pradeep kumar ch. et al. / ijpdt / 3 (2), 2013, 80-96 ... · pradeep kumar ch. et al. / ijpdt / 3...

Pradeep Kumar CH. et al. / IJPDT / 3 (2), 2013, 80-96.

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International Journal of Pharmaceutical

Development & Technology e ISSN - 2248 - 910X

www.ijpdt.com Print ISSN - 2248 - 9096

FORMULATION AND EVALUATION OF MEFENAMIC ACID

EXTENDED RELEASE LIQUISOLID TABLETS

CH.Pradeep Kumar*1, P.Venugopalaiah, CH. Praveen Kumar, K. Gnanaprakash,

M. Gobinath

1Department of Pharmaceutics, Ratnam Institute of Pharmacy, SPSR Nellore, Andhra Pradesh, India-524346

ABSTRACT

Liquisolid system refers to formulations formed by conversion of liquid drugs, drug suspension or drug solution in non-

volatile solvents in to non-adherent, free flowing and compressible powder mixtures by blending the solution or suspension with

selected carriers and coating materials. The aim of the present work was to formulate and evaluate extended release liquisolid

compacts of Mefenamic acid. Liquisolid extended release formulations were prepared by using HPMC K100M as adjuvant for

extended release. Different liquisolid compacts were prepared using a mathematical model to calculate the required quantities of

powder and liquid ingredients to produce acceptable and free flowing compressible mixtures. Avicel PH 102, Aerosil-200 were

employed as carrier and coating materials. The prepared liquisolid compacts were evaluated for their flow properties such as bulk

density, tapped density, angle of repose, Carr’s compressibility index, Hausner’s ratio. Drug-excipients interactions were studied

by FT-IR. Drug release rates of liquisolid compacts shows significant benefit and distinct drug release profiles when compared to

normal extended release tablets and from the results it was concluded that at higher amount of Aerosil 200 (Batch F12), drug

release was found to be retarded as compared to other batches. Increase in concentration of HPMC K100M might be responsible

to get extended effect. The obtained drug release data of liquisolid compacts were fitted into several mathematical models such as

Zero order, First order, Higuchi, Korsemayer-Peppas, and the obtained data was fitted into zero order release pattern followed by

non-fickian transport mechanism. Drug release profiles on model fitting follow Peppas model as best fit model which indicates

drug diffusion in hydrated matrix and polymer relaxation.

Keywords: Liquisolid compacts, Mefenamic acid, Liquid retention potential (Ø), Avicel-PH 102, Aerosil 200, drug release

kinetics.

INTRODUCTION

The oral route is the preferred route for the chronic

drug therapy. Numerous potent lipophilic drugs exhibit low

oral bioavailability due to their poor aqueous solubility

properties. Therapeutic effectiveness of a drug depends up

on the bioavailability and ultimately upon the solubility and

dissolution rate of drug molecules. Solubility and

dissolution rate are the important parameters to achieve

desired concentration of drug in systemic circulation for

pharmaceutical response to be shown [1].

BCS class II drugs pose challenging problems in

their pharmaceutical product development process because

of their low solubility and dissolution rates. They require

enhancement in solubility and dissolution rate in their

formulation development especially solid dosage forms such

as tablets and capsules.

More recently, powdered solution (liquisolid)

technology has been proposed as a technique for the

delivery of water-soluble drugs. The concept of powdered

solutions involves converting drug solutions or liquid drugs

into a dry, non-adherent, free-flowing compressible powder

by admixturing the liquid drugs or drug solutions with a

selected carrier. Although the dosage form is a solid, the

drug was held in a solubilized liquid state, which enhances

diffusion directly into cells. Alternatively, improves the

wetting properties of the drug and therefore enhanced

dissolution [2].

Since drug dissolution is often the rate limiting step

in gastrointestinal absorption, the significant increase in

wetting properties and surface area of drug particles

available for dissolution from liquisolid compacts may be

expected to display enhanced drug release characteristics

and, consequently, improved oral bioavailability.

The technique of liquisolid compacts has been

successfully employed to improve the In Vitro release of

poorly water soluble drugs such as Carvidilol [3],

Corresponding Author :- CH.Pradeep Kumar Email:- [email protected]


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Bromhexine Hydrochloride [4], Furosemide [5],

carbamazepine [6], Fenifibrate [7], Indomethacin [8],

Aceclofenac [9], ketoprofen [10], theophylline [11],

propranolol hydrochloride [12], Lansoprazole [13],

Irbesartan [14], Lornoxicam [15], simvastatin [16], tramadol

hydrochloride [17], and fenofibrate [18].

Mefenamic acid is one of the Anthranilic acid

derivatives of Non-Steroidal Anti-Inflammatory Drugs

(NSAID). Recent clinical studies on Mefenamic acid

revealed that the drug is an effective agent for accumulation

and moderate to severe ulceration in GI tract. Repeated

administration of high doses of mefenamic acid (250-500

mg- 3 times/day) leads to accumulation of drug in GIT

causes Inflammatory bowel diseases, peptic ulcers, and also

due to its sudden release causes local irritation in the

stomach which is a major limitation for mefenamic acid as

conventional release dosage form, and its less half-life

period (< 2hrs). To reduce frequent administration of dosage

form and to improve patient compliance extended release

liquisolid mefenamic acid formulation is desirable.

Hence the main objective of this work was to

retard/sustain the drug release from the dosage form to

eliminate the repeated administration and also to increase

the half-life of mefenamic acid in GI environment.

In the present study, Hydroxy Propyl Methyl

Cellulose (HPMC) K100M was used as adjuvant for

sustaining the drug release from liquisolid compacts. Poly

Ethylene Glycol (PEG-400) was used as non-volatile

lipophilic solvent. Avicel PH 102 (Microcrystalline

cellulose), Pregelatinized Starch and Aerosil 200 (Colloidal

silicon dioxide) were used as carrier and coating materials,

respectively. Precompression studies such as determination

of angle of slide, Hausner’s ratio, Carr’s index and

stereomicroscopic analysis was also studied. The

discrimination of release profiles was compared with normal

extended release tablets of Mefenamic acid (without liquid

lipophilic solvent and Aerosil 200). Model fitting of the

results was also done for different models such as Zero

order, First order, Higuchi plot and Korsemayer-Peppas plot

models. The formulation design of liquisolid systems was

done in accordance with new mathematical model described

by spireas et al., [19].

MATERIALS AND METHODS

Materials

Mefenamic acid was obtained from Alexo pharma

(India). HPMC K100M, Avicel PH-102, Starch

pregelatinized, Aerosil 200 were purchased from Drugs

India Pvt ltd (India). Poly ethylene glycol 400 was obtained

from Fischer scientific. All the remaining ingredients and

chemicals utilized were of analytical grade.

Methods

Application of mathematical model for design of

Liquisolid compacts

Before designing the liquisolid system, the preformulation

studies should be performed first, includes

Carrier-Coating material ratio (R)

Determination of flowable liquid retention potential (Ø

value)

Calculation of liquid load factor (Lf)

Liquid solid compressibility test (LSC)

The flowability and compressibility of liquisolid

compacts are addressed concurrently in the new formulation

mathematical model of liquisolid systems, which was used

to calculate the appropriate quantities of the carrier and

coating materials required to produce acceptably flowing

and compressible powders based on new fundamental

powder properties called the flowable liquid retention

potential (Ø value) and compressible liquid retention

potential (Ψ value) of the consistent powders [20, 21].

Carrier-Coating material ratio (R)

It is the ratio between the quantities of carrier (Q) and

coating (q) present in the formulation. It is represented as

R=Q/q

Determination of flowable liquid retention potential (Ø)

It is defined as maximum weight of liquid that can

be retained per unit powder material in order to produce an

acceptably flowing liquid/powder admixture. This Ø-value

of powders may be determined using a new procedure, the

liquisolid flowability (LSF) test. This test is basically a

titration-like procedure in which 25-30 grams of mixtures of

the powders under investigation, with increasing amounts of

a non-volatile solvent (i.e., liquid/solid weight composition),

such as, for example, poly ethylene glycol, light mineral oil

and clofibrate, are prepared using a standard mixing process

which ensures uniformity, and their flow rate and

consistency are assessed using a recording powder flow

meter (RPF) [19, 22, 23].

Lf= ØCA + ØCO (1 / R)

Where, Ø and Ø are the constant liquid retention potential

values of carrier and coating materials, respectively. By

calculating Lf and W, we can calculate the Q and q required

for liquisolid systems [24].

Calculation of liquid load factor (Lf)

It is defined as ratio of weight of liquid medication

(W) to weight of carrier material (Q). Different

concentrations of nonvolatile solvents are taken and the

drug is dissolved and the carrier coating material is added

and blended.

Lf=W/Q

Where W is ratio of weight of liquid medication and Q is

weight of carrier material [25].

By use of above mathematical model, liquisolid compacts

were formulated.

Formulation of Mefenamic acid Liquisolid compacts

Mefenamic acid liquisolid tablet preparation

method involves, first a mathematically calculated amount

of pure drug was weighed and dissolved in the suitable

amount of lipophilic liquid vehicle in a molecularly


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dispersed state. For attaining good flow properties trial and

error methods were used i.e. changing the carrier: coating

ratio from 50:1 to 5:1 ratios according to new mathematical

model expressions proposed by Liao [26]. This liquid

medication is poured on the suitable amount of carrier

material. The liquid medication is absorbed into the carrier

internally and externally. Finally, coating material was

added for dry looking, adherent to the carrier material for

achieving good compression properties. Liquid medication

is incorporated into carrier material which has a porous

surface and closely matted fibers in its interior as cellulose

[20]. Both absorption and adsorption takes place, i.e. the

liquid absorbed into the interior of the particles is captured

by its internal structure and after saturation of this process,

adsorption of the liquid onto the internal and external

surface of the porous carrier particles occurs.

According to the above mathematical model

calculated quantities of Mefenamic acid and propylene

glycol 400 was accurately weighed in 20 ml glass beaker

and then heated to 80° C. Resulting hot medication was

incorporated into calculated quantities of carrier and coating

materials. Mixing process is carried out in three steps as

described by Spireas et al.,

During first stage, system was blended at an

approximate mixing rate of one rotation per second for

approximately one minute in order to evenly distribute

liquid medication in the powder.

In second stage, the liquid/powder admixture was

evenly spread as a uniform layer on the surfaces of mortar

and left standing for approximately 5 min to allow drug

solution to be absorbed in the interior of powder particles.

In third stage, powder was scraped off the mortar

surfaces by means of aluminum spatula and then blended

with HPMC K100M, for another 30 seconds in a similar to

first stage. This gives final formulation of liquisolid tablets.

Prepared liquisolid formulation was compressed by 16

station Rotary tablet punching machine (Cadmach).

EVALUATION

Standard graph for Mefenamic acid

Step – 1: Preparation of standard stock solution:

An accurately weighed quantity of 100 mg of

mefenamic acid was taken in a 100 ml standard flask. To

this equal volume of 0.1N HCl was added and made up to

the volume.

Step – 2: Preparation of sample solution:

Different aliquots (0.0, 0.5, 1.0,…… , 5.5 mL) of

Mefenamic acid solution were accurately measured from the

above primary stock and transferred into a series of 100 mL

volumetric flasks and volume made up to the mark with 0.1

M HCl. Then all dilutions were scanned by UV

Spectrophotometer at 285nm against blank and the results

were tabulated and a plot was drawn between concentration

(µg/ml) on x-axis and absorbance (nm) over y-axis.

Determination of Solubility of Mefenamic acid in

various lipophilic solvents

Saturated solutions were prepared by adding excess

of Mefenamic acid to different lipophilic solvents includes

Propylene glycol, PEG-400, Sorbitan esters ( Span-80,

Span-60, Tween-80, Tween-60, Tween-20, Glycerin, SLS-

10%) and shaking on the shaker for 48 h at 25 °C under

constant vibrations. The solutions were filtered through a

0.40 micron filter, after this, the solutions are filtered,

diluted and analyzed spectrophotometrically at 285 nm

against blank sample (blank sample was solution containing

same concentration of used without drug). Three

determinations were carried out for each sample to calculate

the solubility of Mefenamic acid.

Drug-Excipient compatibility study: FT-IR spectroscopy

FT-IR patterns were studied by Shimadzu 8400S,

Japan FT-IR spectrometer. The samples (Mefenamic acid

and Excipients) were previously ground and mixed

thoroughly with potassium bromide, an infrared transparent

matrix, at 1:5 (Sample: KBr) ratio, respectively. The KBr

discs were prepared by compressing the powders at a

pressure of 5 tons for 5 min in a hydraulic press. The scans

were obtained at a resolution of 4 cm-1

, from 4000 to 400

cm-1

.

Pre-compression evaluation studies

Pre-formulation studies such as bulk density,

tapped density, angle of repose, compressibility index,

Hausner’s ratio were performed for drug alone and

liquisolid compressible powders as per the standard

procedures and the results were tabulated in table-3 [27-29].

Post-compression evaluation parameters

After compression of desired doses of drug and its

excipients into suitable tablet dosage form, each batch was

subjected to the following evaluation parameters such as

Weight variation, Friability, Tablet dimensions, Drug

content analysis, Hardness and In-vitro drug release studies

according to the standard pharmacopoeial procedures [28,

29].

In-vitro dissolution studies The studies were done on eight station USP

dissolution apparatus I (Lab India). All batches of tablets

were evaluated using 900 ml of sequential gastrointestinal

release medium, i.e. 0.1N hydrochloric acid (pH 1.2) for

first two hours, acetate buffer of pH 4.5 for next 2 hrs and

then phosphate buffer of pH 7.4 for remaining 8 hours.

Temperature was maintained at 37 ± 0.5°C throughout the

study and stirring at 50 rpm was carried out. Samples were

collected periodically, filtered through 0.45 micron filter

and replaced with fresh dissolution medium. After filtration

Samples were properly diluted and Mefenamic acid

concentrations were analyzed spectrophotometrically at 285

nm. The percentage drug released at time interval was

calculated and plotted against time.

Mathematical modeling for drug release profile


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The cumulative amount of Mefenamic acid

released from the formulated tablets at different time

intervals were fitted in to several kinetic models such as

Zero order kinetics, First order kinetics, Higuchi model and

Korsemayer-peppas model to characterize mechanism of

drug release.

Zero order kinetics It describes the system in which the drug release rate is

independent of its concentration.

Qt = Q0+K0 t

Where, Qt = amount of drug dissolved in time “t”

Q0 = initial amount of drug in the solution

K0 = Zero order release constant

If the zero order release kinetic is obeyed, then a

plot of Qt vs. t will give a straight line with a slope of K0 and

an intercept at zero.

To study the release kinetics, data obtained from in

vitro drug release studies were plotted as cumulative amount

of drug released vs. time.

First order kinetics

It describes the drug release from the systems in which the

release rate is concentration dependent.

Log Qt = Log Q0 + K1t/2.303

Where, Qt = amount of drug release in time “t”

Q0 = initial amount of drug in the solution

K1 = first order release constant

If the release pattern of drug follows first order

kinetics, then a plot of log (Q0-Qt) versus t will be a straight

line with a slope of K1/2.303 and an intercept at t=0 of log

Q0.

The data obtained are plotted as log cumulative

percentage of drug remaining vs. time.

Higuchi model

It describes the fraction of drug release from a

matrix is proportional to square root of time.

Mt/Mα = KHt1/2

Where, Mt & Mα = cumulative amounts of rug

release at time “t” and infinite time

KH = Higuchi dissolution constant reflection

formulation characteristics.

If the Higuchi model of drug release (i.e., Fickian diffusion)

is obeyed, then a plot of Mt/Mα vs. t1/2

will be a straight line

with a slope of KH.

The data obtained were plotted as cumulative percentage

drug release vs. square root of time.

Korsemayer-Peppas model

The power law describes that the fractional amount

of drug release is exponentially related to the release time

and adequately describes the release of drug from slabs,

cylinders and spheres.

Mt/Mα = Ktn

Log [Mt/Mα] = Log K + n log t

Where, Mt & Mα = cumulative amounts of rug release at

time “t” and infinite time

K = constant incorporating structural and

geometrical characteristics of CR device

n = diffusional release exponent indicative of the

mechanism of drug release for drug

dissolution.

To study the release kinetics, data obtained from in vitro

drug release studies were plotted as log cumulative

percentage drug release vs. log time.

Table1. Formulation composition of Mefenamic acid Liquisolid Extended release tablets

Formulation

code

Drug

(mg)

PEG-400

(mg)

R Lf Carrier material

(mg)

Coating

material (mg)

AEROSIL-200

HPMC

K100

(mg)

Total

weight

(mg)

F1 200 150 5 0.822

STARCH

425.7 85.1 150 1010.8

F2 200 160 5 0.822 437.9 87.5 160 1045.4

F3 200 170 5 0.822 450.1 90.0 170 1080.1

F4 200 180 5 0.822 462.2 92.4 180 1114.6

F5 200 190 5 0.822 474.4 94.8 190 1149.2

F6 200 200 5 0.822 486.6 97.3 200 1183.9

F7 200 150 5 0.822

AVICEL

PH-102

425.7 85.1 150 1010.8

F8 200 160 5 0.822 437.9 87.5 160 1045.4

F9 200 170 5 0.822 450.1 90.0 170 1080.1

F10 200 180 5 0.822 462.2 92.4 180 1114.6

F11 200 190 5 0.822 474.4 94.8 190 1149.2

F12 200 200 5 0.822 486.6 97.3 200 1183.9

ERT* 200 -- - -- 540.0 ---- 200 1000.0

*- Contains Talc & Magnesium stearate (30mg each) without PEG-400 & Aerosil-200

ERT- Normal Extended Release Tablets


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Table 2. Solubility results of Mefenamic acid in various solvents at 250C

SL.No Solvent / vehicle Solubility (mg/ml)

1 Water 0.208

2 Ethanol 14.78

3 Propylene glycol 0.218

4 Glycerin 0.156

5 Buffer 7.4 0.025

6 S.L.S (10%) 0.313

7 Tween-80 0.371

8 Polyethylene glycol 400 11.50

Table 3. Micromeritic parameters for mefenamic acid liquisolid powders

Sl.No Bulk density Tapped density Angle of Repose (θ)* Carr’s index (%)* Hausner’s Ratio*

Pure drug 0.32 0.47 4201

1 31.9 1.46

F1 0.33 0.41 33061

1±0.34 19.5±0.18 1.24±0.01

F2 0.35 0.43 33042

1±0.64 18.6±0.80 1.22±0.01

F3 0.31 0.41 32048

1±o.44 24.3±0.67 1.32±0.02

F4 0.28 0.36 33054

1±0.76 22.2±0.66 1.28±0.01

F5 0.29 0.36 32098

1±0.39 19.4±0.12 1.24±0.03

F6 0.28 0.34 33013

1±0.33 17.6±0.74 1.21±0.01

F7 0.29 0.35 30012

1±0.79 17.1±0.91 1.20±0.02

F8 0.26 0.33 32077

1±0.97 21.2±0.43 1.26±0.01

F9 0.27 0.32 31031

1±0.42 15.6±0.23 1.18±0.01

F10 0.28 0.33 29012

1±0.44 15.1±0.64 1.17±0.01

F11 0.27 0.32 30010

1±0.55 15.6±0.33 1.18±0.03

F12 0.24 0.28 28019

1±0.93 14.2±0.35 1.16±0.01

ERT 0.29 0.34 29001

1±0.61 14.7±0.84 1.17±0.02

*Mean n=3

Table 4. Post compression parameters for Mefenamic acid Liquisolid tablets

SL.No

Tablet dimensions* Weight

variation* (mg)

Hardness*

(Kg/Cm2)

Friability*

Fines (%) Content uniformity*

(%) Thickness

(mm)

Diameter

(mm)

F1 6.16±0.03 19.5±0.00 1004.8±0.54 5.7±0.19 0.152 97.6±0.3

F2 6.37±0.06 19.5±0.00 1039.4±0.11 5.9±0.27 0.149 98.3±0.5

F3 6.55±0.04 19.5±0.00 1073.1±0.58 6.3±0.31 0.180 98.2±0.6

F4 6.61±0.04 19.5±0.00 1110.6±0.65 6.5±0.72 0.132 98.5±0.1

F5 6.82±0.03 19.5±0.00 1143.2±0.34 6.9±0.63 0.210 99.0±0.5

F6 7.00±0.01 19.5±0.00 1180.9±0.32 7.2±0.54 0.112 97.4±0.4

F7 6.12±0.10 19.5±0.00 1005.8±0.67 5.9±0.92 0.131 97.5±0.1

F8 6.17±0.06 19.5±0.00 1037.4±0.44 6.2±0.65 0.164 99.5±0.7

F9 6.40±0.04 19.5±0.00 1075.1±0.04 6.3±0.83 0.119 98.3±0.3

F10 6.56±0.02 19.5±0.00 1109.6±0.21 6.7±0.44 0.122 98.9±0.2

F11 6.69±0.03 19.5±0.00 1142.2±0.32 7.0±0.12 0.152 98.5±0.5

F12 6.83±0.04 19.5±0.00 1176.9±0.09 7.3±0.34 0.110 99.2±0.2

ERT 5.85±0.05 19.5±0.00 996.0±0.53 6.5±0.75 0.172 97.5±0.4

*Mean n=3

Table 5. In-vitro drug release data for Mefenamic acid Extended release Liquisolid tablets

Time (hrs) Dissolution

medium Cumulative % drug release

F1 F2 F3 F4 F5 F6 F7 F8 F9 F10 F11 F12 ERT

0

o.o1 N

HCl

0 0 0 0 0 0 0 0 0 0 0 0 0

1 27.8 22.9 20.1 19.3 17.2 16.3 39.9 38.1 36.7 35.4 33 28.9 13.8

2 42.1 39.3 37.8 35.2 33.2 31.1 52.1 48.1 46.8 45.7 43.1 38.5 28.8

3 4.5 pH

Phosphate

58.1 55.2 52.1 51.2 48 47.1 59.1 56.4 52.1 51.2 48.2 46.1 37.6

4 65.3 62.1 57.3 59.7 55.9 53.4 65.3 62.1 60.2 59.7 56 54.1 49


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5 buffer 71.5 68.7 65.1 65.9 62.5 59.7 70.1 69.4 67 64.1 63.1 59.7 56.9

6

7.4 pH

phosphate

buffer

76.1 73.1 70.1 71 68.6 64.7 76.1 73.1 71.8 71.4 68.6 64.7 68.4

8 83.9 82.3 80.4 81.3 78 75 85.6 82.3 83.6 81.1 78 75 79.3

10 91.3 89.6 87.6 87.5 84.9 83.7 92.1 90.6 87.6 87.5 84.9 83.7 90.1

12 96.3 95.9 93.6 92.9 91.8 89.2 98.9 97.9 94.3 93.2 91.9 87.5 97.8

Table 6. In-vitro drug release kinetics data for formulation F1

Zero order First order Higuchi’s data Korsemayer-Peppas data

Time

(h)

Cumulative %

drug release

Time (h) log cumulative

percentage

of drug

remaining

SQRT of

time

Cumulative

% drug

release

Log

time

Log Cumulative

% drug release

1 27.8 1 1.858 1 27.8 0 1.444

2 42.1 2 1.762 1.414 42.1 0.301 1.624

3 58.1 3 1.622 1.732 58.1 0.477 1.764

4 65.3 4 1.540 2 65.3 0.602 1.814

5 71.5 5 1.454 2.236 71.5 0.698 1.854

6 76.1 6 1.378 2.44 76.1 0.778 1.881

8 83.9 8 1.206 2.828 83.9 0.903 1.923

10 91.3 10 0,939 3.162 91.3 1 1.960

12 96.3 12 0.568 3.464 96.3 1.079 1.983



Time

(h)

Cumulative %

drug release


percentage

of drug

remaining

SQRT of

time

Cumulative

% drug

release

Log

time

Log

Cumulative %

drug release

1 22.9 1 1.887 1 22.9 0 1.359

2 39.3 2 1.783 1.414 39.3 0.301 1.594

3 55.2 3 1.651 1.732 55.2 0.477 1.741

4 62.1 4 1.578 2 62.1 0.602 1.793

5 68.7 5 1.495 2.236 68.7 0.698 1.836

6 73.1 6 1.429 2.44 73.1 0.778 1.863

8 82.3 8 1.247 2.828 82.3 0.903 1.915

10 89.6 10 1.017 3.162 89.6 1 1.952

12 95.9 12 0.612 3.464 95.9 1.079 1.981



Time

(h)

Cumulative %

drug release


percentage

of drug

remaining

SQRT of

time

Cumulative

% drug

release

Log time Log

Cumulative %

drug release

1 20.1 1 1.902 1 20.1 0 1.303

2 37.8 2 1.793 1.414 37.8 0.301 1.577

3 52.1 3 1.680 1.732 52.1 0.477 1.716

4 57.3 4 1.630 2 57.3 0.602 1.758

5 65.1 5 1.542 2.236 65.1 0.698 1.813

6 70.1 6 1.475 2.44 70.1 0.778 1.845

8 80.4 8 1.292 2.828 80.4 0.903 1.905

10 87.6 10 1.093 3.162 87.6 1 1.942

12 93.6 12 0.806 3.464 93.6 1.079 1.971


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Time

(h)

Cumulative %

drug release


percentage

of drug

remaining

SQRT of

time

Cumulative

% drug

release

Log time Log

Cumulative %

drug release

1 19.3 1 1.906 1 19.3 0 1.285

2 35.2 2 1.811 1.414 35.2 0.301 1.546

3 51.2 3 1.688 1.732 51.2 0.477 1.709

4 59.7 4 1.605 2 59.7 0.602 1.775

5 65.9 5 1.532 2.236 65.9 0.698 1.818

6 71 6 1.462 2.44 71 0.778 1.851

8 81.3 8 1.271 2.828 81.3 0.903 1.910

10 87.5 10 1.096 3.162 87.5 1 1.942

12 92.9 12 0.851 3.464 92.9 1.079 1.968



Time

(h)

Cumulative %

drug release


percentage

of drug

remaining

SQRT of

time

Cumulative

% drug

release

Log time Log

Cumulative %

drug release

1 17.2 1 1.918 1 17.2 0 1.235

2 33.2 2 1.824 1.414 33.2 0.301 1.521

3 48 3 1.716 1.732 48 0.477 1.681

4 55.9 4 1.644 2 55.9 0.602 1.747

5 62.5 5 1.574 2.236 62.5 0.698 1.795

6 68.6 6 1.496 2.44 68.6 0.778 1.836

8 78 8 1.342 2.828 78 0.903 1.892

10 84.9 10 1.178 3.162 84.9 1 1.928

12 91.8 12 0.918 3.464 91.8 1.079 1.962

Table-11. In-vitro drug release kinetics data for formulation F6


Time

(h)

Cumulative %

drug release


percentage

of drug

remaining

SQRT of

time

Cumulative

% drug

release

Log time Log

Cumulative %

drug release

1 16.3 1 1.922 1 16.3 0 1.212

2 31.1 2 1.838 1.414 31.1 0.301 1.492

3 47.1 3 1.723 1.732 47.1 0.477 1.673

4 53.4 4 1.668 2 53.4 0.602 1.727

5 59.7 5 1.605 2.236 59.7 0.698 1.775

6 64.7 6 1.547 2.44 64.7 0.778 1.810

8 75 8 1.397 2.828 75 0.903 1.875

10 83.7 10 1.220 3.162 83.7 1 1.922

12 89.2 12 1.033 3.464 89.2 1.079 1.950



Time

(h)

Cumulative %

drug release


percentage

of drug

remaining

SQRT of

time

Cumulative

% drug

release

Log time Log

Cumulative %

drug release

1 39.9 1 1.778 1 39.9 0 1.600


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2 52.1 2 1.680 1.414 52.1 0.301 1.716

3 59.1 3 1.611 1.732 59.1 0.477 1.771

4 65.3 4 1.540 2 65.3 0.602 1.814

5 70.1 5 1.475 2.236 70.1 0.698 1.845

6 76.1 6 1.378 2.44 76.1 0.778 1.881

8 85.6 8 1.158 2.828 85.6 0.903 1.932

10 92.1 10 0.897 3.162 92.1 1 1.964

12 98.9 12 0.041 3.464 98.9 1.079 1.995



Time

(h)

Cumulative %

drug release


percentage

of drug

remaining

SQRT of

time

Cumulative

% drug

release

Log time Log

Cumulative %

drug release

1 38.1 1 1.791 1 38.1 0 1.580

2 48.1 2 1.715 1.414 48.1 0.301 1.682

3 56.4 3 1.639 1.732 56.4 0.477 1.751

4 62.1 4 1.578 2 62.1 0.602 1.793

5 69.4 5 1.485 2.236 69.4 0.698 1.841

6 73.1 6 1.429 2.44 73.1 0.778 1.863

8 82.3 8 1.247 2.828 82.3 0.903 1.915

10 89.6 10 1.017 3.162 89.6 1 1.952

12 97.9 12 0.322 3.464 97.9 1.079 1.990



Time

(h)

Cumulative %

drug release


percentage

of drug

remaining

SQRT of

time

Cumulative

% drug

release

Log time Log

Cumulative %

drug release

1 36.7 1 1.801 1 36.7 0 1.564

2 46.8 2 1.725 1.414 46.8 0.301 1.670

3 52.1 3 1.680 1.732 52.1 0.477 1.716

4 60.2 4 1.599 2 60.2 0.602 1.779

5 67 5 1.518 2.236 67 0.698 1.826

6 71.8 6 1.450 2.44 71.8 0.778 1.856

8 83.6 8 1.214 2.828 83.6 0.903 1.922

10 87.6 10 1.093 3.162 87.6 1 1.942

12 94.3 12 0.755 3.464 94.3 1.079 1.974



Time

(h)

Cumulative %

drug release


percentage

of drug

remaining

SQRT of

time

Cumulative

% drug

release

Log time Log

Cumulative %

drug release

1 35.4 1 1.810 1 35.4 0 1.549

2 45.7 2 1.734 1.414 45.7 0.301 1.659

3 51.2 3 1.688 1.732 51.2 0.477 1.709

4 59.7 4 1.605 2 59.7 0.602 1.775

5 64.1 5 1.555 2.236 64.1 0.698 1.806

6 71.4 6 1.456 2.44 71.4 0.778 1.853

8 81.1 8 1.276 2.828 81.1 0.903 1.909

10 87.5 10 1.096 3.162 87.5 1 1.942

12 93.2 12 0.832 3.464 93.2 1.079 1.964


88 | P a g e



Time

(h)

Cumulative %

drug release


percentage

of drug

remaining

SQRT of

time

Cumulative

% drug

release

Log time Log

Cumulative %

drug release

1 33 1 1.826 1 33 0 1.518

2 43.1 2 1.755 1.414 43.1 0.301 1.634

3 48.2 3 1.714 1.732 48.2 0.477 1.683

4 56 4 1.643 2 56 0.602 1.748

5 63.1 5 1.567 2.236 63.1 0.698 1.800

6 68.6 6 1.496 2.44 68.6 0.778 1.836

8 78 8 1.342 2.828 78 0.903 1.892

10 84.9 10 1.178 3.162 84.9 1 1.928

12 91.9 12 0.908 3.464 91.9 1.079 1.963



Time

(h)

Cumulative %

drug release


percentage

of drug

remaining

SQRT of

time

Cumulative

% drug

release

Log time Log

Cumulative %

drug release

1 28.9 1 1.851 1 28.9 0 1.460

2 38.5 2 1.788 1.414 38.5 0.301 1.585

3 46.1 3 1.731 1.732 46.1 0.477 1.663

4 54.1 4 1.661 2 54.1 0.602 1.733

5 59.7 5 1.605 2.236 59.7 0.698 1.775

6 64.7 6 1.547 2.44 64.7 0.778 1.810

8 75 8 1.397 2.828 75 0.903 1.875

10 83.7 10 1.212 3.162 83.7 1 1.922

12 87.5 12 1.096 3.464 91.1 1.079 1.942

Table 18. In-vitro drug release kinetics data for ERT formulation


Time

(h)

Cumulative %

drug release


percentage

of drug

remaining

SQRT of

time

Cumulative

% drug

release

Log time Log

Cumulative %

drug release

1 13.8 1 1.935 1 13.8 0 1.139

2 28.8 2 1.852 1.414 28.8 0.301 1.459

3 37.6 3 1.795 1.732 37.6 0.477 1.575

4 49 4 1.707 2 49 0.602 1.690

5 56.9 5 1.634 2.236 56.9 0.698 1.755

6 68.4 6 1.499 2.44 68.4 0.778 1.835

8 79.3 8 1.315 2.828 79.3 0.903 1.899

10 90.1 10 0.995 3.162 90.1 1 1.954

12 97.8 12 0.342 3.464 97.8 1.079 1.990

Table 19. Parameters and determination coefficients of release profile from Mefenamic acid extended release liquisolid

compacts (F1-F12) and extended release tablet (ERT)

Formulation

code

Correlation Coefficient values (R2) Diffusion Exponent value (n)

Zero

order

First

order

Higuchi Korsemayer-peppas

F1 0.8366 0.9803 0.9678 0.971 0.4939

F2 0.8615 09741 0.9717 0.9636 0.5577


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F3 0.8803 0.9889 0.9786 0.963 0.5933

F4 0.8732 0.9959 0.9699 0.9588 0.618

F5 0.893 0.9928 0.9791 0.9612 0.6512

F6 0.902 0.9949 0.982 0.9626 0.663

F7 0.8165 0.8776 0.9981 0.9987 0.4035

F8 0.8371 0.895 0.9991 0.9982 0.4201

F9 0.8424 0.9778 0.9941 0.9932 0.4314

F10 0.8511 0.9848 0.9963 0.9948 0.4376

F11 0.8698 0.9824 0.9973 0.9949 0.4507

F12 0.8844 0.9953 0.9996 0.9984 0.4608

ERT 0.9612 0.9224 0.9957 0.9856 0.7812

Fig 1. Calibration curve for mefenamic acid at 285nm

Fig 2. FT-IR Spectra of Mefenamic acid (pure drug)


90 | P a g e

Fig 3. FT-IR Spectra of Mefenamic acid + Avicel PH-102 + Aerosil-200 + HPMC K100M

Fig 4. FT-IR Spectra of Mefenamic acid + Starch + Aerosil-200 + HPMC K100M


91 | P a g e

Fig 5. FT-IR Spectra of Physical mixture (Mefenamic acid + Avicel PH-102 + Starch + Aerosil-200 + HPMCK100M + Poly

ethylene glycol-400)

Fig 6. In-vitro drug release kinetics data (Zero order plots) for formulation F1, F2, F3


92 | P a g e

Fig 7. In-vitro drug release kinetics data (Zero order

plots) for formulation F4, F5, F6





Fig 10. In-vitro drug release kinetics data (First order







93 | P a g e



Fig 14. In-vitro drug release kinetics data (Higuchi plots)

for formulation F1, F2, F3







Fig 18. In-vitro drug release kinetics data (Korsemayer-

Peppas plots) for formulation F1, F2, F3


94 | P a g e







Fig 22. Structure of mefenamic acid showing the group

responsible for the COX inhibiting activity

RESULTS

Application of new mathematical model for design of

liquisolid systems Mefenamic acid was selected as model drug for

this study as a suitable candidate for extended release.

Liquisolid hypothesis of Spireas et al., states that drug

candidate dissolved in liquid nonvolatile vehicle and

incorporated into carrier material having porous structure

and closely matted fibers in its interior, phenomenon of both

adsorption and absorption occurs. This concludes that drug

in the form of liquid medication is absorbed initially in the

interior of particles of carrier and after saturation of this

process it gets adsorbed into internal and external surfaces

of carrier. Coating materials such as Aerosil 200 which have

high adsorptivity and grater surface area lead the liquisolid

systems desirable flow properties [15].

Mathematical model equation for Avicel PH 102

and Aerosil 200 in poly ethylene glycol can be given

according to values of Phi (Φ) as given by Spireas et.al.

Lf= 0.16+3.31(1/R)

Based on this equation, Lf is calculated by using different R

values.

DISCUSSION

Fig-2 demonstrates the FT-IR spectra of pure drug

(Mefenamic acid) which shows characteristic peaks at

755.40, 1162.57, 1256.39, 1452.10-1595.82 and 1650.45

cm-1

represents C-H bending (Aromatic), O-H bending, C-O

stretching, C=C stretching (Aromatic), N-H bending along

with C-N stretching respectively. Among which C-H

bending (Aromatic), O-H bending, C-O stretching N-H

bending along with C-N stretching are responsible peaks for


95 | P a g e

the formation of acidic group (COOH) which was attached

to an aromatic ring of Mefenamic acid.

From the MOA of NSAID’s

(Anthranilates/Fenamates group) it was observed that the

acidic group (-COOH) attached to an aromatic ring was

responsible for the COX inhibiting activity of Mefenamic

acid.

Hence when fig-2 (pure drug-mefenamic acid) was

compared with fig-3, 4 and 5 (drug with mixture of

excipients) we can conclude that there is no characteristic

change in the above peaks represents there is no any

incompatibilities with the excipients utilized in the

formulation of liquisolid compacts, leads FT-IR results were

confirming there were no any chemical interactions between

the pure drug and physical mixtures.

Solubility of mefenamic acid in water, phosphate

buffer 7.4, propylene glycol, PEG-400, Glycerin, SLS and

Tween-80 was given in table-2. As shown in the table its

solubility was found to be very poor in water (0.208mg/ml).

In propylene glycol, the solubility of mefenamic acid was

found to be 0.218mg/ml, which is slightly greater than that

of water. This slight increase is probably through hydrogen

bonding. It was found that the solubility of mefenamic acid

was very high in PEG-400 (11.50mg/ml) compared with

other nonvolatile solvents. This increase in solubility is due

to the large non polar part and several hydroxyl groups in

PEG were responsible for the enhanced solubility. Thus,

among the solvents tested, PEG-400 could be a better choice

as a non-volatile solvent.

From the micromeritic properties it was observed

that mefenamic acid drug alone due to its amorphous nature

shows poor flow properties when compared to its physical

mixture which shows good flow properties and passable.

From the results of post-formulation parameters it

was concluded that there should be certain amount of

strength or hardness and resistance to friability for the

tablet, so that tablet should not break during handling.

However, it has also effect on drug dissolution. Average

hardness of liquisolid tablet ranges from 5.7±0.19 to

7.3±0.34 kg/cm2. Compactness of tablet may be due to

hydrogen bonding between Avicel PH 102 molecules. As

poly ethylene glycol is an alcoholic compound, it might

show hydrogen bonding due to presence of hydroxyl groups

and may contribute to compactness of compacts. Friability

studies of liquisolid compacts are in the range of 0.110 % to

0.210%. This indicates that acceptable resistance is shown

by liquisolid compacts to withstand handling.

In preparation of liquisolid compacts, liquid

medications containing drug were adsorbed on the surface

of carrier materials. When this system is exposed to the

dissolution medium, drug located onto the surface of

compacts dissolves fast and diffuses into dissolution

medium. This can be assumed to be the cause of the burst

release effect observed. The concentration of drug in liquid

medication is an important aspect as it affects drug release.

As it was proved previously, increase in drug concentration

in liquid medication, lower drug release rate would observe.

It was due to fact that at higher drug concentration, drug

tends to precipitate within silica (Aerosil 200) pores. At

higher amount of Aerosil 200 (Batch F12), drug release was

found to be retarded as compared to other batches. Increase

in concentration of HPMC K100M might be responsible to

get extended effect. This is reflected in batches F5, F6, and

F11, F12. However, normal extended release tablets showed

faster release as compared to liquisolid extended release

formulations. Liquisolid compacts containing Avicel PH

102 retards drug release compared to compacts containing

starch as carrier due to high wettability nature of Avicel.

Although model independent methods are simple

and easy to apply, they lack scientific justification. Hence

different model dependent approaches (Zero order, First

order, Higuchi, Korsemayer- Peppas plots) were performed

for dissolution profile comparison of all liquisolid compacts.

The results of these models indicate all liquisolid compacts

follow Peppas model as “best fit model”. This is due to

previously proved fact depending on R2

value obtained from

model fitting. From the results batches F6 and F12 showed

more release retarding effect. It is thus found that T50 %

value increases as concentration of HPMC K100M

increases. Korsemayer - Peppas release exponent (n) values

of all liquisolid compacts are greater than 0.45 indicating

non - Fickian diffusion.

CONCLUSION

From the results it was concluded that, percent

drug release was decreased with increase in the

concentrations of HPMCK100M. The 12 hour drug release

profile may improve patient compliance with the usage of

carrier and coating materials along with drug retarding

polymer, such that the drug release reduces in the gastric pH

and increases when reaches to the intestinal pH which leads

to decreased gastric cavity disorders and also the total

amount of drug was completely dissolved in to PEG which

was further completely available to the intestinal medium

after passage through GIT which was not observed in non-

liquisolid extended release tablets, because the drug in

conventional dosage form was not in completely dissolved

form hence causes gastric irritation.

Based on the in-vitro drug release studies, the data

were fitted into different kinetic models shows zero order

release pattern followed by non-fickian transport

mechanism. Drug release profiles on model fitting follow

Peppas model as best fit model which indicates drug

diffusion in hydrated matrix and polymer relaxation. Among

the models used for dissolution profile comparison, it was

concluded that model independent methods were found to

be very simple, but discrimination between dissolution

profiles can be found using model dependent approach.


96 | P a g e

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