enhancement of dissolution rate of cilnidipine using .... rpa16172395016.pdf · enhancement of...

154 | P a g e International Standard Serial Number (ISSN): 2319-8141

Full Text Available On www.ijupbs.com

International Journal of Universal Pharmacy and Bio Sciences 6(1): January-February 2017

INTERNATIONAL JOURNAL OF UNIVERSAL

PHARMACY AND BIO SCIENCES IMPACT FACTOR 2.96***

ICV 6.16***

Pharmaceutical Sciences RESEARCH ARTICLE …………!!!

ENHANCEMENT OF DISSOLUTION RATE OF CILNIDIPINE USING

LIQUISOLID TECHNIQUE Shalaka P. Rasal

*1Sheetal B. Gondkar

1 Nikhil P. Mahalpure

1 Ravindra B. Saudagar

2

1Department of Pharmaceutics, Ravindra Gambhirrao Sapkal College of Pharmacy Anjaneri,

Nashik, Maharashtra, India. 2

Department of Pharmaceutical Chemistry, Ravindra Gambhirrao Sapkal College of Pharmacy

Anjaneri, Nashik, Maharashtra, India.

KEYWORDS:

Dissolution rate, Carrier

and Coating

material,Liquisolid

technique, Cilnidipine.

For Correspondence:

Shalaka P. Rasal*

Address:

Department of

Pharmaceutics, Ravindra

Gambhirrao Sapkal

College of Pharmacy

Anjaneri, Nashik,

Maharashtra, India.

.

ABSTRACT

The purpose of this study was to improve the dissolution rate of a poorly

soluble drug, Cilnidipine using Liquisolid technique. Different LS

compacts were prepared using a mathematical model to calculate the

required quantities of powder and liquid ingredients to produce

acceptably flowable and compressible admixture. Polyethylene glycol

was selected as the solvent. Avicel PH 102 and Aerosil 200 were used as

carrier, coating material respectively for preparing the tablets. The

formulation were then evaluated for their flow properties such as bulk

density, tapped density, compressibility index, angle of repose and

Hausner’s ratio. DSC and PXRD analysis were performed to know

whether there is any interaction between drug and excipients and also to

study the changes in drug crystallinity. The dissolution study revealed the

optimized formulation have higher drug release rates than that of plain

drug, marketed and conventional tablets. Among the different

formulations prepared, LS-7 with Lf value of 1.22 and R value of 12.5,

was chosen as the best formulation based on higher percentage drug

release 85.68%. The study has produced encouraging results and it was

concluded that Liquisolid technology can be used as an efficient method

in improving the solubility and dissolution characteristics of poorly

soluble drugs.



INTRODUCTION:

The poor dissolution rate of water insoluble drug is still a substantial problem confronting the

pharmaceutical industry. The numbers of new and, beneficial chemical entities do not reach the

public merely because of their poor oral bioavailability due to inadequate dissolution.

Liquisolid System

The technique of ‘liquisolid compacts’ is a new and promising addition towards such a novel aim.

The term ‘liquid medication’ implies oily liquid drugs and solutions or suspensions of water

insoluble solid drugs carried in suitable non-volatile solvent systems termed the liquid vehicles.

Due to significantly increased wetting properties and surface area of drug available for dissolution,

liquisolid compacts of water-insoluble substances may be expected to display enhanced drug

release characteristics and, consequently, improved oralbioavailability.1

Theoretical Aspects2,4,5

The flowability and compressibility of liquid of liquisolid compacts are addressed simultaneously

in the ‘new formulation mathematically model of liquisolid system’,excipients ratio (R) or the

carrier to coating ratio of the powder system use, where,

R = Q/q

R represents the ratio between the weights of carrier (Q) and coating (q) material liquid load factor

(Lf) defined as the ratio of the weight of liquid medication (W) over the weight of the carrier

material (Q) in the system.

Lf =W/Q

The powder excipients ratio R and liquid load factors Lf of the formulations are related as follows:

ФLf =Ф + Ф (1/R)

Classification of Liquisolid System6,7,8

Liquisolid techniques are categorized as per following consideration2,

A. Based on the type of liquid medication contained in liquisolid systems:

i. Powdered drug solutions

ii. Powdered drug suspensions

iii. Powdered liquid drugs

B. Based on the formulation technique used in liquisolid systems:

i. Liquisolid compacts

ii. Liquisolid microsystems

Advantages of Liquisolid Systems6,7

i.Increase bioavailability of poorly water soluble drugs.



ii.Less production cost compared to soft gelatin capsules.

iii.Suitable for industrial production.

Disadvantages of Liquisolid System8

i.Liquisolid system requires low drug loading capacities

ii.Higher amounts of carrier and coating materials are required.

Cilnidipine9, 10

Cilnidipine is dual blocker of L-type voltage-gated Ca2+ channels in vascular smooth muscle and

N-type Ca2+ channels in symphathetic nerve terminals that supply blood vessels. The inhibition of

N-type Ca2+ channels may provide a new strategy for the treatment of cardiovascular diseases. L-

type calcium channel are the main targets of the CCB. N-type calcium is distributed along the nerve

and in the brain, Cilnidipine is anticipated to exert specific action on nerve activity, such as

inhibition of the sympathetic nervous system. It inhibits the Ca2+ influx in both in vessel & in the

nerve. So causes vasodilation & inhibits the release of nor epinephrine, which causes the

vasodilation and decrease the heart rate & also decreases cardiac contraction in heart. So, used in

treatment of hypertension. Cilnidipine comes under BCS class II (low solubility high permeability).

MATERIALS AND METHODS:

Materials

The following gift samples were received: Cilnidipine (Ajanta Pharma. Mumbai), Avicel PH 102

(Research-Lab Fine Chem. Industry, Mumbai) Aerosil 200 (Research-Lab Fine Chem. Industry,

Mumbai) , Polyethylene glycol 400 (LobaChemie, Mumbai.)

Methods

Solubility Study: The aqueous solubility of a drug is a prime determinant of its dissolution rate and

compound with aqueous solubility less than 0.1 mg/ml often present dissolution limitation to

absorption. Solubility studies of Cilnidipine were carried out in water, polyethylene glycol-400,

propylene glycol, Tween 80, glycerin. The above solution was then filtered, dilutions were made in

o.1N HCl and absorbance was noted in UV Spectrophotometer at 245nm. All experiments were

conducted in triplicate.

Preparation of Liquisolid Tablets:6,7,8

Several liquisolid compacts were prepared as follows. The

desired quantities of the previously weighed drug and the liquid vehicle (PEG) were mixed. The

drug cilnidipine and liquid vehicle were taken. The solution was then sonicated for 15 min until a

homogeneous solution was obtained. Next, the calculated weight of the resulting liquid medications

(equivalent to 5 mg drug) was incorporated into the calculated quantities of the carrier material

(Avicel PH102) and mixed thoroughly. The resulting wet mixture was then blended with the



calculated amount of the coating material (Aerosil 200) using a standard mixing process to form

simple admixture. Factors like carrier:coat ratios (different R* values) ranging from 10 to 23 was

employed. Different liquid load factors (Lf)** ranging from 0.233 to 1.22 were employed. After

that mixed the above mixture for 10 min. Finally liquisolid tablets were compressed by direct

compression method. The Carrier: Coat ratios and liquid load factor was calculated.

Table 1: Composition of Cilnidipine liquid solid tablet as per factorial design

(All values are expressed in mg)

Ingredients Formulation code

Quantity(mg) F1 F2 F3 F4 F5 F6 F7 F8 F9

Cilnidipine 5 5 5 5 5 5 5 5 5

PEG – 400 100 100 100 200 200 200 300 300 300

Avicel PH-102 250 350 450 250 350 450 250 350 450

Aerosil-200 20 20 20 20 20 20 20 20 20

R* 12.5 17.5 22.5 12.5 17.5 22.5 12.5 17.5 22.5

Lƒ* 0.421 0.325 0.233 0.821 0.585 0.455 1.22 0.871 0.677

Total Weight

(mg)

275 375 475 275 375 475 275 375 475

Table 2: Calculated Quantities of Carrier: Coating ratio & Liquid load factor

Batch No. Weight of

Avicel PH 102

(Q)

Weight of

Aerosil

(q)

Weight of

Solvent + Drug

(W)

R*= Q/q Lf= W/Q

F1 250 20 100 12.5 0.421

F2 350 20 100 17.5 0.325

F3 450 20 100 22.5 0.233

F4 250 20 200 12.5 0.821

F5 350 20 200 17.5 0.585

F6 450 20 200 22.5 0.455

F7 250 20 300 12.5 1.22

F8 350 20 300 17.5 0.871

F9 450 20 300 22.5 0.677



PRECOMPRESSION STUDY:11, 12

Flow properties of liquisolid system

The flow properties of liquisolid systems were estimated by determining the angle of repose, Carr’s

index, and Hausner’s ratio. The angle of repose was measured by the fixed funnel method. The bulk

density and tapped densities were determined for the calculation of Hausner’s ratio and Carr’s

index.

Powder X-Ray Diffraction

PXRD analysis was done by irradiating the samples with mono-chromatized Cu Kα radiation

(1.506 Å) and analyzed between 3° and 60° (2θ) employing a Bruker AXS D8 Advance

Diffractometer with Lynx Eye Detector. The step was at rate of 0.0200 with step time of 32.8 sec.

The diffractogram was produced by using Diffract plus Software.

Differential Scanning Calorimetry

The powdered sample (5 mg) was hermetically sealed in aluminum pans and heated at a constant

rate of 10 °C/min, over a temperature range of 30–300 °C with nitrogen flow rate of 30 ml/min.

Thermograms of the samples were obtained using differential scanning calorimetry (DSC-60,

Shimadzu, Japan). Thermal analysis data were recorded with Shimadzu software programs. Indium

standard was used to calibrate the DSC temperature and enthalpy scale.

EVALUATION OF LIQUISOLID TABLETS:13,14,15

Prepared Liquisolid tablets were evaluated for:

Friability Test

As weight of tablet was less than 650 mg so tablets corresponding to 6.5 gm were taken for the test.

All tablets were de-dusted carefully and weighing accurately the required number of tablets were

placed in the drum and rotated about 100 times at an rpm of 25 in friability test apparatus. Tablets

were removed from the drum and loose dust was removed from the tablets, weighed accurately.

Uniformity of weight

20 units were selected at random and were weighed individually using Electronic analytical balance

AY.220 (Shimadzu, Japan) and average weight was calculated.

Uniformity of content

Five tablets were powdered and blend equivalent to 10mg drug. It was dissolved in methanol and

absorbance taken at λmax 240. The tablet preparation complies with the test, only if each

individual’s content lies between 85 to 115% of the average content.



Hardness of tablet

Tablets require a certain amount of strength, or hardness, to withstand the mechanical shocks of

handling in manufacturing, packaging as well as in shipping. The hardness of the tablets was

measured using Monsanto hardness tester (Cadmech). In this, tablet was placed between the

plungers, and was tightened from one end, and pressure required to break tablet diametrically was

measured. The hardness was measured in terms of kg/cm2.

Thickness of tablet

The uniformity of thickness was measured using Digital vernier calliper (Absolute Digimatic,

Mitutoyo Corp., Japan). The average thickness of the tablet was calculated.

Disintegration Test

Disintegration test determines whether dosage forms such as tablets disintegrates within prescribed

time when placed in a liquid medium under prescribed experimental conditions. Disintegration is

defined as that state in which no residue of the unit under test remains on the screen of the

apparatus or, if a residue remains, it consist of fragment of disintegrated parts of tablet component

part such as insoluble coating of the tablets is soft mass with no palpable core.

Dissolution Test

The test is designed to determine compliance with the dissolution requirement for solid dosage

forms administered orally. Dissolution test was performed in dissolution apparatus Type I (IP)/

Type II (USP).Tablet was placed in jar containing 900ml of 0.1M hydrochloric acid for two hours

and samples at different time interval 10ml of aliquots were removed and filtered through

whatmann filter paper no.52 at time interval specified (10- 120 min) and 1ml sample was further

diluted to 10ml using 0.1N HCl and analyzed by UV-Visible spectroscopy at 245nm using 0.1M

hydrochloric acid as blank.

RESULT AND DISCUSSION:

Precompression Study

Flow properties of liquisolid system

The powder blend prepared for tablet compression of different formulation batches were subjected

for measurement of bulk density, tapped density, Hausner’s ratio, Carr’s index, Angle of repose.

Results of pre-compression evaluations of formulation mixtures are shown in (Table-3).From the

results of Compressibility (Carr’s) index and Hausner’s ratio it can be clearly concluded that the

powder blend of drug and polymers is having excellent flow properties, fair to good compressibility

which allow this mixture to be directly compressed into tablets and good flow of the mixture from

hopper with good content uniformity in final tablets.



Table 3: Evaluation of liquisolid dried powder blend

(All experiment were carried out in triplicatesn=3)

Batch

No. Bulk density

(gm/cm3)

±S.D.

Tapped

density

(gm/cm3)

±S.D.

Compressibilit

y index (%)

±S.D.

Hausner’s

ratio ±S.D.

Angle of

repose (ɵ)

±S.D.

F1 0.353±0.039 0.3945±0.019 12.53 ± 0.43 1.166 ± 0.025 29.38±0.34

F2 0.3439± 0.006 0.3974±0.032 12.21± 0.16 1.160 ± 0.019 28.81±0.61

F3 0.3312± 0.026 0.3969±0.017 12.54 ±0.25 1.156 ± 0.053 28.90 ± 0.18

F4 0.3448±0.032 0.3925±0.014 12.29 ±0.22 1.190 ± 0.035 29.14±0.24

F5 0.3561 ±0.009 0.3909±0.016 12.55±0.065 1.160 ± 0.026 29.11±0.47

F6 0.3868±0.025 0.3905±0.01 11.97 ±0.10 1.161 ± 0.020 28.97±0.60

F7 0.3787± 0.042 0.3974±0.016 12.54±0.44 1.200 ± 0.040 28.95±0.39

F8 0.3522±0.033 0.3927±0.026 12.35±0.17 1.115 ± 0.012 28.79 ± 0.67

F9 0.3576±0.012 0.3944 ±0.014 12.64 ±0.0 1.121 ± 0.015 29.05 ±0.39

Powder x-ray diffraction

The LS was studied for prediction of crystallinity. The PXRD pattern of Cilnidipine is shown in

(Figure-1).Based on the diffractogram it can be suggested that Cilnidipine is present in the

crystalline form since it exhibits several well defined peaks at a diffractogram angle of 2θ.The

characteristic peaks observed in Cilnidipine liquisolid system (Figure-2) demonstrating that its

crystalline structure remained unchanged during the physical mixing, and that loss of crystallinity

was due to liquisolid system formation.



Figure 1:PXRD of Cilnidipine

Figure 2: PXRD of Cilnidipine Liquisolid system

Differential scanning calorimetry

DSC thermograph of Cilnidipine is shown in (Figure-3) which shows melting endothermic at

111.420c (114.0

0c-116

0c) at 76.69 J/g i.e. melting point and crystalline state of drug. DSC

thermograph of liquisolid system in (Figure-4) displayed complete disappearance of characteristics

peak of Cilnidipine; a fact that agrees with the formation of drug solution in the liquisolid powdered

system, i.e. drug was molecularly dispersed within the liquisolid matrix. The complete suppression

of all drug thermal features, indicate the formation of an amorphous solid solution.



Figure 3: DSC Thermograph of Cilnidipine

Figure3: DSC Thermograph of Cilnidipine Liquisolid Tablet

Evaluation of Liquisolid Tablet

Thickness of tablets varied between 3.93±0.29 mm to 4.4±0.36mmHardness of tablets varied

between 4.17±0.051 kg/cm2 and 5.08±0.28 kg/cm

2 indicating good binding and satisfactory strength

of tablets. The % friability was found in the range of 0.12±0.035 -0.48±0.051 %.The drug content

of formulations F1 to F9 were found to be in between 95.19±0.15% to 98.31±0.54 %. The %

weight variation of formulations F1 to F9 were found to be in between 0.18% to 0.72%.

Disintegration of tablets varied between 7.37±0.18 min to 8.22±0.22min.



Table 4: Evaluation of Liquisolid tablet

Batch

Name

Parameters

Thickness

(mm)

± S.D.

Hardness

(kg/Cm2)

± S.D.

Friability

(%)

± S.D.

Uniformity

of Content

(%) ± S.D.

Uniformity of Weight

(mg)

Disintegration

time (Min) ±S.D.

AvgWt ±

S.D.

%

Variation

F1 4.4±0.36 4.17±0.46 0.48±0.051 95.92±0.20 272.5±1.70 0.45 7.48 ± 0.25

F2 4.11±0.23 5.0±0.29 0.18±0.034 95.55±0.33 372.4±0.43 0.72 7.37 ± 0.18

F3 3.94±0.87 5.01±0.35 0.27±0.041 95.19±0.15 473.5±0.48 0.25 7.45 ± 0.20

F4 3.94±0.30 5.06±0.29 0.40±0.015 97..13±0.93 272.8±0.37 0.34 8.04 ± 0.08

F5 3.96±0.30 5.03±0.34 0.16±0.055 96.76±0.24 372.6±0.49 0.32 8.22 ± 0.22

F6 3.99±0.30 5.08±0.28 0.12±0.035 96.38±0.16 473.4±0.42 0.23 7.50 ± 0.14

F7 3.93±0.29 4.9±0.094 0.33±0.018 98.31±0.54 272.8±0.48 0.42 7.53 ± 0.21

F8 3.98±0.26 5.02±0.46 0.13±0.022 97.93±0.62 373.2±0.24 0.24 8.12 ± 0.18

F9 4.0±0.38 5.05±0.31 0.14±0.028 97.57±0.31 473.8±1.14 0.18 8.05 ± 0.05

Dissolution study

Dissolution rate of different tablet formulations (F1-F9) with plain drug are given in (Table-5) F7

batch show significant drug release i.e. 85.68 %. Comparison of dissolution profile of f1- f9 batches

with plain drug is shown in (figure 23).Comparison of dissolution profile of different tablet

formulations from solubility enhanced Cilnidipine with plain drug, marketed tablet and

conventional tablet is shown in (Figure-6).



Figure 5: In-vitro study of different formulations

Figure 6: In-vitro study of Plain drug, Marketed Tablet, Conventional tablet and Batch F7

CONCLUSION:

The liquisolid technique was found to be a promising approach for improving the dissolution of a

poorly soluble drug like Cilnidipine. XRD spectra indicate that loss of crystallinity was due to

liquisolid system formation. This amorphization or solubilization of Cilnidipine in the liquisolid

system may contribute to the improvement in the dissolution rate, apparent solubility and therefore

the bioavailability of Cilnidipine and DSC spectra indicate that the complete suppression of all drug

thermal features, indicate the formation of an amorphous solid solution.

0

20

40

60

80

100

0 20 40 60 80 100 120 140

% C

DR

Time (min)

% Cumalative Release of F1-F9 Batches with Plain Drug

PlainDrug F1 F2 F3 F4

F5 F6 F7 F8 F9

0102030405060708090

0 20 40 60 80 100 120 140

% C

DR

Time (min)

% Cumalative Release of Plain Drug, Marketed Tablet Convensional Tablet and Batch

Plain Drug Marketed Convensional F7



The dissolution of Cilnidipine was significantly increased in liquisolid formulation compared to the

Plain drug, conventional tablet and marketed tablet. The increased dissolution rate may be due to

increased wetting and increased surface area of the particles.

REFERENCES:

1. Spireas S. Liquisolid systems and methods of preparing same. U.S. Patent 2002 6423339B1

2. NagabandiVK.,Ramarao T, Jayaveera KN. Liquisolid Compacts: A Novel Approach to

Enhance Bioavailability of Poorly Soluble Drugs. International J Pharmacy and Biological

Sciences. 2011;1:89-102

3. Mahmoud EA, Bendas,ER, Mohamed MI. Preparation and evaluation of self-

nanoemulsifying tablets of carvedilol. AAPS PharmSciTech2009; 10: 183-192

4. Tayel SA, Soliman II; Louis D. Improvement of dissolution properties of carbamezapine

through application of the liquisolid tablet technique. Eur. J. Pharm. Biopharm; 2008; 69:

342-347.

5. Karmarkar AB, Gonjari ID, Hosmani AH, Dhabale PN, BhiseSB. Dissolution rate

enhancement of Fenofibrate using liquisolid tablet technique, Part II: evaluation of in-vitro

dissolution profile comparison method. Lat. Am. J. Pharm. 2009; 28: 538-543.

6. Spireas S et. al. Liquisolid System and Method of Preparing Same. U. S. Patent. 1998

5800834.

7. Spireas S, Bolton M. Liquisolid System and Method of Preparing Same. U. S. Patent; 1999;

5968550.

8. Spireas S et. al. Liquisolid System and Method of Preparing Same. U. S. Patent. 2002;

6423339.

9. Tripathi KD. Essential of Medical Pharmacology, 6th edition: 540.

10. Buchiya FV. A Review: Analytical Methods for Determination of Cilnidipine in Biological

Fluid and Pharmaceutical Dosage Forms.Phrma Tutor; 2014; 2: 22-29

11. Aulton ME. Aulton’s Pharmaceutics: The design and manufacture of Medicines,

3rd

ed.Churchill Livingstone:336-360.

12. Marcel K. Compression and consolidation of powdered solids .in: Liberman HA, Lachman

L, Kaing J. L. ed. The theory and Practice of Industrial Pharmacy .3rd ed. New York,

Marcel Dekker, Inc: 1981.

13. The United States Pharmacopeia 2008, The National formulary NF26. The United States

pharmacopeia convention 21601 Twinbrook Parkway, Rockvile, MD 20852; 3: 2695-2696,

231-232.



14. British Pharmacopoeia 2009, The Department of Health, social services and public safety.

Published 2008; 2; 1361-1364.

15. The Indian pharmacopoeia 2010, Government of India, Ministry of Health and Family

Welfare. The controller of publications, New Delhi, 1; 2; 3: 2013-2014.

enhancement of dissolution rate of cilnidipine using .... rpa16172395016.pdf · enhancement of...

Documents