enhacement of solubility of nifidepine by...

RESEARCH ARTICLE Rajesh kumar Kumpati et.al / IJIPSR / 1 (2), 2013, 296- 307

Department of Pharmaceutics ISSN (online) 2347-2154

Available online: www.ijipsr.com October Issue 296

ENHACEMENT OF SOLUBILITY OF NIFIDEPINE BY LIQUISOLID

COMPACT TECHNIQUE

1Rajesh Kumar Kumpati

*,

2M.Srujan Kumar,

3Dr.K.V.Subrahmanyam

1M.Pharmacy Scholar Samskruti College of Pharmacy, Hyderabad, India.

2Faculty, Samskruti College of Pharmacy, Hyderabad, India.

3Principal, Samskruti College of Pharmacy, Hyderabad, India

.

Corresponding Author:

Rajesh Kumar Kumpati

Samskruti College of Pharmacy

Department of Pharmaceutics

Email: [email protected]

Phone: 9908999540

International Journal of Innovative

Pharmaceutical Sciences and Research www.ijipsr.com

Abstract

The aim of present study was to enhance the solubility by liquidsolid compacts using (PEG 400 and PG) and

Nifedipine as a drug. Nifedipine is an antianginal drug belonging to a class of pharmacological agents, the

calcium channel blockers it inhibits the transmembrane influx of calcium ions into cardiac muscle and smooth

muscle. The solubility of drug remains one of the most challenging aspects in formulation and development.

From literature survey it can be revealed that almost 40 % of all new chemical entities suffer from poor aqueous

solubility and hence suffer from poor absorption and bioavailability problems. It is generally recognized that low

solubility or poor dissolution often become a rate limiting step in absorption of poorly water soluble drug from

gastro intestinal tract and compromise oral bioavailability. Of the several approaches to improve solubility of

poorly water soluble drug, liquid solid compact methods are widely used to improve the water solubility and in

turn dissolution of poorly water soluble drug.

Key words: Nifedipine, Liquisolid Compact, PEG 400, Solubility.




INTRODUCTION [1,2,3]

Liquisolid system refers to powdered forms of liquid medication Formulated by converting the

active substance into a non-volatile liquid to from a mixture, selecting at least one solid carrier

material and admixing these components to produce a non-adherent, free-flowing and

compressible liquid/powder mass admixture. To optimize flow and compressibility amount of

drug and carrier ratio is constant. Liquisolid system is a novel concept of drug delivery via

oral route. This technique is applied to water insoluble drugs and lipophilic drugs to

sustain their release. Formulation and manufacture of the liquisolid tablets is quite simple

method according to new mathematical model described by Spire’s et al. It involves

dissolving the drug in suitable non-volatile solvent and then adding this liquid medication

to the mixture of carrier and coating materials. Mixing of this will lead to liquisolid

system which is subjected to tabletting by direct compression. Increase in dissolution rate

and in turn improvement in bioavailability is observed in case of poorly water soluble

drugs. However, sustained effect is achieved in case of water soluble drugs. By use of this

technique, liquid medications such as solutions or suspensions of water insoluble drugs in

suitable non-volatile liquid vehicles can be easily converted into powder with acceptable

flow properties and compression behavior using suitable powder excipients. The liquisolid

system shows acceptable flow properties and compressibility. Liquid lipophilic drugs or water

insoluble solid drugs dissolved in nonvolatile solvent and this liquid medication can be converted

into free flowing, non-adherent, dry looking and readily compressible powders with use of

carrier and coating materials. As the drug is in the form of liquid medication it is either

solubilized or molecularly dispersed state. Due to increased wetting and surface area for

dissolution liquisolid tablet of water insoluble drugs shows improved dissolution properties and

in turn increase in bioavailability also the low cost incurred during the manufacture of liquisolid

system prove them useful with respect to industrial production using this technique. To achieve

good flow behavior and defined as the maximum weight of liquid that can be retained per

unit weight of the powder material in order to produce an acceptably compressible liquid

or powder admixture compressibility of liquisolid systems a mathematical model designed

by Spire’s et al.8, 9 was used as formulation design model for the liquisolid tablets.

Prerequisites for this include suitable drug candidate, suitable non-volatile solvent, carrier and

coating materials. Dissolution is a kinetic process and the rate of dissolution reflects the amount




of drug dissolved over a given time period. The rate at which a solid dissolves in a solvent was

proposed by Noyes and Whitney in 1897 and elaborated subsequently by other workers. The

equation can be written as:

Where, M is the mass of solute dissolved in time t, dM/dt is the mass rate of dissolution

(mass/time), D is the diffusion coefficient of the solute in solution, S is the surface area of the

exposed solid, h is the thickness of the diffusion layer, Cs is the solubility of the solid (i.e.,

concentration of saturated solution of the compound at the surface of the solid and at the

temperature of the experiment), and C is the concentration of solute in the bulk solution and at

time t. The quantity dC/dt is the dissolution rate, and V is the volume of solution. In dissolution

or mass transfer theory, it is assumed that an aqueous diffusion layer or stagnant liquid film of

thickness h exist at the surface of a solid undergoing dissolution.

The Spire’s et all’s model is based on new fundamental properties of powder called “flowable

liquid retention potential” (Φ value) and “compressible liquid retention potential” (ψ value)

of powdered excipients used in the formulation. The Φ value is defined as the maximum

weight of liquid that can be retained per unit weight of powder material in order to

produce an acceptably flowing liquid/powder admixture while the ψ value is i.e. being

able to yield tablets of satisfactory mechanical strength without presenting any liquid

squeezing out of liquisolid mass during compression. The excipients ratio (R) or the carrier:

coating material ratio is represented as follows

R = Q / q

R is ratio of carrier (Q) and coating materials (q). For, a successful formulation Design, this ratio

R should be suitably selected.

Another term called Liquid load factor (Lf) is defined as ratio of weight of liquid medication

where (W) to weight of carrier material (Q) in system.

Lf = Φ + Φ (1 / R)

Where, Φ and Φ are the constant Φ values of carrier and coating materials, respectively.

By calculating Lf and W, we can calculate the amount of Q and q required for the liquisolid

system.




MATERIALS AND METHODS

Nifedipine, propylene glycol, Polythylene glycol, Polyvinyl pyrolidine, Micro crystalline

cellulose, Dicalcium phosphate, Crospovidone, Aerosil, Magnesium stearate were obtained

from Pharma Train research Lab Ltd.

Drug-Excipient compatibility studies:

Drug-excipients compatibility studies were carried out using FT-IR. The study was

carried out on individual pure drug and its physical mixture with the excipients used in the study.

FTIR Study:

The pure drug and the excipients were mixed separately with IR grade KBr in the ratio

of 100:1, and corresponding discs were prepared by applying 5.5 metric tons of pressure in a

hydraulic press. The discs were scanned over a wave number range of 4,000–400 cm −1

.

U.V Spectrum analysis: Nifedipine contents were estimated by measuring the absorbance at

237nm. The standard curve for Nifedipine was prepared with 6.8pH phosphate buffer. The

method obeyed Beer’s law in the concentration range of 2 to 10 µg/ml.

Preparation of standard stock solution of Nifedipine: Accurately weighed 100 mg Tramadol

hydrochloride and was dissolved in 100 ml phosphate buffer saline of pH 6.8, 7.2, 7.4 separately

where its concentration is 1000μg/ml, from this stock solution 10 ml was withdrawn and

transferred into 100 ml volumetric flask. Volume was made with phosphate buffer saline in order

to get standard stock solution containing 100 μg/ml.

Standard graph of Nifedipine: 10mg of Nifedipine was weighed and dissolved in methanol

(6ml) and then made up to a volume of 10ml with methanol. From the stock solution 1ml was

diluted to 10ml with 6.8pH phosphate buffer. Several dilutions were made from this stock

solution, to obtain a concentration range of 2 to 10 µg/ml. The absorbance was measured at 237

nm.

Preparation of Liquidsolid compacts:

1. A Drug was initially dispersed in the nonvolatile solvent systems (PEG-400, PG) termed as

liquid vehicles with different drug: vehicle ratio.

2. Then a mixture of carrier or different polymers and excipients were added to the above liquid

by continuous mixing in a mortar. These amount of the carrier and excipients are enough to

maintain acceptable flow and compression properties.




3. To the above binary mixture disintegrant like crospovidone and other reaming additives are

added according to their application and mixed for a period of 10 to 20 min in a mortar.

4. The final mixture was compressed using the tableting machine to achieve tablet hardness.

5. Characterize the final liquisolid granules for solubility, dissolution, flowability,

compressibility.

6. The lubricated granules were punched to tablets using tablet punching machine.

Table 1: Formulation chart

Ingredients F1

(mg)

F2

(mg)

F3

(mg)

F4

(mg)

F5

(mg)

F6

(mg)

F7

(mg)

F8

(mg)

F9

(mg)

F10

(mg)

Nifedipine 20 20 20 20 20 20 20 20 20 20

Propylene Glycol 20 0 0 0 0 0 0 0 0 0

Polyethylene Glycol 400 0 20 10 0 15 20 30 30 30 30

Polyvinyl Pyrolidone

(PVP k30)

5 5 5 5 5 5 10 10 10 10

Micro Crystalline

Cellulose

70 70 70 70 70 70 70 70 70 70

Dicalcium Phosphate 0 0 0 0 0 0 - - - -

Crospovidone - - - - - - - 5 - 7.5

Aerosil 1.5 1.5 1.5 1.5 1.5 2 1.5 1.5 1.5 1.5

Extra Granular

Micro Crystalline

Cellulose

50.5 50.5 60.5 70.5 55.5 40 45.5 40.5 55.5 38

Crospovidone 7.5 7.5 7.5 7.5 7.5 7.5 7.5 7.5 7.5 7.5

Magnesium Sterate 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5

Total Weight 175 175 175 175 175 175 175 175 175 175




RESULTS & DISCUSSION:

Preparation of calibration Curve of Nifedipine in 6.8 ph phosphate buffer:

Table 2 : Calibration data of Nifedipine Fig 1: Standard curve of Nifedipine in

in 6.8ph phosphate buffer 6.8 pH buffer

Solubility:

Solubility studies of nifedipine were carried out in water, phosphate buffer 6.8, PEG 400, PG.

Saturated solutions were prepared by adding excess drug to the vehicles and shaking on the

shaker for 48 hr at 25°C under constant vibration. Filtered samples (1ml) were diluted

appropriately with phosphate buffer 6.8, solution and nifedipinewas determined

spectrophotometrically at 237 nm. The average value of three trials was taken. Results are

shown in Table no:3

Table No: 3 Solubility

Solvent Solubility mg/ml

Water 0.005

Phosphate Buffer pH 6.8 0.001

Polyethylene Glycol 400 0.329

Propylene Glycol 0.544

S.N

O

CONCENTRATI

ON (mcg/ml)

ABSORBANCE at

237nm

1 0 0

2 5 0.211

3 6 0.252

4 7 0.301

5 8 0.346

6 9 0.390

7 10 0.432




Drug polymer interaction study:

From the spectra of nifedipine, combination of nifedipine with excipient. It was observed that all

characteristics peak of Nifedipine were present in the combination spectrum, thus indicating

compatibility of the drug and excipient IR spectra are shown as given below.

Table 4: FT-IR interpretation

S.No Wave length Specification

1 3331.50 cm-1

Aromatic- NH stretch

2 1743.65 cm-1

C=O stretch

3 1348.24 cm-1

Aromatic-NO2

4 2841.5 cm-1

-CH stretch

5 2953 cm-1

-CH stretching for methyl group

6 3101 cm-1

Aromatic Benzene ring

Fig 2: IR spectra of Nifedipine Fig 3: IR spectra of Nifedipine + PEG 400

Fig 4: IR spectra of Nifedipine + PVP K30 Fig 5: IR spectra of Nifedipine + MCC




Fig 6: IR spectra of Nifedipine+ Fig 7: IR spectra of Nifedipine +

Dicalcium phosphate crospovidone

Fig 8: IR spectra of Nifedipine + Fig 9: IR spectra of Nifedipine + Aerosil

Magnesium sterate

Fig 10: IR spectra of Nifedipine + PG Fig 11: IR spectra of NIfedipine and all

Excipients




Pre-Formulation Parameters [4, 5, 6]

Precompression parameters such as bulk density, tapped density, angle of repose, Carr’s index

and Hausner ratio which are evaluated for prepared tablets are given in following table

Table 5: Precompression characteristics of blend of all formulation

Formulations Bulk

density

Tapped

density

Angle of

repose

Compressibility

index

Hausners

ratio

F1 0.5833 0.6363 21.8 8.33 1.09

F2 0.5384 0.6363 24.77 15.38 1.18

F3 0.5833 0.6363 23.10 8.33 1.09

F4 0.5833 0.6363 26.56 8.33 1.09

F5 0.6363 0.57 23.1 9.09 1.1

F6 0.5833 0.6363 30.96 8.33 1.09

F7 0.6363 0.7 28.61 9.09 1.1

F8 0.5384 0.6363 30.96 15.38 1.18

F9 0.6363 0.7 28.61 9.09 1.1

F10 0.5400 0.54 25.4 11.3 1.15

Physico-Chemical Properties of tablet: [7, 8]

Weight variation:

Twenty tablets were randomly selected from each batch individually weigh, the average weight

and standard deviation of 20 tablet calculated (Krishanaiah et al., 2003). Table no-6

Thickness:

The thickness of the tablet was measured by using digital venire caliper, twenty tablets from each

batch were randomly selected and thickness was measured (The British Pharmacopoeia, 2005).

Hardness:

Hardness was measured using Pfizer hardness tester, for each batch three tablets were tested

(The United State of Pharmacopoeia, 1995). (Table no-6)

Friability:

Twenty tablets were weight and placed in the Roche friabilator and apparatus was rotated at 25

rpm for 4 min. After revolution the tablets were dusted and weighed. (Chaudhari PD, 2005).

In-vitro disintegration test:

The test was carried out on 6 tablets using Tablet disintegration tester. Distilled water at 37 ˚C±

2˚C was used as a disintegration media and the time in seconds taken for complete disintegration

of the tablet with no palable mass remaining in the apparatus was measured.




Table 6: Physico- chemical properties of all formulations

Table 7: In-vitro release data of Nifedipine compacts

3 Percentage Cumulative Drug Release

Time

(min) F1 F2 F3 F4 F5 F6 F7 F8 F9 F10

10 42 50 40 35 42 55 54 60 41 60

15 53 64 49 44 55 70 69 72 49 76

20 62 77 62 54 66 81 81 83 60 87

30 70 86 70 61 80 92 92 94 73 96

45 77 91 74 65 88 96 96 97 80 98

Fig 12: In-vitro plots for F1, F2, and F3 Fig 13: In-vitro plots for F4, F5, and F6

S.No. Formulation Weight

variation

Hardness

(kg/cm2)

Diamete

r (mm)

Thickness

(mm)

Friability

(%)

Drug

Content

(%)

1 F1 complies 3.6 7.01 5.00 0.60 95

2 F2 complies 3.5 7.03 5.10 0.51 94

3 F3 complies 3.9 7.01 4.95 0.37 93

4 F4 complies 3.8 7.03 5.12 0.49 96

5 F5 complies 3.9 7.03 5.11 0.85 94

6 F6 complies 3.0 7.01 5.00 0.51 96

7 F7 complies 3.3 7.03 5.21 0.49 97

8 F8 complies 3.6 7.03 5.10 0.41 98

9 F9 complies 3.6 7.01 5.10 0.69 97

10 F10 Complies 3.8 7.03 5.03 0.45 98




Fig 14: In-vitro plots for F7, F8, and F9 Fig 15: In-vitro plots for F10

Table 8: Dissolution profile of prepared and optimized formulation

Time

(min)

% cumulative drug

release of prepared

conventional formulation

% cumulative drug

release of optimized

formulation F8

0 0 0

10 35 60

15 44 72

20 54 83

30 61 94

45 65 97

Fig 16: Dissolution profile of comparison of prepared conventional and optimized

formulation




CONCLUSION

The aim of this study was to improve the dissolution profile thereby increase solubility.

Solubility is the major criteria to achieve the desired concentration of the drug in systemic

circulation. About 80% of the drugs are poorly soluble in nature. So in order to overcome that

problem, several techniques have been developed to enhance the solubility of those drugs.

Among them liquisolid compacts is one of the most promising and new technique which

promotes the dissolution rate of water insoluble drugs. Hence, in this study, liquisolid technique

was chosen to enhance the dissolution properties of Nifedipine. The Nifedipine liquisolid

compacts were prepared by using PEG 400, propylene glycol as the non-volatile liquid vehicles.

MCC and Aerosil were used as the carrier and coating material, respectively.

REFERENCES

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Enhancement of Fenofibrate Using Liquisolid Tablet Technique. Part II: Evaluation of In

Vitro Dissolution Profile Comparison Methods. Latin American Journal of Pharmacy

2009; 28 (4): 538-43.

2. Dissolution enhancement of Glipizide using liquisolid tablet technique, Indian drugs,

Vol.45, No-4, April 2008, Page No. 318.

3. D.M Brahmankar, Sunil B jaiswal, Biopharmaceutics and pharmacokinetics A treatise,

first edition,Vallabhprakashan, Delhi, 1995, pp-19-25.

4. Subramanyam CVS. Textbook of Physical Pharmaceutics, Vallabh Prakashan, 2nd ed;

2001.

5. Mehta RM. Pharmaceutics-I, Vallabh Prakashan, 2nd ed; 1997.

6. The United States Pharmacopoeia-National Formulary. 2009 ed, Rockville: The United

States Pharmacopoeial Convention; Vol-I, 226-27.

7. Gwen MJ and Joseph RR and Rhodes CT. Modern Pharmaceutics, Marcel Dekker, Inc.,

New York, 72(3), 1996, 581.

8. Goldstein J L, Femilial hypercholesterolemia, in the metabolic and molecular bases of

coronary heart disease, Basic research cardiol, 98 (2001) 59-68.

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