*2.1. Materials*

LXP dihydrate was purchased from Fujian Hui Tian biological Pharmaceutical Co., Ltd. (99.1% purity, China). Loxonin® tablets were purchased from Daiichi Sankyo Co., Ltd. (Tokyo, Japan). Ketoprofen was purchased from Sigma (St. Louis, MO, USA). Microcrystalline cellulose SH-101 and corn starch were supplied by Sunhere Pharmaceutical Co., Ltd. (Huainan, China). Hydroxypropylmethyl cellulose (Methocel E5LV) and Surelease® E-7-7050 (aqueous ethyl cellulose dispersion) were supplied by Colorcon Ltd. (Dartford, Kent, UK). Hard gelatin capsules were from Suzhou Capsugel Ltd. (Suzhou, China). Other chemicals were of reagen<sup>t</sup> grade or higher grades.

### *2.2. HPLC-Assay for LXP and CA Contents*

HPLC methods were used for the determination of LXP and CA. Chromatograph was carried out on Shimadzu LC-2030 (Shimadzu, Japan), equipped with an autosampler and an SPD-20A UV detector. The mobile phase used for the determination of LXP consisted of a mixture of methanol-water-acetic acid-triethylamine (600:400:1:1, *v*/*v*). Separation was achieved by applying an Inertsil C18 column (5 μm, 4.6 × 150 mm, Shimadzu, Japan), and the chromatogram was recorded at 223 nm. The limit of determination (LOD) and limit of quantitation (LOQ) for LXP were 0.03 and 0.1 μg/mL respectively. The mobile phase performed for the determination of CA was carried out with one part isopropanol and 999 parts 0.018 M phosphate buffer, adjusted to pH 2.5 with phosphoric acid. An Inertsil C18 column (5 μm, 4.6 × 150 mm, Shimadzu, Japan) was employed to separate the CA content. The flow rate was 1 mL/min, and the column temperature was controlled at 40 ◦C with the UV detection at 210 nm. The LOD and LOQ for CA were 0.2 and 0.6 μg/mL respectively. In addition, the calibration curve over the concentration range of 0.6–60 μg/mL had a regression coefficient of 0.9996.

### *2.3. Solubility*/*p<sup>H</sup> Profiles of LXP*

Solubilities of LXP in different pH media were determined by adding excess of LXP to different buffer solutions: hydrochloric acid solutions (pH 1.2, 2.2), phosphate buffers (pH 3.0, 3.5, 4.0, 4.5 and 6.8). After vibrated at 25 ◦C for 24 h in a constant-temperature shaker (SHZ-82, Guohua Co., Ltd., Changzhou, China), 2 mL of the saturated solution was filtered through a membrane filter, and was diluted to avoid crystallization. Sample was determined by HPLC method.

### *2.4. Preparation of Drug-Loaded Pellets*

The core consisted of loxoprofen sodium (37.1%, *w*/*w*), microcrystalline cellulose (41.9%, *w*/*w*), corn starch (19.9%, *w*/*w*), and talc (1.1%, *w*/*w*). Briefly, the mixture was blended in an ERWEKA mixer (Type AR YB5, Heusenstamm, Germany) at a speed of 40 rpm for 30 min. Then it was kneaded with the ethanol water solution (30%, *v*/*v*) in a laboratory kneader (Type LK5, Heusenstamm, Germany) for 10 min. The obtained moist mass was extruded at a speed of 500 rpm through a stainless steel barrel with a die of 0.8 mm diameter. Then, 300 g of the extrudates were processed in a 23 cm radial cut plate of spheronizer (JBZ-300, Liaoning New Drug Research Institute, China) at 1000 rpm for 10 min. The obtained pellets were collected on a Teflon tray and were dried in a hot oven at 60 ◦C for 24 h to remove the residual water and ethanol. Pellets with fraction size between 800 and 1250 μm were used for the following procedure.

### *2.5. Preparation of Sustained-Release Pellets*

#### 2.5.1. Preparation of the Dissolution-Rate Controlling Layer

Methocel E5 LV was added to purified water to achieve a hydroxypropylmethyl cellulose concentration of 4% (*w*/*w*). Then the solution was mixed with critic acid, with a concentration range from 0% to 6% (*w*/*w*), and was plasticized with PEG 6000 (0.5%, *w*/*w*) for 40 min [9]. Then, talc was added to the polymer mixture at a concentration of 2.5% (*w*/*w*). The aqueous suspension was stirred during the coating process. Using bottom spray with a Wurster insert, 50 g pellets were coated in a laboratory-scale fluid bed coater (Hanse, Changzhou, China). The process parameters were as follows: inlet temperature 50 ◦C, material temperature 40 ◦C, atomization pressure 0.15 MPa, spray rate 0.8 mL/min, and air flow rate 35 m<sup>3</sup>/h.

### 2.5.2. Preparation of the Diffusion-Rate Controlling Layer

ADEC was separately used as the diffusion-rate controlling layer. Mainly, aqueous dispersion of Surelease® was diluted in purified water to achieve a solid content of 15% (*w*/*w*), and was stirred for 45 min before coating. Then the aqueous dispersion was sprayed on pellets sub-coated with the dissolution-rate controlling layer in the same equipment. The process parameters for ADEC coating were as follows: inlet temperature 54 ◦C, material temperature 42 ◦C, atomization pressure 0.18 MPa, spray rate 1.0 mL/min and air flow rate 40 m<sup>3</sup>/h. After the coating process, pellets were cured in a hot oven at 60 ◦C for 16 h.
