Arch Pharm Res Vol 32, No 6, 893-898, 2009

DOI 10.1007/s12272-009-1611-5

Physicochemical Characterization of Tacrolimus-loaded Solid

Dispersion with Sodium Carboxylmethyl Cellulose and Sodium
Lauryl Sulfate
Young-Joon Park2, Dong-Sung Ryu1, Dong Xun Li1, Qi Zhe Quan3, Dong Hoon Oh1, Jong Oh Kim1,
Youn Gee Seo1, Young-Im Lee1, Chul Soon Yong1, Jong Soo Woo1, and Han-Gon Choi1
1

College of Pharmacy, Yeungnam University, Gyongsan 712-749, Korea, 2Research Center, Samil Pharmaceutical Co. Ltd.,
Ansan 712-749, Korea, 3Biochemical Engineering College, Beijing Union University, No.18, 3rd Section, Fatouxili, Chaoyang District, Beijing, 100023, China
(Received March 11, 2009/Revisied April 24, 2009/Accepted April 28, 2009)

To develop a novel tacrolimus-loaded solid dispersion with improved solubility, various solid
dispersions were prepared with various ratios of water, sodium lauryl sulfate, citric acid and
carboxylmethylcellulose-Na using spray drying technique. The physicochemical properties of
solid dispersions were investigated using scanning electron microscopy, differential scanning
calorimetery and powder X-ray diffraction. Furthermore, their solubility and dissolution were
evaluated compared to drug powder. The solid dispersion at the tacrolimus/CMC-Na/sodium
lauryl sulfate/citric acid ratio of 3/24/3/0.2 significantly improved the drug solubility and dissolution compared to powder. The scanning electron microscopy result suggested that carriers
might be attached to the surface of drug in this solid dispersion. Unlike traditional solid dispersion systems, the crystal form of drug in this solid dispersion could not be converted to
amorphous form, which was confirmed by the analysis of DSC and powder X-ray diffraction.
Thus, the solid dispersion system with water, sodium lauryl sulfate, citric acid and CMC-Na
should be a potential candidate for delivering a poorly water-soluble tacrolimus with enhanced
solubility and no convertible crystalline.
Key words: Solid dispersion, Tacrolimus, Sodium carboxylmethyl cellulose, Sodium lauryl
sulfate, Solubility

INTRODUCTION
Tacrolimus isolated from Streptomyces tsukubaensis
is a 23-member macrolide lactone with potent immunosuppressive activity (Kino et al., 1987a, 1987b).
It is a poorly water-soluble compound which gave the
low aqueous solubility of about 1-2 g/mL (Hane et al.,
1992; Honbo et al., 1987; Tamura et al., 2002). Various
oral formulations of tacrolimus such as inclusion
complex (Arima et al., 2001), nanoparticle (Nassar et
Correspondence to: Han-Gon Choi, College of Pharmacy, Yeungnam University, Gyongsan 712-749, Korea
Tel: 82-53-810-2813, Fax: 82-53-810-4654
E-mail: hangon@ynu.ac.kr
or Jong Soo Woo, College of Pharmacy, Yeungnam University,
Gyongsan 712-749, Korea
Tel: 82-53-810-2824, Fax: 82-53-810-4654
E-mail: woojongsoo@ynu.ac.kr

al., 2008; Sinswat et al., 2008), Prodrug with poly

(ethylene glycol) esters (Chung and Cho, 2004),
liposome (Lee et al., 1995), microemulsion (Borhade et
al., 2008a; 2008b) and solid dispersion (Yamashita et
al., 2003) were developed to improve the solubility of
tacrolimus.
One of the well established methods for increasing
the solubility of poorly water-soluble drugs is a solid
dispersion system (Chiou and Riegelman, 1971).
Drugs in the solid dispersion systems may exist as an
amorphous form in polymeric carriers, and improved
the solubility and dissolution compared with crystalline material. Furthermore, the drugs dispersed in
polymeric carriers may achieve the highest levels of
particle size reduction and surface area enhancement,
resulting in improved dissolution rates (Craig, 2002;
Taylor and Zografi, 1997). Several traditional methods
such as melting method, solvent evaporation method

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894

and solvent wetting method were previously reported

to prepare solid dispersions (Leuner and Dressman,
2000; Yamashita et al., 2003). However, the solid
dispersion prepared by melting method with high
temperature might chemically decompose the drugs
(Miller et al., 2007; Newa et al., 2008). In the case of
solvent evaporation method and solvent wetting
method, the drug in the solid dispersions changed to
amorphous form, resulting that the drug might be
unstable (Yamashita et al., 2003).
In this study, to improve the solubility of poorly
water-soluble tacrolimus, a novel solid dispersion
system was prepared using spray drying technique
with water and carboxymethyl cellulose sodium
(CMC-Na) and sodium lauryl sulfate (SLS). The effects
of CMC-Na and sodium lauryl sulfate on aqueous
solubility of tacrolimus were then investigated. The
physicochemical properties of solid dispersions were
investigated using SEM, DSC and Powder X-ray diffraction. Furthermore, their solubility and dissolution
were evaluated compared to tacrolimus powder.

MATERIALS AND METHODS

Materials
Tacrolimus was supplied from Shanghai Qiao
Chemical Science Co. (Shanghai, China). Sodium carboxymethyl cellulose (CMC-Na), sodium lauryl sulfate,
polyethylene glycol 4000 and polyethylene glycol 6000
were purchased from Duksan Chemical Co. (Ansan,
Korea). Poloxamer 188 and poloxamer 407 were purchased from BASF (Ludwigshafen, Germany). Hydroxypropylmethyl cellulose (HPMC 2910, viscosity grade
4000 cps), hydroxypropyl cellulose (HPC-L) and polyvinylpyrrolidone (PVP K-30) were of USP grade. All
other chemicals were of reagent grade and used
without further purification.
Effect of carriers on aqueous solubility of tacrolimus
Excess of tacrolimus powder (about 10 mg) were
added to 10 mL of 1% solution containing hydrophilic
polymer or surfactant (Table I). They were shaken in
water bath at 25oC for 7 days, centrifuged at 3,000 g
for 10 min (Eppendorf, USA) and filtered through a
membrane filter (0.45 m) (Choi et al., 2001; Li et al.,
2008). The concentration of tacrolimus in the resulting
solution was then analyzed by HPLC as described
below.
Preparation of tacrolimus-loaded solid dispersion
A Bchi 190 nozzle type mini spray dryer (Flawil,

Y.-J. Park et al.

Table I. Effect of carriers on aqueous solubility of tacrolimus

Carriers

Aqueous solubility of
tacrolimus (g/mL)

Water

0.67 0.19

- Hydrophilic polymers
Sodium carboxymethyl cellulose
Hydrooxypropyl cellulose
Hydroxypropylmethyl cellulose

7.51 0.29
1.75 0.07
1.95 0.14

- Surfactants
Polyethylene glycol 6000
Polyethylene glycol 4000
Poloxamer 188
Poloxamer 407
Sodium lauryl sulfate

1.00 0.15
1.00 0.12
2.02 0.20
25.57 0.782
476.38 150.61

Each value means the solubility of tacrolimus in the

distilled water containing 1% hydrophilic polymer or
surfactant.
Each value represents the mean S.D. (n = 3).

Switzerland) was used for the preparation of tacrolimus-loaded solid dispersion. First, 0.3 g sodium lauryl
sulfate, 0.2 g citric acid, and 1.2 g (solid dispersion I)
or 24 g (solid dispersion II) CMC-Na were dissolved in
100 mL water, respectively. Then, 3 g tacrolimus presieved through 60 mesh screen was dispersed in this
solution. The resulting dispersion pre-warmed to 60oC
was delivered to the nozzle (0.7 mm diameter) at a
flow rate of 5 mL/min using a peristaltic pump and
spray-dried at 125oC inlet temperature and 65-70oC
outlet temperature. The pressure of spray air was 4
kg/cm2 and the flow rate of drying air was maintained
at the aspirator setting of 10 which indicated the
pressure of aspirator filter vessel -25 mbar. The direction of air flow was the same as that of sprayed products (Choi et al., 2001; Li et al., 2008; Yong et al., 2004).
After excessive amount (about 20 mg) of solid
dispersion I and II were added to 10 mL water, the
solubility test of tacrolimus in the solid dispersions
were carried out using the solubility method as
mentioned above.

Dissolution
The solid dispersions (equivalent to 0.5 mg of
tacrolimus) and 0.5 mg of tacrolimus powder were
inserted into a sinker and placed in the dissolution
apparatus (Shinseang Instrument Co., South Korea),
respectively (Choi et al., 1998). Dissolution test was
performed at 37 0.5oC using the paddle method at
50 rpm with 500 mL 0.005% hydroxypropyl cellulose
solution adjusted to pH 4.5 by phosphoric acid. At
predetermined interval, 3 mL of the medium was

Tacrolimus-loaded Solid Dispersion

sampled and filtered through membrane filter (0.45

m) (Newa et al., 2007; Okimoto et al., 1997; Yong et
al., 2006). Then, the concentration of tacrolimus in the
supernatant layer was analyzed by HPLC. The resulting solution (2 mL) was mixed with 0.5 mL of acetonitrile solution, vortexed for 2 min and centrifuged at
10,000 g for 10 min. Then, 100 L of supernatant layer
was analyzed by HPLC (Hitachi, Tokyo, Japan) equipped with an Supecosil LC-CN column (SUPELCOTM, 3
m, 7.5 cm4.6 mm i.d.) and UV detector (Model L2420). The mobile phase was consisted of water,
acetonitrile and isopropanol (7/2/1, volume ratio). The
eluent was monitored at 210 nm with a flow rate of
0.4 mL/min (Borhade et al., 2008; Miao etal., 2008;
Moyano et al., 2006; Nassar et al., 2008; Patil et al.,
2008).

Shape and surface morphology

The shape and surface morphology of tacrolimus
powder and solid dispersions were examined using a
scanning electron microscope (S-4100, Hitachi, Japan).
The samples were fixed on a brass specimen club
using double-side adhesive tape and made electrically
conductive by coating in a vacuum (6 Pa) with platinum (6 nm/min) using Hitachi Iron Sputter (E-1030)
for 300 seconds at 15 mA (Newa et al., 2007; Yamashita
et al., 2003).
Thermal characteristics and crystallinity
The thermal characteristics of tacrolimus powder,
carriers and solid dispersions were investigated using
a differential scanning calorimeter (DSC-2010, TA Instruments, USA). About 2 mg of samples were placed
in sealed aluminum pans, before heating under nitrogen flow (25 mL/min) at a heating rate of 10 oC/min
from 30 to 215oC. Furthermore, the crystallinity of
powder, carriers and solid dispersions were assessed
by powder X-ray diffraction (D/MAX-2500, Rigacu,
Japan) conducted at room temperature using monochromatic Cu K-radiation (=1.54178 ) at 40 mA
and 40 kV in the region of 2.5o 2 40o with an
angular increment of 0.02 per second (Nassar et al.,
2008; Sinswat et al., 2008).

RESULTS AND DISCUSSION

A novel solid dispersion system was prepared using
spray drying technique with water, hydrophilic polymer and surfactant without organic solvent. To select
a hydrophilic polymer and surfactant as carriers
suitable for tacrolimus-loaded solid dispersion, the
solubility of tacrolimus was evaluated in the distilled
water containing 1% hydrophilic polymers or sur-

895

factants, respectively (Table I). The aqueous solubility

of tacrolimus is about 0.667 g/mL, indicated that this
drug was poorly water-soluble (Hane et al., 1992;
Tamura et al., 2002; Watts et al., 2009). Among the
hydrophilic polymers tested, Na-CMC gave a maximum
solubility of drug. Furthermore, among the surfactants tested, the solubility of tacrolimus in 1% sodium
lauryl sulfate was highest as about 476.380 g/mL.
Thus, Na-CMC and sodium lauryl sulfate were selected as carriers in the development of tacrolimus-loaded
solid dispersion.
Na-CMC and sodium lauryl sulfate were dissolved
in water and a poorly water-soluble tacrolimus was
dispersed in this solution (Chutimaworapan et al.,
2000). The resulting dispersion was spray-dried so
that the dissolved hydrophilic polymer and surfactant
could be attached to the surface of dispersed drug
particles. This solid dispersion might change the hydrophobic drug to hydrophilic form, resulting in increased
solubility of the poorly water-soluble drug. Since water
is used as a solvent in this study unlike traditional
solid dispersion method, this solid dispersion method
has several advantages over other methods in an
industry scale, such as no necessity to remove organic
solvent and the strict air-quality controls instituted by
the law-enforcing, potential toxicity and explosion of
organic solvents (Kachrimanis et al., 2000; Khan and
Jiabi, 1998).
Firstly, the aqueous solubility of tacrolimus in the
solid dispersions was investigated compared to tacrolimus powder. The solid dispersion I and II were composed of tacrolimus/CMC-Na/SLS at the weight ratio
of 3/1.2/0.3 and 3/24/3, respectively. The powder, solid
dispersion I and II gave the drug solubility of 0.17
0.19, 1.52 0.44 and 211.67 27.06 g/mL, respectively. The solid dispersions improved the solubility of
drug. Furthermore, the solid dispersion II gave more
enhanced drug solubility than did the solid dispersion
I, indicating that the hydrophilic polymer (CMC-Na)
used in this solid dispersion increased it. In particular, the solid dispersion II increased about 2,000fold solubility of tacrolimus.
The dissolution test on the tacrolimus-loaded solid
dispersions was carried out (Fig. 1). The solid dispersion I gave no improved drug solubility compared
to tacrolimus powder. However, the dissolution rate of
drug from solid dispersion II was significantly high as
compared to the powder and solid dispersion I. Our
results suggested that the amounts of hydrophilic
polymer (CMC-Na) must be enough to improve the
dissolution of drug from the solid dispersion. The
initial dissolution rate of drug in the solid dispersion
II increased compared to tacrolimus powder in water.

896

Y.-J. Park et al.

Fig. 3. Differential scanning calorimetric thermograms : A,

tacrolimus powder; B, CMC-Na; C, SLS; D, solid dispersion
I; E, solid dispersion II. The solid dispersion I and II were
composed of tacrolimus/CMC-Na/SLS at the weight ratio of
3/1.2/0.3 and 3/24/3, respectively.

Fig. 1. The dissolution of tacrolimus from solid dispersions.

The solid dispersion I and II were composed of tacrolimus/
CMC-Na/SLS at the weight ratio of 3/1.2/0.3 and 3/24/3,
respectively. Each value represents the mean S.D. (n = 6).

The amounts of drug dissolved from the solid dispersion II for 15 min increased about 10-fold compared to
tacrolimus powder (23.62 4.40 vs.1.99 0.13%). Thus,
this solid dispersion II was useful for improving the
initial dissolution rate of tacrolimus.
The scanning electron micrographs of tacrolimus
powder, solid dispersion I and II were shown in Fig. 2.
Tacrolimus powder (Fig. 2A) appeared as smoothsurfaced rectangular crystalline in shape (Yamashita
et al., 2003). However, the solid dispersion I (Fig. 2B)
and II (Fig. 2C) gave relatively rough surface and
showed that the hydrophilic polymer and surfactant
might be attached to the surface of the drug.
Thermal behavior of drug powder, carriers, solid
dispersion I and II were shown in Fig. 3. The DSC
curve showed that tacrolimus appeared an endothermic peak at about 130oC corresponding to its melting,

indicating its crystalline nature (Fig. 3A) (Sinswat et

al., 2008). The endothermic peak of sodium lauryl
sulfate was observed at about 195C (Fig. 3C). Furthermore, a peak corresponding to drug was also
observed in the solid dispersion (Fig. 3D). Thus, in the
DSC curve of solid dispersion, the characteristic peaks
of tacrolimus were unchanged, indicating the absence
of strong interactions between the drug and carriers
for the preparation of solid dispersion. These results
suggested that tacrolimus was present in no changed
crystallinity in the solid dispersion (Walser et al.,
1997).
The powder X-ray diffractometry patterns were presented in Fig. 4. Tacrolimus gave sharp peaks at diffraction angles showing a typical crystalline pattern
(Fig. 4A) (Yamashita et al., 2003). Furthermore, all
major characteristic crystalline peaks appeared in
drug were observed in solid dispersion (Fig. 4D and
4E). Thus, like DSC results, tacrolimus was present in
no converted crystallinity in the solid dispersion
(Doherty et al., 1987; Okimoto et al., 1997).
From these findings, unlike traditional solid dispersion system, the enhanced solubility and dissolution of
tacrolimus in this solid dispersion was not due to the

Fig. 2. Scanning electron micrographs (600) : A, tacrolimus powder; B, solid dispersion I; C, solid dispersion II. The solid
dispersion I and II were composed of tacrolimus/CMC-Na/SLS at the weight ratio of 3/1.2/0.3 and 3/24/3, respectively.

Tacrolimus-loaded Solid Dispersion

Fig. 4. Powder X-ray diffraction: A, tacrolimus powder; B,

CMC-Na; C, SLS; D, solid dispersion I; E, solid dispersion
II. The solid dispersion I and II were composed of tacrolimus/CMC-Na/SLS at the weight ratio of 3/1.2/0.3 and 3/24/
3, respectively.

transformation of the crystalline form into the amorphous state but due to the attachment of the carriers
to the surface of poorly water-soluble tacrolimus, resulting in changing the hydrophobic drug to hydrophilic form in this solid dispersion.

CONCLUSION
Unlike traditional solid dispersion systems, this
solid dispersion prepared with water, CMC-Na and
sodium lauryl sulfate gave no changed crystalline
form of drug and no environmental pollution. Furthermore, the solid dispersion of tacrolimus/CMC-Na/
sodium lauryl sulfate at the ratio of 3/24/3 improved
about 2,000-fold solubility and 10-fold dissolution of
drug compared to tacrolimus powder. Thus, this solid
dispersion system with water, sodium lauryl sulfate,
citric acid and CMC-Na would be a potential candidate for delivering a poorly water-soluble tacrolimus
with enhanced solubility and no convertible crystalline. Further study on its pharmacokinetics in rats
and stability will be performed.

ACKNOWLEDGEMENTS
This research was supported by the Yeungnam
University research grants in 2008.

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