Cyclodextrin Inclusion Complex of Racecadotril

Send Orders for Reprints to [email protected] Current Drug Discovery Technologies, 2014, 11, 00-00

1

Cyclodextrin Inclusion Complex of Racecadotril: Effect of Drug-Cyclodextrin Ratio and the Method of Complexation Mona Semalty1, Mitali Panchpuri1, Devendra Singh2 and Ajay Semalty1,* 1 2

Department of Pharmaceutical Sciences, H.N.B. Garhwal University, Srinagar (Garhwal)-246174, Uttarkhand, INDIA; Department of Chemistry, H.N.B. Garhwal University, Srinagar (Garhwal)-246174, Uttarkhand, INDIA Abstract: Racecadotril is an antisecretory and antidiarrheal agent against watery diarrhoea in children. Racecadotril is a class II drug (as per Biopharmaceutical Classification System) with poor aqueous solubility and dissolution rate limited absorption. -cyclodextrin complexation of solubility or dissolution rate limited drugs provides an amphiphilic complex with improved solubility and dissolution profile. Thus Racecadotril – -cyclodextrin complex were prepared to improve its solubility and dissolution by imparting an environment of improved hydrophilicity. Racecadotril was complexed with -cyclodextrin (in 1:1 and 1:2 molar ratios) by two different methods (solvent evaporation and kneading method). These inclusion complexes were evaluated for solubility, drug content, scanning electron microscopy (SEM), differential scanning calorimetry (DSC), X ray powder diffraction (XRPD) and in vitro dissolution study. The highest drug content (30.83%) was found in complex made by kneading method (RK1:1) in 1:1 molar ratio. Complex prepared by solvent evaporation method (RSE1:1, RSE1:2) were found to be showing irregular disc shaped non-porous surface, while the complexes prepared by kneading method (RK1:1, RK1:2) showed rough, fluffy, non-porous and irregular surface in SEM. Solubility of the drug improved up to 2 to 3 folds in the complexes. The complex RK1:1 showed the greatest improvement in solubility (from 28.98 to76.56 μg/ml). The dissolution of the complexes was also found to be improved. Complex prepared by solvent evaporation method in 1:1 molar ratio (RSE1:1) showed a marked improvement in percent drug release (100.33%) than that of pure drug (52.58%) at the end of 1 hour in dissolution study. FTIR, DSC and XRPD data confirmed the formation of inclusion complex. It was concluded that water solubility of all the complexes were increased when the drug was complexed with -CD in 1:1 molar ratio. The complex made in 1:1 molar ratio (irrespective of the method) showed better solubility and the dissolution profile as compared to the complex made in 1:2 molar ratio. It was concluded that the complex prepared by the solvent evaporation method showed better solubility and the dissolution due to better amorphization of the drug.

Keywords: BCD complex, in vitro dissolution, Racecadotril, solubility. 1. INTRODUCTION The solubility of a drug is one of the most critical factors in developing a drug into a dosage form or delivery system. The aqueous solubility governs the amount of compound that will dissolve and hence the amount available for absorption. Therefore, a fair solubility in gastro intestinal medium is an indispensable property for good bioavailability of orally administered drugs. Dissolution and solubility are the two important properties which play an important role in formulation development of the drugs [1, 2]. Poor solubility and the dissolution of drugs is the major challenge for formulation scientists. Various techniques like solid dispersion, solvent deposition, micronization etc. have been investigated for resolving solubility issue in pharmaceutical product development. Each of these techniques has its own merits and demerits. Out of these, the complexation technique has been *Address correspondence to this author at the Department of Pharmaceutical Sciences, H. N. B. Garhwal University, Srinagar (Garhwal) 246 174, Uttarakhand, India; Tel: +91 1370 267395; Fax: +91 1346 252174; E-mail: [email protected] 1570-1638/14 $58.00+.00

employed more precisely to improve the solubility and the dissolution of poorly water soluble drugs [3-10]. Complexation is generally defined as the reversible association of a substrate and ligand to form a new species. Cyclodextrins (CDs) are classic examples of compounds that form inclusion complexes. These complexes are formed when a ‘‘guest’’ molecule is partially or fully included inside a ‘‘host’’ molecule (e.g. CD) with no covalent bonding. When inclusion complexes are formed the physicochemical parameters of the guest molecule are disguised or altered and improvements in the molecule’s solubility, stability, taste, safety, bioavailability, etc., are commonly seen. Cyclodextrins are the cyclic carbohydrates formed during the bacterial (Bacillus macerans) degradation of cellulose and used as the potential complexing agents to form inclusion complex with poorly water soluble drugs. These are amphiphilic molecules (cyclic oligosaccharides) consist of (-1,4) linked -D-glucopyranose units with lipophilic central cavity and a hydrophilic outer surface. The 3D structure of the parent CD provides a cavity that is hydrophobic relative to an aqueous environment. Cyclodextrins are shaped © 2014 Bentham Science Publishers

2 Current Drug Discovery Technologies, 2014, Vol. 11, No. 2

like a truncated cone because of chair conformation of glucopyranose units, with hydroxyl group oriented towards the exterior (primary hydroxyl group towards the narrow edge of cone and secondary hydroxyl groups towards the wider edge). Due to this conformation cyclodextrin contain the lipophilic central cavity that is lined by the skeletal carbons and ethereal oxygen of glucose residues and hydrophilic outer surface [11]. It has been found that for the solubility or dissolution rate limited drugs (specially BCS class II drugs) cyclodextrins complexation may be a potential approach to improve the dissolution, absorption and the bioavailability [12-17]. Racecadotril (N-[2-[(Acetylthio)methyl]-1-oxo-3-phenylpropyl]-glycine phenylmethyl ester) is an antisecretory agent and an important antidiarrheal agent against watery diarrhoea in children (Fig. 1). According to WHO guideline, it is the only medicine which has a proven efficacy in reducing water and electrolyte and the stool output without any complication [18-20]. Racecadotril is a BCS class drug (low solubility, high permeability). The class II drugs like racecadotril often show poor gastrointestinal (GI) absorption due to inadequate drug solubility in GI fluids. Because of its very low aqueous solubility, the oral absorption of the drug is dissolution-rate limited. The particle size and morphology are also the critical parameters in the development of formulations for effective GI drug delivery. Therefore, a system with improved solubility and amorphous state of the drug can be developed for improving solubility, dissolution and hence the oral bioavailability. In the present study, to enhance the solubility and dissolution rate the inclusion complex of racecadotril was prepared with -CD. The prepared complexes were characterized for various physico-chemical investigations like drug content, chemical interaction (FTIR), phase transition behavior (DSC), crystallinity (XRPD), surface morphology (SEM) and in-vitro dissolution study in comparison with pure racecadotril.

Fig. (1). Chemical Structure of Racecadotril.

2. MATERIALS AND METHODS 2.1. Materials Racecadotril was obtained from as a gift sample from Torrent pharmaceutical Pvt. Ltd. Chandigarh. -cyclodextrin and sodium lauryl sulphate were purchased from Hi-media Lab. Pvt. Mumbai. All other chemicals and reagents were of analytical grade. 2.2. Methods of Preparation of Inclusion Complexes of Racecadotril In the present study, racecadotril- cyclodextrin (-CD) complex (in the different molar ratio 1:1 and 1:2) were prepared by the following two different methods namely- solvent evaporation and kneading methods.

Semalty et al.

Solvent evaporation method- The racecadotril- CD complexes - RSE1:1 and RSE1:2 were prepared by taking two different molar ratios of drug: -CD as 1:1 and 1:2, respectively with the solvent evaporation method. The desired molar weight of racecadotril (dissolved in sufficient quantity of acetonitrile:water in 50:50) and -CD (which was pretreated with hot water) was mixed. The resultant solution was refluxed for 2 hour and then evaporated under vacuum at 85C in rotary vacuum evaporator (Perfit Modle NO. 5600 Buchi type). When the solution remained to 3-4 ml, the solution was freeze dried at – 45oC and a compression pressure of 0.5 torr. The dried residues were collected and placed in vacuum desiccator overnight and then subjected to characterization. Kneading method- With the kneading method, racecadotril--CD complexes- RK 1:1 and RK1:2 were prepared by taking two different molar ratios of racecadotril to -CD as 1:1 and 1:2, respectively. Accurately weighed racecadotril and -CD were taken in a mortar and a paste was made with the help of 1 ml of 50% methanol; then this paste was dried for 30-60 min in oven at 50-60C. The resultant dry solid mass was powdered well, passed through a 60-mesh sieve and stored in a sealed glass vial until subjected to characterization. 2.3. Drug Content To determine the drug content in racecadotril--CD complex, 5 mg of complex was taken and 100 ml of distilled water was added to it. The volumetric flask was stirred continuously for 4-5 hr on a magnetic stirrer (Remi 5MLH). Dilution were made suitably and measured for the drug content at 231 nm spectrophotometrically (Lamda 25 Perkin Elmer UV/Visible spectrophotometer). 2.4. Solubility Study To determine the change in solubility due to complexation, solubility of drug and the complex was determined in distilled water by the shake flask method at 25 ± 0,1 o C [21, 22]. An excess amount of drug and the complexes were added to 5 ml distilled water in different screw capped vials. The vials were allowed to shake at 250 for 24 h. After the equilibrium was attained, the saturated solutions were centrifuged to remove excess drug (15min, 1000rpm). The supernatant was filtered immediately and rapidly through a 0.45 mm membrane filter and analyzed spectrophotometrically. 2.5. Scanning Electron Microscopy (SEM) To detect the shape and surface morphology of the prepared complex Scanning Electron Microscopy was performed at Wadia Institute of Himalayan Geology Dehradun by scanning electron microscope (Zeiss EVO 40 US). 2.6. FTIR Analysis FTIR spectra for the various powders were obtained on a Perkin Elmer FTIR spectrometer (Perkin Elmer Life and Analytical Sciences, MA, USA) in the transmission mode with the wave number region 4,000- 500 cm-1. KBr pellets were prepared by gently mixing 1 mg sample powder with 100mg KBr.

Cyclodextrin Inclusion Complex of Racecadotril

Current Drug Discovery Technologies, 2014, Vol. 11, No. 2

3

2.7. X-ray Powder Diffractometry (XRPD)

3.2. Solubility Study

The crystalline state of drugs in the different samples was evaluated with X-ray powder diffraction. Diffraction patterns were obtained on a Bruker Axs- D8 Discover Powder X-ray diffractometer (Germany). The X-ray generator was operated at 40 KV tube voltages and 40 mA of tube current, using the Ka lines of copper as the radiation source. The scanning angle ranged from 1 to 60 o of 2 in step scan mode (step width 1 o/min). Drug, -CD, and -CD complexes were analyzed with X-ray diffractions.

The pure racecadotril showed aqueous solubility of 28.98 μg/ml. On the other hand, all the complexes showed up to 3 fold increase in solubility (Table 1). The complex prepared in 1:1 ratio (RSE 1:1 and RK1:1) improved the solubility to higher values as compared to as that of 1:2 complexes (RSE 1:2 and RK1:2). The complex RSE1:1 showed the greatest improvement in solubility (from 28.98 to 76.56 μg/ml).

2.8. Dissolution Study In vitro dissolution studies for racecadotril complex as well as plain drug were performed in triplicate in a USP XXIII six station dissolution test apparatus (Veego Model No. 6DR India) at 100 rpm and at 37C as per Indian Pharmacopoeia [23]. An accurately weighed amount of the complex equivalent to 50 mg of drug was put into 900 ml of 1% SLS in 0.05 molar acetate buffer solution (pH 4.5). Samples of dissolution fluid were withdrawn at different intervals and replaced with the equal volume of fresh media. Withdrawn samples were filtered through a 0.45 μm membrane filter and diluted suitably and then analyzed spectrophotometrically at 231 nm. 2.9. Differential Scanning Calorimetry (DSC) Thermograms of racecadotril, -CD and racecadotril-CD complex were recorded using a differential scanning calorimeter (2910 Modulated DSC V4.4, TA Instrument, US). The thermal behaviour was studied by heating 2.0 ± 0.2 mg of each individual sample in a covered sample pan under nitrogen gas flow. The investigation were carried out over the temperature range 25-350C with a heating range of 10 C min-1. 2.10. Statistical Analysis Results were expressed as mean values and standard deviations (± SD). 3. RESULTS AND DISCUSSION In the present study racecadotril- CD complexes were prepared in two different molar ratios 1:1 and 1:2 with two different methods (solvent evaporation and kneading method) to improve solubility and dissolution rate of the drug. The percent yields were found to be 91.3, 87.11, 85.0 and 85.2 % (w/w) for RSE 1:1, RSE 1:2, RK1:1 and RK1:2, respectively. 3.1. Drug Content Drug content of all the formulations were estimated by UV spectrophotometic method. The percent loading efficiency of the different formulation were in the range of 14.83 to 30.83% (w/w). Complex prepared in 1:1 molar ratio viz. RSE 1:1 and RK 1:1 showed the highest drug loading efficiency of 29.66% and 30.83%, respectively; while the complex prepared in 1:2 molar ratio (RSE 1:2 and RK1:2) showed lower percent loading of 14.86 and 14.83%, respectively. The rank order of percent drug loading was found to be as followed RK1:1>RSE1:1>RSE1:2>RK1:2.

Table 1.

Solubility Study of Racecadotril and Its -CD Complexes at 25 oC

Drug/ Complex

Solubility in water (g/ mL)*

Racecadotril

28.98 ± 0.56

RSE1:1

76.56 ± 0.48

RSE1:2

53.54 ± 0.22

RK1:1

74.24 ± 1.02

RK1:2

56.57± 1.20

*Data expressed as mean values and standard deviations (± SD); n=3

3.3. Surface Morphology (SEM) The scanning electron microscopy (SEM) of racecadotril and the complexes are given in Fig. 2. -CD appeared as irregular shaped crystals. Racecadotril appeared as crystals of regular size needle shaped structure with an apparently rough surface. In contrast, a clear change in the morphology and shape of particles was observed in -CD complexes. Complexes prepared by solvent evaporation method (RSE1:1 and RSE1:2) showed irregular disc shaped non-porous surface (Fig. 2c & 2d). On the other hand, complexes prepared by kneading method (RK1:1, RK1:2) showed rough, fluffy, non-porous irregular surface (Fig. 2e & 2f). In particular, with the kneaded systems it was impossible to differentiate crystals of both components indicating the better interaction of drug particles with CDs. 3.4. Infrared Absorption (FTIR) The possible interaction between racecadotril and -CD was studied by IR spectroscopy (Fig. 3). Racecadotril showed the main characteristic bands for hydroxyl group (OH) stretching at 3388.47 while the complex showed this bands for hydroxyl group (-OH) at 3380.54, 3368.99, 3382.97, 3367.87. Racecadotril showed the characteristic peak for keto (C=O) group at 1728.61 and while the complex showed the same peak at 1732.22, 1744.57, 1731.72, 1745.90 for RSE1:1, RSE1:2, RK1:1, RK1:2, respectively. The -CD showed the characteristic peak for hydroxyl (-OH) group at 3368.61 and for keto (C=O) group at 1618.53. The FTIR of the complex showed the significant change in the spectrum. The absorption peak of hydroxyl (-OH) group shifted to lower wave number and keto (C=O) group of racecadotril shifted to higher wave no. in the complex. The FTIR study showed that there was possible interaction of drug with cyclodextrin which was confirmed by hydroxyl (-OH) group interaction (i.e. shifting of peak toward


Semalty et al.

Fig. (2). SEM Photographs of (a) Racecadotril, (b)-CD, and its complexes (c) RSE1:1, (d) RSE1:2, (e) RK1:1, (f) RK1:2.

lower wave no.). It was concluded that the same interaction might be responsible for the increase in solubility and the dissolution rate of racecadotril complex. 3.5. Crystallinity Study (XRPD) The X-Ray diffraction pattern of the racecadotril, -CD and the complex were studied for the evaluation of change in crystallinity of the drug in the complex (Fig. 4). The peak position (angle of diffraction) is an indication of crystal structure and peak heights are the measures of sample crystallinity (crystallite size) in a diffractogram. In the X-ray diffractogram, racecadotril showed intense diffraction peaks of crystallinity and suggested that the drug is present as a crystalline material. X-ray diffraction pattern of racecadotril-

-CD complex exhibited disappearance and reduction in the intensity of large diffraction peaks in which it was no longer possible to distinguish the characteristic peak of the drug indicating the decrease in crystallinity or partial amorphization of the drug. The result confirmed that racecadotril was no longer present as a crystalline material in its -CD complex and existed in the amorphous state [24-26]. These results imply that no alteration was produced in the crystal structure of the drug but crystallinity was modified. The maximum amorphization was observed in RSE 1:1 and RSE1:2 (followed by RK 1:1) which was evident due to disappearance of crystalline peaks corresponding to the drug. While other systems showed intermediate crystallinity and hence the partial amorphization was confirmed. Similar



Fig. (3). FTIR Spectra of (a) Racecadotril, (b)-CD, and its complexes (c) RSE1:1, (d) RSE1:2, (e) RK1:1, (f) RK1:2.

5


Semalty et al.

Fig. (4). X-ray diffraction (XRD) study of Racecadotril and its complexes.

results were reported for other drugs with amorphous -CD and its derivatives [27, 28]. 3.6. Dissolution Study The racecadotril--CD complex (RSE1:1, RSE1:2, RK1:1, RK1:2) showed better dissolution profile than the racecadotril (Fig. 5). Unlike the pure drug racecadotril (which showed a total of only 52.58% drug release at the end of 60 min), complexes showed 100.33%, 94.73%, 99.97%, 90.54 % drug released at the end of 60 min of dissolution study (in 1 % SLS solution of pH 4.5 with acetic acid) for RSE1:1, RSE1:2, RK1:1, RK1:2, respectively. RSE 1:1 and RK 1:1 showed the better dissolution which might be due to their better amorphous nature (as confirmed by the XRD data). Formulation RSE1:1 showed the maximum drug release while formulation RK1:2 showed the minimum drug release after 60 min. At the end of 60 min, the rank order of percent drug release was found to be RSE 1:1> RK1:1> RSE 1:2> RK1:2> racecadotril. The data from the dissolution study supported the SEM analysis which confirmed that the more porous surface bearing complexes show the improved solubility and enhanced dissolution rate as compared to pure drug. The various previous studies have reported that the -CDs are able to form water soluble complex with many lipophilic water insoluble drug and these complexes show a significant improvement in dissolution of the drug [29, 30]. Hence the formation of betacyclodextrin inclusion complex of the drug improved the dissolution profile. 3.7. Thermal Analysis (DSC) In differential scanning calorimetry (DSC) an interaction is indicated by elimination of endothermic peaks, appearance of new peaks, change in peak, shape and its onset, peak temperature, melting point and relative peak area or enthalpy. The complex prepared by solvent evaporation method (in 1:1

ratio) showed highest percent yield, good percent drug content, best amorphization and dissolution profile. Therefore, the formulation RSE1:1 was subjected to DSC analysis. The DSC thermogram of the crystals of racecadotril (Fig. 6) showed a well defined melting peak at about 81.9C while The DSC curve of -CD exhibited a broad endothermic phenomenon between 60°C to 150°C (due to the loss of water). On the other hand, the DSC thermogram of racecadotril-CD complex prepared by solvent evaporation method in 1:1 ratio showed no endothermic peak corresponding to the melting point of racecadotril. The absence of the endothermic peak (corresponding to that of racecadotril) suggested the formation of an inclusion complex without any free racecadotril. Hence, the complete disappearance of the endothermic peak of the drug in these systems indicated the formation of a true inclusion complex. Other studies also well supported the results [31-34]. CONCLUSION In order to improve solubility and dissolution profile of a BCS Class II drug-racecadotril, -cyclodextrin complexes were prepared by two different methods (solvent evaporation and kneading method) in two different molar ratios (1:1 and 1:2). These complexes were characterized for various parameters such as FTIR, SEM, DSC, XRD and dissolution study. It was concluded that the complex made in 1:1 molar ratio (irrespective of the method) showed better dissolution profile as compared to the complex prepared with 1:2 molar ratio. Racecadotril- -CD complex prepared by solvent evaporation method showed the best performance with respect to good percent drug content, highest percent yield, highest solubility, amorphization and dissolution profile as compared to that of kneading method. The results can be substantiated further by in- vivo studies. It can be concluded that -CD complexation of drugs may be very promising approach for improving the bioavailability of BCS class II drugs.



7

Fig. (5). Dissolution study of Drug and the prepared BCD complexes. [3] [4]

[5] [6] [7] [8]

Fig. (6). DSC thermogram of Racecadotril -CD complex by kneading method in 1:1 ratio.

[9] [10]

CONFLICT OF INTEREST The authors confirm that this article content has no conflicts of interest.

[11] [12]

ACKNOWLEDGEMENTS Authors are thankful to Wadia Institute of Himalayan Geology, Dehradun, Uttarakhand for providing SEM facility. Facilities provided by the UGC-DAE Consortium for Scientific Research, Indore (M.P.) are thankfully acknowledged. REFERENCES [1]

[2]

Vilarnovo BP, Lopez IP, Lopez ME, et al. Improvement of water solubility of sulfamethizole through its complexation with and HP--CD characterization of the interaction in solution and in solid state. Eur J Pharm Sci 2001; 13: 325-31. Ozkan Y, Atay T, Dikmen N, Iimer A, Aboul-Enein HY. Improvement of water solubility and in vitro dissolution rate of gliclazide by complexation with - cyclodextrins. Pharm Acta Hel 2000; 74: 365-70.

[13] [14] [15] [16] [17] [18] [19]

Semalty A, Semalty M, Rawat MSM. Essential of Pharmaceutical Technology. Pharma Med Press, Hyderabad, India, 2011; pp-4. Moneghini M, Kikic I, Perissutti B, Franceschinis E, Cortesi A. Characterization of nimesulide--cyclodextrin system prepared by supercritical fluid impregnation Eur J Pharm Bioparm 2004; 58: 637-44. Pralhad T, Kumar R. Study of freez-dried quercetin- cyclodextrin binary system by DSC, FTIR, X-ray diffraction and SEM analysis. J Pharm Biomed Ana 2004; 34: 333-9. Babu RJ, Pandit JK. Effect of cyclodextrin on the complexation and transdermal delivery of bupranolol through rat skin. Int J Pharm 2004; 271: 155-65. Rawat S, Jain SK. Solubility enhancement of celecoxib using cyclodextrin inclusion complexes. Eur J Pharm Biopharm 2004; 5: 263-7. Sajeesh S, Sharma CP. Cyclodextrin – insulin complex encapsulated polymethacrylic acid based nanoparticles for oral insulin delivery. Int J Pharm 2006; 325: 147-54. Chen X, Chen R, Guo Z, Li C. The preparation and stability of the inclusion complex of astaxanthin with -CD. Food Chem 2007; 101: 1580-4. Semalty A, Semalty M, Singh D, Rawat MSM. Preparation and characterization of phospholipid complexes of naringenin for effective drug delivery. J Incl Phenom Macrocycl Chem 2010; 67: 25360. Magnusdottir M, Lofisson T. Cyclodextrins. J Incl Phenom Macroc Chem 2002; 44: 213-8. Rasheed A, Kumar A. Cyclodextrin as drug carrier molecule. Sci Pharm 2008; 76: 567-98. Magnusdottir A, Masson M, Loftsson T. Cyclodextrin in drug delivery. Expert Opin Drug Deliv 2005; 2: 335-51. Irie T, Uekama K. Pharmaceutical application of cyclodextrin, Toxicological issues and safety evaluation. J Pharma Sci 1997; 85: 147-62. Del VE. Cyclodextrins and their uses: a review. Process Biochem 2004; 39: 1033-46. Rinaki E, Valsami G, Macheras P. Quantitative biopharmaceutical classification system: the central role of dose/solubility ratio. Pharma Res 2003; 20: 1917-19. Vekama K. Design and evaluation of cyclodextrin based drug formulation. Chem Pharm Bull 2004; 52: 900-15. Mosely RH, Kaplowith N, Deleve LD. Quinolones, Antibacterial and Antifungal agents, Informa Healthcare USA, 2007: pp- 532-33. Petri WA, Bruton LL, Lazo JS, Parken KL. Quinolones, Agents for urinary tract infection, Textbook of Pharmacology and Therapeutics. 2006: 1119-22.

8 Current Drug Discovery Technologies, 2014, Vol. 11, No. 2 [20] [21] [22] [23] [24]

[25]

[26] [27]

Semalty et al.

Blam A. Racecadotril-induced acute severe hepatitis. South Med J 1991; 84: 1158. OECD, Paris, 1981, Test Guideline 107, Decision of the Council C(81) 30 final Semalty A, Semalty M, Rawat BS, Singh D, Rawat MSM. Development and evaluation of pharmacosomes of aceclofenac. Indian J Pharm Sci 2010; 72: 571-5. Monograph, Indian Pharmacopeia- 2007, Available at http://ipc.nic.in/super/users/writecomm1main.asp?id=316&cuid=& EncHid=, accessed on July 7, 2011. Singh D, Rawat MSM, Semalty A, Semalty M. Gallic acidphospholipid complex: drug incorporation and physicochemical characterization. Letters in Drug Design & Discovery 2011; 8(3): 284-291. Singh D, Rawat MSM, Semalty A, Semalty M. Emodin– phospholipid complex: A potential of herbal drug in the novel drug delivery system. J Therm Anal Calorim DOI 10.1007/s10973-0111759-3 Semalty A, Semalty M, Singh D, Rawat MSM. Phyto-phospholipid complex of catechin in value added herbal drug delivery. J Incl Phenom Macrocycl Chem 2012; 69: 253-60. Sathigari S, Chadha G, Lee YH, et al. Physicochemical characterization of efavirenz–cyclodextrin inclusion complexes. AAPS PharmSciTech 2009; 10: 81-7.

Received: May 24, 2013

[28] [29]

[30] [31]

[32] [33] [34]

Rajendrakumar K, Madhusudan S, Pralhad T. Cyclodextrin complexes of valdecoxib: Properties and anti-inflammatory activity in rat. Eur J Pharm Biopharm 2005; 60: 39-46. Tommasini S, Raneri D, Ficarra R, Calabro ML, Stancanelli R, Ficarra P. Improvement in solubility and dissolution rate of flavonoids by complexation with - cyclodextrin. J Pharm Biomed Ana 2004; 35: 379-87. Gibau S, Zirar SB, Mutzenhardt P, Fries I, Alain A. Melarsoprolcyclodextrin inclusion complexs. Int J Pharm 2005; 306: 107-21. Nalluri BN, Chowdary KPR, Murthy KVR, Hayman AR, Becket G. Physico-chemical characterization and dissolution properties of nimesulide-cyclodextrin binary systems. AAPS PharmSciTech 2003; 4(1): E2. Wen J, Liv B, Yun E, Ma Y, Znu Y. Preparation and physicochemical properties of the complex of neringenin with hydroxypropyl--CD. Molecule 2011; 15: 4401-7. Moriwaki C, Costa GL, Ferracini CN, et al. Enhancement of solubility of albendazole by complexation with -cyclodextrin. Braz J Chem Eng 2008; 25: 255-67. Singh D, Rawat MSM, Semalty A, Semalty M. Quercetinphospholipid complex: An amorphous pharmaceutical system in herbal drug delivery. Current Drug Disc Tech 2012; 9: 17-24.

Revised: October 19, 2013

Accepted: October 25, 2013