FORMULATION OF NICERDIPINE HYDROCHLORIDE INCLUSION COMPLEX FOR DISSOLUTION ENHANCEMENTHTML Full Text
FORMULATION OF NICERDIPINE HYDROCHLORIDE INCLUSION COMPLEX FOR DISSOLUTION ENHANCEMENT
Saroj Makwana 1, Rajesh Kharadi 1 and Sanman Samova * 2
B. K. Mody Government Pharmacy College 1, Rajkot - 360003, Gujarat, India.
Department of Zoology 2, University School of Sciences, Gujarat University, Ahmedabad - 380009, Gujarat, India.
ABSTRACT: The purpose of this study was to improve the dissolution rate of poorly soluble Nicardipine hydrochloride with cyclodextrin complexation by using different techniques like physical mixing, solvent evaporation and kneading method. Nicardipine hydrochloride is a calcium channel blocker. It is belonging to BCS class - II having poor solubility and high permeability. It is used to treat Angina having low bioavaibility about 10 - 40% orally is attributed to the hepatic first pass metabolism. The present invention relates to the inclusion complex made by β-Cyclodextrins and the methods for enhancing the bioavailability of Nicardipine hydrochloride. Solid inclusion complexes were prepared by conventional methods like physical mixing, solvent evaporation and kneading techniques. Optimized complex was characterized by using powder X-ray diffractometer and FTIR. Ex-vivo studies showed that the dissolution rate of Nicardipine hydrochloride was significantly improved by the complexation with β-cyclodextrin with respect to the drug alone. Physical mixing method showed highest dissolution rate than the other techniques.
Nicardipine hydrochloride, β-Cyclodextrin, PVP K 30, Crospovidone, Ex-vivo Permeation study, Flux
INTRODUCTION: The Bio-pharmaceutics classification system is a system to differentiate the drugs on the basis of their solubility and permeability 1. This system of classification is helpful in formulation development to know solubility and permeability of drug. BCS class II drug having problem of poor water solubility and high intestinal permeability problem of poor solubility can be overcome by making inclusion complex of drug with different carrier like different grade of cyclodextrin like HP-β-CD, β-CD or different grade of Poloxamer like Poloxamer 188 2, 3.
Nicardipine hydrochloride is a Ca+2 channel blocker 5 used to treat angina 4, 5. It is belonging to BCS class-II having 10 - 40% bioavaibility on oral administration 6, 7, 8, 9. Poor solubility of a drug is a major challenge for formulation scientist which can be solved by different technological approaches during the pharmaceutical product development work by formulating complex of drug with cyclodextrin mask bitter taste of drug and also leads to improve solubility of drug 3, 4, 10, 11, 12.
Nicardipine hydrochloride is a poorly water soluble drug 9, 11. The chemical name of the Nicardipine hydrochloride is 2- (Benzylmethylamino) ethyl methyl 1,4-dihydro-2,6-dimethyl-4-(m-nitrophenyl) -3, 5-pyridinedicarboxylate monohydrochloride 13. It is a Ca+2 channel blocker acting by selective inhibition of calcium influx through cell membranes or on the release and binding of calcium in intracellular pools 11, 14.
Since they are inducers of vascular and other smooth muscle relaxation, they are used in the drug therapy of hypertension and cerebrovascular spasms, as myocardial protective agents, and in the relaxation of uterine spasms 14. The aqueous solubility of Nicardipine hydrochloride is 2.47 mg/l when determined in vitro at pH 7 and 37 °C. Thus, it is important to enhance the solubility and dissolution rate of Nicardipine hydrochloride to improve its oral bioavailability 9, 15, 16.
FIG. 1: NICARDIPINE HYDROCHLORIDE 15
Cyclodextrin is used as the solubility enhancement application, CDs can also be used as membrane permeability enhancer and stabilizing agents 16. The permeability through biological membrane is enhanced by the presence of Cyclodextrins 17. These acts as permeation enhancers by carrying the drug through the aqueous barrier which exists before the lipophilic surface of biological membranes 18, 19, 20, 21. Cyclodextrins having sweet taste so they are also used for taste masking purpose. Different grade of cyclodextrin molecules have different solubility based on improve in solubility pattern suitable grades are used 20, 21.
FIG. 2: STRUCTURE OF CYCLODEXTRINS 16
MATERIALS AND METHODS:
Materials: Nicardipine hydrochloride was obtained as a gift sample from Cadila Pharmaceuticals (Baroda), β- Cyclodextrin was obtained as a gift sample from Sunrise Remedies Pvt. Ltd., All other reagents and chemicals were of analytical grade.
Preparation of Nicardipine Hydrochloride Inclusion Complex: 22, 23, 24 Solid dispersion were prepared by using different ratio of drug with complexation agent by different method which are mention in Table 1.
TABLE 1: NICARDIPINE HYDROCHLORIDE INCLUSION COMPLEX
|Drug carrier complex||Carrier||Method|
|F15(1:1)||Poloxamer 188||Physical mixture|
|F16(1:2)||Poloxamer 188||Physical mixture|
|F17(1:3)||Poloxamer 188||Physical mixture|
Evaluation of Solid Dispersion for Solubility Study:
Phase Solubility Studies: 21, 22, 23, 24, 25 Excess amounts of Nicardipine hydrochloride and Nicardipine hydrochloride – β-cyclodextrin complex were suspended in distilled water in tightly closed screw cap vials, equilibrated in a magnetic stirrer at room temperature for 24 h, then filtered using a 0.45 mm Millipore filter and assayed spectrophotometrically (Shimadzu 2450, Japan) at pre-determined λmax. Three determi-nations were carried out to calculate the saturated solubility of Nicardipine hydrochloride.
Stoichiometry Determination by the Continuous Variation Method (Job’s Plot): 26 Stoichiometry of inclusion was determined by the method developed by Job. Equimolar solutions of NCH and β-CD were mixed to a standard volume varying the molar ratio but keeping the total concentration of the species constant. The complex formed for each reaction mixture has been allowed to stand for 24 h. The absorbance at 239 nm was measured for all solutions and ΔA = A-Ao, the difference in absorbance in the presence and in the absence of CDs, was plotted against r;
r = [Drug] / [Drug] + [CD]
[CD] = Conc. of β-CD
Ex-vivo Permeation Study: 27, 28 The permeation study of Nicardipine hydrochloride through the goat sublingual mucosa will be performed using Franz diffusion cell at 37 ± 0.5 °C. Fresh goat sublingual mucosa will mount between donor and receptor compartments. The inclusion complex will placed with the core facing the mucosa, and the compartments will clamped together. The donor compartment will be filled with phosphate buffer pH 6.8 containing 1% SLS. The receptor compartment (16 ml capacity) will be filled with phosphate buffer pH 6.8 and hydrodynamics in the compartment will be maintained by stirring with a magnetic bead at uniform slow speed. Five millilitre samples will with-drawn at predetermined time intervals and analysed for drug content by UV spectrophotometer.
TABLE 2: INTERPRETATION OF DRUG AND DRUG+ β-CD COMPLEX FTIR SPECTRA
|Functional Group||Wave number
Drug + Excipients
|N=O stretching||1527.62 & 1489.06||1525.04 & 1488.09|
RESULT AND DISCUSSION:
Nicardipine Hydrochloride β-CD Interaction Study: 29, 30
FIG. 3: FTIR SPECTRA OF NICARDIPINE HYDROCHLORIDE
FIG. 4: NICARDIPINE HYDROCHLORIDE + β-CD
DSC of Nicardipine Hydrochloride: 31, 32
FIG. 5: DSC OF NICARDIPINE HYDROCHLORIDE
FIG. 6: DSC OF DRUG + β-CD
FIG. 7 SELECTION OF METHOD OF PREPARATION OF INCLUSION COMPLEX
FIG. 8: SELECTION OF METHOD OF PREPARATION OF INCLUSION COMPLEX
For quick dissolution of dosage form high solubility of drug is necessary and this can achieve by enhancing the solubility of drug at its higher level. Here F12 (1:6) batch was selected because, there was higher solubility observed in this batch.
Selection of Solubility Enhancing Agent and Method: 33 Phase solubility study of Nicardipine hydrochloride was conducted and the result of phase solubility study is given in Table 3. Here β-cyclodextrin was selected as solubility enhancing agent and physical mixture as solid dispersion method, because drug:β-cyclodextrin (1:1) complex gave higher solubility of Nicardipine hydrochloride.
TABLE 3: RESULT OF PHASE SOLUBILITY
|Drug carrier complex||Carrier||Method||Solubility (μg/ml)|
|F14(1:1)||Poloxamer 188||Physical mixture||2.3|
|F15(1:2)||Poloxamer 188||Physical mixture||1.5|
|F16(1:3)||Poloxamer 188||Physical mixture||1.02|
|F17(1:1)||Poloxamer 407||Physical mixture||1.36|
|F18(1:2)||Poloxamer 407||Physical mixture||1.2|
|F19(1:3)||Poloxamer 407||Physical mixture||0.95|
TABLE 4: PHASE SOLUBILITY
|Molar conc. of β-CD||Molar conc. of drug|
FIG. 9: RESULT OF PHASE SOLUBILITY
Inference: As shown in Fig. 9 Phase solubility diagrams revealed a linear increase in drug solubility with an increase in the concentration of β-CD. Nicardipine hydrochloride solubility increased linearly with cyclodextrin concentration and the slope was smaller than unity, over the entire concentration range studying indicating an AL type diagram with the formation of a complex with 1:1 Stoichiometry according to Highuchi and Connors. AL slope of Diagram was < 1.0; it was possible to assess a 1:1 Stoichiometry.
Jobs Plot: 34
TABLE 5: JOB’s PLOT
|Nicardipine hydrochloride||β-Cyclodextrin||R = NCH/ (NCH+β-CD)||ΔA *r
FIG. 10: JOB’s PLOT
Inference: According to the continuous variation method, if a physical parameter directly related to the concentration of the complex can be measured for a set of samples with continuously varying molar fraction of its components. The maximum concentration of the complex was present in the sample where the molar ratio r corresponds to the complexation stoichiometry.
Ex-vivo Permeation Study:
TABLE 6: FLUX
|Time (Min)||% CPR||% CPR/A|
As shown in Fig. 10 the maximum absorbance variation for Nicardipine hydrochloride in CDs was Observed for r = 0.5 which might indicate the main stoichiometry is 1:1, in agreement with the stoichiometry suggested from the Phase solubility study.
FIG. 11: FLUX
Inference: For determination of flux ex-vivo permeation study of drug β-CD Complex using goat buccal mucosa was carried out and the flux value found was 40 sec which is described in following calculation:
Slope = 0.8404 mg/cm2/min
Which indicates, from 1 cm2 area 0.8404 mg drug permeated in 1 min. So, from total sublingual mucosal area (26.5 cm2) 22.27 mg drug permeated in 1 min. Here, dose of formulation was 10 mg so time required to permeate drug was found 40 sec.
Physical Properties of Solid Dispersion: 32, 33
TABLE 7: PHYSICAL PROPERTIES OF SOLID DISPERSION
|Bulk density (gm/ml)||0.37|
|Tapped density (gm/ml)||0.5|
|Angle of repose (°)||33.53|
Angle of repose was within the range of 30, 31, 32, 33, 34; moreover, Hausner ratio was less than 1.25 which indicates passable flow property of the solid dispersion. While in terms of Carr’s index, it showed good compressibility. Flow property can be improved by adding glidant.
CONCLUSION: Nicardipine hydrochloride is a BCS class II drug having poor solubility, the solubility of drug can be enhanced by preparing inclusion complex using various complexation agent like β-cyclodextrin, Poloxamer 188 and Poloxamer 407. Amongst this solubility of drug was improved by using (1:1) molar ratio of Drug: β- cyclodextrin. The result of FTIR and DSC showed that there was no interaction between drug and selected excipients used. Bioavaibility of drug may be enhanced by avoiding hepatic first pass metabolism. Bitter taste of Nicardipine hydrochloride was also be masked by using β-cyclodextrin. By ex-vivo permeation study Flux was set disintegration time of complex was 40 sec.
CONFLICTS OF INTEREST: Nil
- Mehta M: Pharmaceutical classification System (BCS): Development, Implementation, and Growth. Wiley, First Edition 2016.
- Szejtili J and Szente L: Limitation of bitter, disgusting tastes of drugs and foods by Cyclodextrins. European Journal of Pharmaceuticals and Biopharmaceutical Sciences 2005; 61: 115-25
- Sharma V: Role of taste and taste masking of bitter drug in pharmaceutical industry. International Journal of Pharmacy and Pharmaceutical Sciences 2010; 2: 14-8
- Ghasy FS, Sammour OA and Ghareeb SA: Inclusion complex of Nicardipine - HCl for oral administration. Bull Pharma Science 2005; 28: 119-29
- Savi L and Montebelli MR: Sublingual Nicardipine versus Nifedipine to treat hypertensive urgencies. International Journal of Clinical Pharmacology, therapy and toxicology 1992; 30: 41-5
- Sweetman SM: The Complete Drug Reference. UK: Royal Pharmaceutical Society 2009.
- Mehta D: British National Formulary (BNF). Royal Pharmaceutical Society of Great Britain 2006.
- Harvey R: Lippincott’s Illustrated Review: Pharmacology. Lippincott Williams and Wilkins 2008; 2: 187-189.
- https://pubchem.ncbi.nlmnih.gov/compound/nicardipine_hydrochloride. Nicardipine hydrochloride. Pubchem 2017; 1-27.
- Qingliang Dong and Erdong Y: Increased solubility and taste masking of a ternary system of neodiosmin with b-cyclodextrin and lysine Starch 2017; 68: 1-9.
- Pein M, Maren P and Carolin E: Taste masking assessment of solid oral dosage forms. International Journal of Pharmaceutics 2014; 1-2: 1-16.
- Vummaneni VDN: Taste Masking Technologies. International Journal of Research in Pharmaceutical and Biomedical Sciences 2012; 3: 510-25.
- Nicardipine hydrochloride 2017. www.drugbanks.ca/salts/DBSALT000499
- Alborch EJBS: Comparison of the ant constrictor action of dihydropyridine (nimodipines and nicardipine) and Mg2+ in isolated human cerebral arteries. European Journal of Pharmacology 1992; 229: 83-9.
- Nicardipine hydrochloride Sigma-Aldrich Co. LLC. 2017. http://www.sigmaaldrich.com/catalog/product/sigma/n7510?lang=en®ion=IN
- O’Neil MJ and Heckelman PEKC. The Merck Index. Whitehouse Station, NJ; Merck Research Laboratories 2006.
- Rowe RC and Sheskey PJQM. Handbook of Pharmaceutical Excipients. 6th Pharmaceutical press 2009.
- Ai F, Wang J, Li Y and Wang J: Effect of Drug Particle / size on Complexation, Physicochemical Properties and Dissolution of Cyclodextrin Inclusion Complexes: Indian Journal of Pharmaceutical Sciences 2017; 79: 131-8
- Patil JS, Kadam DV, Marapur SC and Kamalapur MV: Inclusion complex system: A Novel Technique to Improve the Solubility and Bioavaibility of Poorly Soluble drugs 2010; 2: 29-34.
- Davi CR, Davies NM and Tucker IG: Mechanisms by which cyclodextrin modify drug release from polymeric drug delivery systems. International Journal of Pharamceutics 2009; 197: 1-11.
- Ding J, Li J and Mao S: Development and evaluation of Vinpocetine inclusion complex for brain targeting. Asian Journal of Pharmaceutical Sciences 2015; 10: 114-120.
- Loftson T and Brewster ME: Pharmaceutical applications of Cyclodextrins. Drug solubilization and stabilization. Journal of Pharmaceutical Science 1996; 85: 1017‐
- Ansari MJ: Formulation and physicochemical Characterization of sodium carboxy methyl cellulose and β-cyclodextrin mediated ternary Inclusion complex of silymarin. International Journal of Pharmaceutical science and research 2016; 7: 984-900.
- Jafar M, Malpani A and Khan MI: Ameliorated Solubility and Dissolution Rate of Glimepiride by Cyclodextrin Ternary complexes employing Amino acids. International journal of pharmaceutical sciences and Research 2017; 8: 2443-2451.
- Tarkase KN and Kadu PV: Design and Optimization of Nicardipine hydrochloride push pull osmotic pump tablets Using 32 full factorial design: International Journal of Drug Research and Technology 2013; 4: 155-63.
- Shah DK: Formulation and characterization of inclusion complex of acetyl salicylic acid (aspirin) and β-cyclodextrin by solvent evaporation and its comparative study to aspirin alone. International Journal of Pharma-ceutical Sciences and Research 2012; 3: 2831-2836.
- Goud BA and Kumara S: Formulation and evaluation of bioadhesive buccal tablets of simvastatin. Journal of Advanced Pharmaceutical Sciences 2011; 1: 29-38.
- Verma H, Verma S, Prasad SB and Singh H: Sublingual Delivery of Frovatriptan: An Indication of Potential Alternative Route. International Scholarly Research Notices 2014; 1: 1-6.
- Radjaram A and Hafid A: Dissolution enhancement of Curcumin by hydroxypropyl- β-cyclodextrin complex. International Journal of Pharmacy and Pharmaceutical Sciences 2013; 5: 2-6.
- Chatap VK, Maurya AR, Deshmukh PK and Zawar LR: Formulation and Evaluation of Nisoldipne Sublingual Tablets Using Pullulan and Chitosan for Rapid Oromucosal Absorption. Advances in Pharmacology and Pharmacy 2013; 1: 18-25.
- Bhopate SB and Dhole SN: Preparation and characterisation of β-cyclodextrin Nebivolol Inclusion complex. International journal of pharmaceutical sciences and research 2015; 6: 2205-2213.
- Bhattacharjee S, Majumdar S, Guha N and Dutta G: Taste masking technologies in oral pharmaceuticals: Recent Developments and approaches. World journal of Pharmacy and pharmaceutical science 2016; 5: 1752-1782.
- Kapse VN, Chemate SZ and Dharashive VM: Formulation Development and Solubility Enhancement of Rosuvastatin. International Journal of Pharmaceutical Sciences and Research 2016; 7: 4882-4892.
- Renny JS, Tomasevich LL, Tallmadge EH and Collum DB: Method of Continuous Variations: Application of Job plots to the study of Molecular Associations in Organometallic Chemistry. Angewante Chem International Edition 2013; 52: 2-18.
How to cite this article:
Makwana S, Kharadi R and Samova S: Formulation of nicerdipine hydrochloride inclusion complex for dissolution enhancement. Int J Pharm Sci Res 2018; 9(7): 3060-65. doi: 10.13040/IJPSR.0975-8232.9(7).3060-65.
All © 2013 are reserved by International Journal of Pharmaceutical Sciences and Research. This Journal licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License.
S. Makwana , R. Kharadi and S. Samova *
Department of Zoology, University School of Sciences, Gujarat University, Ahmedabad, Gujarat, India.
02 October, 2017
05 March, 2018
11 March, 2018
01 July, 2018