Enhanced dissolution rate of celecoxib using PVP a

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R E S E A R C H A R T I C L E

Enhanced dissolution rate of celecoxib using PVP and/or HPMC- based solid dispersions prepared by spray drying method

Jung Hwan Lee^•Min Jeong Kim^• Hyeon Yoon^•Cho Rok Shim ^• Hyun Ah Ko^• Sun Ah Cho^•Dongwon Lee^•Gilson Khang

Received: 12 February 2013 / Accepted: 27 March 2013 / Published online: 14 April 2013 Ó The Korean Society of Pharmaceutical Sciences and Technology 2013

Abstract Celecoxib with low solubility and high permeability (BCS class II) in water is a non-steroidal anti- inflammatory drug used in the treatment of pain and inflammation, associated with rheumatoid arthritis, and several other inflammatory disorders. Also, it is a selective cyclooxygenase 2 inhibitor with low water solubility and high crystallinity. The objective of this study was to improve dissolution rate of celecoxib which was water- insoluble drug. Solid dispersions were prepared by spray drying as the solvent evaporation method. The dissolution behavior of solid dispersions was compared with Celeb- rex^Ò(Pfizer) as a control group in simulated gastric juice (pH 1.2, 0.5 % SLS. The characterization of the prepared solid dispersions is analyzed by scanning electron microscope, powder X-ray diffractometer, Fourier transform infrared spectroscopy and reverse phase-high performance liquid chromatography The best formulation was SD 8 in this study. It was the cumulative release of 97 % at 120 min. This study suggests that the solubility and bioavailability of poorly water-soluble celecoxib improved through the prepared solid dispersions by spray drying method.

Keywords Amorphous Celecoxib Encapsulation Solid dispersion Spray drying Water-soluble polymer

Introduction

IUPAC name of celecoxib is 4-[5-(4-methylphenyl)-3-(tri- fluoromethyl) pyrazol-1-yl]benzenesulfonamide (Rose et al.

2000). Chemical structure of celecoxib is shown in Fig.1.

The pharmacokinetic characterization of celecoxib is including bioavailability of 40 %, half-life by 11 h, protein binding of 97 %, hepatic metabolism of mainly CYP2C9 and excretion of renal 27 % and faecal 57 % (Paulson et al.

1999; Shi and Klotz2008). Also, the chemical formula is C₁₇H₁₄F₃N₃O₂S, and molecular weight is 381.373 g/mol.

Typically, celecoxib is selective cyclooxygenase 2 inhibitor (COX-2) and non-steroidal anti-inflammatory drug (NSAID) (Goldenberg1999). Cyclooxygenase (COX) as enzyme changing arachidonic acid to prostaglandin is including isoform of COX-1 and COX-2 (Hoozemans et al.

2008; Axelsson et al. 2010). Anti-inflammatory drugs are largely classified with steroidal anti-inflammatory drug (SAID) and NSAID (Luu et al. 2001). Unlike SAID, NSAID cannot interact on leukotriene, can only interact on enzyme synthesizing prostaglandin (Colin 1991). Thus, NSAID has fewer side effects than SAID.

Celecoxib belongs to biopharmaceutical classification system (BCS) II and has a very low solubility in hydrophilic medium (Yazdanian et al. 2004). BCS category is assorted by I–IV. BCS I class has a high solubility and permeability. BCS II class has a low solubility and high permeability. BCS III class has a high solubility and low permeability. BCS IV class has a low solubility and permeability. The solubility of poorly water-soluble drugs has increased by various methods such as decreasing crystallinity of drug, micro-sizing method of powder, solid dispersion, self-microemulsifying drug delivery system (SMEDDS) and increasing surface area (Craig 2002; Cui et al.2005). It has been reported that solid dispersions can J. H. Lee M. J. Kim H. Yoon C. R. Shim

H. A. Ko S. A. Cho D. Lee G. Khang (&)

Department of BIN Fusion Technology, Department of Polymer- Nano Science and Technology and Polymer BIN Research Center, Chonbuk National University, 567 Baekje-daero, Deokjin, Jeonju 561-756, Korea

e-mail: [email protected] DOI 10.1007/s40005-013-0067-2

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improve oral drug absorption by enhancing drug solubility (Urbanetz and Lippold2005). There are many preparation methods of solid dispersion such as co-evaporation, freeze- drying, co-grinding, co-precipitation and spray drying. We used spray drying method as a solvent evaporation technique to improve solubility of celecoxib in this study. The spray drying method was used to generate amorphous state from crystalline state. Furthermore, it is a potential technique of decreasing particle size and increasing surface area in particle engineering. In spray drying method, carriers are the most significant parameter. Water soluble polymers are commonly used in carriers of solid dispersion in spray drying method (Paudel et al.2012).

In this study, hydroxypropyl methyl cellulose (HPMC) and poly vinyl pyrrolidone (PVP) well-known as water soluble polymers are used in carriers of solid dispersions (Won et al.2005; Karavas et al.2007; Konno et al.2008). Phar- maceutical cellulosic polymers are mainly semi-synthetic–

alkyl and hydroxyl alkyl substituted derivates of natural cellulose such as methyl cellulose (MC), ethyl cellulose (EC), HPMC and hydroxypropyl cellulose (HPC), or the esters of these polymers such as cellulose acetate phthalate (CAP), HPMC phthalate (HPMC-P) and HPMC acetate succinate (HPMC-AS) (Ishikawa et al.2000). The physicochemical properties of these polymers depend on the degree of substitution for methyl or propyl group. HPMC has widely used in a carrier in spray drying method. The

physicochemical property of polymer ranging from high to low viscosity, solubility and surface activity was determined by degree of methyl and hydroxypropyl substitution of the hydroxyl groups (Kavanagh and Corrigan2004). In partic- ular, PVP which is a hydrophilic polymer of N-vinyl pyrrolidone (povidone) is widely used in carrier (Fukuda et al.

1986). PVP with several molecular weights ranging from 2.4 kDa (PVP K-12) to 100 kDa (PVP K-90) reported that has been used in carrier on solid dispersion preparations (Kubo et al. 2011). PVP K-90 has a very high viscosity.

Especially, PVP K-30 was mainly used in carrier of solid dispersion (Chokshi et al.2005). Also, sodium lauryl sulfate (SLS) reported that has been used in a surfactant, and widely used to prepare nano-suspensions (Dolenc et al.2009).

The aim of this study is to improve the solubility of a poorly water-soluble drug. Solid dispersions were prepared by spray drying method from ratios of HPMC, PVP and SLS. We conducted in vitro test to confirm dissolution behavior of solid dispersions, pure celecoxib (API) and Celebrex^Ò(Pfizer).

Materials and methods Materials

Celecoxib (Aarti Drugs Ltd., India) used in a model drug in this study presented by Kolon Pharmaceutical Inc. Carriers Fig. 1 Structure of celecoxib

(a), PVP (b), HPMC (c) and possible hydrogen bonding between celecoxib and PVP/

HPMC (d)

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that are used in a preparation of solid dispersion were HPMC (Whawon Pharm, Korea), and PVP (BASF, Lud- wigshafen, Rheinland-Pfalz, Germany). Celebrex^Ò(Pfizer, Korea) and pure celecoxib (API) were used as a control group. These are capsule forms. All other materials and reagents were used a high performance liquid chromatography (HPLC) grade.

Preparation of solid dispersion using spray drying method

Celecoxib, HPMC and PVP were taken in ratios presented in Table1. Celecoxib and HPMC were dissolved in a co- solvent of methanol, and celecoxib and PVP were dissolved in a co-solvent of methanol. The prepared all solutions stirred for 30 min, and then prepared solid dispersions using spray dryer (Spray Dryer SD-1000, Eyela, Tokyo, Japan). Temperature conditions of spray dryer for solid dispersions were in-let temperature of 140°C and out-let temperature of 85 ± 5°C. Pressure condition of spray dryer was 10 kPa, and flow rate was 0.30 m³/min, pump speed was 3 ml/min. The prepared solid dispersions stored in a desiccator.

Encapsulation efficiency

Solid dispersions of 5 mg as celecoxib were dissolved in 20 ml of methanol as proportions between drug and polymer, and then filtering through a 0.45 lm PTFE filter (Tokyo Roshi Kaisha, Ltd., Tokyo, Japan). Encapsulation efficiency of solid dispersions was measured by RP-HPLC at a wavelength of 238 nm. Encapsulation efficiency was defined by the actual amounts of celecoxib in the prepared

solid dispersions according to the following Eq. (1) (Ma- nojlovic et al.2008);

Encapsulation Efficiency¼ Actual Drug Loading Theoretical Drug Loading

100 %:

ð1Þ Confirmation of surface morphology

The surface morphology characterization of celecoxib, Celebrex^Ò, carriers and the prepared solid dispersions was observed by scanning electron microscope (SEM) (LV- SEM, S-3000N, Hitachi Co., Tokyo, Japan). We fixed a sample on a carbon fiber tape, and were coating sample by platinum–palladium during 100 s under argon gas at twice.

The samples were observed on 15.0 kV.

Crystallinity studies

Powder X-ray diffraction (PXRD, MAX 2500 X-ray diffractometer, Rigaku, Japan) analyzed the crystallinity of celecoxib, Celebrex^Ò, carriers and the prepared solid dispersions. The step size is 0.02°. The angle of PXRD analysis is from 5° to 50° at scan speed of 4°/min on 30 mA, 40 kV conditions.

Thermal analysis

Thermal studies of crystallinity were performed by DSC 4000 (Perkin Elmer Inc.). The samples of *5 mg were sealed in aluminum pans and heated at a rate of 10°C/min over a temperature range from 0 to 180°C.

Structural analysis

FT-IR assay conducted to confirm changes in the physicochemical characterization in solid dispersions (Perkin Elmer, Waltham, Massachusetts, USA) over a spectra range of wavenumbers from 4,000 to 650 cm^-1. The pellet used FT-IR analysis was prepared by KBr disk method that is ratios of KBr: sample = 100:1 (Meyer et al.2004).

Dissolution studies

Dissolution study was performed by USP dissolution apparatus II (paddle method) with 900 ml of the first dissolution medium (the simulated gastric juice pH 1.2, 0.5 % SLS) specified by USP dissolution medium apparatus at 37 ± 0.5°C and the paddle rotating speed of 50 rpm using dissolution tester (DST-610, Fine Sci, Instr, Korea). Dis- solution study of Celebrex^Òas control group and the prepared solid dispersions was performed by the first fluid (the Table 1 The preparation formulation of solid dispersions using spray

dryer

Component: Ratios (drug:polymer)

Drug Polymer Surfactant

Batch Celecoxib PVP

K-30 HPMC E5

Sodium lauryl sulfate (%)

SD 1 1:1 1 1 0.5

SD 2 1:2 2

SD 3 1:3 3

SD 4 1:1 1

SD 5 1:2 2

SD 6 1:3 3

SD 7 1:2 1 1

SD 8 1:3 1 2

SD 9 1:3 2 1

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simulated gastric juice pH 1.2, 0.5 % SLS). Dissolution fluid was setting up to each 900 ml on the dissolution bath.

The sample was taken each 1 ml for 5, 10, 15, 30, 45, 60, 90 and 120 min as the predetermined time from the dissolution fluid in bath, and then refilled the first fluid of 1 ml in bath. The taken sample on the dissolution bath was analyzed by reverse phase-high performance liquid chromatography (RP-HPLC) after filtering by 0.45 lm PTFE membrane filter.

RP-HPLC analysis

We confirmed the dissolution behavior of celecoxib through RP-HPLC system composed with NS-4000 HPLC system (Futecs, Korea) and NS-6000 autosampler (Futecs, Korea). The flow rate of mobile phase and sample was 1.0 ml/min. The reverse-phase column used in RP-HPLC system was 5 lm C₁₈ column (250 9 4.6 mm, Bischoff Chromatography). The wavelength of UV detection was 238 nm, and the injection volume of sample was 100 lL whenever measured it. The mobile phase of RP-HPLC system was prepared by the proportion of acetoni- trile:deionized water = 6:4 (v/v%). The mobile phase was used after removal of the residual gas by sonication.

Data statistical analysis

The results of HPLC were analyzed by MultiChro^TM V 5.03 (Yullin Technologies). The chromatogram peaks were integrated to quantify the release degree of drug by Mul- tiChro^TMV 5.03. Also, the experimental groups were three groups to reduce the deviation of release data (n = 3).

Results and discussion

Encapsulation efficiency of prepared solid dispersions The encapsulation efficiency of the prepared solid dispersions in proportions of polymers was shown by Table2. It was different by proportions of polymer in solid dispersions. Solid dispersions with the low encapsulation efficiency were due to non-encapsulated drug in polymer, whereas solid dispersions with the high encapsulation efficiency were great encapsulated in polymer. The encapsulation efficiency was enhanced by increasing ratios of polymer.

As results of the encapsulation efficiency, it has been reported that these results were caused by a solubility difference as solvents, a difference as encapsulated contents of drug by solvent-evaporation rate and a loss difference of drug and polymer by spray drying processing.

Also, it is considered that solid dispersions with the rela- tively low encapsulation efficiency were due to well non- loading drug in carriers. On the other hands, it is considered that the high encapsulation efficiency of solid dispersions on drug was well encapsulated in carriers (Seong et al. 2002). Thus, the encapsulation efficiency of solid dispersions was increased by increasing ratios of polymer.

Morphological studies

The study of SEM was carried out to confirm the surface morphology of celecoxib, polymers and solid dispersions.

These were shown in Fig.2. Celecoxib had a crystalline rod-shape, and the size was between 100 and 200 lm. PVP used in a carrier had a globular shape. And the size of PVP was between 50 and 70 lm. Also, HPMC used in a carrier had bigger size than PVP, and the size was between 50 and 100 lm. Solid dispersions of SD 1, 2 and 3 appeared to have almost round shape such as shape of PVP, and the size of them significantly decreased from 1 to 10 lm. More- over, solid dispersions of SD 4, 5 and 6 disappeared to have an initial shape of HPMC, but the size largely decreased from 1 to 10 lm. And solid dispersions of SD 7, 8 and 9 appeared to have an original shape of PVP and HPMC, the size dramatically decreased from 1 to 10 lm.

In solid dispersions of SD 1, 2 and 3, the original morphology characterization of drug and polymer disappeared, and novel morphology characterization appeared by the spray drying method using high temperature and pressure. In this case of solid dispersions as SD 4, 5 and 6, the original shape of drug and polymer disappeared, and appeared new morphological shape. Also, in solid dispersions as SD 7, 8 and 9, these had all shape of the prepared solid dispersions by only PVP, only HPMC, and both PVP and HPMC in carriers of solid dispersions.

Moreover, these results of SEM are considered that celecoxib as crystalline drug is changed to amorphous state by high drying and fast spray rate during spray drying.

Also, there is no significant difference of the particle size on solid dispersions, and it is considered due to spray drying under constant conditions. It has been reported that

Table 2 The encapsulation efficiency of solid dispersions

Batch 1 2 3 4 5 6 7 8 9

Encapsulation efficiency (%) 85.6 90.1 94.5 83.3 86.7 89.9 88.4 87.6 85.7

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the spray drying method is leading to a novel morphological shape of solid dispersions (Lee et al.2008).

Physicochemical characterizations of solid dispersions FT-IR assay was conducted to confirm the physicochemical characterization of celecoxib, carriers and solid dispersions as shown in Fig.3. As shown in Fig.3, FT-IR result of celecoxib appeared that symmetric and un-symmetric

stretching peaks of S=O group on sulfonamide (SO₂NH₂) were at both 1,347 and 1,164 cm^-1. Also, double peak at 3,350 and 3,250 cm^-1, and peak of 1,550 cm^-1 were appeared in FT-IR result of celecoxib, these peaks were the stretching and bending peak of N–H group on sulfonamide (SO₂NH₂). The C=C peak of aromatic ring group appeared at 1,650–1,350 cm^-1.

PVP appeared an initial peak of C=O at 1,725–1,705 cm^-1, also appeared an initial peak of cyclic

(a) Celecoxib (b) PVP (c) HPMC

(d) SD 1 (e) SD 2 (f) SD 3

(g) SD 4 (h) SD 5 (i) SD 6

(j) SD 7 (k) SD 8 (l) SD 9

Fig. 2 The surface morphology of celecoxib, polymers and solid dispersions

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amide at 1,705–1,690 cm^-1. Moreover, peak of CH₂ appeared at 1,465 cm^-1. The N–H peak of cyclic lactam on PVP appears at 3,700–3,200 cm^-1.

The initial stretching peak of O–H group on HPMC appeared at 3,400–3,300 cm^-1, peak of C–O–H group appeared at 1,440–1,220 cm^-1. At 1,260–1,000 cm^-1, peak of C–O group appeared.

Celecoxib appeared to have an initial peak of sulfonamide. We confirmed that the prepared solid dispersions by spray drying processing as a solvent evaporation method disappeared symmetric and un-symmetric stretching peaks of S=O group on an initial sulfonamide of celecoxib, also disappeared original stretching and bending peaks of N–H group on celecoxib.

The prepared solid dispersions by celecoxib and PVP as SD 1, 2 and 3 were shown in Fig.3. The initial peak of

sulfonamide on celecoxib disappeared, and peaks of cyclic amide and C=O on PVP strongly appeared by increasing contents of PVP. These results indicated that celecoxib was encapsulated in PVP, and initial peaks of PVP strongly appeared by increasing its contents.

Solid dispersions of SD 4, 5 and 6 were shown in Fig.3. In this case of the prepared solid dispersions by celecoxib and HPMC, an initial peak of sulfonamide on celecoxib disappeared, and peaks of O–H, C–O–H and C–O group on HPMC strongly appeared by increasing ratios of HPMC. It indicated that celecoxib was encapsulated in HPMC, also initial peaks of HPMC strongly appeared by increasing its ratios.

FT-IR results on the prepared solid dispersions of celecoxib by ratios of PVP and HPMC as SD 7, 8 and 9 were shown in Fig.3. Increasing PVP and HPMC as water soluble polymers, initial peaks of sulfonamide on celecoxib disappeared. Moreover, peaks of cyclic amide and C=O on PVP strongly appeared by increasing its ratios, peaks of O–

H, C–O–H and C–O on HPMC also appeared by increasing its ratios. As these results, celecoxib was encapsulated by water soluble polymers of PVP and HPMC used as carriers.

The initial peaks of polymers used as carriers strongly appeared by increasing ratios of polymers.

In results of FT-IR, all solid dispersions were confirmed that the initial peaks of sulfonamide on celecoxib disappeared by spray drying. It is considered that initial sulfonamide peaks of celecoxib disappears due to hydrogen bonding between celecoxib and PVP, celecoxib and HPMC, and among celecoxib, PVP and HPMC. Therefore, it is considered that the amorphous state of solid dispersions is due to the disappeared sulfonamide peak of celecoxib. Also, it has been reported that the re-crystallinity of solid dispersions is interrupted by PVP and HPMC. These results are considered because of hydrogen bonding between drug and polymer (Ahn et al. 2004).

4000 3500 3000 2500 2000 1500 1000

% Transmittance

Wavenumbers (cm^-1) ( SD 3 )

( SD 2 )

(celecoxib) (PVP) (HPMC) ( SD 1 ) ( SD 9 ) ( SD 8 ) ( SD 7 ) ( SD 6 ) ( SD 5 ) ( SD 4 )

Fig. 3 FT-IR spectra of celecoxib, PVP, HPMC and solid dispersions as SD 1, 2, 3, 4, 5, 6, 7, 8 and 9

10 20 30 40 50

Intensity

2θ (degrees)

(Celecoxib) (Celebrex®) ( PVP ) ( HPMC ) ( SD 3 ) ( SD 2 ) ( SD 1 ) ( SD 9 ) ( SD 8 ) ( SD 7 ) ( SD 6 ) ( SD 5 ) ( SD 4 )

Fig. 4 X-ray diffraction of Celebrex^Ò, celecoxib, polymers and solid dispersions

60 80 100 120 140 160 180

( SD 9 ) ( SD 8 ) ( SD 7 ) ( SD 6 ) ( SD 5 ) ( SD 4 ) ( SD 3 ) ( SD 2 ) ( SD 1 ) (HPMC) (PVP)

Heat Flow

Temperature (°C) (celecoxib)

(Celebrex^®)

Fig. 5 DSC thermograms of celecoxib, PVP, HPMC and solid dispersions as SD 1, 2, 3, 4, 5, 6, 7, 8 and 9

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Crystallinity of solid dispersions

PXRD assay was performed to confirm the crystallinity of Celebrex^Ò, celecoxib, polymers and solid dispersions. The results of PXRD were shown in Fig.4. As shown in Fig.4, celecoxib appeared to have most high crystallinity of all excipients. Also, the crystallinity of Celebrex^Òwas lower than celecoxib, but it was higher than the crystallinity of polymers and solid dispersions. Both PVP and HPMC did not appear the crystalline peak unlike celecoxib. Thus, it is confirmed that carriers are amorphous state. Also, it confirmed that the initial crystalline peak of celecoxib disappeared on solid dispersions. Solid dispersions are amorphous state.

DSC study conducted to confirm the melting point of celecoxib, polymers and solid dispersions as shown in Fig.5. The endothermic peak of melting point on celecoxib was observed at about 165°C, also Celebrex^Òappeared to have smaller endothermic peak than peak of celecoxib.

However, the endothermic peak of celecoxib on all solid dispersions was not confirmed in DSC results. The crystallinity of celecoxib in solid dispersions disappeared by spray drying.

Also, it confirmed that the initial crystalline peak of celecoxib disappeared on solid dispersions as shown in results of PXRD. It is considered that the prepared solid dispersions are amorphous state. These results are considered that celecoxib is well encapsulated in polymers. In results of DSC, it is considered that the crystallinity of celecoxib in solid dispersions disappeared by spray drying.

As results of XRD and DSC, it confirmed that celecoxib was crystalline state. However, the prepared solid dispersions by spray dryer were amorphous state. It is considered that amorphous state of solid dispersions is considered due to high temperature and pressure during spray drying. It has been reported that the prepared solid dispersions by spray drying are changing crystalline state to amorphous state (Boghra et al.2011).

Dissolution studies

API and Celebrex^Òwere used as a control group. Disso- lution studies were conducted in simulated gastric juice (pH 1.2, SLS 0.5 %) according to USP apparatus II (paddle method). As shown in Figs.6, 7 and 8, Celebrex^Ò of a commercial drug used as a control group gradually released without capsule effects for 2 h, and was released by 52 % at 120 min. Also, API of celecoxib used as a control group was released by 32 % at 120 min. Furthermore, API and all mixtures were slowly released by capsule effects for an initial 5 min.

As shown in Fig.6, the dissolution rate was increased by increasing ratios of a carrier as 1:1, 1:2 and 1:3 on the

0 20 40 60 80 100 120

0 20 40 60 80 100

Cumulative release (%)

Time (min) (celecoxib)

( SD 1 ) ( SD 2 ) ( SD 3 )

(celebrex^®)

Fig. 6 Release behavior of solid dispersions as SD 1, 2 and 3 in simulated gastric juice (pH 1.2, 0.5 % SLS)

0 20 40 60 80 100

(celecoxib) ( SD 4 ) ( SD 5 ) ( SD 6 )

0 20 40 60 80 100 120

Time (min) (celebrex^®)

0 20 40 60 80 100

(celecoxib) ( SD 7 ) ( SD 8 ) ( SD 9 )

0 20 40 60 80 100 120

Time (min) (celebrex^®)

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prepared solid dispersions by PVP. In this case of solid dispersions as SD 1, 2 and 3, the cumulative release at 120 min was enhanced by 58, 68 and 79 %. Thus, we confirmed that the dissolution rate of solid dispersions was improved as comparing to API and Celebex^Ò(Pfizer) used as control groups.

The dissolution behavior of the prepared solid dispersions by HPMC was shown in Fig.7. We confirmed that the dissolution rate was increased by increasing ratios of HPMC. Moreover, in the prepared solid dispersions from proportions of celecoxib:HPMC = 1:1, 1:2 and 1:3, the cumulative release of solid dispersions as SD 4, 5 and 6 was released by 79, 91 and 89 % at 120 min. These results are considered that the cumulative release at 120 min of the prepared solid dispersions by HPMC is higher than cumulative release of the prepared solid dispersions by PVP.

The prepared solid dispersions by proportions as celecoxib:PVP:HPMC = 1:1:1, 1:1:2 and 1:2:1 was released by 77, 97 and 94 % as shown in Fig.8. The cumulative release at 120 min of the prepared solid dispersions by PVP and HPMC as SD 7, 8 and 9 was higher than the cumulative release of API and Celebrex^Ò. It is considered that the dissolution rate of the prepared solid dispersions by both PVP and HPMC is much higher than the dissolution rate of the prepared solid dispersions by only PVP or HPMC. Therefore, it is possible to improve the release of celecoxib effectively as ratios of PVP and HPMC.

As results of in vitro test, it is considered that the dissolution rate is affected by crystallinity and particle size of drug. Also, it is considered that the dissolution rate of celecoxib is improved by spray drying. This is considered due to the physicochemical change of hydrogen bonding between drug and polymer during spray drying (Paradkar et al.2004).

Conclusion

The aim of this study was to improve the dissolution rate of celecoxib. Therefore, we prepared solid dispersions of celecoxib with water soluble polymers such as PVP and HPMC using spray drying method. API and Celebrex^Ò were used as control groups. Also, it is confirmed that the particle size of celecoxib reduced and crystalline state of celecoxib changed to amorphous state by SEM assay.

Amorphous state of solid dispersions is confirmed through PXRD and DSC assays. Also, we confirmed the formation of salts on hydrogen bonding and chemical interactions between celecoxib and polymer by FT-IR assay. In the dissolution study, the prepared SD 8 and 9 from ratios of PVP and HPMC appeared the highest dissolution rate. It is considered due to the encapsulation degrees of celecoxib in

polymers. These results are suggested that solid dispersions by spray drying method are very effective to enhance the dissolution rate of celecoxib. Thus, the prepared solid dispersions by spray drying method have a fantastic potential in the pharmaceutical oral formulation.

Acknowledgments This research was supported by WCU (R31- 20029).

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