1. CELECOXIB (BCS CLASS II MODEL DRUG) SOLUBILITY ENHANCEMENT BY CYCLODEXTRIN COMPLEXATION. Abhishek Juluri 1,Carmen Popescu 2, Prashanth Manda 1, Leon Zhou 2,Michael A.Repka 1, S. Narasimha Murthy 1 1 Roquette America Inc., 2211 Innovation Dr., Geneva, IL 60134, 2 Department of Pharmaceutical Sciences, University of Mississippi, University, MS 38677 carmen.popescu@roquette.com To evaluate the phase solubility curve profile, stability constant ( K 1:1 ) and the complexation efficiency (CE) Celecoxib a BCS class II compound in native Beta-Cyclodextrin (BCD, Kleptose ® ), Hydroxypropyl Beta-Cyclodextrin (HPB-CD, KLEPTOSE ® HPB), Methylated Beta- Cyclodextrin (Crysmeb ® ) and Beta-Cyclodextrin Sulfobutyl Ethers Sodium Salts (SBE, Captisol ® ). To evaluate the complex formation and stability of liquid and lyophilised samples Objectives Material and Methods Summary Stability Constants (K 1:1 ) and Complexation Efficiency (CE) Results Celecoxib (CELE) is a cyclooxygenase-2 (COX-2) inhibitor used in the treatment of osteoarthritis, rheumatoid arthritis, acute pain, dysmenorrhoea and anticancer therapy. Cele being a potent drug is classified as a BCS class II compound whose oral bioavailability is highly limited owing to its poor aqueous solubility. The primary aim of this project was to examine the abilities of native and modified cyclodextrin to enhance celecoxib solubility by CD complexation. where m is the slope of the curve of the drug solubility versus cyclodextrin concentration determined by linear regression and S 0 is the drug solubility in DI water as determined after 7 days of mixing Table 1. CDs Relevant information Figure 2. Phase-solubility profiles of Celecoxib in BCD,HPB-CD, Crysmeb and SBE. All the four CDs in the phase solubility diagram (Fig. 2) are displaying a linear solubility increase as a function of molarity increase indicating an A L type complexation. The affinity (stability) constants ( K 1:1 ) and complexation efficiencies ( CE) of each compound were calculated based on the parameters of the phase solubility graphs. The values are shown in Table 3. Table 2. API-cyclodextrin stability constants and complexation efficiencies Introduction References The phase solubility profile, K 1:1 and CE of Celecoxib were evaluated by adding excess amount of the API to different concentrations of BCD, HPB-CD, Crysmeb and SBE (as in Table 1) in deionized water. Samples were evaluated at day 1, 3 (data not shown) and 7 for saturation solubility in order to determine the necessary mixing time at 25 o C. At equilibrium, samples were filtered using Millipore (0.45μm) syringe filter ( as in Fig.1). The filtrates were analyzed using HPLC method for Celecoxib after appropriate dilution.. Differential scanning calorimeter (DSC) (Perkin-Elmer Diamond DSC instrument, Norwalk, CT) studies were carried to evaluate the complex formation. Stability studies were also carried out for a period of 30 and 60 days at 30 0 C and 45 0 C. Figure 3. Celecoxib complex stability evaluation at 30 ⁰ and 45 ⁰ C. An A L type phase solubility was observed with all the cyclodextrins. A high complexation efficiency and stability constants were obtained for Crysmeb and SBE. Celecoxib solubility increased by aproximative 713,182, 47 and 30 times in presence of Crysmeb, SBE, HPBCD and BCD respectively, compared to its solubility in water. The stability of the complexes formed in presence of Crysmeb>SBE> HPBCD>BCD following 30 and 60 days at 30 ⁰ C and 45 ⁰ C. The solubility enhancement and stability constant of CELE by Crysmeb may be an yet to come solution for overcoming the solubility issue which may enhance the oral bioavailability. The complex formation is conformed by Celecoxib peak disappearance in DSC thermograms ( fig.4). However, HPBCD and BCD can also be used by the formulator based on the fact that there are many existing drugs on the market formulated with them. Fig.1 Phase solubility experiment design Table 3. Celecoxib Solubility Enhancement. 1. C Popescu, C Wiley, L Zhou, P Lefevre, and L Felton. Influence of b-Cyclodextrin Side Chain Substitutions on the Complexation Efficiency of Two Model BCS Class II Compounds. CyclodextrinMWConcentrations (mM) BCD11352,4,8,12,16 Crysmeb11915,10,20,30,40,50 HPBCD14005,10,20,30,40,50 SBE21605,10,20,30,40,50 Conc. of BCD (M) Solubility Increase ratio (mg/mL, S/S 0 ) Conc. of HPBCD (M) Solubility Increase ratio (mg/mL, S/S 0 ) Conc. of Crysmeb (M) Solubility Increase ratio (mg/mL, S/S 0 ) Conc. of SBE (M) Solubility Increase ratio (mg/mL, S/S 0 ) 01010101 0.0026.7840.0054 61.1170.00514.714 0.00415.4050.019 119.5820.0132.563 0.00835.1290.02180.02238.0210.0268.411 0.01236.2370.03270.03372.6650.0391.956 0.01630.4560.04360.04518.6890.04137.310 0.05480.05713.4680.05182.309 Summary of Celecoxib-Cyclodextrin Stability constant (K 1:1) and Complexation efficiencies (CE) Cyclodextrinm (Slope)S 0 2 (M)K 1:1 CE Crysmeb 0.00144.562E-074833.1700.0022 HPβ-CD 0.00044.562E-07877.1760.0004 β-CD 0.00174.562E-0713897.5460.0063 SBE-CD 0.00174.562E-073732.8510.0017 Figure 4. DSC Thermograms of Celecoxib Solid Dispersions