Effect of Hydroxypropyl-β-Cyclodextrin on the Solubility of an

Article pubs.acs.org/IECR

Effect of Hydroxypropyl-β-Cyclodextrin on the Solubility of an Antiarrhythmic Agent Oana Maria Păduraru,† Andreea Bosînceanu,‡ Gladiola Ţ an̂ taru,‡ 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 increase the solubility of this active agent. Drug−cyclodextrin interactions in solution were investigated using phase solubility studies. The Fourier transform infrared spectroscopy (FT-IR) spectra revealed the presence of the interactions between the components of the 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 drug thermal behavior due to the interactions with the host cyclodextrin. The dissolution rate of amiodarone from the inclusion complex was considerably increased as compared to dissolution of the pure drug. It has been established that the complexation of amiodarone with HP-β-CD offers the possibility to increase its aqueous solubility without the modification of its original structure.

1. INTRODUCTION To improve the solubility/dissolution rate of slightly soluble drugs, different methods have been used. One of the most useful methods to improve the stability, the solubility, and the bioavailability of a poorly soluble drug is the encapsulation into cyclodextrins (CDs), cyclic oligosaccharides obtained from amylose fraction of the starch.1 CDs have a rigid conical molecular structure with a hydrophilic exterior (all the hydroxyl groups in the ring are situated on the exterior of the conical structure) and a hydrophobic interior (there are skeletal carbons with hydrogen atoms and oxygen bridges inside the cavity).2 Their hydrophobic cavity can interact with a variety of guest molecules of the same polarity and form inclusion complexes, while the hydrophilic exterior is responsible for CDs water solubility. The driving forces of inclusion complex formation are noncovalent interactions such as hydrophobic interactions, van der Waals forces, electronic effects, and steric factors.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 lipophilic groups, results in an enhancement of its solubility.5 Hydroxypropyl-β-cyclodextrin (HP-β-CD) is a valuable alternative to natural CDs, having an enhanced aqueous solubility (500 mg/mL) and being more toxicologically benign than its parent β-CD.6 Over the past years several papers were published concerning the improvement of solubility and bioavailability of various bioactive agents using HP-β-CD such as ascorbic acid,7 trazodone hydrochloride,8 repaglinide,9 sanguinarine,10 5flucytosine,11 meloxicam,12 and progesterone.13 On our knowledge, no such studies were realized for aminodarone, even if the main problem with this drug is its very low water solubility (0.7 mg/mL), associated with low bioavailability. Two pharmacological agents contributed to the advances of the cardiac arrhythmology therapy: beta-blockers and amiodar© 2013 American Chemical Society

one. In contrast to other antiarrhytmic agents, the studies showed that these agents can reduce cardiac arrhythmic mortality.14 Amiodarone (2-butyl-3-benzofuranyl 4-[2-(diethylamino)-ethoxy]-3,5-diiodophenyl ketone hydrochloride; Figure 1) is a benzofuranic-derivative, iodine-rich drug, widely

Figure 1. Chemical structure of amiodarone.

used for the treatment of both supraventricular and ventricular arrhythmias. It is a white crystalline powder that is freely soluble in chloroform and dichloromethane, soluble in methanol and ethanol, and very slightly soluble in propanol and water.15 This drug has multiple and complex electrophysiologic effects, being classified as a class III antiarrhythmic agent according to Vaughan−Williams classification,16 but it possesses electrophysiological characteristics of all four classes of antiarrhythmic drugs. Its main effect is to delay the repolarisation and to extend the duration of the action potential of atrial and ventricular muscle, without altering the resting membrane potential.17 It also blocks Na+ channels decreasing conduction velocity (class I effect), produces an antiadrenergic effect by reducing the numbers of β-adrenergic receptors (class II) and suppresses Ca2+-mediated action potential (class IV).18 Received: December 13, 2012 Accepted: January 9, 2013 Published: January 9, 2013 2174

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

Industrial & Engineering Chemistry Research

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by mixing previously weighted powders in a ceramic mortar for 15 min. 2.3. Complex Characterization. 2.3.1. UV Measurements. UV measurements were performed with a UV−vis Hewlett-Packard 8540A spectrophotometer on solutions of various 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 done with a resolution of 4 cm−1, from 4000 to 500 cm−1. The concentration of the sample in pellets was 5 mg/500 mg KBr. Five recordings were performed for each sample, the evaluations being made on the average spectrum obtained. 2.3.3. Near Infrared Spectroscopy (NIR). NIR spectra were recorded on a SPECIM Ltd. (Oulu, Finland) SisuCHEMA device. The measurements were realized in the 1000−2400 nm range. 2.3.4. X-ray Diffraction Measurements (XRD). The diffractograms were obtained by means of a Bruker AXS D8 Advance 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 DSC studies were performed using a NETZSCH DSC 200F3 device. A constant amount (3.5 mg) of each sample was heated in closed aluminum crucibles, heated from 27 to 180 °C with a heating rate of 10 °C min−1 in a nitrogen atmosphere with a flow rate of 50 mL min−1. 2.3.6. Thermogravimetric Analysis (TGA). Thermal analysis was performed on a Paulik−Paulik-Erdey Derivatograph (MOM- Budapest), in the temperature range 30−750 °C, at a heating rate of 10 °C min−1, in air flow (30 mL min−1), on 50 mg sample. 2.3.7. Scanning Electron Microscopy (SEM). Scanning electron microphotographs were taken of powders using a Quanta 200 instrument. The magnifications are given on the images. 2.3.8. Dissolution Studies. The drug release study was carried out using the USP paddle method at 37 °C and 50 rpm, using a SR 8PlusSeries (AB&L Jasco) instrument. A constant amount of drug or inclusion complex was introduced into a dialysis membrane bag. 100 mL phosphate buffer solution (PBS) was used as the dissolution medium. The pH values of the PBS solutions were 6.8 and 1.2. The release experiment was initiated by placing the end sealed dialysis bag in the dissolution medium. Sample solution (2 mL) was withdrawn at different time intervals for the drug release analysis and replaced with another 2 mL fresh dissolution medium, previously heated at 37 °C. The amount of amiodarone released was determined by high performance liquid chromatography (HPLC), using as a solid phase octildodecylsilyl and as a mobile phase a solution of formic acid 0.5%/methanol 25:75. The temperature used for HPLC experiments was 45 ± 0.2 °C.28

One of the side effects of intravenous amiodarone is systemic hypotension, which requires intervention, in some cases in the form of pressor therapy. This effect is thought to be related to the cosolvents (polysorbate 80 and benzyl alcohol) and not to the pure amiodarone.19,20 There were several attempts to overcome this problem, such as the development of an emulsion with tocopherol,21 a suspension of amiodarone in lactate buffer,22 and solubilization of amiodarone using sulfobutylether-7-β-cyclodextrin23 or methoxy poly(ethylene oxide)-block-poly(ester) micelles.24 Due to the fact that cyclodextrins are used for the improvement of solubility and bioavailability of poorly soluble drugs, it was supposed that the complexation of this drug with HP-β-CD offers the possibility to increase its aqueous solubility without the modification of its original structure. This paper deals with the synthesis and characterization of the HP-β-CD/ amiodarone inclusion complex and the evaluation of HP-β-CD as solubilizing agent for amiodarone. Freeze-dying is an environmentally friendly method used for the synthesis of soluble complexes of cyclodextrins, so the inclusion complex between amiodarone and HP-β-CD was obtained by this method.

2. EXPERIMENTAL SECTION 2.1. Materials. 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) was purchased from Aldrich. Amiodarone (Cordarone) has been bought from Zhejlang Sanmen Hengkang Pharmaceuticals (China). The chemicals have been used as received, without further purification. Double distilled water was used in all determinations. 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 excess amount of amiodarone was added to aqueous solutions containing different concentrations of HP-β-CD, ranging between 3 × 10−3 and 15 × 10−3 M. Flasks containing the mixed solutions were sealed to avoid evaporation and then magnetically stirred at 25 °C for 24 h. After reaching equilibrium, the solutions were filtered. The drug concentration in each solution was determined spectrophotometrically at 254 nm, 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/HPβ-CD inclusion complex was calculated from the initial linear segment of the phase solubility diagram, according to eq 1,25 using the slope of the experimental phase solubility line and the intrinsic solubility of the drug (the solubility in the absence of cyclodextrin), which is noted with S0: K1:1 =

Slope S0(1 − Slope)

(1)

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

3. RESULTS AND DISCUSSION 3.1. Phase Solubility Studies. The complexation between amiodarone and HP-β-CD has been evaluated using the phase solubility method.25 The phase-solubility diagram is obtained by plotting the total solubility of the guest against cyclodextrin concentration. The obtained diagrams can be classified in two main categories: A type and B type. The A type diagram indicates the formation of the soluble inclusion complexes and is divided in three types: AL, when the guest solubility increases 2175



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linearly with the cyclodextrin concentration, AP, when there is a positively deviation from the straight line (the cyclodextrin is more effective at high concentration), and AN, when there is a negatively deviation (the cyclodextrin is less effective). The B type diagram suggests the formation of the inclusion complexes with poor solubility. Figure 2 presents the solubility diagram obtained for amiodarone in the presence of HP-β-CD. As it can be seen,

Figure 2. Phase solubility diagram of amiodarone in the presence of HP-β-CD.

Figure 3. FT-IR spectra of pure amiodarone (a), inclusion complex (b), and HP-β-CD (c).

the drug solubility increased linearly with increasing HP-β-CD concentration, the diagram being a straight line with a slope less than 1. According to Higuchi and Connors,25 the phase solubility diagram of amiodarone can be classified as an AL type (linear positive isotherm), indicating the formation of a 1:1 inclusion complex between the drug and the host cyclodextrin. Compared to the solubility of amiodarone in water, the increase in dissolution rate is significant (more than 3 times) in the presence of HP-β-CD. This can be explained by the formation of the inclusion complex. The apparent solubility constant (K1:1) was calculated from Figure 2 using eq 1, and it was found to be 1.7 × 104 M−1, which indicated the presence of strong interactions between amiodarone and HP-β-CD. 3.2. FT-IR Measurements. Infrared analysis can give important information about the inclusion complexation process. The spectra of pure amiodarone, HP-β-CD, and inclusion complex between HP-β-CD and the drug are presented in Figure 3. As it can be seen, the position and the relative intensities of some bands from both the drug and the host are being influenced by the formation of the inclusion complex. The broad band between 3600 and 3100 cm−1 from the spectrum of HP-β-CD is assigned to the OH stretching vibration. The same broad band is observed in the spectrum of the inclusion complex. The bands from 2970 and 2931 cm−1 corresponding to the C−H stretching vibration are present both in the HP-β-CD spectrum, as well as in the spectrum of the inclusion complex. The absorption band at 1645 cm−1 is related to H−O−H bending. The band from 1157 cm−1, assigned to OH bending/CO stretching of COH group is shifted in the inclusion complex spectrum at 1155 cm−1. Referring to the bands from 948, 854, and 757 cm−1, which are specific to cyclodextrin, these correspond to skeletal vibration due to the α-1,4 glycosidic bonds, anomeric CH deformation,

and pyranose ring vibration, respectively. All these three bands are 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−H stretching, while the region between 2960 and 2800 cm−1 is assigned to aliphatic C−H stretching (sym and asym). The absorption bands characteristic to tert-amine NH+ stretching are located in the 2700−2200 cm−1 wavenumber range. These bands are strong in the pure amiodarone spectrum, but their intensities decrease very much or disappear (2732 cm−1) in the spectrum of the amiodarone/HP-β-CD inclusion complex, being a consequence of some interactions between the two components of the complex. The amiodarone spectrum presents specific bands at 1631 cm−1 for the diaromatic C O stretching, at 1558 and 1529 cm−1 related to aromatic CC ring quadrant stretching, at 1477 and 1454 cm−1 for the aromatic CC ring-semicircle stretching, at 1284 cm−1 specific to ketonic CO binding, at 1245 and 1076 cm−1 assigned to aromatic ether C−O−C stretch, and at 750 cm−1, which is specific to aromatic C−H out of plane binding of the four adjacent aromatic hydrogen atoms. The intensity of these peaks is decreased in the spectrum of the inclusion complex. The amiodarone spectrum presents two bands related to tert-amine C−N at 1224 and 1024 cm−1. These bands disappear from the spectrum of the inclusion complex, being an indication of the complexation process, together with the strong reduction of the bands from 2700 to 2200 cm−1. The FT-IR results indicate that the inclusion complex between the two components was obtained and the complexation process was realized at the tert-amine end from the drug molecule. 2176



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

3.3. NIR Spectroscopy. Figure 4 and Table 1 summarize the NIR spectra results for amiodarone, HP-β-CD and of the inclusion 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. In the same time, the band from 2076 nm, which corresponds to the N−H deformation overtone, disappears from the spectrum of the inclusion complex. These results prove the interactions between HP-β-CD and the tert-amine end of amiodarone, in accordance with the FT-IR results. The loading degree was evaluated based on near-infrared chemical imaging maps. The PLS-DA (partial least-squaresdiscriminate analysis) model for the inclusion complex is presented in Figure 5. In the score images, the pixels with higher score values are coded with white (for amiodarone) and those 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-DA prediction, an amiodarone loading into inclusion complex of about 24 wt % was recorded. These results are close to a 1:1 molar ratio (a weight ratio HP-β-CD/amiodarone of 71/29 wt %), which was used for the preparation of the inclusion complex. 3.4. X-ray Diffraction Measurements. XRD is a method frequently used in the study of inclusion complexes. It is known that the CD complexation alters the crystalline structure of the drug, making it more amorphous.26 The XRD pattern of

amiodarone show several intense and sharp peaks, indicating its almost 100% crystalline structure. The X-ray diffractogram of the inclusion complex differs from that of the pure drug and pure HP-β-CD, showing peaks considerable diminished in intensities, as a result of the drug amorphization (XRD diffractograms not shown). Moreover, the crystallinity degree of the inclusion complex shows an important decrease, having a value of only 39.6% with respect to ∼100% for aminodarone. 3.5. DSC. Thermal analysis (mainly DSC and/or TGA) is applied in pharmaceutical industry to reveal important information about the physicochemical properties of the drugs and of their excipients and also for the characterization of the inclusion complexes in solid state.15 In the DSC curves (Figure 6), the pure drug shows a peak at 166 °C corresponding to the drug melting. The DSC curve of HP-βCD exhibits one broad endothermic process (40−160 °C) assigned to the water loss (residual humidity for T < 100 °C and 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 the DSC curve of the inclusion complex, the melting peak of the crystalline guest disappeared, indicating the amorphous character, as it was also found by XRD. 3.6. Thermogravimetry. The thermograms of the pure components and of their inclusion complex are presented in Figure 7. The pure amiodarone TG curve shows two stages of decomposition. The main process begins at 155 °C and ends at 2177



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Table 1. Wavelength Corresponding to the Functional Groups on NIR Spectra of the Studied Samples wavelength (nm) 1117 1187 1225 1309 1468 1497 1678 1684 1787 1935 1936 1937 2076 2087 2089 2281 2263 2295 2301 2327 2339 2356 2375 2401 2494

amiodarone

IC

HPCD

C−H second overtone C−H second overtone C−H combination C−H combination N−H stretch first overtone N−H stretch first overtone C−H stretch first overtone

C−H stretch first overtone C−H stretch first overtone C−H stretch/HOH deformation combination O−H stretch/HOH deformation combination

C−O combinations O−H stretch/HOH deformation combination N−H deformation overtone C−H combination C−H combination C−H stretch/CH2 deformation C−O stretch combination C−H stretch/CH2 deformation

C−O stretch combination C−H bend second overtone C−H stretch/C−H deformation

C−H combination C−H stretch/C−C stretch combination

C−H combination

C−H stretch/CH2 deformation combination C−H stretch/C−H deformation CH2 bend second overtone C−H stretch/C−C stretch combination C−H combination

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

417 °C, when the drug loses 62.5% of its mass. The second decomposition step starts at 417 °C and ends at 668 °C. The total 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 absorbed water and water of crystallization.27 The second stage occurring between 268 and 428 °C is associated with the biggest weight loss and the char formation. The oxidation process occurs at temperatures higher than 428 °C, up to 577 °C. During these three steps of thermal degradation, HP-β-CD has a weight loss of 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

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

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3.7. Scanning Electron Microscopy (SEM). Although this method is not decisive for the confirmation of the inclusion complex formation, nevertheless, it helps to demonstrate the existence of a single component in the final product. The scanning electron microphotographs of amiodarone, HP-β-CD, their physical mixture, and inclusion complex are shown in Figure 8. Pure amiodarone appeared as cyclindrical crystals that have a tendency to form aggregates. HP-β-CD consisted of shrunken spheres with concave shapes. In the physical mixture, the drug crystals only adhere to the surface of HP-β-CD spheres and no interactions took place between the amiodarone and the HP-β-CD. In the case of the inclusion complex obtained by freeze-drying, the shape and morphology change completely. The regular morphology of both components disappears, and the sample appears as irregular sheets with a high surface area. The microphotograph of the inclusion complex suggests the presence of an amorphous homogeneous phase. 3.8. In Vitro Dissolution Studies. To evaluate whether the complexation process affected the dissolution rate of amiodarone, dissolution studies were performed for this drug and its inclusion complex with HP-β-CD, at two pH values: 1.2 and 6.8. The dissolution profiles of pure amiodarone and of the inclusion complex are presented in Figure 9 and data extracted from these profiles are summarized in Table 2. These data are related to the amount of amiodarone used for obtaining the inclusion complex. The quantitative determination 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 (--), and HP-β-CD (-•-).

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

Figure 8. SEM images of pure amiodarone (a), HP-β-CD (b), the physical mixture (c), and the inclusion complex (d). 2179



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AUTHOR INFORMATION

Corresponding Author

*Tel: + 40 232 217454; Fax: + 40 232 211299. E-mail: [email protected] Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS This research was financially supported by the grant of the Romanian National Authority for Scientific Research, CNCS− UEFISCDI, Project No. PN-II-ID-PCE-2011-3-0187. The authors thank Ph. D. student Manuela Pintilie for the NIR determinations.

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

Table 2. Dissolution Data for Inclusion Complex and Amiodaronea pH 1.2

pH 6.8

param.

IC

amiodarone

IC

amiodarone

Qmax released (%) t1/2 (min) tmax (min)

21.2 2.5 15

3.2 2.44 120

34.1 2.4 5

4.9 4.35 120

REFERENCES

(1) Uekama, K.; Hirayama, F.; Irie, T. Cyclodextrin Drug Carrier Systems. Chem. Rev. 1998, 98, 2045. (2) Cal, K.; Centkowska, K. Use of Cyclodextrins in Topical Formulations: Practical Aspects. Eur. J. Pharm. Biopharm. 2008, 68, 467. (3) He, Y.; Fu, P.; Shen, X.; Gao, H. Cyclodextrin-Based Aggregates and Characterization by Microscopy. Micron 2008, 39, 495. (4) Yuan, H. N.; Yao, S. J.; Shen, L. Q.; Mao, J. W. Preparation and Characterization of Inclusion Complexes of β-Cyclodextrin-BITC and β-Cyclodextrin-PEITC. Ind. Eng. Chem. Res. 2009, 48, 5070. (5) Brewster, M. E.; Loftsson, T. Cyclodextrins as Pharmaceutical Solubilizers. Adv. Drug Delivery Rev. 2007, 59, 645. (6) Gould, S.; Scott, R. C. 2-Hydroxypropyl-β-Cyclodextrin (HP-βCD): A Toxicology Review. Food Chem. Toxicol. 2005, 43, 1451. (7) Garnero, C.; Longhi, M. Study of Ascorbic Acid Interaction with Hydroxypropyl- β-Cyclodextrin and Triethanolamine, Separately and in Combination. J. Pharm. Biomed. Anal. 2007, 45, 536. (8) Misiuk, W.; Zalewska, M. Investigation of Inclusion Complex of Trazodone Hydrochloride with Hydroxypropyl-β-Cyclodextrin. Carbohydr. Polym. 2009, 77, 482. (9) Nicolescu, C.; Aramă, C.; Nedelcu, A.; Monciu, C. M. Phase Solubility Studies of the Inclusion Complexes of Repaglinide with βCyclodextrin and β-Cyclodextrin Derivatives. Farmacia 2010, 58, 620. (10) Boldescu, V.; Kacso, I.; Borodi, G.; Bratu, I.; Duca, G. Physicochemical Characterization of Sanguinarine-Hydroxypropyl-βCyclopdextrin 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 5FC Complexes, Preliminary Pharmacological Studies. J. Inclusion Phenom. Macrocyclic Chem. 2009, 65, 431. (12) Baboota, S.; Agarwal, S. P. Preparation and Characterization of Meloxicam 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 Progesterone and Hydroxypropyl-β-cyclodextrin in Aqueous Solution by NMR Study. J. Inclusion Phenom. Macrocyclic Chem. 2007, 57, 317. (14) Ghuran, A. V.; Camm, A. J. Amiodarone and Beta BlockadeIs the 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 Amiodarone Hydrochloride Under Isothermal Conditions. Drug Dev. Ind. Pharm. 2011, 37, 638. (16) Data, S.; Waghray, T.; Torres, M.; Glusman, S. Amiodarone Decreases Heat, Cold, and Mechanical Hyprealgesia in a Rat Model of Neuropathic Pain. Anesth. Analg. 2004, 98, 178. (17) Plomp, T. A. Analytical Profile of Drug Substances; Academic Press: San Diego, CA, 1991. (18) Cohen-Lehman, J.; Dahl, P.; Danzi, S.; Klein, I. Effects of Amiodarone Therapy on Thyroid Function. Nat. Rev. Endocrinol. 2010, 6, 34.

a

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

HP-β-CD:amiodarone, used for preparation and found by phase solubility study. After 120 min, only a small quantity of pure drug (between 3.2 and 4.0%) is dissolved at both values of pH, while in the case of inclusion complex the maximum amount of drug (34% and 21%, respectively) is dissolved in 5 min for pH 6.8 and in 15 min for pH 1.2. The dissolution rate is higher for pH 6.8; this value of pH being close to the amiodarone pKa. A strong increase of the maximum dissolution amount was observed for the inclusion complex in respect with the pure drug. The amount of amiodarone dissolved in the case of inclusion complex increased about 6.6 folds for the pH = 1.2 and 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 drug crystallinity and thus the increase of solubility, which is a consequence of the specific interactions between HP-β-CD and amiodarone.

4. CONCLUSIONS An inclusion complex between amiodarone and HP-β-CD has been prepared by freeze-drying method. The phase solubility diagram indicated the formation of a 1:1 inclusion complex between the guest drug and the host cyclodextrin. The FT-IR spectra, together with the NIR results, point out the formation of the inclusion complex through the tert-amine end of the amiodarone molecule. The XDR and DSC results demonstrated 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 solubility and dissolution rate. 2180



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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-Based Intravenous Formulation of Amiodarone Devoid of Adverse Hemodynamic Effects. Eur. J. Pharmacol. 2009, 607, 167. (20) Van Herendael, H.; Dorian, P. Amiodarone for the Treatment and 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 Microemulsion Injectable Formulation. AAPS Pharm. Sci. 2002, 4, 4122. (22) Kipp, J. E.; Doty, M. J.; Rebbeck, C. L.; Eilert, J. Y. AmiodaroneContaining Parenteral Administration. United States Patent No. 6479541, 2002. (23) Mosher, G. L.; Johnson, K. T.; Gayed, A. A. Formulations Containing Amiodarone and Sulfoalkyl Ether Cyclodextrin. United States Patent No. 6869939B2, 2005. (24) Elhasi, S.; Astaneh, R.; Lavasanifar, A. Solubilization of an Amphiphilic 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 Physicochemical Characteristics and Bioavailability of Indomethacin from β-Cyclodextrin, Hydroxyethyl-β-Cyclodextrin, and Hydroxypropyl-β-Cyclodextrin Complexes. Int. J. Pharm. 2004, 270, 149. (27) Trotta, F.; Zanetti, M.; Camino, G. Thermal Degradation of Cyclodextrins. 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 for Amiodarone Determination from HP-β-CD/Amiodarone Inclusion Complex and from Tablets. Rev. Chim., submitted.

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Effect of Hydroxypropyl-β-Cyclodextrin on the Solubility of an

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