Effect of Types of Cyclodextrin on Rosuvastatin … and dissolution profile of Rosuvastatin by...

Effect of Types of Cyclodextrin on Rosuvastatin Calcium Inclusion Complex

Vol. 2, No. 1, January-June 2011 1

Corresponding author: E-mail: [email protected]

INDIAN JOURNAL OF PHARMACEUTICSVolume 2 • Number 1 • January-June 2011 • pp. 1-8I J P

Effect of Types of Cyclodextrin on Rosuvastatin Calcium InclusionComplex

Akbari B. V.1*, Valaki B. P1., Maradiya V. H1, Akbari A. K.1 and G. Vidyasagar2

1Shree Dhanvantary Pharmacy College, Kim, Surat, Gujarat, India2Dean, Faculty of Pharmaceutical Sciences, Kachchh University, Bhuj, Kutch, Gujarat.

Abstract: Rosuvastatin Calcium is poorly water soluble drug and it exhibit unsatisfactory dissolution profilesand, consequently, problems of absorption and poor bioavailability. The aim of this work was to improvesolubility and dissolution profile of Rosuvastatin by exploiting the solubilizing effect of β-cyclodextrin andhydroxy propyl β-cyclodextrin (HP-β-CD).Rosuvastatin Calcium (RST), a poorly water-soluble 3-hydroxy3-methyl glut aryl CoA (HMG-CoA) Reductase inhibitor through inclusion complexation with β-cyclodextrinand hydroxy propyl β-cyclodextrin (HP-β-CD) aqueous solubility was improved. Phase solubility studies werecarried out according to the method reported by Higuchi and Connors. Apparent solubility constant (KC) ofdrug was found to be 42.003M-1and 48.477M-1 with β-cyclodextrin and hydroxy propyl β-cyclodextrin (HP-β-CD) respectively. Drug–CD complex systems, prepared by different techniques, were characterized by differentialscanning Calorimetry (DSC), X-ray diffractometry, and Fourier transform infra-red (FT-IR) spectroscopy. Physicalmixture shows release up to 49.29% of the drug in 20 min and up to 67.04% after 30 min. whereas 69.79% and80.26% drug release after 30 min from precipitated and co-evaporated respectively. Kneaded products showedhighest dissolution profile among all complex 89.46% drug release in 20 min. that shows that there wasimprovement in dissolution rate of drug from hydroxy propyl β-cyclodextrin inclusion complex as comparedto β-cyclodextrin inclusion complex, physical mixture and pure drug.Keywords: β-cyclodextrin, hydroxy propyl ²-cyclodextrin,Rosuvastatin Calcium, Inclusion Complex.

INTRODUCTIONThe rate of absorption and bioavailability of poorwater soluble drugs is often controlled by the rateof dissolution of the drug in the gastrointestinaltract. Many technological methods of enhancing thedissolution characteristics of slightly water-solubledrugs are solid dispersions, micronization, solventdeposition, prodrugs, use of surfactants andinclusion complexation etc. Among the variousmethods, cyclodextrin complexation isanindustrially accepted technique1.

Rosuvastatin Calcium (RST), a poorly water-soluble 3-hydroxy3-methyl glut aryl CoA (HMG-CoA) Reductaseinhibitor, apotentlipid-loweringagent, and usedashypolipidemicagent.

Itisals ousedinthetreatmentofosteoporosis,benignprostatichyperplasia, and Alzheimer’sdisease2. RST iscrystalline nature so it reduces itsaqueous solubility and finally thatresultsinanoralbioavailabilityof 20%. Afteroraladministration ofRST, the peak plasma Concentration is reachedwithin 3–5 h, the volume of distributionis 1.1-1.4liter/Kg, andplas maproteinbinding is 90%. RSTisextensively metabolized by oxidation,lactonisation, a ndglucuronidation and themetabolitesareel iminated by biliary secretion anddirect secretion from the blood to the intestine3,4,5.

Cyclodextrins are cyclic oligosaccharides,containing six, seven or eight glucopyranoseunits(α, β or γ respectively) obtained by the enzymaticdegradation of starch. These are torus shapedmolecules with a hydrophilic outer surface andlipophilic central cavity, which can accommodate

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Akbari B. V., Valaki B. P., Maradiya V. H., Akbari A. K. and G. Vidyasagar

2 Indian Journal of Pharmaceutics

a variety of lipophilic drugs. Cyclodextrins are ableto form inclusion complexes with poorly water-soluble drugs and have been shown to improvepharmaceutical properties like solubility,dissolution rate, bioavailability, stability and evenpalatability without affecting their intrinsiclipophilicity or pharmacological properties. Naturalcyclodextrins have limited water solubility.However, a significant increase in water solubilityhas been obtained by alkylation of the free hydroxylgroups of the cyclodextrins resulting in hydroxylalkyl, methyl and sulfobutyl derivatives. The abilityof cyclodextrins to form inclusion complexes mayalso be enhanced by substitution on the hydroxylgroup6, 7.

The objective of present study is to prepareinclusion complexes of RosuvastatinCalciumwithcyclodextrins by different methodssuch as physical, kneading and co-evaporation,precipitation method and increase the solubility ofRosuvastatin Calcium (RST) for improvement ofdissolution rate and bioavailability of the drug.

EXPERIMENTAL STUDIES

MATERIALSRosuvastatin Calcium (RST) was gifted from AstronResearch limited. Ahmedabad, India. Hydroxylpropyl Beta-cyclodextrinwas obtained fromLykalaboratory, Ankleshwar, Gujarat, India. Allother chemicals and reagentsused were ofanalyticalgrade.

METHODS

Phase Solubility Studies8

Phase solubility studies were carried out accordingto the method reported by Higuchi and Connors8.An excess of Rosuvastatin Calcium RST (5 mg) wasadded to 10 ml portions of distilled water, eachcontaining variable amount of β-CD and HP-β-CDsuch as 0, 2, 4, 6, 8, and 10milimoles/liter. Allthe above solutions with variable amount ofcyclodextrinwere shaken in rotary shaker for 72hours. After shaking, the solutions were filtered andtheir absorbance was noted at 248nm. The apparent1:1 stability constants were calculated from thephase solubility diagrams, according to thefollowing equation:

=−(1 )o

slopeKcS slope

PREPARATION OF CYCLODEXTRININCLUSION COMPLEXESAllthebinary mixtures were preparedina1 : 1 molarratio of drug and cyclodextrin on the basis of theresults obtained from the preliminary phasesolubility studies.

Physical Mixture9, 10

The physical mixture of Rosuvastatin-cyclodextrinprepared by mixing RST withcyclodextrinin1:1molar ratio were in a mortar for about one hourwith constant trituration, passed through sieve No.100.

Kneading Method9, 10

RST with cyclodextrinin1:1 molar ratio were taken.First cyclodextrin is added to the mortar, smallquantity of 50% ethanol is added while trituratingto get slurry like consistency. Then slowly drug isincorporated into theslurry and trituration is furthercontinued for one hour. Slurry is then air dried at25 °C for 24 hours, pulverized and passed throughsieve No. 100.

Co-evaporation Method10, 11

Inclusion complex (1:1)was prepared by dissolvingequimolar amount of cyclodextrin and RSTCa inrequired amount of 50% aqueousethanol. Thesolution was stirredtillac lear solution was observedand the obtained solution was the nevaporatedunder vacuumata temperature of 45°C and 100rpm.The solid residues was further dried completelyat45°C for 48h, the driedcom plex was pulverized intoafine powder and sieved throughsieve No. 100.

Precipitation Method11, 12

Inclusion complex of RST and cyclodextrin in 1:1molar ratio was prepared by drug and CD, whichdispersed in water and the solution, was heated toobtain concentrated, viscous and translucent liquid.The solution was left to give a precipitation ofinclusion complex. Precipitate obtained wasseparated and dried to get solid inclusioncomplex.



Drug Content Estimation13

100 mg of drug cyclodextrincomplex was accuratelyweighed and transferred to 100 ml volumetric flaskand volume was made up to the mark withmethanol. From this 1ml was taken in 10 mlvolumetric flask and the volume is adjusted up tothe mark with same solvent. The absorbance of thesolution was measured at 248 nm using appropriateblank. The drug content of Rosuvastatin Calciumwas calculated using calibration curve.

Fourier Transforminfrared (FTIR) Spectroscopy13,

14

Fourier transform IR spectra were recorded on FT/IR-4100 type A. The spectra were recorded forRosuvastatin-Cyclodextrin physical mixture,kneaded, Co-evaporation and precipitationmethod. Samples were prepared in KBr disc (2 mgsample in 200 mg KBr).The scanning range was 400-4000 cm-1, resolution was 4 cm

Differential Scanning Calorimetry (DSC) 13, 14

The samples were analyzed by DSC using a MettlerToledo SR system. The samples (5 mg each) wereplaced into pierced aluminum container. Thestudies were performed under static air atmospherein the temperature rangeof 20°C to 400°C at aheating rate of 10° C/min. The peak temperatureswere determined after calibration with standard.

Powder X-ray Diffractometry (PXRD) 13, 14

The powder X-RD patterns of drug, Cyclodextrin,and complexes were recorded by using automatedPhilips Holland -PW 1710 scanner with filter Curadiation over the interval 5-60°/2¸. The operationdata were as follows: voltage 35 kV, current 20 mA,filter Cu and scanning speed 1° / min.

In Vitro Dissolution Studies for RST-CDComplexes15, 16

In-vitro dissolution of RSTinclusion complex wasstudied in USP XXIV dissolution apparatus(Electrolab) employing a paddle stirrer. 900 ml ofphosphate buffer of pH 6.8 was used as dissolutionmedium at 50 rpm. The temperature of 37 ± 0.5 °Cwas maintained throughout the experiment.Complex equivalent to 5 mg of RST was used ineach test. 5 ml of sample of dissolution medium

were withdrawn by means of syringe fitted withpre-filter at known intervals of time and analyzedfor drug release by measuring the absorbance at 248nm after suitable dilution with phosphate buffer.The volume withdrawn at each time interval wasreplaced with fresh quantity of dissolution medium.The amount of RST released was calculated andplotted against time and compared with pure drug.The % drug release profile of inclusion complexesshown in Table 1, 2 and Figure 2, 3.

Table 1In-vitro % Drug Release Profile of -CD Inclusion

Complexes and Pure DrugTime Cumulative % drug Release(min) PM COE PPT KM Pure5 21.6 24.03 28.08 36.34 11.310 24.24 28.12 40.56 52.73 17.5815 34.81 35.78 53.31 70.81 30.2820 49.29 50.2 62.1 89.46 44.6925 55.45 62.15 72.32 97.21 52.8730 67.04 69.79 80.26 99.26 64.28

Table 2In-vitro % Drug Release Profile of HP--CD

Inclusion Complexes and Pure DrugTime Cumulative % drug Release(min) PM COE PPT KM Pure5 21.6 24.03 28.08 36.34 11.310 24.24 28.12 40.56 52.73 17.5815 34.81 35.78 53.31 70.81 30.2820 49.29 50.2 62.1 89.46 44.6925 55.45 62.15 72.32 97.21 52.8730 67.04 69.79 80.26 99.26 64.28

RESULTS AND DISCUSSION

Phase Solubility StudiesThe phase solubility diagrams of RST Ca: CD wasobtained by plotting the changes in guest solubilityas a function of CD concentration. The solubilitycurves were classified as the AL type according toHiguchi and Connors8. Figure 1 shown that theapparent solubility of RST Ca increases linearly asa function of CD over the entire concentration rangeand was the characteristic of the AL-type of curve,which suggests that water-soluble complex, wasformed insolution. The slope values obtained wereless than 1, which indica test hatinclusion complexin the molar ratio of 1:1 between theguest andthehost molecule was enough to increase the



Drug Content EstimationUV spectrophotometry was used to determine thedrug content of the binary system of thecyclodextrin: drug molar ratio (1:1). The Drugcontent in all β-CDinclusion complex system wasfound to be 49.86% w/w to 52.5% w/w (99.77 % to105.01%) which indicated that there was 1:1complex was established. The hydroxy propylβ-cyclodextrin drug ratio would therefore remain1:1 in the final solution to calculate the drug content.The Drug content in all the system was found tobe 49.59 % w/w to 51.15% w/w (99.18 % to102.31%).

Fourier Transform Infra-Red SpectroscopyIR Spectra of pure drug and inclusion complexes ofRosuvastatin with CD prepared by differentmethods are given in figure 4, 5. As clearly seenfrom the spectra, the characteristic peaks ofRosuvastatin Ca at 564, 844, 965, 1335, 2360, 2973and 3300 cm-1 were modified significantly as a resultof complex formation. As shown Figure 5C slightlyshifting in absorbance of Rosuvastatin it indicates

Figure 1: Phase Solubility Diagram for Rosuvastatin Ca with-CDand HP--CD at 25 °C

Figure 2: Comparative % Cum. Drug Release from -CDInclusion Complexes and Pure Drug

Figure 3: Comparative % Cum. Drug Release from HP--CDInclusion Complexes and Pure Drug

solubility of poor water soluble Rosuvastatin.Apparent solubility constant (KC) of drug was foundto be 42.003M-1and 48.477M-1 with β-cyclodextrinand hydroxy propyl β-cyclodextrin (HP-β-CD)respectively. The phase solubility proûle indicatedthat the solubility of Rosuvastatin Ca wassigniûcantly increased in the presence of HP-β-CDas compared to β-CD.

Figure 4: FTIR Spectra of (A) Rosuvastatin Pure (B) Pure -CD (C) Physical Mixture (D) Kneading Method (E)Co-evaporation Method (F) Precipitation Method



no strong interaction between drug andcyclodextrin. Figure 5D, 5E and 5F shows thatcharacteristic peaks of drug at 564, 1335, 2360 and2973 cm-1 drastically modified or absence due toformation of complex between drug andcyclodextrin.

Differential Scanning Calorimetry (DSC)The thermal behavior RST-CD complex was studiedusing DSC in order to confirm the formation ofcomplex. DSC thermogram of RST, CD and allinclusion complexes are shown in figure 6, 7. TheDSC thermogram of RST showed an endothermicpeak at 105 oC corresponding to its melting point.The DSC thermogram of RST-CD complex showedendothermic peak at different temperature orabsence of sharp endothermic peak by differentmethod of preparation, which is different from thepure drug, which gives clear evidence that there isformation of the complex.

X-Ray Diffraction Studies (XRD)The X-RD pattern (Figure 5A) of pure drugpresented several diffraction peaks at 11.2, 15.7,

Figure 5: FTIR Spectra of (A) Rosuvastatin Pure (B) Pure HP--CD (C) Physical Mixture(D) Kneading Method (E)Co-evaporation Method (F) Precipitation Method Figure 6: DSC Thermogram of (A) Rosuvastatin Pure (B) Pure

-CD (C) Physical Mixture (D) Kneading Method (E)Co-evaporation Method (F) Precipitation Method

Figure 7: DSC Thermogram of (A) Rosuvastatin pure (B) PureHP--CD (C) Physical Mixture(D) Kneading Method(E) Co-evaporation Method (F) Precipitation Method



16.6, 19.4, 20.4, 21.8 and 23.4 indicating thecrystalline nature of the drug. The HP-β-CD is avery amorphous material as there is no any sharppeak present as shown in Figure 9B. The PM shows(Figure 9C) the characteristic peaks of the drug atidentical angles, which proves that no interactionstake place during mixing. Almost all drugdiffraction peaks were slightly reduced in intensityin the kneaded products with HP-β-CD (Figure 9D,9E & 9F) with respect to the corresponding physicalmixture, thus revealing some interaction betweenthe components, as a consequence of their intimatecontact obtained during complex preparation.Crystallinity was determinedby comparing somerepresentative peak heights in the diffractionpatterns of the binary systems with those of areference.The relation used for the calculation ofthe crystallinity was the relative degree ofcrystallinity (RDC) = ISAM/IREF, where ISAM isthe peakheight of the sample under investigation and IREFisthe peak height of the same angle for the referencewith thehighest intensity.

In Vitro Dissolution StudyIn-vitro dissolution study showed that 44.69% ofthe pure Rosuvastatin was released in 20 min, andup to 64.28% after 30 min where as 84.99%, 87.23%and 98.96% drug release after 30 min fromprecipitated, co-evaporated and kneaded drug-cyclodextrin complex respectively that shows thatthere was improvement in dissolution rate of drugfrom inclusion complex as compared to physicalmixture and pure drug. Since the presence ofcyclodextrin showed that there was decreased inextinction coefficient of the drug, since the hydroxypropyl β-cyclodextrin is highly water soluble it wasexpected to instantly dissolve in the medium underthe condition of dissolution test .The release rateprofile was drawn as the cumulative percent releaseon y-axis and time on x-axis which showed in figure2 and 3. It showed that 44.69% of the pureRosuvastatin was released in 20 min, and up to64.28% after 30 min. Physical mixture shows releaseup to 49.29% of the drug in 20 min and up to 67.04%after 30 min whereas 69.79% and 80.26%drugrelease after 30 min from precipitated and co-evaporated respectively. Kneaded products showedhighest dissolution profile among all complex89.46% drug release in 20 min. that shows that there

Figure 9: XRDPatterns of (A) Rosuvastatin Pure (B) PureHP--CD (C) Physical Mixture(D) Kneading Method (E)Co-evaporation Method (F) Precipitation Method

Figure 8: XRD Patterns of (A) Rosuvastatin Pure (B) Pure -CD (C) Physical Mixture (D) Kneading Method (E)Co-evaporation Method (F) Precipitation Method



was improvement in dissolution rate of drug fromdrug-HP-β-CD inclusion complex as compared tophysical mixture and pure drug.

DISCUSSIONFrom the result it is observed that the solubility ofRosuvastatin in the presence of hydroxy propyl β-cyclodextrin can be classified as the AL type. Thisindicated that the complexes at 1:1 ratio areadequately stable. In case of complexes, a diffractionpattern was significantly modified to that of puredrug, hydroxy propyl β-cyclodextrin, with areduction inpeak intensities. This confirms partialcomplexes formation i.e. some part of Rosuvastatinentrapped in cyclodextrin cavity.

The DSC thermogram for the complexesshowed the persistence of the endothermicpeak ofRosuvastatin for the physical mixture, soliddispersion, kneaded and precipitation systemproduct. The thermal behavior of physical mixture,solid dispersion, kneadedand precipitation systemis similar to the untreated samples, indicating thatthe physical mixture, solid dispersion, kneaded andprecipitation system processes did not affecttheirsolid state properties. For physical mixture, soliddispersion, kneaded and precipitation systemcomplexes, there isreduction in peaks intensity; thiscan be explained on the basis of majorinteractionbetween the drug andcyclodextrin.Furthermore, the characteristic endothermic effectof cyclodextrin and Rosuvastatin is slightly shiftedto lower temperature for the Co-evaporated,kneaded and precipitation system complexes,indicating that Rosuvastatin got complex withCyclodextrin. The enhancement in dissolutionprofile hasbeen attributed due to the formation ofinclusion complexes in the solid state and reductionin the crystallinity of the product, asconformed bypowder X-RD study. The dissolution rate increasefor the physicalmixture, kneaded, co-evaporatedand precipitation mixtures is due to the wettingeffect of the cyclodextrin, this effect is more evidentfor the kneaded product, wherethe mixing processbetween the two components is more intensive. Theeffect ofcomplexation with cyclodextrin on thesolubility of Rosuvastatin can be explained in termsof the reduction in the crystallinity of the drugcaused by the Co-evaporated, kneaded andprecipitation process and the inclusion into the

hydrophobic cavity of thecyclodextrin. The FTIRspectra of physical mixture, co-evaporated,kneaded and precipitation system shows significantshift of hydroxyl functional group absorption bandat 2360 cm-1. This may be indicative that the drug-cyclodextrin complex, as a consequence of theinteraction with cyclodextrin through hydrogenbonding, which could result in its inclusion into thehydrophobic cavity of the HP-β-cyclodextrin.

CONCLUSIONThisstudyshowsthatthereisformationofaHP-β-CD:Rosuvastat incomplex in aqueous solution and thiscomplex, prepared by the various inclusioncomplexation methods, also exist in the solid state.The inclusion complex prepared with HP-β-CD bykneading method showed highest solubility andfastest dissolution profile (more than 90% drugrelease in 15 min) as compared to β-CD-druginclusion complex. Improved dis solution rate maybe as a result of the increase in solubility, broughtabout by complex ation. From the results wecanassumethat the aqueous solubility and dissolution rateof Rosuvastat in can be significantly in creased byform in ganinclusion complex with HP-β-CD.

ACKNOWLEDGMENTWe are sincerely thankful to Shree Dhanvantary PharmacyCollege, Kim, Surat, for providing us Infrastructure facilitiesand moral support to carry out this research work. Isincerely express my gratitude to Astron Research limited,Ahmedabad for providing RosuvastatinCalcium as a giftsample. We are also grateful to Lyka laboratory,Ankleshwar, for providing us Beta-cyclodextrin andHydroxy Propyl Beta-cyclodextrin.

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