In order to retain the powder mixtures (2.0 g) that were packed into the calibrated

cylindrical glass tubes whose internal diameter is 8 mm, 3 mm absorbent cotton and

thin gauze were placed at the bottom of glass tubes. We tapped the tubes lightly

with a glass rod until the height of powders tended to be constant. Then the tube
was vertically hung in an analytical balance (JA2003A, Shanghai, China) and the scale

was tared. Finally, the platform under the tube rose slowly and the mass values were

collected every ten seconds when the redistilled water began to penetrate into the

powder bed. The relative contact angle or slope of the curve derived from these data

was applied to assess the water penetration ability of powder mixtures. The swelling

capacity was evaluated according to the Eq. (3):

𝑆 = (𝑉t − 𝑉0 )⁄𝑉0 (3)

t
ip
where S is the coefficient of swelling, V0 the volume before the wetting of powders

cr
and Vt the volume after the completely wetting of powders.

Optical microscopy
us
The surface morphology of dried and wet disintegrant powders was viewed under an
an
optical microscope (LW100P, Shanghai, China) at 100 × magnification.
M

Scanning electron microscopy (SEM)

ed

Dried disintegrant powders that placed on double-sided tapes were sprayed with

gold and then the surface morphologies of resulting samples were detected by
pt

scanning electron microscope (SEM, S-3440N, Japan).

ce

Evaluation of wettability and swelling of blank tablets by SDT

Ac

The same quality of powders was accurately weighed and compressed compacts or

discs. The change in contact angles of all compacts and water was monitored using a

drop angle apparatus (Model: JCY series, Shanghai, China) by the sessile drop

technique (SDT), which could estimate the dynamic wetting behavior of water on

compacts and further get insight into the water permeation into tablets. The specific
operations could be found in our previous research31. Besides, the swelling shape of

compacts was similar to a part of sphere that namely spherical segment, therefore

the swelling volume (SV) of compacts was calculated by the formula of spheroidal

volume. All measurements were performed on more than three different compacts.

Evaluation of water absorption and swelling of blank tablets by modified WAS test

A modified water absorption and swelling (WAS) test was carried out to observe the

water absorption and swelling of tablets simultaneously, which contributed to

t
ip
explore the tablet disintegration mechanism. Rhodamine B (0.2 g) was dissolved in

cr
500 ml redistilled water, which was employed to wet blank tablet allowing for the

us
convenience of visual observation. The water-filled graduated pipette and a swinnex

filter holder PP were linked up through two rubber pipes and a glass three-way valve
an
(Figure 1). When there was insufficient water in the pipette, a water-filled syringe
M

would be required to refill it again. The swinnex filter holder PP was closely covered
ed

with filter membrane, which was located in the middle position between the high

brightness LED light source and a CCD digital camera that was connected to a
pt

personal computer. Eventually, the compact prepared was placed on the surface of
ce

the filter membrane. At this moment, the amount of water uptake into compact was
Ac

observed and recorded at 5-second interval. Besides, the swelling of compact was

captured by CCD camera.

All the captured images were transformed into 3-bit images with Adobe

illustrator CS 6. The lateral and vertical swelling variations were determined by

accurately measuring the length and height of every binary image with Ai ruler after
the outline of compact was described clearly.

Tablets disintegration in vitro

The experiment was performed with disintegration tester ZB-1E (Tianda Tianfa

technology co., Ltd. (Tianjin, China)) according to the method described in USP.

Redistilled water in a volume of approximately 900 ml was used as a disintegration

medium, and the temperature was maintained at 37 ± 0.5℃. Each tablet (n = 6) was

placed into the tubes of disintegration apparatus. At this moment, the disintegration

t
ip
started and time was noted with stopwatch.

cr
us
an
M
ed
pt
ce
Ac
Results and discussion

Mechanical properties of tablets

The diameter and thickness of all tablets were uniform (Tablet 2). Compared to those

tablets without loratadine, tablets with loratadine showed the smaller hardness

values, which could be attributed to the drug property. Friability data met the

requirement of the USP and the tensile strength of C10 was smallest among blank

tablets.

t
ip
Water penetration and swelling of powders

cr
Generally, after the bottom of glass tube contacted with liquid, there were a series of

us
stages. At first the liquid penetrated up quickly through the thin gauze and then

advanced continually through the absorbent cotton, the packed powder beds next
an
and finally the air32. On one hand, the size of gauzes and the packing density of
M

cottons were controlled identically. On the other hand, water penetration and
ed

swelling of excipient powders only associated with the third stage, hence the first

two stages would be neglected in these experiments. Taking C1 as an example, the

pt

squared mass of redistilled water or n-hexane in the third stage was plotted as a
ce

function of the penetrating time, which was shown in Figure 2. The remaining data
Ac

was provided by supplemental document (S1). Either the slope of each black line or

relative contact angle of powders could be employed to estimate the water

penetrating rate of all samples because there was a similar capillary coefficient on

the strength of the similar penetrating rate profiles of n-hexane through all the

packed excipient powder beds (S1) except for C11. As the major part of powder beds,
MCC with substantial -OH groups is a kind of porous granule and possess good

capillary ability24, which results in the good wicking of all samples.

Table 3 showed that, from C1 to C8, the relative contact angle values of C3

(69.1°) and C6 (63.8°) were lower than C1 (74.2°), which demonstrated that both

PVPP and mannitol improved water penetration through MCC powders because of

the porous structure of PVPP and the hydrophilicity of mannitol33. On the contrary,

the strong hydrophobicity of MgSt inhibited the action above. In the case of pure

t
ip
L-HPC, CMS-Na and CCMC-Na powder beds, an obvious gel-like layer was observed at

cr
the lower position of the packed tubes (not shown) and water was hindered due to

us
the high viscosity surface of these powder beds. Therefore, for C2, C4 and C5, the

formation of highly viscous gel would plug the porous channels and further impede
an
water penetration as expected. Interestingly, the relative contact angle of C8 (74.8°)
M

was pretty close to that of C1. One hypothesis was that the water penetration
ed

enhancement effect produced by mannitol (10%, w/w) might just neutralize the

opposite effect of MgSt (1%, w/w), which could also be verified from the other
pt

relative contact angle comparison between C3 and C10, C4 and C11, or C5 and C12.
ce

Distinct decrease of contact angle value of C9 (54.3°) should be noticed compared to

Ac

C2 (74.8°), suggesting that the water penetration speed into the powder beds of

L-HPC and MCC increased with the addition of mannitol.

The swelling capacity of C11 was the biggest in comparison with others. As seen

in Figure 3, CCMC-Na and L-HPC exhibited obvious fiber-like structures, CMS-Na

spherical structure, and PVPP irregular structure. Apparently, all particle volumes
increased in the presence of water, among which CMS-Na and CCMC-Na particles

displayed excellent swelling property34 owing to the existence of hydrogen bonding.

Nevertheless, excessive hydrogen bonding between particles may slightly reduce the

swelling ability of powders, such as L-HPC35. The results in Table 3 also gave a clear

indication that the addition of mannitol and MgSt together rarely affected the

swelling capacity of powders, which was similar to the conclusion summarized in the

water penetration of powders. But no direct correlation between water penetration

t
ip
and swelling capacity of powders was found. What’s more, it further revealed that

cr
intrinsic particle swelling was likely to be the major disintegration mechanism of

us
tablets containing CMS-Na or CCMC-Na, but not for PVPP, which was consistent with

the studies36.
an
Wettability and swelling of blank tablets by SDT
M

All compacts would swell after a certain time when the droplet was attached to their
ed

surface. As a result, the measured time was unified in 10 seconds and the images

were captured per 0.5 second in the test. The trendency of values in Figure 4 (A) and
pt

(B) presented the dynamic wetting behavior of water on compacts. The cos θ values
ce

increased prominently at initial stage and subsequently maintained a steady increase

Ac

that caused by the stable spreading of droplet on the surface. The absolute contact

angle after 5 seconds could not be measured with the rapid swelling of water on C3

compacts, illustrating the higher wetting rate of C3. Although the cos θ values of C5

were smaller than C4 at each time point, the wetting of the former was slightly faster

than that of the latter. From C9 to C12, the wetting rate order was C10, C12, C11 and
C9 according to the contrast of linear slopes in Figure 4 (B), which was similar with

the results above regardless of the presence of mannitol and MgSt.

As shown in Table 3, absolute contact angle values of all compacts at 4.5 s were

smaller than 90°, which stated that the wettability of water on these compacts was

good. The better wettability of water on compacts (from C2 to C6) than C1 could be

inferred from the decrease of absolute contact angles, while the wettability of C7

was reduced due to the addition of MgSt. It should be noted that the contact angle

t
ip
of C8 (52.8°) was distinctly higher than C1 (37.4°), which was inconsistent with the

cr
results obtained from the water penetration of powders. These findings revealed

us
that the compaction of powders changed their physical property in a way,

particularly wettability. Furthermore, there was no relationship between absolute

an
contact angle and the wetting rate (WR).
M

The complete swelling shape of compact surface looks like spheroidal segment
ed

(Figure 4(C)), hence the SV of compacts would be computed in terms of the

corresponding equation. C2 displayed the greatest SV while the smallest swelling

pt

capacity (Table 3), suggesting that PVPP possessed powerful deformation ability or
ce

strain recovery37. Based on the phenomenon it can be concluded that the

Ac

disintegration of tablets containing PVPP might be mainly induced by its strain

recovery. The larger SV and smaller swelling capacity of C5 than C4 obviously

indicated that strain recovery might also be one of the disintegration mechanism of

tablets containing CCMC-Na. Similar to the consequences above-mentioned, MgSt

and mannitol had a little influence on the swelling of compacts when they were
compressed simultaneously. The better wettability did not produce the better

swelling of water on compacts, whereas the higher wetting rate, the faster swelling

on compacts, thus generating the larger SV of compacts in the end.

Water absorption and swelling of blank tablets by modified WAS test

Modified WAS test can investigate the water absorption of tablets, determining the

swelling work of tablets simultaneously. Water absorption profile of C1 was shown in

Figure 5 and the others were supplied by supplemental document (S2). Basically,

t
ip
water absorption increased rapidly at first and then gently until the equilibrium. In

cr
order to get a deep insight into the water absorption process, both the exponent n

us
that explains the mechanism of water absorption and the constant A of the system

were calculated in the light of the empirical equation38 and listed in Table 3. The
an
values of n were around 1.0 apart from C6 and C8, which elucidated that the
M

mechanism of water absorption into tablets was case-Ⅱ transport. Water wetted
ed

the tablet surface initially and diffused into the tablet pores or the network of the

polymer. The polymer chain was relaxed gradually with the water penetration into
pt

the interior of polymer. Moreover, the process was accompanied by the dissolution
ce

of mannitol.
Ac

It can be seen that the hardness of C7 (207.8 N) decreased prominently

compared to C1 (323.4 N) due to the lower interparticle binding force of the former.

Therefore, although MgSt reduced the powder wicking and wettability of compacts,

it might facilitate water absorption into compacts. The mildly smaller water

absorption rate (WAR) of C6 compared with C1 might be ascribed to the higher

particles cohesion between mannitol and MCC, while the former showed the larger

maximal water absorption volume because of the high solubility of mannitol. The

tinily greater maximal water absorption volume of C8 than C1 as expected confirmed

that the effect of mannitol and MgSt on water absorption was almost negligible,

which suggested that disintegrant had a critical role in water uptake of tablet. The

fact that C3 exhibited the quickest water absorption could be accepted according to

the wettability determined by SDT. The maximal water absorption volume of C4 was

t
ip
the same with that of C5 even though the WCR of the former was larger than that of

cr
the latter. Similar results would be found from C9 to C12 as predicted.

us
Take C1 for example, several images that captured by CCD camera and

processed by Adobe illustrator CS 6 were exhibited in Figure 6 (A). Both tablet

an
thickness and diameter swelled in different extent. It was clear that with the
M

absorption of water, tablet swelled not only from the bottom to top (0 ~ 30 s) but
ed

also from the outside to inside (30 ~ 40 s) until its swelling was completed (40 ~ 50 s).

The calculated values were termed as apparent thickness, diameter or swelling

pt

volume respectively.
ce

The two similar profiles in Figure 6 (B) proved that the total swelling volume of
Ac

tablet largely depended on the variation of tablet thickness. In the presence of

mannitol or MgSt (C6 ~ C8), tablets showed the slowest swelling, while no

measurable difference in the maximal swelling volume was obtained, which indicated

that they had no impact on the ultimate swelling volume of tablets, corresponding to

the conclusion summarized in the water absorption. What calls for special attention
is that the apparent diameter of C4 increased extremely (supplemental document S3)

in spite of its relatively larger apparent thickness among them. It confirmed again

that CMS-Na showed the unexceptionable swelling that has been observed in the

powder swelling. The slow but persistent swelling in the longitudinal direction made

sure that the maximal swelling volume of C5 exceeded 0.26 ml that was around three

times that of C1. Thus it was not a surprise that the maximal swelling volume of C9

was lower than that of C11 or C12. All the SR of tablets was bigger than the WAR of

t
ip
tablets in 60 s. However, swelling did not happen unless tablet contacted with water.

cr
For tablets containing disintegrant, the faster water absorption, the faster swelling,

as previously assayed by SDT.

us
an
M
ed
pt
ce
Ac
Tablets disintegration

The disintegration time of tablets without API was greater than that of tablets with

API (Figure 7 (A)) correspondingly, which might be ascribed to the different tablet

hardness in the presence of API. Directly proportional relation between them

illustrated that the tablet disintegration was free from API. As shown in Figure 7 (B),

(C) and (D), whether SDT or WAS method was employed, disintegration time of blank

tablets was closely associated with the parameters including initial WAR, initial SR,

t
ip
WR and SV, which was consistent with the research39. The disintegration of tablets

cr
that is a compressed product including multifunctional excipients and API mainly

us
refers to the mechanical tablet breakdown into particles, which derived from the

destruction of interparticle bonds, such as mechanical interlocking, solid bridges and

an
intermolecular bonds40. The tardy water penetration into tablets by wicking as a
M

result of the porosity of MCC (not shown) caused the slightly delayed spreading or
ed

wettability of water on compacts when compacts contacted with water. Hence

absolute contact angle values at a particular time had an inappreciable role in the
pt

tablet disintegration for similar formulation (Table 3). However, during the wetting
ce

process, the presence of water weakened the particles intermolecular bonds, which
Ac

further heightened the swelling of tablets that generated the enlargement of tablet

porosity and promoted the beginning of tablet disintegration. Meanwhile, the

mechanical interlocking of PVPP chains might be destroyed41, taking the lowest

swelling capacity and the highest SV of C10 into account. The larger WR of tablets,

the larger SV, thus resulting in the shorter disintegration time of tablets. When
conducting a contrastive analysis of Figure 7 (C) and (D), we could find that tablet

disintegration could also be predicted by comparing the WR or SV of disintegrant

with SDT. It can be concluded that the primary wettability of water on tablets greatly

affected the tablet disintegration. Unfortunately, these results on the basis of a tiny

water droplet by SDT simply provided the information about rudimentary stage of

tablet disintegration.

The thorough wetting or swelling of compacts with more water was monitored

t
ip
by modified WAS test. From C9 to C12, swelling that arose from the loose water-filled

cr
interparticle bonds in the initial stage of tablet disintegration, in turn, accelerated the

us
following water uptake into tablets. But the higher viscous forces caused by the

dissolution of polymer would fight the water movement, which increased the solid
an
bridges that retarded the disintegration, such as C12. The deformation existed in
M

each tablet according to the phenomenon that the SV in compressed direction was
ed

higher than that in uncompressed direction. In addition, the dissolution of mannitol

increased the tablet porosity dramatically, leading to the improvement of

pt

disintegration performance7 as well. Even though tablet disintegration was

ce

influenced by various factors, the relations shown in Figure 7 (A) and (B) suggested
Ac

that tablet disintegration was mainly related to the excipient physicochemical

property, especially water uptake. Furthermore, there was no direct association

between tablet disintegration and the water penetration or swelling of powders

determined by WCR.

Conclusion
This research showed that parameters about wettability, water absorption or

swelling of excipients in forms of powders or dosage were successfully evaluated

through various methods including Washburn capillary rise, sessile drop technique

and modified water absorption and swelling test. Besides, these properties mainly

relied on the structure of excipients. MgSt improved the water penetration into

tablet, while impeded tablet swelling that could lengthen the tablet disintegration

time. Mannitol inhibited not only the water uptake but also the swelling of tablets.

t
ip
Moreover, the disintegration of tablets with or without loratadine was closely related

cr
to these parameters, especially wetting rate and initial water absorption rate. On one

us
hand, the swelling rate of tablet with a tiny water droplet increased with the increase

of wetting rate of water on tablet, thus accelerating the tablet disintegration. On the
an
other hand, the faster initial swelling of tablets, caused by the faster initial water
M

absorption, lead to the shorter disintegration time of tablets.

ed

Acknowledgements

This work was financially supported by National Natural Science Foundation of China
pt

(No.81473161 and No.81273445).

ce

Declaration of interest
Ac

The authors report no declarations of interests.

References
1. Desai PM, Liew CV and Heng PW. Review of Disintegrants and the Disintegration Phenomena.
Journal of pharmaceutical sciences. 2016; 105: 2545-55.
2. Slavkova M and Breitkreutz J. Orodispersible drug formulations for children and elderly. European
Journal Of Pharmaceutical Sciences. 2015; 75: 2-9.
3. AM G-H. Tablet disintegration and disintegrating agents. Stp Pharma Sciences. 1992: 445-62.
4. Chamsai B and Sriamornsak P. Novel disintegrating microcrystalline cellulose pellets with
improved drug dissolution performance. Powder Technology. 2013; 233: 278-85.
5. Sieber D, Lazzari A, Quodbach J and Pein M. Applicability of two automated disintegration
apparatuses for rapidly disintegrating (mini)tablets. Pharmaceutical Development And Technology.
2017; 22: 198-205.
6. Yoshida M, Hazekawa M, Haraguchi T and Uchida T. Evaluation of the palatabilities in 10 different

t
famotidine orally disintegrating tablets by combination of disintegration device and taste sensor. Drug

ip
development and industrial pharmacy. 2015; 41: 1387-92.
7. Quodbach J and Kleinebudde P. A critical review on tablet disintegration. Pharm Dev Technol.

cr
2016; 21: 763-74.
8. Markl D and Zeitler J A. A Review of Disintegration Mechanisms and Measurement Techniques.

us
Pharmaceutical Research. 2017; 34: 890-917.
9. Quodbach J and Kleinebudde P. Systematic classification of tablet disintegrants by water uptake
and force development kinetics. The Journal of pharmacy and pharmacology. 2014; 66: 1429-38.
an
10. Yamamoto Y, Fujii M, Watanabe K, et al. Effect of powder characteristics on oral tablet
disintegration. International Journal Of Pharmaceutics. 2009; 365: 116-20.
11. Yoshinori Onuki AK, Masashi Hamaguchi, Yuki Marumo, Shungo and Kumada DH, Junko Ikeda,
M

Yoshihiro Hayashi. A comparative study of disintegration actions of various disintegrants using

Kohonen's self-organizing maps. Journal of Drug Delivery Science and Technology. 2017.
12. Chaheen M, Soulairol I, Bataille B, Yassine A, Belamie E and Sharkawi T. Chitin's Functionality as a
ed

Novel Disintegrant: Benchmarking Against Commonly Used Disintegrants in Different Physicochemical

Environments. Journal of pharmaceutical sciences. 2017; 106: 1839-48.
13. Wang C, Huang H, Jia M, Jin S, Zhao W and Cha R. Formulation and evaluation of nanocrystalline
pt

cellulose as a potential disintegrant. Carbohydrate polymers. 2015; 130: 275-9.

14. Kamiya T, Kondo H, Hiroma H, et al. Impact of process parameters on Mg–St content and tablet
ce

surface wettability in the external lubrication method for a rotary tablet press. Advanced Powder
Technology. 2016; 27: 193-8.
Ac

15. Alghunaim A, Kirdponpattara S and Newby B-mZ. Techniques for determining contact angle and
wettability of powders. Powder Technology. 2016; 287: 201-15.
16. Kirdponpattara S, Phisalaphong M and Newby BM. Applicability of Washburn capillary rise for
determining contact angles of powders/porous materials. Journal of colloid and interface science.
2013; 397: 169-76.
17. Hammes MV, Englert AH, Noreña CPZ and Cardozo NSM. Effect of water activity and gaseous
phase relative humidity on microcrystalline cellulose water contact angle measured by the Washburn
technique. Colloids and Surfaces A: Physicochemical and Engineering Aspects. 2016; 500: 118-26.
18. Bormashenko E. Contact angles of rotating sessile droplets. Colloids and Surfaces A:
Physicochemical and Engineering Aspects. 2013; 432: 38-41.
19. Hooper P, Lasher J, Alexander KS and Baki G. A new modified wetting test and an alternative
disintegration test for orally disintegrating tablets. Journal of pharmaceutical and biomedical analysis.
2016; 120: 391-6.
20. Harada T, Narazaki R, Nagira S, Ohwaki T, Aoki S and Iwamoto K. Evaluation of the disintegration
properties of commercial famotidine 20 mg orally disintegrating tablets using a simple new test and
human sensory test. Chemical & Pharmaceutical Bulletin. 2006; 54: 1072-5.
21. Iwao Y, Tanaka S, Uchimoto T, Noguchi S and Itai S. An easy-to-use approach for determining the
disintegration ability of disintegrants by analysis of available surface area. Int J Pharm. 2013; 448: 1-8.
22. Bele MH and Derle DV. Mechanism of disintegrant action of polacrilin potassium: Swelling or
wicking? Acta Pharmaceutica Sinica B. 2012; 2: 70-6.
23. KEN WELCH MS. Simultaneous Measurement of Drug Release and Liquid Uptake in
Pharmaceutical Tablets. Journal of pharmaceutical sciences. 2003; 92: 1242-9.
24. Thoorens G, Krier F, Leclercq B, Carlin B and Evrard B. Microcrystalline cellulose, a direct

t
compression binder in a quality by design environment—A review. International Journal of

ip
Pharmaceutics. 2014; 473: 64-72.
25. Gamble JF, Chiu W-S and Tobyn M. Investigation into the impact of sub-populations of

cr
agglomerates on the particle size distribution and flow properties of conventional microcrystalline
cellulose grades. Pharmaceutical Development and Technology. 2010; 16: 542-8.

us
26. Elkomy MH, El Menshawe SF, Abou-Taleb HA and Elkarmalawy MH. Loratadine bioavailability via
buccal transferosomal gel: formulation, statistical optimization, in vitro/in vivo characterization, and
pharmacokinetics in human volunteers. Drug Delivery. 2017; 24: 781-91.
an
27. Rodriguez Amado JR, Prada AL, Duarte JL, et al. Development, stability and in vitro delivery
profile of new loratadine-loaded nanoparticles. Saudi Pharmaceutical Journal. 2017.
28. Heshmati M and Piri M. Experimental investigation of dynamic contact angle and capillary rise in
M

tubes with circular and noncircular cross sections. Langmuir : the ACS journal of surfaces and colloids.
2014; 30: 14151-62.
29. Ji L and Shi B. A novel method for determining surface free energy of powders using Washburn's
ed

equation without calculating capillary factor and contact angle. Powder Technology. 2015; 271: 88-92.
30. Holysz ECaL. Use of the Washburn Equation for Surface Free Energy Determination. Langmuir :
the ACS journal of surfaces and colloids. 1992; 8: 710-6.
pt

31. Yang B, Xu L, Wang Q and Li S. Modulation of the wettability of excipients by surfactant and its
impacts on the disintegration and release of tablets. Drug development and industrial pharmacy. 2016;
ce

42: 1945-55.
32. Alghunaim A and Zhang Newby B-m. Influence of tube wettability on water contact angle of
Ac

powders determined by capillary rise. Colloids and Surfaces A: Physicochemical and Engineering
Aspects. 2016; 492: 79-87.
33. Dai Y, Meng Q, Mu W and Zhang T. Recent advances in the applications and biotechnological
production of mannitol. Journal of Functional Foods. 2017; 36: 404-9.
34. Chen XY, Chen C, Zhang ZJ and Xie DH. Synthesis and capacitive performance of nitrogen doped
porous carbons derived from sodium carboxymethyl starch. Powder Technology. 2013; 246: 201-9.
35. Kawashima Y, Takeuchi H and Hino T. Low-substitued Hydroxypropylcelluose as a Sustained-Drug
Release Matrix Base or Disintegrant Depending on Its Particle Size and Loading in Formulaiton.
Pharmaceutical Research. 1993; 10: 351-5.
36. Pabari R and Ramtoola Z. Effect of a disintegration mechanism on wetting, water absorption, and
disintegration time of orodispersible tablets. Journal of young pharmacists : JYP. 2012; 4: 157-63.
37. Quodbach J and Kleinebudde P. Performance of tablet disintegrants: impact of storage conditions
and relative tablet density. Pharmaceutical Development and Technology. 2014; 20: 762-8.
38. Kim B, La Flamme K and Peppas NA. Dynamic swelling behavior of pH-sensitive anionic hydrogels
used for protein delivery. Journal of Applied Polymer Science. 2003; 89: 1606-13.
39. Harada T, Narazaki R, Nagira S, Ohwaki T, Aoki S and Iwamoto K. Evaluation of Disintegration
Properties of Orally Rapidly Disintegrating Tablets Using a Novel Disintegration Tester. Chemical &
Pharmaceutical Bulletin. 2006; 60: 1240-8.
40. Nyström C AG, Duberg M, Karehill PG. Bonding surface area and bonding mechanism - two
important factors for the understanding of powder compactability. Drug Development and Industrial
Pharmacy. 1993; 19: 2143-96.
41. Quodbach J, Moussavi A, Tammer R, Frahm J and Kleinebudde P. Tablet Disintegration Studied by
High-Resolution Real-Time Magnetic Resonance Imaging. Journal of pharmaceutical sciences. 2014;

t
103: 249-55.

ip
cr
us
an
M
ed
pt
ce
Ac
Figure captions

Figure 1. Schematic of modified WAS test. 1- Personal computer; 2-The captured images by CCD

camera; 3- graduated pipette; 4- CCD digital camera; 5- Three-way valve; 6- syringe; 7- Swinnex

filter holder PP; 8- Filter membrane; 9- Compact; 10- LED light source.

Figure 2. Squared mass of water (black dots) or n-hexane (red dots) penetration by using WCR

versus time for C1.

Figure 3. The optical micrographs of dried (From A1 to D1) and corresponding wet (From A2 to D2)

t
ip
disintegrant powders at 100 × magnification and SEM micrographs of disintegrants in the present

cr
study (From A3 and D3).

us
Figure 4. The variation about cosine values of contact angle of compacts as time elapsed (A and B)

and the completely swelling image (C9) captured by CCD camera (C).
an
Figure 5. Water absorption profile of C1.
M

Figure 6. The swelling process of C1 compact determined by modified WAS test (A) and the
ed

apparent thickness, diameter or swelling volume of C1 versus time (B).

Figure 7. (A): The disintegration time of tablets with or without API and their relevance. (B):
pt

Relationship between the reciprocal of initial WAR or SR and the disintegration time of blank
ce

tablets. (C) and (D): Relationship between the reciprocal of WR of water on compacts (black lines)
Ac

or SV of compacts with 2.0 μl water (red lines) and the disintegration time of blank tablets.
Figure 1. Schematic of modified WAS test. 1- Personal computer; 2-The captured images by CCD

camera; 3- graduated pipette; 4- CCD digital camera; 5- Three-way valve; 6- syringe; 7- Swinnex

filter holder PP; 8- Filter membrane; 9- Compact; 10- LED light source.

t
ip
cr
us
an
Figure 2. Squared mass of water (black dots) or n-hexane (red dots) penetration by using WCR
M

versus time for C1.

ed
pt
ce
Ac
Figure 3. The optical micrographs of dried (From A1 to D1) and corresponding wet (From A2 to D2)

disintegrant powders at 100 × magnification and SEM micrographs of disintegrants in the present

study (From A3 and D3).

t
ip
cr
us
an
M

Figure 4. The variation about cosine values of contact angle of compacts as time elapsed (A and B)
ed

and the completely swelling image (C9) captured by CCD camera (C).
pt
ce
Ac
Figure 5. Water absorption profile of C1.

t
ip
cr
Figure 6. The swelling process of C1 compact determined by modified WAS test (A) and the

us
apparent thickness, diameter or swelling volume of C1 versus time (B).
an
(A)
M
ed
pt
ce

(B)
Ac
Figure 7. (A): The disintegration time of tablets with or without API and their relevance. (B):

Relationship between the reciprocal of initial WAR or SR and the disintegration time of blank

tablets. (C) and (D): Relationship between the reciprocal of WR of water on compacts (black lines)

or SV of compacts with 2.0 μl water (red lines) and the disintegration time of blank tablets.

t
ip
cr
us
an
M
ed
pt
ce
Ac
 Table 1. Formulation composition of powder or tablet batches investigated in the present work.

Ingredients
C1 C2 C3 C4 C5 C6 C7 C8 C9 C10 C11 C12 T1 T2 T3 T4
(%, w/w)
MCC 100 94.4 94.4 94.4 94.4 89.4 98.8 88.4 84 84 84 84 79.8 79.8 79.8 79.8
L-HPC - 5.6 - - - - - - 5 - - - 4.75 - - -
PVPP - - 5.6 - - - - - - 5 - - - 4.75 - -
CMS-Na - - - 5.6 - - - - - - 5 - - - 4.75 -
CCMC-Na - - - - 5.6 - - - - - - 5 - - - 4.75
Mannitol - - - - - 10.6 - 10.5 10 10 10 10 9.5 9.5 9.5 9.5
MgSt - - - - - - 1.2 1.1 1 1 1 1 0.95 0.95 0.95 0.95
Loratadine - - - - - - - - - - - - 5 5 5 5

t
ip
Table 2. Mechanical properties of tablets with or without loratadine.

cr
Labels Diameter/mm Thickness/mm Weight/g Hardness/N Friability/% Ts/MPa

C9

C10
7.07 ± 0.01

7.06 ± 0.01
4.10 ± 0.02

4.21 ± 0.03
0.200 ± 0.05

0.200 ± 0.05 us
233.2 ± 2.9

202.9 ± 4.9
0.00

0.30
5.12

4.35
an
C11 7.06 ± 0.01 4.11 ± 0.01 0.200 ± 0.05 235.2 ± 5.9 0.15 5.16

C12 7.06 ± 0.01 4.12 ± 0.02 0.200 ± 0.05 284.2 ± 5.9 0.30 6.22
M

T1 7.06 ± 0.02 4.04 ± 0.01 0.200 ± 0.05 174.5 ± 3.9 0.20 3.89

T2 7.10 ± 0.01 4.08 ± 0.03 0.200 ± 0.05 163.7 ± 4.9 0.10 3.60
ed

T3 7.06 ± 0.02 4.00 ± 0.02 0.200 ± 0.05 161.7 ± 4.9 0.10 3.65

T4 7.10 ± 0.01 3.94 ± 0.02 0.200 ± 0.05 193.1 ± 5.9 0.30 4.39
pt
ce
Ac
 Table 3. Evaluation parameters about wettability, water absorption or swelling of excipients by
using various methods.

Methods Parameters C1 C2 C3 C4 C5 C6 C7 C8 C9 C10 C11 C12

Relative 74.2 74.8 ± 69.1 ± 84.6 ± 81.1 ± 63.8 77.3 74.8 54.3 ± 69.1 83.0 ± 84.1 ±
Washburn contact angle/° ± 1.9 1.3 1.8 0.9 0.8 ± 3.8 ± 1.3 ± 0.5 5.4 ± 4.8 2.9 4.0
capillary 0.39 0.33 0.29 0.41 0.44 0.33 0.67
Swelling 0.50 0.42 1.42 0.75 1.21
rise ± ± ± ± ± ± ±
capacity ± 0.01 ± 0.04 ± 0.09 ± 0.06 ± 0.10
0.01 0.05 0.06 0.19 0.05 0.04 0.12
Absolute 37.4 19.6 ± 13.8 ± 32.2 ± 36.5 ± 24.6 39.0 52.8 50.7 ± 46.1 51.4 ± 46.5 ±
contact angle/° ± 0.4 0.9 0.6 1.6 2.5 ± 2.3 ± 1.9 ± 1.0 1.8 ± 4.4 1.1 4.8
Wetting rate of
Sessile
water on 5.2 2.87 - 6.62 10.69 2.43 5.87 6.92 7.73 18.28 15.06 12.56
drop
compacts/×10-3

t
technique

ip
32.89 30.49 6.43
Swelling 29.10 104.74 45.94 81.93 24.30 32.09 3.41 4.10 4.75
± ± ±
volume/cm3 ± 0.2 ± 10.9 ± 5.0 ± 7.9 ± 2.8 ± 2.5 ± 1.0 ± 1.0 ± 0.5

cr
0.1 4.7 1.4
Initial water

us
absorption 1 3.6242 14.2 9.4849 6.6182 0.92 2.01 1.38 2.1969 7.95 4.8571 5.2571
rate/×10-4
0.078 0.109 0.153 0.290 0.284 0.101 0.094 0.105 0.125 0.154 0.252 0.248
an
Maximal water
± ± ± ± ± ± ± ± ± ± ± ±
absorption/ml
0.003 0.001 0.010 0.001 0.006 0.009 0.007 0.013 0.025 0.006 0.007 0.022
Modified A/×103 0.27 0.20 0.67 0.86 1.19 1.03 0.31 1.10 0.05 1.09 0.50 1.07
M

WAS test n 1.20 1.36 1.21 1.19 0.97 0.75 1.25 0.71 1.44 0.96 1.16 0.93
Initial apparent
ed

Swelling 2.32 2.51 8.51 6.68 3.68 0.89 1.45 0.54 1.5 4.44 3.12 2.47
rate/×10-3
Maximal 0.10 0.11 0.10 0.11 0.19
0.07 0.19
pt

swelling ± > 0.26 > 0.26 > 0.26 ± ± ± ± > 0.34 > 0.34
± 0.04 ± 0.05
volume/ml 0.02 0.01 0.01 0.03 0.03
ce
Ac