Effect of Hydroxypropyl-β-Cyclodextrin on the Solubility of anAntiarrhythmic AgentOana Maria Paduraru,† Andreea Bosînceanu,‡ Gladiola Tantaru,‡ and Cornelia Vasile*,†

†Romanian Academy, Petru Poni Institute of Macromolecular Chemistry, 41A Grigore Ghica Voda Alley, 700487 Iasi, Romania‡Gr. T. Popa University of Medicine and Pharmacy, Faculty of Pharmacy, 16 University Str., 700115 Iasi, Romania

ABSTRACT: The aim of this work was to obtain an inclusion complex between HP-β-CD and amiodarone in order to increasethe solubility of this active agent. Drug−cyclodextrin interactions in solution were investigated using phase solubility studies. TheFourier transform infrared spectroscopy (FT-IR) spectra revealed the presence of the interactions between the components ofthe inclusion complex. Changes in crystallinity of the drug inside the inclusion complex were confirmed by X-ray diffractometry(XRD) and differential scanning calorimetry (DSC). Thermogravimetric (TG) results demonstrated the modification of the drugthermal behavior due to the interactions with the host cyclodextrin. The dissolution rate of amiodarone from the inclusioncomplex was considerably increased as compared to dissolution of the pure drug. It has been established that the complexation ofamiodarone with HP-β-CD offers the possibility to increase its aqueous solubility without the modification of its originalstructure.

1. INTRODUCTION

To improve the solubility/dissolution rate of slightly solubledrugs, different methods have been used. One of the mostuseful methods to improve the stability, the solubility, and thebioavailability of a poorly soluble drug is the encapsulation intocyclodextrins (CDs), cyclic oligosaccharides obtained fromamylose fraction of the starch.1 CDs have a rigid conicalmolecular structure with a hydrophilic exterior (all the hydroxylgroups in the ring are situated on the exterior of the conicalstructure) and a hydrophobic interior (there are skeletalcarbons with hydrogen atoms and oxygen bridges inside thecavity).2 Their hydrophobic cavity can interact with a variety ofguest molecules of the same polarity and form inclusioncomplexes, while the hydrophilic exterior is responsible for CDswater solubility. The driving forces of inclusion complexformation are noncovalent interactions such as hydrophobicinteractions, van der Waals forces, electronic effects, and stericfactors.3,4

The pharmaceutical application of the natural β-cyclodextrin(β-CD) is limited by its low aqueous solubility (18 mg/mL).The substitution of any hydroxyl groups, even by lipophilicgroups, results in an enhancement of its solubility.5

Hydroxypropyl-β-cyclodextrin (HP-β-CD) is a valuablealternative to natural CDs, having an enhanced aqueoussolubility (500 mg/mL) and being more toxicologically benignthan its parent β-CD.6

Over the past years several papers were published concerningthe improvement of solubility and bioavailability of variousbioactive agents using HP-β-CD such as ascorbic acid,7

trazodone hydrochloride,8 repaglinide,9 sanguinarine,10 5-flucytosine,11 meloxicam,12 and progesterone.13 On our knowl-edge, no such studies were realized for aminodarone, even if themain problem with this drug is its very low water solubility (0.7mg/mL), associated with low bioavailability.Two pharmacological agents contributed to the advances of

the cardiac arrhythmology therapy: beta-blockers and amiodar-

one. In contrast to other antiarrhytmic agents, the studiesshowed that these agents can reduce cardiac arrhythmicmortality.14 Amiodarone (2-butyl-3-benzofuranyl 4-[2-(dieth-ylamino)-ethoxy]-3,5-diiodophenyl ketone hydrochloride; Fig-ure 1) is a benzofuranic-derivative, iodine-rich drug, widely

used for the treatment of both supraventricular and ventriculararrhythmias. It is a white crystalline powder that is freelysoluble in chloroform and dichloromethane, soluble inmethanol and ethanol, and very slightly soluble in propanoland water.15

This drug has multiple and complex electrophysiologiceffects, being classified as a class III antiarrhythmic agentaccording to Vaughan−Williams classification,16 but itpossesses electrophysiological characteristics of all four classesof antiarrhythmic drugs. Its main effect is to delay therepolarisation and to extend the duration of the action potentialof atrial and ventricular muscle, without altering the restingmembrane potential.17 It also blocks Na+ channels decreasingconduction velocity (class I effect), produces an antiadrenergiceffect by reducing the numbers of β-adrenergic receptors (classII) and suppresses Ca2+-mediated action potential (class IV).18

Received: December 13, 2012Accepted: January 9, 2013Published: January 9, 2013

Figure 1. Chemical structure of amiodarone.

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© 2013 American Chemical Society 2174 dx.doi.org/10.1021/ie303440w | Ind. Eng. Chem. Res. 2013, 52, 2174−2181

One of the side effects of intravenous amiodarone is systemichypotension, which requires intervention, in some cases in theform of pressor therapy. This effect is thought to be related tothe cosolvents (polysorbate 80 and benzyl alcohol) and not tothe pure amiodarone.19,20 There were several attempts toovercome this problem, such as the development of anemulsion with tocopherol,21 a suspension of amiodarone inlactate buffer,22 and solubilization of amiodarone usingsulfobutylether-7-β-cyclodextrin23 or methoxy poly(ethyleneoxide)-block-poly(ester) micelles.24

Due to the fact that cyclodextrins are used for theimprovement of solubility and bioavailability of poorly solubledrugs, it was supposed that the complexation of this drug withHP-β-CD offers the possibility to increase its aqueous solubilitywithout the modification of its original structure. This paperdeals with the synthesis and characterization of the HP-β-CD/amiodarone inclusion complex and the evaluation of HP-β-CDas solubilizing agent for amiodarone. Freeze-dying is anenvironmentally friendly method used for the synthesis ofsoluble complexes of cyclodextrins, so the inclusion complexbetween amiodarone and HP-β-CD was obtained by thismethod.

2. EXPERIMENTAL SECTION2.1. Materials. 2-hydroxypropyl-β-cyclodextrin (HP-β-CD)

was purchased from Aldrich. Amiodarone (Cordarone) hasbeen bought from Zhejlang Sanmen Hengkang Pharmaceuticals(China). The chemicals have been used as received, withoutfurther purification. Double distilled water was used in alldeterminations.2.2. Methods of Investigation. 2.2.1. Phase Solubility

Studies. Phase solubility studies were performed at 25 °C,according to Higuchi and Connors method.25 An excessamount of amiodarone was added to aqueous solutionscontaining different concentrations of HP-β-CD, rangingbetween 3 × 10−3 and 15 × 10−3 M. Flasks containing themixed solutions were sealed to avoid evaporation and thenmagnetically stirred at 25 °C for 24 h. After reachingequilibrium, the solutions were filtered. The drug concentrationin each solution was determined spectrophotometrically at 254nm, with reference to an appropriate calibration curve.The phase solubility diagram was obtained by plotting the

HP-β-CD concentration against amiodarone concentration.The apparent stability constant (K1:1) of the amiodarone/HP-β-CD inclusion complex was calculated from the initial linearsegment of the phase solubility diagram, according to eq 1,25

using the slope of the experimental phase solubility line and theintrinsic solubility of the drug (the solubility in the absence ofcyclodextrin), which is noted with S0:

=−

KS

Slope(1 Slope)1:1

0 (1)

2.2.2. Preparation of the Solid Complex. The inclusioncomplex (IC) of amiodarone with HP-β-CD at 1:1 molar ratiowas prepared by a freeze-drying method. A known amount ofHP-β-CD was dissolved in double distilled water, at 25 °C. Anequimolar amount of amiodarone was added to this solution.The mixture was stirred for 24 h at 25 °C and then immersed inliquid nitrogen and freeze-dried in a LABCONCO 117freezing-dryer.2.2.3. Preparation of the Physical Mixture. Physical mixture

of amiodarone and HP-β-CD in 1:1 molar ratio was prepared

by mixing previously weighted powders in a ceramic mortar for15 min.

2.3. Complex Characterization. 2.3.1. UV Measure-ments. UV measurements were performed with a UV−visHewlett-Packard 8540A spectrophotometer on solutions ofvarious concentrations in double distilled water ranging from 3× 10−3 to 15 × 10−3 M.

2.3.2. Fourier Transform Infrared Spectroscopy (FT-IR).The FT-IR analysis was performed on a Vertex-70 (Bruker)apparatus, using KBr tablets technique. The scans were donewith a resolution of 4 cm−1, from 4000 to 500 cm−1. Theconcentration of the sample in pellets was 5 mg/500 mg KBr.Five recordings were performed for each sample, theevaluations being made on the average spectrum obtained.

2.3.3. Near Infrared Spectroscopy (NIR). NIR spectra wererecorded on a SPECIM Ltd. (Oulu, Finland) SisuCHEMAdevice. The measurements were realized in the 1000−2400 nmrange.

2.3.4. X-ray Diffraction Measurements (XRD). Thediffractograms were obtained by means of a Bruker AXS D8Advance X-ray diffractometer with a Cu Kα radiation source.The data were collected in the 2θ region of 2−40°.

2.3.5. Differential Scanning Calorimetry (DSC). The DSCstudies were performed using a NETZSCH DSC 200F3 device.A constant amount (3.5 mg) of each sample was heated inclosed aluminum crucibles, heated from 27 to 180 °C with aheating rate of 10 °C min−1 in a nitrogen atmosphere with aflow rate of 50 mL min−1.

2.3.6. Thermogravimetric Analysis (TGA). Thermal analysiswas performed on a Paulik−Paulik-Erdey Derivatograph(MOM- Budapest), in the temperature range 30−750 °C, ata heating rate of 10 °C min−1, in air flow (30 mL min−1), on 50mg sample.

2.3.7. Scanning Electron Microscopy (SEM). Scanningelectron microphotographs were taken of powders using aQuanta 200 instrument. The magnifications are given on theimages.

2.3.8. Dissolution Studies. The drug release study wascarried out using the USP paddle method at 37 °C and 50 rpm,using a SR 8PlusSeries (AB&L Jasco) instrument. A constantamount of drug or inclusion complex was introduced into adialysis membrane bag. 100 mL phosphate buffer solution(PBS) was used as the dissolution medium. The pH values ofthe PBS solutions were 6.8 and 1.2. The release experiment wasinitiated by placing the end sealed dialysis bag in the dissolutionmedium. Sample solution (2 mL) was withdrawn at differenttime intervals for the drug release analysis and replaced withanother 2 mL fresh dissolution medium, previously heated at 37°C. The amount of amiodarone released was determined byhigh performance liquid chromatography (HPLC), using as asolid phase octildodecylsilyl and as a mobile phase a solution offormic acid 0.5%/methanol 25:75. The temperature used forHPLC experiments was 45 ± 0.2 °C.28

3. RESULTS AND DISCUSSION3.1. Phase Solubility Studies. The complexation between

amiodarone and HP-β-CD has been evaluated using the phasesolubility method.25 The phase-solubility diagram is obtainedby plotting the total solubility of the guest against cyclodextrinconcentration. The obtained diagrams can be classified in twomain categories: A type and B type. The A type diagramindicates the formation of the soluble inclusion complexes andis divided in three types: AL, when the guest solubility increases

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linearly with the cyclodextrin concentration, AP, when there is apositively deviation from the straight line (the cyclodextrin ismore effective at high concentration), and AN, when there is anegatively deviation (the cyclodextrin is less effective). The Btype diagram suggests the formation of the inclusion complexeswith poor solubility.Figure 2 presents the solubility diagram obtained for

amiodarone in the presence of HP-β-CD. As it can be seen,

the drug solubility increased linearly with increasing HP-β-CDconcentration, the diagram being a straight line with a slope lessthan 1. According to Higuchi and Connors,25 the phasesolubility diagram of amiodarone can be classified as an AL type(linear positive isotherm), indicating the formation of a 1:1inclusion complex between the drug and the host cyclodextrin.Compared to the solubility of amiodarone in water, the increasein dissolution rate is significant (more than 3 times) in thepresence of HP-β-CD. This can be explained by the formationof the inclusion complex. The apparent solubility constant(K1:1) was calculated from Figure 2 using eq 1, and it was foundto be 1.7 × 104 M−1, which indicated the presence of stronginteractions between amiodarone and HP-β-CD.3.2. FT-IR Measurements. Infrared analysis can give

important information about the inclusion complexationprocess. The spectra of pure amiodarone, HP-β-CD, andinclusion complex between HP-β-CD and the drug arepresented in Figure 3. As it can be seen, the position and therelative intensities of some bands from both the drug and thehost are being influenced by the formation of the inclusioncomplex.The broad band between 3600 and 3100 cm−1 from the

spectrum of HP-β-CD is assigned to the OH stretchingvibration. The same broad band is observed in the spectrum ofthe inclusion complex. The bands from 2970 and 2931 cm−1

corresponding to the C−H stretching vibration are presentboth in the HP-β-CD spectrum, as well as in the spectrum ofthe inclusion complex. The absorption band at 1645 cm−1 isrelated to H−O−H bending. The band from 1157 cm−1,assigned to OH bending/CO stretching of COH group isshifted in the inclusion complex spectrum at 1155 cm−1.Referring to the bands from 948, 854, and 757 cm−1, which arespecific to cyclodextrin, these correspond to skeletal vibrationdue to the α-1,4 glycosidic bonds, anomeric CH deformation,

and pyranose ring vibration, respectively. All these three bandsare also presented in the spectrum of the inclusion complex.In the case of the amiodarone spectrum, the peaks in the

3070−3000 cm−1 region are specific to the aromatic C−Hstretching, while the region between 2960 and 2800 cm−1 isassigned to aliphatic C−H stretching (sym and asym). Theabsorption bands characteristic to tert-amine NH+ stretchingare located in the 2700−2200 cm−1 wavenumber range. Thesebands are strong in the pure amiodarone spectrum, but theirintensities decrease very much or disappear (2732 cm−1) in thespectrum of the amiodarone/HP-β-CD inclusion complex,being a consequence of some interactions between the twocomponents of the complex. The amiodarone spectrumpresents specific bands at 1631 cm−1 for the diaromatic CO stretching, at 1558 and 1529 cm−1 related to aromatic CCring quadrant stretching, at 1477 and 1454 cm−1 for thearomatic CC ring-semicircle stretching, at 1284 cm−1 specificto ketonic CO binding, at 1245 and 1076 cm−1 assigned toaromatic ether C−O−C stretch, and at 750 cm−1, which isspecific to aromatic C−H out of plane binding of the fouradjacent aromatic hydrogen atoms. The intensity of these peaksis decreased in the spectrum of the inclusion complex. Theamiodarone spectrum presents two bands related to tert-amineC−N at 1224 and 1024 cm−1. These bands disappear from thespectrum of the inclusion complex, being an indication of thecomplexation process, together with the strong reduction of thebands from 2700 to 2200 cm−1.The FT-IR results indicate that the inclusion complex

between the two components was obtained and the complex-ation process was realized at the tert-amine end from the drugmolecule.

Figure 2. Phase solubility diagram of amiodarone in the presence ofHP-β-CD. Figure 3. FT-IR spectra of pure amiodarone (a), inclusion complex

(b), and HP-β-CD (c).

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3.3. NIR Spectroscopy. Figure 4 and Table 1 summarizethe NIR spectra results for amiodarone, HP-β-CD and of theinclusion complex in the full range of the near-infrared region.The results presented in Table 1 show that there is a shift of

the band involving the amino group, from 1497 to 1468 nm. Inthe same time, the band from 2076 nm, which corresponds tothe N−H deformation overtone, disappears from the spectrumof the inclusion complex. These results prove the interactionsbetween HP-β-CD and the tert-amine end of amiodarone, inaccordance with the FT-IR results.The loading degree was evaluated based on near-infrared

chemical imaging maps. The PLS-DA (partial least-squares-discriminate analysis) model for the inclusion complex ispresented in Figure 5. In the score images, the pixels withhigher score values are coded with white (for amiodarone) andthose with lower score values with dark colors (for HP-β-CD).The gray color, intermediate between white and dark colors,corresponds to the inclusion complex. Based on PLS-DAprediction, an amiodarone loading into inclusion complex ofabout 24 wt % was recorded. These results are close to a 1:1molar ratio (a weight ratio HP-β-CD/amiodarone of 71/29 wt%), which was used for the preparation of the inclusioncomplex.3.4. X-ray Diffraction Measurements. XRD is a method

frequently used in the study of inclusion complexes. It is knownthat the CD complexation alters the crystalline structure of thedrug, making it more amorphous.26 The XRD pattern of

amiodarone show several intense and sharp peaks, indicating itsalmost 100% crystalline structure. The X-ray diffractogram ofthe inclusion complex differs from that of the pure drug andpure HP-β-CD, showing peaks considerable diminished inintensities, as a result of the drug amorphization (XRDdiffractograms not shown). Moreover, the crystallinity degreeof the inclusion complex shows an important decrease, having avalue of only 39.6% with respect to ∼100% for aminodarone.

3.5. DSC. Thermal analysis (mainly DSC and/or TGA) isapplied in pharmaceutical industry to reveal importantinformation about the physicochemical properties of thedrugs and of their excipients and also for the characterizationof the inclusion complexes in solid state.15 In the DSC curves(Figure 6), the pure drug shows a peak at 166 °Ccorresponding to the drug melting. The DSC curve of HP-β-CD exhibits one broad endothermic process (40−160 °C)assigned to the water loss (residual humidity for T < 100 °Cand water from the cyclodextrin cavity for T > 100 °C).The DSC curve of physical mixture shows both peaks, that of

the HP-β-CD water loss and that of amiodarone melting. In theDSC curve of the inclusion complex, the melting peak of thecrystalline guest disappeared, indicating the amorphouscharacter, as it was also found by XRD.

3.6. Thermogravimetry. The thermograms of the purecomponents and of their inclusion complex are presented inFigure 7. The pure amiodarone TG curve shows two stages ofdecomposition. The main process begins at 155 °C and ends at

Figure 4. NIR reflectance spectra of amiodarone (a), inclusion complex (b), and HP-β-CD (c).

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417 °C, when the drug loses 62.5% of its mass. The seconddecomposition step starts at 417 °C and ends at 668 °C. Thetotal mass loss of amiodarone was 94.7%.HP-β-CD exhibits three stages of thermal degradation. The

first stage, from 50 to 268 °C is due to the loss of absorbedwater and water of crystallization.27 The second stage occurringbetween 268 and 428 °C is associated with the biggest weightloss and the char formation. The oxidation process occurs attemperatures higher than 428 °C, up to 577 °C. During thesethree steps of thermal degradation, HP-β-CD has a weight lossof 91.9%.There are some modifications in the thermal behavior of the

drug in the presence of HP-β-CD. The inclusion complex has a

Table 1. Wavelength Corresponding to the Functional Groups on NIR Spectra of the Studied Samples

wavelength (nm) amiodarone IC HPCD

1117 C−H second overtone1187 C−H second overtone1225 C−H combination1309 C−H combination1468 N−H stretch first overtone1497 N−H stretch first overtone1678 C−H stretch first overtone C−H stretch first overtone1684 C−H stretch first overtone1787 C−H stretch/HOH deformation combination1935 O−H stretch/HOH deformation combination1936 C−O combinations1937 O−H stretch/HOH deformation combination2076 N−H deformation overtone2087 C−H combination2089 C−H combination2281 C−H stretch/CH2 deformation2263 C−O stretch combination C−O stretch combination2295 C−H stretch/CH2 deformation2301 C−H bend second overtone2327 C−H stretch/CH2 deformation combination2339 C−H stretch/C−H deformation C−H stretch/C−H deformation2356 CH2 bend second overtone2375 C−H stretch/C−C stretch combination2401 C−H combination C−H combination C−H combination2494 C−H stretch/C−C stretch combination

Figure 5. PLS-DA model for the inclusion complex betweenamiodarone and HP-β-CD.

Figure 6. DSC curves of the inclusion complex (a), amiodarone (b),physical mixture (c), and HP-β-CD (d).

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small peak for water loss between 50 and 190 °C. Compared toHP-β-CD, which loses 7.46% of its mass on the first step ofdegradation, the inclusion complex looses only 3% of its mass,due to the fact that part of the water from the HP-β-CD cavityhas been replaced with the drug molecule. The total mass lossof the inclusion complex is 86.6%, less than the weight loss ofthe pure amiodarone.

3.7. Scanning Electron Microscopy (SEM). Although thismethod is not decisive for the confirmation of the inclusioncomplex formation, nevertheless, it helps to demonstrate theexistence of a single component in the final product. Thescanning electron microphotographs of amiodarone, HP-β-CD,their physical mixture, and inclusion complex are shown inFigure 8. Pure amiodarone appeared as cyclindrical crystals thathave a tendency to form aggregates. HP-β-CD consisted ofshrunken spheres with concave shapes. In the physical mixture,the drug crystals only adhere to the surface of HP-β-CDspheres and no interactions took place between the amiodaroneand the HP-β-CD. In the case of the inclusion complexobtained by freeze-drying, the shape and morphology changecompletely. The regular morphology of both componentsdisappears, and the sample appears as irregular sheets with ahigh surface area. The microphotograph of the inclusioncomplex suggests the presence of an amorphous homogeneousphase.

3.8. In Vitro Dissolution Studies. To evaluate whether thecomplexation process affected the dissolution rate ofamiodarone, dissolution studies were performed for this drugand its inclusion complex with HP-β-CD, at two pH values: 1.2and 6.8. The dissolution profiles of pure amiodarone and of theinclusion complex are presented in Figure 9 and data extractedfrom these profiles are summarized in Table 2.These data are related to the amount of amiodarone used for

obtaining the inclusion complex. The quantitative determi-nation of amiodarone in the complex was realized by HPLC,28

and the results were in agreement with the molar ratio of 1:1

Figure 7. TG curves of amiodarone (), inclusion complex (--), andHP-β-CD (-•-).

Figure 8. SEM images of pure amiodarone (a), HP-β-CD (b), the physical mixture (c), and the inclusion complex (d).

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HP-β-CD:amiodarone, used for preparation and found byphase solubility study. After 120 min, only a small quantity ofpure drug (between 3.2 and 4.0%) is dissolved at both values ofpH, while in the case of inclusion complex the maximumamount of drug (34% and 21%, respectively) is dissolved in 5min for pH 6.8 and in 15 min for pH 1.2. The dissolution rateis higher for pH 6.8; this value of pH being close to theamiodarone pKa. A strong increase of the maximum dissolutionamount was observed for the inclusion complex in respect withthe pure drug. The amount of amiodarone dissolved in the caseof inclusion complex increased about 6.6 folds for the pH = 1.2and about 6.8 folds for a value of pH = 6.8.The faster dissolution rate of the amiodarone from the

inclusion complex is caused by the decrease of the drugcrystallinity and thus the increase of solubility, which is aconsequence of the specific interactions between HP-β-CD andamiodarone.

4. CONCLUSIONSAn inclusion complex between amiodarone and HP-β-CD hasbeen prepared by freeze-drying method. The phase solubilitydiagram indicated the formation of a 1:1 inclusion complexbetween the guest drug and the host cyclodextrin. The FT-IRspectra, together with the NIR results, point out the formationof the inclusion complex through the tert-amine end of theamiodarone molecule. The XDR and DSC results demon-strated the drug amorphization inside the inclusion complex.The TG results, together with the SEM microphotographs,confirmed also that the complexation process took place.Complexation with HP-β-CD increased amiodarone solubilityand dissolution rate.

■ AUTHOR INFORMATIONCorresponding Author*Tel: + 40 232 217454; Fax: + 40 232 211299. E-mail:cvasile@icmpp.roNotesThe authors declare no competing financial interest.

■ ACKNOWLEDGMENTSThis research was financially supported by the grant of theRomanian National Authority for Scientific Research, CNCS−UEFISCDI, Project No. PN-II-ID-PCE-2011-3-0187. Theauthors thank Ph. D. student Manuela Pintilie for the NIRdeterminations.

■ REFERENCES(1) Uekama, K.; Hirayama, F.; Irie, T. Cyclodextrin Drug CarrierSystems. Chem. Rev. 1998, 98, 2045.(2) Cal, K.; Centkowska, K. Use of Cyclodextrins in TopicalFormulations: Practical Aspects. Eur. J. Pharm. Biopharm. 2008, 68,467.(3) He, Y.; Fu, P.; Shen, X.; Gao, H. Cyclodextrin-Based Aggregatesand Characterization by Microscopy. Micron 2008, 39, 495.(4) Yuan, H. N.; Yao, S. J.; Shen, L. Q.; Mao, J. W. Preparation andCharacterization of Inclusion Complexes of β-Cyclodextrin-BITC andβ-Cyclodextrin-PEITC. Ind. Eng. Chem. Res. 2009, 48, 5070.(5) Brewster, M. E.; Loftsson, T. Cyclodextrins as PharmaceuticalSolubilizers. Adv. Drug Delivery Rev. 2007, 59, 645.(6) Gould, S.; Scott, R. C. 2-Hydroxypropyl-β-Cyclodextrin (HP-β-CD): A Toxicology Review. Food Chem. Toxicol. 2005, 43, 1451.(7) Garnero, C.; Longhi, M. Study of Ascorbic Acid Interaction withHydroxypropyl- β-Cyclodextrin and Triethanolamine, Separately andin Combination. J. Pharm. Biomed. Anal. 2007, 45, 536.(8) Misiuk, W.; Zalewska, M. Investigation of Inclusion Complex ofTrazodone Hydrochloride with Hydroxypropyl-β-Cyclodextrin. Car-bohydr. Polym. 2009, 77, 482.(9) Nicolescu, C.; Arama, C.; Nedelcu, A.; Monciu, C. M. PhaseSolubility Studies of the Inclusion Complexes of Repaglinide with β-Cyclodextrin and β-Cyclodextrin Derivatives. Farmacia 2010, 58, 620.(10) Boldescu, V.; Kacso, I.; Borodi, G.; Bratu, I.; Duca, G.Physicochemical Characterization of Sanguinarine-Hydroxypropyl-β-Cyclopdextrin Binary and Ternary Systems. J. Inclusion Phenom.Macrocyclic Chem. 2008, 62, 143.(11) Spulber, M.; Miron, L.; Mares, M.; Nastasa, V.; Pinteala, M.;Fifere, A.; Harabagiu, V.; Simionescu, B. C. Water Soluble 5FCComplexes, Preliminary Pharmacological Studies. J. Inclusion Phenom.Macrocyclic Chem. 2009, 65, 431.(12) Baboota, S.; Agarwal, S. P. Preparation and Characterization ofMeloxicam Hydroxy Propyl β-Cyclodextrin Inclusion Complex. J.Inclusion Phenom. Macrocyclic Chem. 2005, 51, 219.(13) Torri, G.; Bertini, S.; Giavana, T.; Guerrini, M.; Puppini, N.;Zoppetti, G. Inclusion Complex Characterization Between Progester-one and Hydroxypropyl-β-cyclodextrin in Aqueous Solution by NMRStudy. J. Inclusion Phenom. Macrocyclic Chem. 2007, 57, 317.(14) Ghuran, A. V.; Camm, A. J. Amiodarone and Beta BlockadeIsthe Whole Better Than Parts? J. Clin. Basic Cardiol. 2000, 3, 205.(15) Yoshida, M. I.; Gomes, E. C. L.; Soares, C. D. V.; Oliveira, M. A.Thermal Behavior Study and Decomposition Kinetics of AmiodaroneHydrochloride Under Isothermal Conditions. Drug Dev. Ind. Pharm.2011, 37, 638.(16) Data, S.; Waghray, T.; Torres, M.; Glusman, S. AmiodaroneDecreases Heat, Cold, and Mechanical Hyprealgesia in a Rat Model ofNeuropathic Pain. Anesth. Analg. 2004, 98, 178.(17) Plomp, T. A. Analytical Profile of Drug Substances; AcademicPress: San Diego, CA, 1991.(18) Cohen-Lehman, J.; Dahl, P.; Danzi, S.; Klein, I. Effects ofAmiodarone Therapy on Thyroid Function. Nat. Rev. Endocrinol.2010, 6, 34.

Figure 9. Dissolution profiles of amiodarone and inclusion complex(IC) at different values of pH.

Table 2. Dissolution Data for Inclusion Complex andAmiodaronea

pH 1.2 pH 6.8

param. IC amiodarone IC amiodarone

Qmax released (%) 21.2 3.2 34.1 4.9t1/2 (min) 2.5 2.44 2.4 4.35tmax (min) 15 120 5 120

aQmax released: maximum release amount. t1/2: half release time. tmax:time to reach maximum amount released.

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(19) Cushing, D. J.; Kowey, P. R.; Cooper, W. D.; Massey, B. W.;Gralinski, M. R.; Lipicky, R. J. PM101: A Cyclodextrin-BasedIntravenous Formulation of Amiodarone Devoid of AdverseHemodynamic Effects. Eur. J. Pharmacol. 2009, 607, 167.(20) Van Herendael, H.; Dorian, P. Amiodarone for the Treatmentand Prevention of Ventricular Fibrillation and Ventricular Tachycardia.Vasc. Health Risk Manage. 2010, 6, 465.(21) Kessler, D.; Palepu, N.; Tustian, A.; Rockwell, K.; Leo, A.;Hughes, M. P.; Guthrie, R. A Novel Amiodarone MicroemulsionInjectable Formulation. AAPS Pharm. Sci. 2002, 4, 4122.(22) Kipp, J. E.; Doty, M. J.; Rebbeck, C. L.; Eilert, J. Y. Amiodarone-Containing Parenteral Administration. United States Patent No.6479541, 2002.(23) Mosher, G. L.; Johnson, K. T.; Gayed, A. A. FormulationsContaining Amiodarone and Sulfoalkyl Ether Cyclodextrin. UnitedStates Patent No. 6869939B2, 2005.(24) Elhasi, S.; Astaneh, R.; Lavasanifar, A. Solubilization of anAmphiphilic Drug by Poly(ethylene oxide)-block-Poly(ester) Micelles.Eur. J. Pharm. Biopharm. 2007, 65, 406.(25) Higuchi, T.; Connors, K. A. Phase-Solubility Techniques. Adv.Anal. Chem. Instr. 1965, 4, 117.(26) Jambhekar, S.; Casella, R.; Maher, T. The PhysicochemicalCharacteristics and Bioavailability of Indomethacin from β-Cyclo-dextrin, Hydroxyethyl-β-Cyclodextrin, and Hydroxypropyl-β-Cyclo-dextrin Complexes. Int. J. Pharm. 2004, 270, 149.(27) Trotta, F.; Zanetti, M.; Camino, G. Thermal Degradation ofCyclodextrins. Polym. Degrad. Stab. 2000, 69, 373.(28) Bosinceanu, A.; Paduraru, O. M.; Ochiuz, L.; Tantaru, G.;Vasile, C.; Popovici, I. Validation of the HPLC Method forAmiodarone Determination from HP-β-CD/Amiodarone InclusionComplex and from Tablets. Rev. Chim., submitted.

Industrial & Engineering Chemistry Research Article

dx.doi.org/10.1021/ie303440w | Ind. Eng. Chem. Res. 2013, 52, 2174−21812181