Saudi Pharmaceutical Journal 27 (2019) 756–766

Contents lists available at ScienceDirect

Saudi Pharmaceutical Journal

journal homepage: www.sciencedirect.com

The effect of the source and the concentration of polymers on the release
of chlorhexidine from mucoadhesive buccal tablets
Enas Al-Ani a,b,⇑, Claire Martin c, Stephen T. Britland d, Khalid Doudin e, David J. Hill b,f,⇑
a
School of Pharmacy, Faculty of Science and Engineering, University of Wolverhampton, Wolverhampton, UK
b
Research Institute in Healthcare Science, Faculty of Science and Engineering, University of Wolverhampton, Wolverhampton, UK
c
Department of Biological Sciences, Institute of Science and the Environment, University of Worcester, Worcester, UK
d
School of Health Sciences, York St John University, York, UK
e
Chemical Engineering and Applied Chemistry, Aston University, Birmingham, UK
f
School of School of Biology, Chemistry and Forensic Science, Faculty of Science and Engineering, University of Wolverhampton, Wolverhampton, UK

a r t i c l e i n f o a b s t r a c t

Article history: In the current work, two groups of chlorhexidine mucoadhesive buccal tablets were prepared, using
Received 21 December 2018 either rod or irregularly-shaped spherical particles of hydroxypropyl methylcellulose and different ratios
Accepted 19 April 2019 of poloxamer 407 (P407). The tablets were designed to release the drug over two hours. Their physico-
Available online 20 April 2019
chemical properties and drug release profiles were investigated. The impact on dry granulation, the ex-
vivo mucoadhesion, the swelling index, the morphology of swollen tablets and the drug release kinetic
Keywords: were investigated. Drug-polymers chemical interaction was studied using Fourier Transforms Infrared
Buccal tablet
Spectroscopy (FTIR) and differential scanning calorimetry (DSC). Due to different particle shapes, the
Mucoadhesion
Particle morphology
preparation of dry granules required a 40 KN force for rod-shaped particles compared to 10 KN for the
Poloxamer 407 irregularly-shaped spherical particles. All formulations showed at least two-hours residence time using
Hydroxypropyl methylcellulose ex-vivo mucoadhesion. Statistically, there was no significant difference in the swelling index, drug release
Chlorhexidine nor its kinetic for both groups. However, the microscopical morphology of the swollen tablet and the size
Surfactant polymer of the pores were affected by particle shape. Increasing the ratio of P407 to 62.5% resulted in a pro-
nounced increase in drug release from around 60% to >90% after two hours. Following the FTIR and
DSC analyses, no chemical interaction was noted apart from the steric hindrance effect of P407, which
was observed even with the physical mixtures.
Ó 2019 Production and hosting by Elsevier B.V. on behalf of King Saud University. This is an open access
article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

1. Introduction investigated in buccal drug delivery and is included in marketed

products (Sudhakar et al., 2006). There are several factors which
Hydroxypropyl methylcellulose (HM) has widely been used in affect drug release from HM matrices, for instance, particle size
the preparation of hydrophilic controlled release matrices due to (Wan et al., 2001), force of compression (Velasco et al., 1999),
its water solubility, pH stability and resistance to enzymatic degra- molecular weight (Gao et al., 1996), viscosity (Campos-Aldrete,
dation, ease of manufacturing and low cost. It gels and swells upon 1997), drug polymer ratio (Velasco et al., 1999), and the incorpora-
contact with water forming a gelatinous layer that controls drug tion of other polymers or excipients (Xie et al., 2017). There have
release (Ghori and Conway, 2015; Maderuelo et al., 2011). Due to been only a limited number of investigations which have high-
its mucoadhesive and hydrogel-forming properties, it has been lighted the effect of particle shape on tablet swelling and drug
release. For instance, Gustafsson et al. (1999) assumed that fibrous
or rod-shaped HM particles have a lower hydration rate compared
⇑ Corresponding authors at: Faculty of Science and Engineering, University of
to irregular particles, which results in a lower gelling rate and con-
Wolverhampton, Wulfruna Street, Wolverhampton WV1 1LY, UK.
E-mail addresses: E.Al-Ani2@wlv.ac.uk (E. Al-Ani), D.Hill@wlv.ac.uk (D.J. Hill).
sequently decreases the rate of drug release. Moreover, the mor-
Peer review under responsibility of King Saud University.
phology of the powder affects its flow properties and
compactability. Rod-shaped interlocked upon compaction and pro-
duced higher tensile strength tablets, which consequently resulted
in a decreased drug release rate (Gustafsson et al., 2003). Li et al.
Production and hosting by Elsevier (2005) found that the rod-shaped particles in Methocel powder

https://doi.org/10.1016/j.jsps.2019.04.012
1319-0164/Ó 2019 Production and hosting by Elsevier B.V. on behalf of King Saud University.
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
 E. Al-Ani et al. / Saudi Pharmaceutical Journal 27 (2019) 756–766 757

also interlocked, producing a stronger matrix which affected tablet 2.2. Solubility of CHD
swelling and decreased the rate of drug release.
Poloxamer 407 (P407) or Pluronic F127 is a non-ionic surfactant The solubility of CHD was investigated in ultra-pure water and a
polymer and has a thermo-reversible hydrogel-forming ability phosphate buffer saline (PBS) solution pH 6.8, as a simulated sali-
with a mucoadhesive property. It gels at a concentration of >20% vary pH to select the most appropriate dissolution medium with a
at 25 °C (Ruel-Gariépy and Leroux, 2004). It is a copolymer of poly- sink condition.
ethylene oxide and polypropylene oxide, with the hydrophilic nat- The solubility of CHD was determined by adding excess CHD to
ure of the former and the hydrophobic nature of the latter resulting 3 mL of water or a PBS solution at pH 6.8. The samples were shaken
in an amphiphilic molecule with consequent surfactant properties at 37 ± 0.1 °C for 24 h. The suspensions were filtered through a
(Kabanov et al., 2002). It has a wide application in drug delivery, for 0.45 mm Millipore membrane filter and the concentration of CHD
example, in parenteral, ophthalmic, inhaler, oral solution, suspen- was measured by UV detection at k254 nm (Biochrom WPA Bio-
sion, and topical formulations (Dumortier et al., 2006). In the cur- wave II UV-Spectrophotometry, UK).
rent work, P407 was chosen due to its pronounced gelling
properties and high viscosity of 3100 cP which is attributed to its 2.3. Particle size and morphological analyses
high molecular weight compared to other poloxamers and its
availability as microprills (Matanovi et al., 2014). Although, it is The raw materials were assessed for their size. The volume-
not commonly used in controlling the release of the drug from weighted particle size of Methocel, HPMC, P407 and CHD was
solid dosage forms, in the current work it was formulated in tablet assessed by laser diffraction using a Malvern Mastersizer 3000
dosage form to control the release of chlorhexidine (CHD) together with an Aero S dry dispersion unit system (Malvern Instruments,
with HM by exploiting its thermo-reversible hydrogel-forming Malvern, UK). The cumulative particle sizes at 10, 50 and 90% were
properties which promotes tablet wetting as a result of its surfac- displayed as D0.1, D0.5 and D0.9, respectively.
tant property. The morphology of the granules and the raw materials was
CHD is cationic at physiologic pH, its bactericidal and fungicidal assessed by scanning using electron microscopy (SEM), (Zeiss
activity results from its ability to bind to phosphate-containing EvoÒ 50EP SEM, Germany).
proteins in the bacterial or fungal cell walls and membranes which
leads to structural disruptions and leakage of cytoplasmic compo- 2.4. Preparation of tablets using the dry granulation technique
nents (Lim and Kam, 2008). The main advantage of oral formula-
tions of CHD is their lack of a specific cellular target for The formulations of CHD mucoadhesive tablets were prepared
microbiocidal activity which results in the retardation of the devel- as shown in Table 1. The powders were blended for 5 min in a V-
opment of resistance against CHD (Ankola et al., 2008). CHD shaped powder blender (CapsulCNÒ, China). Then, dry granules
mouthwashes are prescribed as adjuvant for the treatment of were prepared following the slugging method (Tuǧcu-Demiröz
oropharyngeal candidiasis (OPC) (Pereiro Ferreirós et al., 2012). et al., 2004) using a manual hydraulic hand press (diameter = 4 cm,
The greatest disadvantage of current CHD formulations is their weight = 5.5 ± 0.5 g). Slugs prepared using HPMC and Methocel
short retention and activity time in the oral cavity. Consequently, were formed with a compression force of 10 and 40 KN, respec-
there is a real need for a new approach to the localised, prolonged tively. The slugs were crushed into granules and passed through
delivery of antifungal agents for enhanced OPC therapy. The advan- a 1 mm screen (mesh no. 18). Magnesium stearate (0.5%) was
tages of this mode of drug delivery are that it reduces the systemic added and mixed for 3 min prior to the compression of the gran-
side effects of the drug, minimizes the dose of the drug required ules into tablets.
and provides targeted drug delivery (Sankar et al., 2011). The tablets were pressed using a heavy duty mini rotary tablet
In the present study, the impact of HM particle shape and/or the machine (STC ZPS Shanghai, China) with a biconvex 6 mm diame-
ratio of P407 on the properties and the release of CHD from ter round shape punch. The average central thickness was 1.5 mm
mucoadhesive matrices are investigated. To the best of our knowl- and the wall thickness (edge) was 1.0 mm.
edge, there has been no previous investigation into the impact of
the shape of HM particles on tablet behaviour and release profile, 2.5. Flow properties and compressibility index
after being dry granulated. The effects on the physicochemical
properties of CHD matrix tablets for local oral drug delivery of The bulk and the tapped volume of the powder blends and the
HM rod and irregularly-shaped spherical particles were studied. granules were assessed using a tapped Density tester (Varian, UK).
The tablets were designed to control the release for two hours The tapped volumes were obtained by subjecting the powders to
which might not be achieved by HM. Accordingly, P407 was added 200 taps each time until a constant volume was achieved. Carr’s
to increase the hydrophilicity and maintain the hydrogel network Compressibility index (CI) was calculated using the flowing
structure. The effect of P407 on tablet behaviour and the CHD equation
release profile was investigated. 0
Carr s Index ¼ ð1  V t =V 0 Þ
2. Materials and method where V0 is bulk volume and Vt is the tapped volume.

2.1. Materials 2.6. Characterisation of the buccal tablets

MethocelTM F4M premium hydroxypropyl methylcellulose 2.6.1. Friability and tensile strength
(Methocel, viscosity of 2663–4970 cps for 2% solution at 20 °C, A sample of approximately 1 g of each formulation was evalu-
27–30% methoxyl and 4–7.5% hydroxypropyl substitution) was ated for their friability using a friability tester (Charles Ischi AG,
kindly donated by the Dow-Colorcon Company in the U.K. Hydrox- AE-1, UK), and rotated 100 times at 25 rpm. The mechanical
ypropyl methylcellulose (HPMC, Mn
86,000, viscosity of 4000 strength of the biconvex tablet was calculated using the following
cps for 2% solution at 20 °C, 29% methoxyl and 7% hydroxypropyl equation (Pitt et al., 1988).
substitution), poloxamer 407 (P407) and chlorhexidine diacetate
salt hydrate (CHD) were purchased from Sigma Aldrich in the UK rx ¼ 10F=pD2 ½2:84H=D  0:126H=W þ 3:15W=D þ 0:011
and Magnesium stearate from Alfa Aesar, also in the UK.
758 E. Al-Ani et al. / Saudi Pharmaceutical Journal 27 (2019) 756–766

Table 1
Formulations of CHD mucoadhesive buccal tablets.

Formulations Weight (mg)/tablet

CHD HPMC Methocel P407 Tablet weight
F1 5 25.0 – – 30
F2 20.5 – 4.5
F3 17.5 – 7.5
F4 11.5 – 13.5
F5 6.25 – 18.75
F6 – 25.0 –
F7 – 20.5 4.5
F8 – 17.5 7.5
F9 – 11.5 13.5
F10 – 6.25 18.75

where rx is the tensile strength, F is tablet hardness (Newtons), D is 2.6.4. Tablet morphology (SEM)
tablet diameter, H is tablet thickness, and W is central cylinder The morphology of aqueous media swollen tablets was investi-
thickness (tablet wall height), with all tablet dimensions in mm. gated. They were prepared by adding 0.5 mL distilled water to each
Tablet hardness was measured using a Varian VK 200, (UK) tablet in a 5 mL test tube and left until swollen. They were then
hardness tester (n = 10). freeze-dried using a Beta 1–8 LSC Freeze Dryer (Christ, UK). The
tablets were cut in half and analysed using SEM as previously
2.6.2. Ex-vivo mucoadhesion analysis described. The surface area of the pores was measured using Ima-
The mucoadhesion was determined as a function of dosage geJ 1.51n software.
form residence time using a modified protocol adopted from
Nafee et al. (2003). Freshly harvested chicken crops were carefully 2.6.4.1. Comparison of dissolution rate. Similarity and difference fac-
washed to remove any residue of food the chicken had consumed, tors were applied to compare the dissolution profiles of both
and they were subsequently stored at 80 °C. The crops were groups of formulations. The similarity factor (f2) was calculated
defrosted before use, cut into small pieces (1 cm  2 cm) and fixed using the equation below. The results fell between 0 and 100%,
to a glass slide using cyanoacrylate glue. The crop was hydrated and an f2 of 50 suggests a similarity between the standard and
using one drop of ultrapure water before a CHD tablet was placed the test (Costa and Lobo, 2001).
on top and weighed down with a 4 g weight for 20 s to aid the h Xn i0:5 
adhesion process. The glass slide was then placed into the disinte- f 2 ¼ 50  log 1 þ ð1=nÞ t¼1
ðRt  T t Þ2  100
gration apparatus tubes (cylinders) (Varian VK 100, UK), prefilled
with 37 ± 0.2 °C of ultrapure water (Fig. 1). A test, similar to the where n is the number of time points, Rt is the percent release of the
disintegration test, was performed at 50 rpm for 120 min with standard and Tt is the percent release of the test.
periodic sample examination for every 15 min to evaluate if the The difference factor (f1) was calculated using the equation
tablets had become detached from the chicken crops. The formula- below. Values of between 0 and 15 indicate that the difference
tion of each tablet was performed in triplicate. between the samples is acceptable. When f1 = 0, the two samples
are considered identical (Costa and Lobo, 2001).
2.6.3. Swelling index nhXn i hXn io
The swelling index was determined by weighing an individual f1 ¼ t¼1
jRt  T t = t¼1
ðRt þ T t Þ=2  100
CHD tablet (W0) and sticking it to a previously weighed glass cov-
erslip using a single water droplet and allowing it to equilibrate for
30 s. The coverslip was then placed vertically in a beaker in a 2.6.5. In-vitro dissolution of CHD (Apparatus I)
37 ± 0.2 °C water bath (Clifton, Nickel-Electro Ltd, UK). The weight The dissolution was performed using Varian 705 DS BP Dissolu-
of the swollen tablet (Ws) was recorded at 30, 60, 90 and 120 min. tion Apparatus type I (basket method) (Varian, UK). One tablet of
The swelling index (SI) was calculated using the following equation each formulation was placed in 500 mL of ultrapure distilled water
(Kassem et al., 2014). at 37 ± 0.1 °C, with the basket rotating at 50 ± 1 rpm. At predeter-
mined time intervals, 4 mL was withdrawn from the dissolution
SI ¼ ðW s  W 0 Þ=W 0
medium and replaced with the same volume of fresh media. The
CHD concentration was determined spectrophotometrically at
k254 (Biochrom WPA Biowave II UV-Spectrophotometry, UK).

2.6.5.1. Kinetics of drug release. The kinetics of CHD release were

investigated to further understand the mechanism of CHD release
and the effect of the different ratios of the polymers. Five models
(Costa and Lobo, 2001) were used to analyse the release of CHD
from the tablet matrices (Table 2).

2.7. Fourier transform Infrared Spectroscopy (FTIR) and differential

scanning calorimetry (DSC)

FTIR was used to investigate the possibility of interaction

between the polymers and CHD. Spectra were obtained using a
Bruker Alpha spectrometer (Germany) scanning and ranged from
Fig. 1. Ex-vivo mucoadhesion using the disintegration apparatus. 4000 to 400 cm1.
 E. Al-Ani et al. / Saudi Pharmaceutical Journal 27 (2019) 756–766 759

Table 2 Particle size analysis of Methocel showed a broadening of the

Kinetic drug release models. distribution peak and a higher span value compared to HPMC
Model Equation (Fig. 2) which can be attributed to the rod-like shape of the parti-
Zero order Q ¼ Q 0 K 0 t cles seen under SEM (Fig. 3) (Naito et al., 1998). The particle size
First order logQ ¼ LogQ 0 K 1 t=2:303 distribution of HPMC approximates to a nearly normal distribution
Higuchi Q t ¼ K H t1=2 pattern with SEM revealing more spherical or irregular spheres.
Hixon-Crowell 1=3
Q 1=3 ¼ Q 0  K c t
Korsmeyer-Peppas Q t =Q 1 ¼ Kt n 3.3. Effect of particle morphology on tablet preparation
Where Q is the amount of drug released or dissolved
at time t; Q0 is the amount of drug release or dissolved The morphology of both the HPMC and Methocel samples
at time t (usually t = 0); Qt/Q1 is the fraction of drug (Fig. 3) strongly influenced their flow behaviour’ HPMC displays a
released at time t; K is constant, and n indicates the ‘‘passable” powder flow (CI of 21.67), whereas Methocel has ‘‘poor”
release mechanism.
flow (CI of 33.33) (British Pharmacopoeia Comission, 2017). This
finding was not unexpected as Hassan and Lau (2009) had reported
DSC analysis was performed to investigate the interaction the impeded flow of needle-shaped calcium carbonate particles (CI
between CHD and the polymers during the processing steps. Sam- of 40) which resulted from inter-particulate interactions and
ples of 5.0 ± 0.2 mg each of CHD, HPMC, P407, F10 Physical mix, aggregation. Moreover, the span value of Methocel is higher than
F10 granules and F10 tablet were investigated. Each was heated HPMC which resulted in a decrease in the flowability. This con-
in an aluminium pan under a nitrogen flow of 40 mL/min from firms a previous finding by Liu et al. (2008), who found that the
25 °C to 300 °C at a scan rate of 10 °C/min. The analysis was per- flowability is affected by both particle size and distribution. A par-
formed using Mettler Toledo DSC823e (Switzerland). ticle size of below 100 mm resulted in increased cohesiveness and
decreased flowability (Table 3) (Liu et al., 2008), whereas a nar-
rower distribution indicated better flowability. The various powder
3. Results and discussion formulation blends were found not to be flowable (Table 4) and
this may be due to the smaller mean particle size population of
3.1. Solubility of CHD the formulations, resulting in a relatively high surface area and
the potential for increased inter-particulate interactions which
The solubility of CHD was investigated to determine the most can decrease flowability. Dry granulation improved the flow prop-
appropriate dissolution medium to achieve sink condition. Its sol- erties of all formulation blends with most improving from ‘very,
ubility in water and phosphate buffer saline (PBS) at pH 6.8 was very poor’ to ‘very poor’, or from ‘very poor’ to ‘poor’ based on
23.069 ± 1.928 and 0.047 ± 0.0124 mg/mL, respectively. The vol- the British Pharmacopoeia.
ume of the dissolution media should be at least 3–10 times that The applied force used to prepare the HPMC granules was 10
of the saturated volume (Rohrs, 2001). Simulated pH saliva using KN. In contrast, Methocel granules were initially prepared at 10
PBS did not achieve sink condition, which is an important criterion and 40 KN, but the 10 KN samples were rejected due to no
in dissolution. Water showed more than 10 times the saturated improvement in flowability. This may be attributed to the rod-
volume and was therefore selected as the dissolution medium. like shape of Methocel particulates, which results in weak granules
compact which is unable to maintain its shape. The flowability of
granulated formulations of HPMC and Methocel prepared by both
3.2. Particle size and morphology forces (10 or 40 KN) was similar. Increasing the P407 content
decreased the flowability of the powder blends, most likely
The particle sizes of CHD and their distribution and excipients because of the irregular shape, small particle size and cohesive
are shown in Fig. 2 and Table 3. Both Methocel and HPMC have lar- properties of P407, which increases inter-particulate interactions
ger particles than CHD and P407, which is confirmed by the SEM and decreases packing efficiency as evidenced by a relatively high
micrographs (Fig. 3). CI of 40 (Garg et al., 2018). Again, flow properties were improved
The SEM micrographs (Fig. 3) correspond with the laser diffrac- after granulation, possibly as a result of the low melting point
tion results. Both CHD and P407 have smaller particle sizes and the and the waxy nature of the P407, which may have decreased
latter tend to be more spherical. However, HPMC and Methocel inter-particulate interactions and improved the packing efficiency.
possess larger particle sizes with irregular spherical and rod Granulated formulations with a high P407 ratio had a CI of 27. The
shapes, respectively. SEM images confirmed that there was no great improvement in the
flowability of granules (Fig. 4) due to the generation of fine parti-
cles when using dry granulation (Herting and Kleinebudde, 2007).
9
8
3.4. Tensile strength and friability
Volume Density (%)

7
6 All the tablets showed a tensile strength of less than 1 MP, with
5 Methocel formulations showing relatively higher tensile strengths
4 than HPMC formulations. This might be due to the higher force
3 used in the granulation for the former. All had acceptable levels
2 of friability of less than 1% (Table 5).
1
0 3.5. Ex-vivo mucoadhesion
0.01 0.1 1 10 100 1000 10000
Size Classes ( m)
Tablets were prepared with a convex surface. The advantage of
CHD Methocel F4M HPMC P407 this type of surface is that it prevents the tablet from dislodging
due to movement of the mouth and reduces contact with the ton-
Fig. 2. Particle size distribution of CHD, Methocel F4M, HPMC and P407. gue and the teeth (Maurya et al., 2010). It makes the tablet less
760 E. Al-Ani et al. / Saudi Pharmaceutical Journal 27 (2019) 756–766

Table 3
Particle size distribution of CHD, Methocel F4M, HPMC and P407.

Raw material D 0.1 (mm) D 0.5 (mm) D 0.9 (mm) Span (mm)
CHD 5.14 21.00 69.00 3.04
HPMC 33.00 84.60 172.00 1.64
Methocel 26.50 70.80 202.00 2.48
P 407 11.50 34.50 74.30 1.82

Fig. 3. SEM images of (a) CHD (b) P407, (c) HPMC and (d) Methocel x500.

Table 4
Compressibility index (CI%) for tablet blends before and after granulation.

Formulations Powder blends Granules

CI% Flow character CI% Flow character
F1 36.59 ± 4.00 Very poor 29.41 ± 1.03 Poor
F2 42.31 ± 1.61 Very, very poor 32.38 ± 1.58 Very poor
F3 42.86 ± 1.55 Very, very poor 32.29 ± 1.47 Very poor
F4 31.43 ± 2.91 Very poor 26.38 ± 0.00 Poor
F5 34.21 ± 3.62 Very poor 27.92 ± 0.92 Poor
F6 43.74 ± 1.32 Very, very poor 34.92 ± 1.37 Very poor
F7 39.28 ± 2.24 Very, very poor 34.85 ± 0.00 Very poor
F8 41.36 ± 2.12 Very, very poor 30.33 ± 3.21 Poor
F9 38.45 ± 4.43 Very, very poor 27.50 ± 0.87 Poor
F10 42.36 ± 5.81 Very, very poor 26.83 ± 0.76 Poor

brittle during manufacturing and handling. Furthermore, upon with the mucin component of mucous as they are both uncharged
application, it promotes rapid hydration around the perimeter (Sosnik et al., 2014).
and facilitates adhesion (Foreman et al., 2006).
All tablets successfully adhered to the chicken crop when
3.6. Swelling index (SI) and tablet morphology
repeatedly immersed, using the disintegration tester, in the aque-
ous medium for two hours, which corresponds to the selected res-
The swelling index for both Methocel and HPMC formulations
idence time for CHD release from the tablets in the buccal cavity.
(Fig. 5, supplemental data) increased with time. Statistical analysis
This successful mucoadhesion may be due to the chain entangle-
(two-way ANOVA with replication) revealed no statistical signifi-
ment and physical interlinking interaction of both the Hydrox-
cance (p > 0.05) between HMPC and Methocel formulations (F1
ypropyl methylcellulose polymers and the P407 with the chicken
and F6). This indicates that the morphology of HPMC and Methocel
crop mucous membrane. Neither polymer is capable of interacting
particles does not have any impact on the swelling index. However,
 E. Al-Ani et al. / Saudi Pharmaceutical Journal 27 (2019) 756–766 761

F1 F6

F3 F8

F4 F9

F5 F10

Fig. 4. SEM images of selected granules of HPMC and Methocel formulations, x200.

there was a significant difference for each group of formulations SEM micrographs of swollen tablets (Fig. 6) show a sponge-like,
(p < 0.001) for HPMC (F1 and F5) and Methocel (F6–F10). porous network with a strong relationship between the shape of
Increasing P407 led to a significant decrease in the swelling the pores and the morphology of the particles in Methocel and
index (p < 0.001), for both HPMC formulations. Upon hydration, HPMC polymers (Fig. 3) and their ratios in the formulations. F1
the mobility of the macromolecules in Methocel and HPMC and F2 show smaller and more spherical pores compared to F6,
increases along with the rate of water movement (Siepmann and F7 and F8 which have elongated, larger pores. The effect is promi-
Peppas, 2012). Moreover, hydrated P407 arranges itself into micel- nent when the ratio is greater than 50% in the tablet. For instance,
lar structures that subsequently adopt a cubic shape once the the average cross-sectional surface area of the pores in F1 and F6
hydrogel is formed. Intriguingly, the presence of HPMC in some was 0.46 ± 0.86 and 1.86 ± 2.95 mm2, respectively. Although the
of these formulations might facilitate the formation of a network average size of pores in F5 is
4 times that of F1, the total surface
of interconnected P407 micelles (Koffi et al., 2006). area of the pores was 0.203 mm2 for the former and 0.234 mm2 for
762 E. Al-Ani et al. / Saudi Pharmaceutical Journal 27 (2019) 756–766

Table 5 respectively. Both F5 and F10 can be considered similar with a f2

Tensile strength (n = 10) and friability (1 g) of CHD tablets. of 77.68% and a f1 of 6.36.
Formulations Tensile strength (MPa) Friability (%) Although different compression forces of 10 KN for HPMC for-
F1 0.57 ± 0.19 0.48 mulations and 40 KN for Methocel formulations were used to pre-
F2 0.49 ± 0.19 0.28 pare the granules, this should not affect drug release. Velasco et al.
F3 0.51 ± 0.14 0.12 (1999) reported that compression force has a minimal effect on
F4 0.73 ± 0.21 0.09 drug release or the kinetics of release but can influence initial
F5 0.62 ± 0.15 0.36
F6 0.78 ± 0.14 0.04
matrix porosity (before hydration).
F7 0.78 ± 0.18 0.02 The kinetics of CHD release was investigated by fitting the
F8 0.66 ± 0.21 0.01 release data to the following models: zero order, first order, Higu-
F9 0.74 ± 0.28 0.06 chi, Hixson-Crowell and Korsmeyer-Peppas models (Table 2).
F10 0.88 ± 0.20 0.25
Using the correlation coefficient (R2) values, the tablets fitted most
closely with the Korsmeyer-Peppas kinetic model and the expo-
nent n was found to be 0.45 < n < 0.89 (Table 6). This indicates that
the latter, with a ratio of 0.9. This indicates that although the size drug release is anomalous from cylindrical tablet (0.45 represent-
and the morphology of the pores are different, the total surface ing diffusional control and 0.89 indicating case-II transport which
area is not greatly affected by the morphology of the polymeric corresponds to zero order kinetic). Thus, CHD release is anomalous
particles. Increasing P407 leads to the formation of irregular pores, (Siepmann and Peppas, 2012). This leads to the conclusion that
possibly because of its surfactant properties which increase the neither the morphology of polymer particles nor the ratio of
solubility of other polymers and distorts their shapes. Another pos- P407 had an effect on the mechanism of drug release.
sibility is that it might be affected by the thermosensitive proper-
ties of P407, which melts at a low temperature, meaning that pore
damage may occur during the freeze-drying process or during the 3.8. Drug polymer interaction (FTIR and DSC)
sample cutting of freeze-dried tablets.
The FTIR spectra revealed that HPMC and Methocel are identical
in terms of chemical composition. Moreover, analyses were per-
formed (Fig. 8) to evaluate possible interactions during the granu-
3.7. In-vitro dissolution of CHD and data analysis lation and tableting process which might have resulted from the
low melting point of P407. CHD displayed peaks at 3325 and
The cumulative CHD release from both groups of tablets was 3119 cm1 (asymmetric and symmetric NH stretching vibrations),
affected by the ratio of P407. Increasing P407 content elevates drug 2938 and 2886 cm1 (asymmetric and symmetric CH stretching),
release by as much as 30% for HPMC formulations (F1 to F5). For 1624 cm1 (CN stretching vibration of imine group),
example, 60.53% of CHD was released from F1 compared to 1522,1483 cm1 (NH bending vibration of secondary amine and
94.27% of CHD which was released from F5. Moreover, the cumu- imine groups), 1406 cm1 (C@C stretching vibrations of aromatic
lative CHD release from Methocel formulations F6 and F10 with rings), 1290 and 1245 cm1 CN stretching, 819 cm1 (out of plane
the same composition as F1 and F5 were 57.77% and 94.58%, vibration of the aromatic ring and the CCl) group’s spectra at
respectively. The increase in drug release was attributed to the sol- 718 cm1 (Holešová et al., 2014, and Yang et al., 2007). The charac-
ubilising activity of P407 (Fig. 7). The copolymer P407 is a surfac- teristic peaks of HPMC are at 3445 cm1 (OH stretching) and
tant which is widely used to improve the aqueous solubility of 2897 cm1 (CH stretching), 1375 cm1 (asymmetric CH3 bending
poorly soluble drugs (Dumortier et al., 2006), and can also form a vibration), 1049 cm1 (CAO asymmetric stretching vibration) and
hydrogel at body temperature. However, the morphology of the 942 cm1 (CAO symmetric stretching vibration (Ding et al.,
particles of Methocel and HPMC did not affect CHD release, which 2015). P407 is characterised by principal peaks at 2875 cm1 (CH
might be explained by the equivalent cross-sectional surface area stretching), 1346 cm1 (OH bending) and 1094 cm1 (CO stretch-
of pores in F1 and F6. Moreover, both formulations are similar in ing) (Vyas et al., 2009). The analyses of tablet formulations (Fig. 8
terms of cumulative drug release based on similarity factor (f2) a and c) reveal that increasing the concentration of P407 leads to
and difference factor (f1), with values of 81.1% and 6.87, respec- a decreased intensity of CHD and the disappearance of hydrogen
tively. F1 and F6 showed a cumulative release after two hours of bonding peaks at 3325 and 3119 cm1. This is prominent in F5
60.7% and 57.7%, while F5 and F10 showed 93.0% and 94.6%, and F10. In contrast, F1, F2, F6 and F7 show a combination of the

6 6
a b
5 5
Swelling Index

Swelling Index

4 4

3 3

2 2

1 1
0 0
0 30 60 90 120 0 30 60 90 120
Time (min) Time (min)
F1 F2 F3 F4 F5 F6 F7 F8 F9 F10

Fig. 5. swelling index of CHD tablets (a) HPMC formulations and (b) Methocel formulations in ultrapure water and at 37 °C, Data are expressed as mean ± SD, n = 3.
 E. Al-Ani et al. / Saudi Pharmaceutical Journal 27 (2019) 756–766 763

F1 F6

F2 F7

F3 F8

F4 F9

F5 F10

Fig. 6. SEM micrographs of cross-section of freeze-dried swollen tablets.

peaks of all ingredients. The concentration-dependent interaction Müller, 2005). The peaks of HPMC overlap with those of P407, with
between CHD and P407 is attributed to the steric hindrance prop- the CO stretching of HPMC, Methocel and P407 combining into one
erties of P407, resulting in the shielding of CHD (Göppert and peak at around 1097 cm1 in F2, F8 and F5 and F8-F10. However, in
764 E. Al-Ani et al. / Saudi Pharmaceutical Journal 27 (2019) 756–766

100 100
a b

Chlorhexidine Percent Release

Chlorhexidine Percent Release
80 80

60 60

40 40

20 20

0 0
0 30 60 90 120 0 30 60 90 120
F1 F2 F3 F4 F5 Time (min)
Time (min) F6 F7 F8 F9 F10

Fig. 7. Cumulative percentage release of CHD from (a) HPMC formulations and (b) Methocel formulations in ultrapure water at 37 ± 0.1 °C and 50 rpm, n = 3 ± SD.

Table 6
CHD release kinetics using different models.

Zero Order (R2) First order (R2) Higuchi (R2) Hixon crowel (R2) K-Peppas (R2) K-Peppas (n)
F1 0.9702 ± 0.0227 0.9826 ± 0.0149 0.9723 ± 0.0262 0.9697 ± 0.0285 0.9979 ± 0.0010 0.717 ± 0.139
F2 0.9795 ± 0.0143 0.9825 ± 0.0078 0.9655 ± 0.0244 0.9757 ± 0.0188 0.9967 ± 0.0023 0.747 ± 0.137
F3 0.9329 ± 0.0378 0.8943 ± 0.0843 0.9818 ± 0.0063 0.8567 ± 0.1076 0.9872 ± 0.0029 0.541 ± 0.105
F4 0.9776 ± 0.0028 0.9867 ± 0.0078 0.9773 ± 0.0031 0.9777 ± 0.0130 0.9985 ± 0.0008 0.686 ± 0.027
F5 0.9850 ± 0.0048 0.9806 ± 0.0035 0.9648 ± 0.0050 0.9940 ± 0.0014 0.9984 ± 0.0012 0.764 ± 0.029
F6 0.9712 ± 0.0054 0.9833 ± 0.0067 0.9736 ± 0.0063 0.9483 ± 0.0128 0.9965 ± 0.0007 0.698 ± 0.033
F7 0.9663 ± 0.0025 0.9854 ± 0.0028 0.9796 ± 0.0019 0.9714 ± 0.0042 0.9959 ± 0.0005 0.671 ± 0.018
F8 09791 ± 0.0107 0.9972 ± 0.0010 0.9606 ± 0.0071 0.9942 ± 0.0030 0.9983 ± 0.0015 0.796 ± 0.009
F9 0.9727 ± 0.0117 0.9952 ± 0.0012 0.9703 ± 0.0105 0.9894 ± 0.0081 0.9981 ± 0.0015 0.740 ± 0.044
F10 0.9907 ± 0.0079 0.9700 ± 0.0143 0.9475 ± 0.0190 0.9872 ± 0.0059 0.9987 ± 0.0005 0.870 ± 0.113

a b
F5

F4

F3 F5 Tab

F2

F1 F5 Gran

P407

HPMC F5 PM
CHD

4000 3000 2000 1000

4000 3500 3000 2500 2000 1500 1000 500
Wavenumber cm-1
-1
Wavenumber cm

c d
F10

F10 Tab
F9

F8

F10 Gran
F7

F6
P407

Methocel F10 PM

CHD

4000 3500 3000 2500 2000 1500 1000 500

4000 3500 3000 2500 2000 1500 1000 500
Wavenumber cm-1
Wavenumber cm-1

Fig. 8. FTIR spectra of (a) HPMC formulations, (b) F5 physical mix (PM), granules (Gran) and tablet (Tab), (c) Methocel formulations and (d) F10 PM, Gran and Tab.
 E. Al-Ani et al. / Saudi Pharmaceutical Journal 27 (2019) 756–766 765

F1 and F6, this peak shifts to 1049 cm1. Further investigation was for the F5 physical mix, the granules and the tablet showed identi-
performed to analyse F5 and F10, the physical mix, the granules cal spectra with that of the F10. This indicates that no interaction
and the tablets (Fig. 8 b and d). All FTIR spectra have identical occurred during the process of tableting and the sources of the
peaks, meaning that during the mixing process of the excipient, polymer showed no differences in behaviour. Moreover, DSC anal-
hydrophobic interactions occur between CHD and P407 ending in ysis was performed on the F10 formulation only and showed no
steric hindrance by the latter. Although this interaction is more interactions between the drug and the polymers in the prepared
common in liquid formulations, in the current formulation the table.
interaction is aggravated by the small particle size of both CHD
and P407. 4. Conclusions
Fig. 9 shows the DSC thermograms for raw materials, the phys-
ical mixture, the granules and the tablet of F10 formulation, which CHD buccal tablets were successfully prepared using two differ-
has the highest drug release. CHD has two melting peaks at 158 ent sources of hydroxypropyl methylcellulose polymer. Both
and 176 °C, which indicates its polymorphic nature. Methocel groups of formulations showed comparable drug release and kinet-
reflects its amorphous nature while P407 has a melting peak at ics of drug release. The addition of the thermosensitive hydrogel-
57 °C. The F10 physical mix, the granules and the tablet thermo- forming polymer P407 to the formulations improved CHD release
grams showed that the endothermic peak of poloxamer occurred from the tablets without negatively impacting on the duration of
at around the same temperature. The first melting peak of CHD mucoadhesion. In vivo work will be undertaken in the future to fur-
was shifted to 156 °C in the physical mix and to 153 °C in the gran- ther investigate the safety and efficacy of the prepared buccal
ules and the compressed tablet. The small melting peak disap- tablets for future application in the treatment of OPC.
peared in the physical mix and granules but in the tablet, it
shifted to 173 °C. The shifting and the disappearance of the melting Appendix A. Supplementary material
peaks in the physical mix and the granules indicate there is an
interaction between the chlorhexidine and the P407. However, Supplementary data to this article can be found online at
the re-appearance of the second endothermic peak in the tablet https://doi.org/10.1016/j.jsps.2019.04.012.
is attributed to phase separation resulting from tablet compression
(Singh et al., 2016).
The interaction between the excipients and CHD were tested
using FTIR and DSC. The FTIR spectra revealed that increases in
References
the ratio of P407 led to a decrease in the intensity of CHD which
can be attributed to steric hindrance by P407. The FTIR spectra Ankola, A.V., Hebbal, M., Mocherla, M., 2008. A review of efficacy of various modes
of chlorhexidine delivery. J. Oral Biosci. 50, 239–242. https://doi.org/10.1016/
S1349-0079(08)80013-8.
British Pharmacopeia Comission, 2017. Appendix XVII N. Powder Flow1 - British
Pharmacopoeia [WWW Document]. URL https://www-pharmacopoeia-com.
ezproxy.wlv.ac.uk/bp-2014/appendices/appendix-17/appendix-xvii-n–powder-
flow1.html?date=2014-01-01&text=Powder+Flow (accessed 12.2.18).
Costa, P., Lobo, J.M.S., 2001. Modelling and comparison of dissolution profiles. Eur. J.
Pharm. Sci. 13, 123–133. https://doi.org/10.1016/S0928-0987(01)00095-1.
Ding, C., Zhang, M., Li, G., 2015. Preparation and characterization of collagen/
hydroxypropyl methylcellulose (HPMC) blend film. Carbohydr. Polym. 119,
194–201. https://doi.org/10.1016/j.carbpol.2014.11.057.
Dumortier, G., Grossiord, J.L., Agnely, F., 2006. A review of poloxamer 407
pharmaceutical and pharmacological characteristics. Pharm. Res. 23, 2709–
2728. https://doi.org/10.1007/s11095-006-9104-4.
Elena Campos-Aldrete, M., 1997. Influence of the viscosity grade and the particle
size of HPMC on metronidazole release from matrix tablets. Eur. J. Pharm.
Biopharm.
Foreman, P., Zhang, Y., Puri, R., 2006. Mucosal delivery tablet. US 2007/0048369 A1.
Gao, P., Skoug, J.W., Nixon, P.R., Robert Ju, T., Stemm, N.L., Sung, K.-C., 1996. Swelling
of hydroxypropyl methylcellulose matrix tablets. 2. Mechanistic study of the
influence of formulation variables on matrix performance and drug release. J.
Exothermic

Pharm. Sci. 85, 732–740. https://doi.org/10.1021/js9504595.

Garg, V., Mallick, S.S., Garcia-Trinanes, P., Berry, R.J., 2018. An investigation into the
flowability of fine powders used in pharmaceutical industries. Powder Technol.
336, 375–382. https://doi.org/10.1016/J.POWTEC.2018.06.014.
Ghori, M.U., Conway, B.R., 2015. Hydrophilic matrices for oral control drug delivery.
Am. J. Pharmacol. Sci. 3, 103–109. https://doi.org/10.12691/AJPS-3-5-1.
Göppert, T.M., Müller, R.H., 2005. Protein adsorption patterns on poloxamer- and
Tab F10 poloxamine-stabilized solid lipid nanoparticles (SLN). Eur. J. Pharm. Biopharm.
60, 361–372. https://doi.org/10.1016/j.ejpb.2005.02.006.
Gran F10 Gustafsson, C., Bonferoni, M.C., Caramella, C., Lennholm, H., Nyström, C., 1999.
PM F10 Characterisation of particle properties and compaction behaviour of
hydroxypropyl methylcellulose with different degrees of methoxy/
P407 hydroxypropyl substitution. Eur. J. Pharm. Sci. 9, 171–184. https://doi.org/
Methocel 10.1016/S0928-0987(99)00054-8.
Gustafsson, C., Nyström, C., Lennholm, H., Bonferoni, M.C., Caramella, C.M., 2003.
CHD Characteristics of hydroxypropyl methylcellulose influencing compactibility
and prediction of particle and tablet properties by infrared spectroscopy. J.
Pharm. Sci. 92, 494–504. https://doi.org/10.1002/jps.10323.
Hassan, M.S., Lau, R.W.M., 2009. Effect of particle shape on dry particle inhalation:
study of flowability, aerosolization, and deposition properties. AAPS
0 50 100 150 200 PharmSciTech 10, 1252–1262. https://doi.org/10.1208/s12249-009-9313-3.
Herting, M.G., Kleinebudde, P., 2007. Roll compaction/dry granulation: effect of raw
Time (min) material particle size on granule and tablet properties. Int. J. Pharm. 338, 110–
118. https://doi.org/10.1016/j.ijpharm.2007.01.035.
Fig. 9. DSC thermograms of F10 physical mix (PM), Granules (GRAN), tablet (TAB), Holešová, S., Valášková, M., Hlaváč, D., Madejová, J., Samlíková, M., Tokarský, J.,
CHD, Methocel and P407. Pazdziora, E., 2014. Antibacterial kaolinite/urea/chlorhexidine nanocomposites:
766 E. Al-Ani et al. / Saudi Pharmaceutical Journal 27 (2019) 756–766

experiment and molecular modelling. Appl. Surf. Sci. 305, 783–791. https://doi. Ruel-Gariépy, E., Leroux, J.C., 2004. In situ-forming hydrogels – review of
org/10.1016/j.apsusc.2014.04.008. temperature-sensitive systems. Eur. J. Pharm. Biopharm. 58, 409–426. https://
Kabanov, A.V., Batrakova, E.V., Alakhov, V.Y., 2002. P luronic block copolymers for doi.org/10.1016/j.ejpb.2004.03.019.
overcoming drug resistance in cancer. Adv. Drug Deliv. Rev. Sankar, V., Hearnden, V., Hull, K., Juras, D.V., Greenberg, M., Kerr, A., Lockhart, P.,
Kassem, M.A.A., Elmeshad, A.N., Fares, A.R., 2014. Enhanced bioavailability of Patton, L., Porter, S., Thornhill, M., 2011. Local drug delivery for oral mucosal
buspirone hydrochloride via cup and core buccal tablets: formulation and diseases: challenges and opportunities. Oral Dis. 17, 73–84. https://doi.org/
in vitro/in vivo evaluation. Int. J. Pharm. 463, 68–80. https://doi.org/10.1016/j. 10.1111/j.1601-0825.2011.01793.x.
ijpharm.2014.01.003. Siepmann, J., Peppas, N.A., 2012. Modeling of drug release from delivery systems
Koffi, A.A., Agnely, F., Ponchel, G., Grossiord, J.L., 2006. Modulation of the rheological based on hydroxypropyl methylcellulose (HPMC). Adv. Drug Deliv. Rev. 64,
and mucoadhesive properties of thermosensitive poloxamer-based hydrogels 163–174. https://doi.org/10.1016/j.addr.2012.09.028.
intended for the rectal administration of quinine. Eur. J. Pharm. Sci. 27, 328– Singh, A., Bharati, A., Frederiks, P., Verkinderen, O., Goderis, B., Cardinaels, R.,
335. https://doi.org/10.1016/j.ejps.2005.11.001. Moldenaers, P., Van Humbeeck, J., Van Den Mooter, G., 2016. Effect of
Li, C.L., Martini, L.G., Ford, J.L., Roberts, M., 2005. The use of hypromellose in oral compression on the molecular arrangement of itraconazole-soluplus solid
drug delivery. J. Pharm. Pharmacol. 57, 533–546. https://doi.org/10.1211/ dispersions: induction of liquid crystals or exacerbation of phase separation?
0022357055957. Mol. Pharm. 13, 1879–1893. https://doi.org/10.1021/
Lim, K.S., Kam, P.C.A., 2008. Chlorhexidine – pharmacology and clinical applications. acs.molpharmaceut.6b00046.
Anaesth. Intensive Care 36, 502–512. https://doi.org/10.1016/S0140-6736(08) Sosnik, A., Das Neves, J., Sarmento, B., 2014. Mucoadhesive polymers in the design of
60601-7.Anaesthesia. nano-drug delivery systems for administration by non-parenteral routes: a
Liu, L.X., Marziano, I., Bentham, A.C., Litster, J.D., White, E.T., Howes, T., 2008. Effect review. Prog. Polym. Sci. 39, 2030–2075. https://doi.org/10.1016/j.
of particle properties on the flowability of ibuprofen powders. Int. J. Pharm. 362, progpolymsci.2014.07.010.
109–117. https://doi.org/10.1016/j.ijpharm.2008.06.023. Sudhakar, Y., Kuotsu, K., Bandyopadhyay, A.K., 2006. Buccal bioadhesive drug
Maderuelo, C., Zarzuelo, A., Lanao, J.M., 2011. Critical factors in the release of drugs delivery – a promising option for orally less efficient drugs. J. Control. Release.
from sustained release hydrophilic matrices. J. Control. Release 154, 2–19. https://doi.org/10.1016/j.jconrel.2006.04.012.
https://doi.org/10.1016/J.JCONREL.2011.04.002. Tuǧcu-Demiröz, F., Acartürk, F., Takka, S., Konusß-Boyunaǧa, Ö., 2004. In-vitro and in-
Matanovi, M.R., Kristl, J., Grabnar, A., 2014. Thermoresponsive polymers: Insights vivo evaluation of mesalazine-guar gum matrix tablets for colonic drug
into decisive hydrogel characteristics, mechanisms of gelation, and promising delivery. J. Drug Target. 12, 105–112. https://doi.org/10.1080/
biomedical applications. Int. J. Pharm. 472, 262–275. https://doi.org/10.1016/j. 10611860410001693751.
ijpharm.2014.06.029. Velasco, M.V., Ford, J.L., Rowe, P., Rajabi-Siahboomi, A.R., 1999. Influence of drug:
Maurya, S., Pathak, K., Bali, V., 2010. Therapeutic potential of mucoadhesive drug hydroxypropylmethylcellulose ratio, drug and polymer particle size and
delivery systems – an updated patent review. Recent Pat. Drug Deliv. Formul. 4, compression force on the release of diclofenac sodium from HPMC tablets. J.
256–265. https://doi.org/10.2174/187221110793237529. Control. Release 57, 75–85. https://doi.org/10.1016/S0168-3659(98)00110-2.
Nafee, N.A., Ismail, F.A., Boraie, N.A., Mortada, L.M., 2003. Mucoadhesive buccal Vyas, V., Sancheti, P., Karekar, P., Shah, M., Pore, Y., 2009. Physicochemical
patches of miconazole nitrate: In vitro/in vivo performance and effect of ageing. characterization of solid dispersion systems of tadalafil with poloxamer 407.
Int. J. Pharm. 264, 1–14. https://doi.org/10.1016/S0378-5173(03)00371-5. Acta Pharm. 59, 453–461. https://doi.org/10.2478/v10007-009-0037-4.
Naito, M., Hayakawa, O., Nakahira, K., Mori, H., Tsubaki, J., 1998. Effect of particle Wan, P., Heng, S., Chan, L.W., Easterbrook, M.G., Li, X., 2001. Investigation of the
shape on the particle size distribution measured with commercial equipment. influence of mean HPMC particle size and number of polymer particles on the
Powder Technol. 100, 52–60. https://doi.org/10.1016/S0032-5910(98)00052-7. release of aspirin from swellable hydrophilic matrix tablets. J. Controlled
Pereiro Ferreirós, M., García-Martínez, F.J., Alonso-González, J., 2012. Update on the Release.
treatment of superficial mycoses. Actas Dermosifiliogr. 103, 778–783. https:// Xie, T., Gao, W., Taylor, L.S., 2017. Impact of Eudragit EPO and hydroxypropyl
doi.org/10.1016/j.ad.2012.01.009. methylcellulose on drug release rate, supersaturation, precipitation outcome
Pitt, K.G., Newton, J.M., Stanley, P., 1988. Tensile fracture of doubly-convex and redissolution rate of indomethacin amorphous solid dispersions. Int. J.
cylindrical discs under diametral loading. J. Mater. Sci. 23, 2723–2728. Pharm. 531, 313–323. https://doi.org/10.1016/j.ijpharm.2017.08.099.
https://doi.org/10.1007/BF00547442. Yang, D., Yuan, P., Zhu, J.X., He, H.P., 2007. Synthesis and characterization of
Rohrs, B.R., 2001. Dissolution method development for poorly soluble compounds. antibacterial compounds using montmorillonite and chlorhexidine acetate. J.
Dissolution Technol. 29, 1171–1178. https://doi.org/10.14227/DT080301P6. Therm. Anal. Calorim. 89, 847–852. https://doi.org/10.1007/s10973-006-8318-3.