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Enhanced Solubility and Dissolution Rate of Raloxifene Using Cycloencapsulation Technique

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Enhanced Solubility and Dissolution Rate of Raloxifene Using Cycloencapsulation Technique Journal of Analytical & Pharmaceutical Research Enhanced Solubility and Dissolution Rate of Raloxifene using Cycloencapsulation Technique Research Article Abstract Volume 2 Issue 5 - 2016 The aim of this study was to improve the water solubility of raloxifene by aqueous solution and solid state was evaluated by the phase solubility diagram, powdercomplexing X-ray it diffractometer,with sulphobutylether-β-cyclodextrin. Fourier-transform infrared Inclusion spectroscopy, complexation nuclear in magnetic resonance, scanning electron microscopy, hot stage microscopy and transmission electron microscopy. The inclusion complex behavior of raloxifene 1Department of Pharmaceutical Technology (Formulation), National Institute of Pharmaceutical Education and Research, classifiedand sulphobutylether-β-cyclodextrin as AL-type curve, indicating the were formation examined of 1:1 by stochiomatric molecular modelinginclusion India method. The phase solubility diagram with sulphobutylether-β-cyclodextrin was complex. The apparent solubility constants calculated from phase solubility 2 -1 Technology Development Center, National Institute of diagram was 753 M . Aqueous solubility and dissolution studies indicated that Pharmaceutical Education and Research, India the dissolution rates were remarkably increased in inclusion complex, compared 3Department of Pharmacoinformatics, National Institute of with the physical mixture and drug alone. In conclusion, inclusion complexation Pharmaceutical Education and Research, India 4 solubility and dissolution rate which could have implications in its bioavailability Department of Process Chemistry, National Institute of Pharmaceutical Education and Research, India consideringwith sulphobutylether-β-cyclodextrin it a Biopharmaceutical Classification is an easy approach System Class to increase II drug. raloxifene *Corresponding author: Sarasija Suresh, Department of Keywords: Pharmaceutical Technology (Formulation), National Institute Phase solubility; Dissolution rate; Molecular modeling of Pharmaceutical Education and Research (NIPER), Sector Raloxifene; Sulphobutylether-β-cyclodextrin; Hot stage microscopy; 67, S.A.S. Nagar (Mohali) Punjab- 160062, India, Tel: +91 8762002557; Email: Received: June 01, 2016 | Published: June 29, 2016 Introduction in its pharmaceutical applications due to its limited aqueous The main rate limiting step in the absorption of poorly soluble [16]. The most widely used natural cyclodextrin, β-CD, is limited drugs across biological barriers is its dissolution rate. All the have been synthesized to overcome this problem. Examples new chemical entities (~70%) entering into the drug discovery solubility (1.85 g/100 ml). Therefore, chemically modified β-CDs media to allow consistent gastrointestinal absorption of high include heptakis-(2, 6-O-dimethyl) (DM-β-CD), hydroxypropyl-β- orderprogramme of magnitude do not exhibit required sufficiently for further solubility therapeutic in the activities. physiological The CD Literature(HP-β-CD) andlacks sulphobutylether-β-CD any data about the (SBECD)effect of [17,18]. RAL-SBECD solubility of a drug in the GI tract is governed by multiple factors complexation to enhance the solubility and dissolution rate. RAL- and is inherently a complex phenomenon often resulting in erratic SBECD inclusion complexation was investigated to evaluate its absorption of poorly soluble drugs. Therefore, it is important to introduce effective methods to enhance the solubility and RAL and SBECD by phase solubility. Characterization of complex dissolution rate of the drug aiming to improve its bioavailability, impact on solubility of RAL. We confirmed the stoichiometry of increase the predictability of the response and/or reduce the We evaluated the solubilization effect of SBECD on RAL by in dose. To overcome these problems, various approaches have vitroand its release evaluation study. was An byattempt XRD, FTIR,was made SEM, HSMto investigate and TEM theanalysis. host- been developed, such as pro-drugs, addition of surfactants, salt guest interaction by in silico molecular modeling studies, which selection, particle size reduction, solid dispersion [1-3] inclusion essentially involve determining the ease which RAL can be docked complexes with cyclodextrins and phospholipid complex [4-6]. within the CD molecule. Complexation with cyclodextrins (CDs) has been widely used to enhance the bioavailability of poorly soluble drugs by increasing Materials and Methods the drug solubility, dissolution and/or permeability [6-15]. Chemicals Raloxifene (RAL) belongs to benzothiophene class of RAL was obtained as a gift sample from Wuhan Better Organic compounds and is a BCS class II drug with poor solubility (0.25 Pvt. Ltd. China. SBECD was obtained as a kind gift sample from mg/L) and high permeability. Owing to the poor solubility and high Cydex Pharmaceuticals.USA. All other solvents used in the study were of analytical grade and used as such. first pass metabolism, RAL absolute oral bioavailability is only 2% Submit Manuscript | http://medcraveonline.com J Anal Pharm Res 2016, 2(5): 00032 Enhanced Solubility and Dissolution Rate of Raloxifene using Cycloencapsulation Copyright: 2/8 Technique ©2016 Puramdas et al. Preparation of raloxifene-SBECD complex minimization by Sybyl7.1 installed on a silicon graphics fuel work with 0.05 kcal/mol energy gradient convergence criterion was RAL and SBECD were dissolved in alcoholic aqueous solution adoptedstation. Theas the conjugate minimization gradient parameter. method Thewith RAL Tripos molecule force fieldwas RAL-SBECD complex was prepared by freeze drying. Briefly, under constant stirring and were freeze dried (Virtis advantage, docked into the obtained SBECD structure to form a complex by 2.0 EL Bench Top freeze drier, USA) at -20°C for 24 h to obtain the GOLD program. The obtained complex is further submitted to geometry optimization by the b3lyp method with 6-31+g(d) basis a physical mixture of RAL with SBECD by dispersing individual set using Gaussian-03 [22]. The energy of complex was calculated the final complex as a solid dispersion. In addition, we prepared components at 1:1 molar ratio. corresponding to the molecular form of SBECD, RAL and their Standard curve of raloxifene docked complex by the following equation: A standard curve was prepared by dissolving RAL in E = E -(E +E -β - ) (3) complex docked_complex raloxifene sulpobutyl ether cyclodextrain Japan) at 287 nm. The equation obtained was A = 76950C + 1762 (R2methanol = 0.999) (0.1-100 [16]. µg/ml) and estimating by HPLC (Shimadzu, = Energy of complex formation Determination of raloxifene in SBECD complex Here,Ecomplex The drug content was determined by dissolving 10 mg of the Edocked_complex =Energy of docked complex complex in 10 ml of methanol and analyzing an aliquot ( 20 µl) Ereloxifene =Energy of raloxifene 5m), was selected as the stationary phase, which was operated Ecyclodextrin atby HPLCroom attemperature. 287 nm. Phenomenex The mobile C18 phasecolumn consisted (250 mm×4.6 of ACN: mm, Characterization= Energy of sulphobutyl ether-β- cyclodextrin was maintained at 1ml/min. The percentage yield was calculated FTIR: FTIR was employed for preliminary characterization of asPhosphate follows: buffer (10 mM) in the 64:36 proportions. The flow rate RAL-SBECD complex. Spectra of RAL, SBECD, physical mixture and RAL-SBECD complex were recorded on a FTIR spectrophotometer (Nicolet, Impact 410, USA) equipped with a deuterated triglycine Practical yield Percentage yield = Χ100 (1) sulfate detector. Potassium bromide pellet method was employed, Theoritical yield and background spectrum was collected under identical conditions. Each spectrum was derived from averaged scans Phase solubility study collected in the region 400–4000 cm at a spectral resolution of 2cm , Fourier transformed and ratioed−1 against background The stoichiometry of RAL and SBECD was determined by interferogram.−1 Spectra obtained were analyzed with Omnic 5.1a software (Thermo Nicolet, USA). containingphase solubility SBECD study at concentration by the method ranging described from 1by to Higuchi 20mM. Theand PXRD: Powder X-ray diffraction patterns were recorded with mixturesConnors [19]. were Briefly, shaken an in excess shaker RAL water was bathadded for to 2415ml h at glass 37±5°C. vials (1.542 A°) radiation (40 kV, 40am) for RAL, RAL-SBECD complex and α physicalD8 advanced mixture. (Bruker Samples Germany) were mountedusing Ni-filtered on the sample Cu K holder After equilibrium was attained, samples were filtered through and scanned from 4° to 40° °/min. 0.45 membrane filter and analyzed by HPLC at 26=87nm. The RAL vs. concentrations of SBECD. The apparent stability constant, SEM: The surface morphology of RAL, SBECD, physical mixture phase solubility profiles were obtained by plotting solubility of in 2θ at a speed of 0.01 KC, of the RAL and SBECD complex is calculated from the slope and the intercept of the linear segment of the phase solubility line by: onand to RAL-SBECD a double-sided complex adhesive were examined tape pasted by SEM over (Hitachi sample S-3400 stubs k N, Japan). Samples were prepared by affixing powder samples Stability constant (Kc) = (2) under vacuum of 1-10 Pascal. The samples were scanned with an − S0 ( 1k) electronand sputter beam coated of acceleration with gold potential using ion of sputter 1.2 kV and E-1010, images Hitachi were Where S0 is the solubility of the drug in the absence of cyclodextrin, and k is the slope of the straight line. The study was
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