EVALUATION OF DRUG-EXCIPIENT INTERACTION IN THE ...

1 Acta Poloniae Pharmaceutica drug Research, Vol. 68 No. 3 pp. 423 433, 2011 ISSN 0001-6837 Polish Pharmaceutical SocietyInteraction between drugs and excipients canalter stability and bioavailability of drugs, thereby,affecting its safety and/or efficacy (1). The success-ful formulation of a stable and effective solid dosageform depends on the careful choice of the excipients (2). The pharmaceutical development of soliddosage forms should imply a previous preformula-tion study of the drug and excipients (3). A numberof experimental techniques ( , DSC, FT-IR spec-troscopy, X-ray powder diffraction, ScanningElectron Microscopy, High Performance LiquidChromatography (HPLC), etc.) have been used toinvestigate the INTERACTION between drug and excipi-ents (4, 5). These analyses can be applied to provideinformation on physicochemical properties of sub-stances with respect to compatibility by predictingfuture problems of stability prior to the final soliddosage formulation (6).

2 Celecoxib (CXB), nonsteroidal anti-inflamma-tory drug (NSAID), is the first cyclooxygenase-2(cox-2) inhibitor used in the treatment ofosteoarthritis and rheumatoid arthritis in adultpatients. In spite of its high gastrointestinal (GI) per-meability, CXB shows incomplete and poor oralbioavailability. This could be attributed to lowaqueous solubility of CXB, which causes inadequatedissolution in GI fluids and hence poor absorption,distribution, and target organ delivery (7). A majority of the drug absorption in the gas-trointestinal tract occurs in the small intestine (8).Human colon adenocarcinoma (Caco-2) cells arewell characterized and currently most prevalent cellculture systems as a suitable in vitromodel for theintestinal drug transport study (9).

3 Caco-2 cells arealso used to investigate the impact of excipients ondrug absorption, involved mechanisms, absorptionrelated drug - drug /excipient INTERACTION , and associ-ated cytotoxicities (8).The aim of this study was to prepare CXB con-taining tablet formulations and determine the possi-ble interactions between CXB and some excipients (colloidal silicon dioxide (Aerosil ), microcrys-talline cellulose (Avicel PH 102), lactose anhy-drous; magnesium stearate, cross-povidone and talc)which are commonly used in solid dosage formulations were also investigated to showthe effect of DRUG-EXCIPIENT interactions on dissolu-tion and permeability profiles using human colonadenocarcinoma (Caco-2) OF DRUG-EXCIPIENT INTERACTION IN THE FORMULATION OF CELECOXIB TABLETSSIBEL BOZDA -PEHLIVAN1*, B RSEL SUBA 1,2, MRAN VURAL1, NUR EN NL 1and Y LMAZ APAN11 Department of Pharmaceutical Technology, Faculty of Pharmacy, Hacettepe University, Ankara, Turkey2 Refik Saydam National Public Health Agency, Ankara, TurkeyAbstract.

4 In the present study, the possible interactions between celecoxib and some excipients (colloidal sili-con dioxide (Aerosil ), microcrystalline cellulose (Avicel PH 102), lactose anhydrous, magnesium stearate,cross-povidone and talc) were evaluated by examining the pure drug or DRUG-EXCIPIENT powder mixtures whichwere stored under different conditions (25 2OC, 60% RH 5% RH or 40 2OC, 75% RH 5% RH) and dif-ferent period (30 or 60 days) using DSC, FT-IR and HPLC. In order to investigate the possibility of celecoxib-excipient INTERACTION in aqueous medium, dispersions of the pure drug or drug in physical powder mixture (1:1w/w) in water (1%, w/v) were also prepared and evaluated by FT-IR and HPLC at day 0 and day 7 (40 2OC).The INTERACTION between celecoxib and magnesium stearate or colloidal silicon dioxide were determined in theaqueous dispersions by FT-IR.

5 Different tablet formulations with or without excipients tested were prepared,and assessed for drug dissolution and permeability. Keywords: Celecoxib, DRUG-EXCIPIENT INTERACTION , permeability, Caco-2 cells423* Corresponding author: e-mail: ++903123051241; fax: ++903123114777424 SIBEL BOZDA -PEHLIVAN et was obtained from Fako Pharm. Co.(Turkey). Lactose anhydrous, magnesium stearateand talc were supplied from Merck (Germany).Colloidal silicon dioxide (Aerosil 200) and micro-crystalline cellulose (Avicel PH 102) were pur-chased from Degussa (Germany) and SelectchemieAG (Switzerland), respectively. Cross-povidonewas supplied from GAF Chem. (USA).Caco-2 celllines were purchased from American Type CultureCollection (USA). L-glutamine, fetal bovine serum(FBS) and penicillin G sodium-streptomycin sulfatesolution were provided by Biochrom (Germany).

6 All other chemicals were obtained commercially asHPLC or analytical grade methodsAssay of celecoxibDetermination of CXB was performed byHPLC according to the modified method of Abdel-Hamid et al. (10). The modular HPLC consisted ofHewlett Packard Co. Model 9012 constant flowpump, a Varian Co. Model 9100 autosampler andHewlett Packard Co. chromatography were analyzed on a Phenomenex C18column (5 mm particle size, 25 cm mm ) and CXB was quantitated in a VarianCo. Model 9050 UV detector set at 254 nm. Themobile phase consisted of methanol : 1% acetic acidsolution (80:20, v/v) and was run through the HPLC system at a rate of mL/min at room peak area used throughout this study and thechromatographic method were validated by lineari-ty, sensitivity, precision, accuracy and specifity.

7 Differential scanning calorimetry (DSC)DSC experiments were carried out with aDuPont Ins. 9900 Computer Thermal Analyzer(USA). Samples about 3 mg were weighed inpierced Al pans and scanned under static air over atemperature range of 25 205OC at a heating rate of10OC/min, and the thermograms were reviewed forevidence of any INTERACTION . Entalpy calculationswere completed using TA-60 software ( ).Fourier transform-infrared spectroscopy (FT-IR)Fourier Transform-Infrared Spectra wererecorded on a Nicolet 520 (USA) apparatus usingKBr discs in the range of 4000 400 cm-1. The spec-trum was a mean of ten consecutive scans on thesame methodsPreparation of physical powder mixturesIn order to evaluate the CXB-excipient interac-tion in solid state mixture, physical powder mixturesof drug and some excipients were cellulose (Avicel PH 102) (MCC),colloidal silicon dioxide (Aerosil 200) (CSD), lac-tose anhydrous (LA), magnesium stearate (MS),cross-povidone (CP) and talc (TA) were used asexcipients.

8 The drug : excipient (1:1, w/w, totalamount: 500 g) were firstly homogeneously mixedwith a pestle in a mortar, and blended in a laborato-ry powder mixer at 50 rpm (Erweka AR 400 CubeBlender, Berlin, Germany) for 10 min, then powdermixture was placed in a glass vial with rubber composition of the physical powder mixturesare shown in Table of dispersions of physical powder mix-turesAqueous dispersions of physical powder mix-tures of CXB and the excipients were prepared toexamine the DRUG-EXCIPIENT INTERACTION in aqueousmedium. The dispersions were prepared by additionof CXB (1%, w/v) or DRUG-EXCIPIENT physical pow-der mixtures (1:1, w/w) (1%, w/v) to distilled waterunder continuous stirring until the powders werecompletely dispersed. The dispersions were storedat 40 2OC for 7 days in an oven (Dedeo lu,Turkey) and then filtered through Whatman filterpaper No.

9 41 in order to collect dispersed , the particles were dried under ambientconditions to FT-IR analyses. Preparation of tabletsIn order to assess the CXB-excipient interac-tion in solid dosage form, tablet formulations con-taining excipients as the physical powder mixtureswith different combination were produced. Thecompositions of the tablets prepared are presented inTable 1. Celecoxib, lactose anhydrous, microcrys-talline cellulose and cross-povidone were mixedconsecutively with mortar and pestle, and after-wards blended in a laboratory powder mixer at 50rpm (Erweka AR 400 Cube Blender, Berlin,Germany) for 10 min. This powder mixture wasblended with magnesium stearate and colloidal sili-con dioxide (for formulation F1) or talc (for formu-lation F2) in a powder mixer (mixing time: 5 min).

10 The resulting powder mixture was compressed intotablets at a compression force of 750 N and thespeed of 10 mm/s using an eccentric compressionmachine (Erweka AR 400, Berlin, Germany)equipped with 12 mm circular flat-faced punches toEvaluation of DRUG-EXCIPIENT INTERACTION in the formulation of celecoxib tablets425obtain 692 mg tablets. The resistance to crushing oftablets was 68 N. The diametrical crushingstrength of 20 tablets from each batch was measuredusing a bench-top hardness tester (Schleuniger-2E,Switzerland).Conditions for storage studyOne of the approaches to investigate the DRUG-EXCIPIENT INTERACTION is the conducting short-termstability studies using drug and excipients understressed conditions (11). Thus, in the present study,the effect of temperature and humidity has been con-firmed by examining the samples stored at differentconditions (25 2OC, 60% relative humidity (RH) 5% RH or 40 2OC, 75% RH 5% RH) and at dif-ferent periods (30 or 60 days).