Preparation and Characterization of Lercanidipine Hydrochloride Inclusion complex with β-cyclodextrin and effect of Complexation on Solubility and Dissolution

 

Farhatjahan I. Shaikh, Meenakshi B. Patel, Naazneen I. Surti, Vandana B. Patel*

Babaria Institute of Pharmacy, BITS Educational Campus, Varnama, Vadodara, Gujarat, India

 

ABSTRACT:

Lercanidipine Hydrochloride (LER) is widely used antihypertensive drug belonging to BCS Class II and showing pH dependent solubility. The bioavailability of LER is limited because of its poor water solubility. Inclusion complexes of LER were prepared with β-Cyclodextrin (βCD) using kneading and freeze drying techniques in different molar ratios to enhance solubility of LER and improve dissolution characteristic of the same. The phase solubility study was performed to study interaction between βCD and LER in solution. Phase solubility graph showed a linear diagram classified as A_L type. From the slope of phase solubility diagram, stability constant K was calculated and was found to be 428.28 M^-1 suggesting strong interaction between guest and host molecule. Water solubility and dissolution was significantly increased when inclusion complex was prepared by freeze drying technique in 1:1.5 Molar ratio. Further formation of inclusion complex was confirmed by Fourier transformation-infrared (FT-IR), powder X-ray diffractometry (PXRD) and ¹H Nuclear Magnetic Resonance (NMR). Solid state characterization suggested strong interaction of LER in βCD forming inclusion complex. From the result of XRD, it was confirmed that the decrease in crystal structure of LER takes place upon formation of inclusion complex. Freeze dried inclusion complex of LER with βCD in 1:1.5 molar ratio showed 5.4 fold increase in solubility of LER along with 80 % release in 60 minutes. The study concludes that Cyclodextrin complexation can influence solubility and dissolution of LER positively and thus can be used to design novel formulation of LER with improved dissolution and bioavailability.

 

 

 

INTRODUCTION:

Cyclodextrins (CDs) are a group of cyclic oligosaccharides compounds made up of glucopyranose units which are linked by (α-1, 4) linkage and obtained after enzymatic action of starch molecules.  Cyclodextrins are having unique molecular structure in which they are having skeletal carbons and ethereal oxygens of glucose residing in the inner side ^{1, 2, 3}.

 

This characteristic structure (Figure 1(a)) produces a lipophilic interior environment whereas exterior structure of Cyclodextrin is made up of hydroxyl groups which confer hydrophilicity. Hence central cavity provides a hydrophobic environment in which a drug molecule can enter to form complex and hydrophilic exterior which impart water solubility to the complex formed ⁴. Structurally cyclodextrin exists in a cone shape having narrow and wide rims, this cavity is a structure in which guest molecules/drug enters and forms inclusion complex with non-covalent interactions such as hydrophobic interaction, electronic effects, Van Der Waals forces and steric factors ^{5, 6, 7}. Effective Inclusion Complex formation between Cyclodextrin and guest/drug molecule alters the physicochemical properties of drugs like stability, solubility, dissolution rate and pharmacodynamics properties such as drug bioavailability ^{8, 9, 10}. Inclusion complexes can be formed using various techniques such as physical mixing, kneading, spray drying, freeze drying, co precipitation and solvent evaporation methods^11,12. Method of preparation of inclusion complex has a prominent effect on efficiency of complexation and thus on the effect of the drug in complex form¹³. As such there is no any ideal method available to form CD-Drug inclusion complexes, however based on the guest and host characteristics, suitable method and best experimental conditions can be identified in order to achieve the goal of Cyclodextrin complexation¹⁴.

 

Figure 1 Structure of (a) β- Cyclodextrin (b) Lercanidipine Hydrochloride

 

Lercanidipine hydrochloride belongs to 1,4– dihydropyridine class (Figure 1(b)) and exerts its action by blocking the entry of calcium into L- type calcium channels of smooth muscles. This results in peripheral vasodilatation and reduction in blood pressure¹⁵. Chemically it is 2(3, 3- diphenylpropyl) (methyl) amino-1,1-dimethylethyl methyl 2, 6- dimethyl-4- (3-nitrophenyl)-1, 4-dihydropyridine-3, 5- dicarboxylate hydrochloride¹⁶. Lercanidipine Hydrochloride is BCS Class II drug which is practically insoluble in water due to its highly lipophilic structure. Because of high lipophilicity and low solubililty, Lercanidipine Hydrochloride shows only 10% of oral bioavailability and an erratic absorption from gastrointestinal tract ^{17, 18}. The objective of present work is to study the interaction of Lercanidipine hydrochloride (LER) and β-cyclodextrin (βCD) in terms of formation on inclusion complex. The LER/ βCD inclusion complexes were prepared by two different methods namely kneading method and freeze drying method. Phase solubility was carried out to calculate stability constant and to know the inclusion stoichiometry of complexes. Saturation solubility and dissolution profile was obtained for all products and based on the results obtained, optimized inclusion complex was identified. The formation and conformation of the inclusion complex in the optimized inclusion complex was studied in detail by fourier-transform infrared spectroscopy (FT-IR), powder X-ray diffractometry (PXRD) and Proton nuclear magnetic resonance (NMR). Results obtained from this study showed promising approach to obtain the LER inclusion complex with high water solubility, higher dissolution properties and in turn better bioavailability.

 

MATERIALS AND METHOD:

Materials:

Lercanidipine Hydrochloride (LER) was received as a gift sample from Alembic Research centre, Vadodara, Gujarat, India. β-Cyclodextrin (βCD) was purchased from Sigma-Aldrich. All the reagents used were of analytical grade. Double distilled water was used for preparation of dissolution media.

 

Methods:

Analytical Method Development:

Selection of wavelength:

Accurately weighed Lercanidipine Hydrochloride (10 mg) was dissolved in methanol to obtain stock solution containing 1 mg/ml of LER. Stock solution so prepared was diluted with methanol and with 0.1 N HCl to obtain final concentration of 10µg/ml. 10µg/ml solutions of LER in methanol and 0.1 N HCl were scanned between 400 to 200 nm in double beam UV Vis Spectrophotometer and spectra were recorded (UV-1800PC, Shimadzu, Japan).

 

Preparation of standard calibration curve of Lercanidipine Hydrochloride:

Stock solution of LER having concentration of 1mg/ml was further diluted appropriately with methanol and 0.1 N HCl to prepare a concentration series of 2.5 -60 µg/ml and 2-20 µg/ml in methanol and 0.1 N HCl respectively. The absorbance of all the solutions were measured against blank in double beam UV Vis Spectrophotometer UV-1800 PC, Shimadzu, Japan). Standard calibration curve was then obtained by plotting the graph of absorbance versus concentration and data were analysed by linear regression analysis.

 

Phase Solubility Study:

Higuchi and Connors’ method was used to carry out phase solubility studies¹⁹. Solutions with various concentrations of βCD (0-30.86 mM) in 50 ml water containing excess amount of LER (100 mg) was prepared. The resulting dispersions were mixed by vortex mixture and kept on rotary flask shaker for 72 hours at RT. Once equilibrium was achieved, samples were filtered using 0.45 µ Cellulose Acetate membrane filter. Filtered solution was diluted appropriately and amount of dissolved LER was measured at 236 nm using a UV–Visible dual-beam spectrophotometer (UV-1800 PC, Shimadzu, Japan) with 1 cm quartz cuvette. Solubility studies were performed in triplicate. Stability constant Ks was obtained from following. To calculate Ks, initial straight portion of phase solubility curve was considered.

 

          slope

Ks=-----------

       S0 (1- slope)

 

Where Ks = Stability constant

Slope is the slope of phase solubility diagram

S0 = solubility of LER without βCD

 

Preparation of Inclusion Complexes:

Inclusion complexes of LER with βCD were prepared in different molar ratio of drug to βCD. The molar ratios were decided on the basis of phase solubility studies. Two methods namely kneading and freeze drying were used to prepare inclusion complexes with different molar ratios (Table 1).

 

Table 1 Composition and coding of Inclusion complexes

Formulation code	Method of preparation	Molar Ratio
BCDK1	Kneading	1:1
BCDK2	Kneading	1:1.5
BCDK3	Kneading	1:2
BCDF1	Freeze drying	1:1
BCDF2	Freeze drying	1:1.5
BCDF3	Freeze drying	1:2
BCDPM1	Physical Mixture	1:1
BCDPM2	Physical Mixture	1:1.5
BCDPM3	Physical Mixture	1:2

 

Kneading method:

The amounts of βCD and LER for complex preparation were calculated on molar ratio basis. Accurately weighed amount of βCD and LER were transferred to a glass mortar pestle followed by trituration with small volume of ethanol-water (1:1 v/v). Resulted slurry was kneaded uniformly for 45 minutes. Obtained paste was dried under vacuum at room temperature ²⁰. Dried mass thus obtained was grounded in mortar, passed through sieve no. 100 and stored in amber coloured vials for further characterization.

 

Freeze drying method:

Calculated amount of βCD and LER was dissolved in water and ethanol respectively. Resulting solutions were mixed and magnetically stirred for 10 hours at RT. Obtained solution was filtered through 0.45 µ membrane filter and freeze dried in a freeze dryer for 24 hours ²¹.

 

Physical Mixture:

To prepare a physical mixture, LER and βCD were weighed accurately, sieved through 65 # sieve and mixed uniformly by adding LER slowly into βCD in a mortar with slow but continuous trituration. Resulting mass was then passed through 65 # sieve and stored in an amber colored vial⁴.

Characterization of Inclusion Complexes:

Saturation Solubility studies :

Solubility of pure drug, physical mixtures and inclusion complexes was determined in water and 0.1 N HCl. To measure solubility, excess amount of pure drug, physical mixtures and inclusion complexes were added in flasks containing 100 mL of distilled water. The flasks were then subjected to ultra-sonication for 5 minutes followed by agitation for 24 hours at 37 ± 0.5 ° C in an orbital shaker ²². Once the equilibrium was achieved samples were filtered through Whatman filter paper no. 41 and after making suitable dilutions, amount of LER was measured at 236 nm. Solubility determinations were carried out in triplicate.

 

In vitro Dissolution studies:

Drug release behavior from physical mixtures and inclusion complexes was studied by in vitro dissolution performance. Dissolution of pure drug, physical mixtures and inclusion complexes were carried out in USP dissolution apparatus type II (Electrolab (TDT-08), Mumbai, India) using 900 ml of 0.1 N HCl (pH 1.2) as a dissolution medium at 100 rpm and 37 ± 0.5 ° C for 1 hour. At predetermined interval of 5 minutes, 10 ml aliquots of dissolution medium was withdrawn followed by addition of same amount of fresh dissolution medium for replacement²³. Withdrawn samples were filtered through whatman filter paper no. 41 and amount of LER was measured spectrophotometrically at 240 nm using 0.1 N HCl as a blank in double beam UV Vis Spectrophotometer. The dissolution studies were carried out in triplicate and % cumulative drug release was plotted against time to obtain dissolution profiles of pure drug, physical mixtures and inclusion complexes.

 

Drug Content:

Formulations equivalent to 10 mg of LER were weighed accurately and assayed to obtain the drug content. Weighed samples were transferred to volumetric flask containing methanol. Volumetric flasks were subjected to ultrasonication for 15 minutes and filtered through Whatman filter paper no. 41. Filtrates were suitably diluted to follow Lambert beer law and estimated at 236 nm using UV spectrophotometer (UV-1800PC, Shimadzu, Japan) with the help of standard curve²⁴.  The measurements were done in replicates (n=6).

 

Solid State Characterization:

Solid state studies for LER, pure βCD, Physical mixtures and optimized inclusion complex was performed.

 

Fourier Transform Infrared Spectroscopy (FTIR):

The FTIR spectra of LER, pure βCD, Physical mixture and optimized inclusion complex were recorded between 4000-600 cm^-1 using FTIR Spectrophotometer make Alpha, Bruker, Germany.

Powdered X-ray Diffraction (PXRD):

To study physical state of the LER, Powdered X-ray diffraction pattern of LER, pure βCD, Physical mixtures and optimized inclusion complex was obtained using X'Pert Model, Phillips. Diffraction patterns were recorded at 2θ range of 0-90 ° using copper target tube with the step size of 0.0500.

 

Nuclear Magnetic Spectrometry (NMR):

The most accurate formation of an inclusion complex of LER with βCD was studied through NMR Spectroscopy. ¹H and ¹³C NMR spectra were recorded using 400 MHz NMR Spectrometer model AVANCE II make Bruker. The spectrometer was equipped with a 5 mm multinuclear direct detection BBO probe with z-gradient. Pure LER, βCD, physical mixture and inclusion complex were subjected to NMR spectroscopy using DMSO as solvent and chemical shifts were reported as ppm. 

 

RESULTS AND DISCUSSION:

Standard calibration curve of Lercanidipine Hydrochloride:

From the spectra obtained it was concluded that LER shows wavelength maxima of 236 nm in Methanol and 240 nm in 0.1 N HCl. Standard solutions of LER in methanol and 0.1 N HCl obeys Beer-Lamberts law in the range of 2.5-60 µg/ml and 2-10 µg/ml respectively(Figure 2 and 3).

 

Figure 2 Standard calibration curve of LER in methanol

 

Figure 3 Standard Calibration cure of LER in 0.1 N HCl

The linear regression analysis of standard calibration curves are shown in table 2 which suggests that Lercanidipine Hydrochloride shows good correlation coefficients for both the solvents.

 

Table 2 Linear Regression Analysis data for standard calibration curve

S.N.	Solvent used for standard calibration	χ maxima	Linear equation	Correlation coefficient
1	Methanol	λmax 236 nm	y = 0.032x - 0.0624	R² = 0.999
2	0.1 N HCl	λmax 240 nm	y =0.0261x - 0.0171	R² = 0.999

 

Phase solubility study:

The Phase solubility diagram of LER in βCD at 25 º C is depicted in Figure 4. The phase diagram obtained is classified as type A_L type of linear host-guest relationship according to Higuchi and Connors ¹.

 

Figure 4 Phase Solubility Diagram of LER with βCD

 

Result obtained of phase solubility study suggests that increase in concentration of βCD can affect water solubility of LER to a great extent. Assuming a 1:1 stoichiometry, the value of apparent stability constant Ks was found to be 428.18 M ^-1 for βCD. The ideal value of a stability constant lies within 100 and 1,000 M−1, value smaller than this indicates weak interaction between drug and βCD and value higher than this shows incomplete drug release from the inclusion complex ²⁵.

 

Saturation Solubility studies:

Saturation solubility studies results are shown in table 3, which suggests that all the inclusion complexes showed increased in solubility of LER in distilled water. Method of preparation showed significant effect on solubility as inclusion complexes prepared by freeze drying method resulted in higher solubility than the inclusion complexes prepared by kneading method. Out of all the molar ratio that has been selected for preparation of inclusion complexes, inclusion complex prepared with molar ratio of 1:1.5 showed nearly 5.4 fold increase in the solubility of Lercanidipine Hydrochloride. Increase in the molar ratio of βCD from 1:1.5 to 1:2 did not show any significant increase in the solubility thus the molar ratio of 1:1.5 was considered suitable for the preparation of inclusion complex ⁴.

 

Table 3 Saturation solubility of Lercanidipine Hydrochloride from inclusion complexes

S. N.	Inclusion Complexes	Solubility in distilled water (mg/ml) (n=3)
1	Lercanidipine Hydrochloride	0.0507± 0.0006
2	BCDF1	0.2045± 0.0022
3	BCDF2	0.2792± 0.0037
4	BCDF3	0.2238± 0.0033
5	BCDK1	0.1013± 0.0012
6	BCDK2	0.1438± 0.0022
7	BCDK3	0.1215± 0.0019

 

In vitro Dissolution Studies:

Mean dissolution profiles of LER powder and prepared inclusion complexes are shown in Figure 5. It is evident from the dissolution profiles that Lercanidipine hydrochloride in the complex with βCD exhibited faster dissolution than LER pure powder. Kneaded complex and freeze dried complex in all the molar ratio prepared exhibited better dissolution profile than pure drug. LER in pure powder form showed only 50 % release over 60 min whereas the inclusion complex prepared by freeze drying in molar ratio of 1:1.5 showed 80% release in 20 minutes. Drug release pattern confirmed the results of saturation solubility as increase in the molar ratio of 1:1.5 to 1:2 didn’t show any significant increase in the dissolution behavior of the drug. Sudden increase in the dissolution of drug from inclusion complex is seen may be because of increase in the amorphous character of drug, forming the soluble inclusion complex and thus increasing the solubility and wettability of drug ^21,26.

 

Figure 5 Mean dissolution profiles of LER pure and different inclusion complexes

Drug Content:

In the inclusion complexes, content of LER was found to be within range of 98.60 to 114% (Table 4). It is evident from the content that the content was much higher in the inclusion complex formed with the molar ratio of 1:2. Moreover the % RSD for the inclusion complex formed in 1:2 molar ratio for both kneaded product and freeze dried product are more than 2 %. This might be the result of non-uniform distribution of drug in high amount of βCD. Uniform distribution of LER in βCD was observed in inclusion complexes formed in molar ratio of 1:1 and 1:1.5.

 

Table 4 Content of Inclusion Complexes

Inclusion Complex	Content (% w/w) ± SD  (n=3)
BCDK1	102.87 ± 1.59
BCDK2	101.52 ± 1.55
BCDK3	114.64 ± 2.06
BCDF1	98.60 ± 1.69
BCDF2	101.20 ± 0.89
BCDF3	111.35 ± 2.24

 

Solid State Characterization:

Based on results obtained of saturation solubility and dissolution release, inclusion complex of Lercanidipine Hydrochloride prepared by freeze drying method in molar ration of 1:1.5 was considered as an optimized inclusion complex. Solid state characterization of pure LER, βCD, physical mixture (1:1.5 molar ratio) and optimized inclusion complex was carried out to study the detailed structure of inclusion complex formed.

 

Fourier Transform Infrared Spectroscopy (FTIR):

Functional group and structure of organic compounds are well understood and predicted by FTIR study. Structure of prepared inclusion complex was studied in detail with the help of FTIR spectra. FTIR spectra of LER, βCD, Inclusion complex and physical mixture is depicted in Figure 6.LER (Figure 6(a)) shows characteristic peaks of N-H stretching vibration at 3184 cm^-1, C-O-CH₃ stretching vibration at 2839 cm^-1, C=O stretching vibration at 1672 cm^-1 and C=C vibration at 1452 cm^-1. βCD (Figure 6(b)) shows , maximum absorption at 3320 cm^-1 because of O-H bonds of primary hydroxyl groups,2920 cm ^-1 of C-H stretching , broad absorption band within 1400-1200 cm^-1 corresponding to C-H vibrations4. FTIR spectra of physical mixture of LER and βCD (Figure 6(c)) shows the bands of LER at3204 cm^-1,3084 cm^-1,1680 cm^-1 and 1661 cm^-1 which are undetected in the FTIR of inclusion complex. Absence of these peaks is explained by the complexation of drug into host moiety ²⁷. Moreover ,in the spectra of inclusion complex (Figure 6 (d)), peaks of LER at 1520 cm ^-1, 1485 cm ^-1,1344  cm ^-1and 1232 cm ^-1 showed shifting to 1524 cm ^-1,1487 cm ^-1,1347 cm ^-1 and 1215 cm ^-1 . This shift supports the strong interactions taking place between LER and βCD and can be explained by the dissociation of the intermolecular hydrogen bonds associated with crystalline drug molecules²⁰. These observations suggest possible entrapment of LER into cavities of βCD which is the indication of formation of inclusion complex of LER and βCD . This explains the presence of weak interaction between LER and βCD ²⁸. 

 

Figure 6 FTIR spectrum of (a) Lercanidipine Hydrochloride (b) βCD (c) Physical mixture of LER : βCD (1:1.5) (d) Freeze dried inclusion complex of LER: βCD (1:1.5)

 

 

Powdered X-ray Diffraction (PXRD):

Figure 7 depicts PXRD patterns of LER, βCD, Physical mixture and freeze dried inclusion complex. XRD is most commonly used to confirm inclusion complex of βCD in powdered state. The diffraction pattern of inclusion complex differs from that of pure drug because of super position of peaks of both the components. ²⁹.LER and βCD show multiple peaks at various 2θ in its PXRD pattern which suggests their crystalline structure. Physical mixture in its PXRD pattern showed characteristic crystallinity peaks of drug and βCD both but with lesser intensity than that was obtained with pure compounds. Physical mixture PXRD pattern suggests that inclusion complex formation doesn’t take place by simply triturating LER with βCD ³⁰. PXRD pattern of inclusion complex formed by freeze drying method showed presence of new peaks and loss of few peaks from LER and βCD which suggests change in crystalline structure of βCD. This observed change is attributed to the formation of inclusion complex ³¹.

 

Figure 7 PXRD pattern of (a) Lercanidipine Hydrochloride (b) βCD (c) Physical mixture (d) Inclusion complex BCDF2

 

¹H Nuclear Magnetic Spectrometry (NMR):

Proton NMR Spectroscopy is used to characterize inclusion complex based on the changes in chemical shifts of proton of both the drug and βCD. ¹HNMR spectra of LER , βCD, Phyical mixture and inclusion complex is shown in figure 8. LER shows NMR signals corresponding to its proton over the δ values of 2-5 and 7-8. Similar signals along with basic signals of βCD are visible in NMR spectrum of physical mixture in Figure 8 (c). However, chemical shifts of LER were decreased in intensity or went undetected in the NMR spectra of inclusion complex Figure 8 (d).Also sharpness of signals have been reduced and widening is seen in the inclusion complex in comparison with LER and physical mixture spectra. Downfield change in the chemical shifts of proton of LER is clearly observed and reported in the Table 5. Thus overall behaviour of LER along with βCD in physical mixture and in inclusion complex suggests that a strong hydrophobic interaction is taking place between the cavity of βCD and a portion of LER which can be the result of incorporation of LER into the βCD. The formation of inclusion complex is also supported by the results obtained in FTIR and PXRD studies ³².

 

Figure 8 1H NMR spectra of (a) Lercanidipine Hydrochloride (b) βCD (c) Physical mixture (d) Inclusion complex BCDF2

 

 

Table 5 Chemical shifts (ppm) for LER protons and LER-βCD inclusion complex

 

CONCLUSION:

Present study demonstrated that Lercanidipine Hydrochloride can form inclusion complex with β Cyclodextrin in the molar ratio of 1:1.5.LER gave A_L type of diagram when phase solubility study was performed. The inclusion complexes were formed in different molar ration with two preparation methods namely kneading method and freeze drying. It was observed that inclusion complex formed in a molar ration of 1:1.5 with free drying technique showed 5.4 fold increases in saturation solubility of LER with more than 80 % drug release in 20 minutes. The results obtained of FTIR, PXRD and 1HNMR further confirmed the formation of inclusion complex between LER and βCD. The outcome of the study suggests that inclusion complexation can greatly enhance solubility of Lercanidipine Hydrochloride to an extent that it may result in increase in the bioavailability and hence increase its pharmaceutical potential.

 

CONFLICT OF INTERESTS:

No conflict of interests

 

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Accepted on 03.04.2017           © RJPT All right reserved