international journal of innovative pharmaceutical ... · levodropropizine, polymer hpmc (k4m,...

RESEARCH ARTICLE Sunnam venkata Pragnam et.al / IJIPSR / 2 (5), 2014, 1068-1082

Department of Pharmaceutics ISSN (online) 2347-2154

Available online: www.ijipsr.com May Issue 1068

FORMULATION AND IN VITRO EVALUATION OF CONTROLLED

RELEASE MATRIX TABLETS OF LEVODROPROPIZINE USING

HYDROPHILIC (HPMC) POLYMERS

1Sunnam venkata pragna*,

2Akulwar radhika,

3Shivadeep Goud Kallem,

4Srikanth

Paripalli, 5Arvind,

6Y madhusudhan rao

1,2,3,4,5Department of pharmaceutics, Vaagdevi college of pharmacy, #2-2-457/A, Ramnagar,

Hanamkonda, Warangal, Andhrapradesh, INDIA 6Director of Vaagdevi college of pharmacy, Department of pharmaceutics, #2-2-457/A, Ramnagar,

Hanamkonda, Warangal, Andhrapradesh, INDIA

Corresponding Author:

Sunnam venkata pragna

#3-59/1, Palivelpula, Bheemaram,

Hanamkonda,Warangal, AndhraPradesh-506015, INDIA

Email: [email protected]

Phone: +91-8801314256

International Journal of Innovative

Pharmaceutical Sciences and Research www.ijipsr.com

Abstract

The investigation was concerned with design and characterization of oral controlled release matrix tablets of

Levodropropizine (150 mg), in order to improve efficacy, reduce dosing and better patient compliance against

cough. Tablets were prepared by wet granulation technique using hydrophilic polymer HPMC (K4M, K15M,

K100M) of various ratios. Tablets were evaluated for both pre and post-compressional parameters and found to be

within the limits. In vitro release of drug from the tablet was studied in 1000 mL of 0.1 N HCl for first 2 hrs and

then 900 mL of phosphate buffer pH 6.8 as dissolution medium for rest of hrs till 24 hrs using a USP type II

dissolution apparatus (paddle assembly) at 50 rpm and 37oC± 0.5

oC. Among all the formulations F3 was selected

as optimized formulation based on the evaluation parameters and in-vitro release profile of 95.5% drug release

for 24 hrs. The FT-IR results of optimized formulation showed no drug excipient interaction. For optimized

formulation (F3), the drug release mechanism was explored and explained by zero-order (R2=0.827), first-order

(R2=0.977), Higuchi (R

2=0.981) and Korsmayer-peppas (R

2=0.990 & n=0.410) equations, which explained

the drug release follows first-order and is fit for equation Korsmayer-peppas & mechanism was fickian diffusion.

The manufacturing procedure was found to be reproducible and formulations were found to be stable after three

months of accelerated stability studies.

Keywords: Levodropropizine, Controlled release, In vitro release, Fickian diffusion, Matrix tablets.

mailto:[email protected]




INTRODUCTION

Oral route still remains the most popular for drug administration by virtue of its convenience to

the patient. A sizable portion of orally administered dosage forms, so called conventional, are

designed to achieve maximal drug bioavailability by maximizing the rate and extent of

absorption. While such dosage forms have been useful, frequent daily administration is

necessary, particularly when the drug has a short biological half life. This may result in wide

fluctuation in peak and trough steady-state drug levels, which is undesirable for drugs with

marginal therapeutic indices. Moreover, patient compliance is likely to be poor when patients

need to take their medication three to four times daily on chronic basis. Fortunately, these short

comings have been circumvented with the introduction of controlled release dosage forms [1]. A

controlled release drug delivery system delivers the drug locally or systemically at a

predetermined rate for a specified period of time. These dosage forms are capable of controlling

the rate of drug delivery, leading to more sustained drug levels and hence therapeutic action [2].

The simplest and least expensive way to control the release is to dispense it with in an inert

polymeric matrix. The hydrophilic matrices are an interesting option when CR formulations are

done for a drug. A successful hydrophilic matrix system should possess a polymer that will wet,

hydrate and swell to form a gelatinous layer and avoid disintegration of the tablet. The

development of CR formulation of Levodropropizine is therefore of therapeutic relevance and

can be used to provide substantially constant blood levels for a prolonged period of time [2, 3].

Levodropropizine is a peripherally acting agent inhibiting the afferent pathways that mediate the

generation of the cough reflex having lower central nervous system depressant actions.

Levodropropizine is the L-enantiomer of dropropizine, a racemic non-opiate antitussive agent

which it is rapidly absorbed and distributed after oral administration. The bioavailability of

Levodropropizine is 75% and the half life time is 1-2 hours, 11-14% human plasma proteins

bound, Volume of Distribution of 3.4L, Time of peak action is 0.5-1hr and having partition

coefficient of 0.61. Due to short biological half-life (1-2hrs), frequent daily dosing (3 times) of

Leodropropizine is required. Therefore its formulation in CR dosage form is advantages [4]. No

study has been reported so far regarding the preparation of Levodropropizine controlled-release

matrix tablets. The present study was aimed at the development of controlled release tablet of

Levodropropizine to avoid fluctuations of drug concentrations in blood and in turn, to reduce

frequency of dosing, the side effects for improvement in compliance. A hydrophilic matrix




polymer of different HPMC grades and in different ratios was used to exploit their good

characteristics for getting extended drug release with first order kinetics.

MATERIAL & METHOD

Levodropropizine was received as a gift sample from Eurodrugs Pvt. Ltd, Hyderabad. HPMC

K4M, K15M, K100M were obtained as gifts from Colorcon India Pvt. Ltd, Hyderabad.

Microcrystalline cellulose (MCC), PVP, Talc, Magnesium stearate (all these were obtained from

S.D. Fine chemicals Ltd, Mumbai). Other materials used were of analytical grade and procured

from commercial sources.

METHODOLOGY

Drug and polymer compatibility studies:

Compatibility study by FT-IR: This can be confirmed by carrying out with Infrared light

absorption scanning spectroscopy (IR) studies. Infrared spectra of pure drug, polymer and

physical mixture of formulations in ratio 1:1 was recorded by dispersing them in a suitable

solvent (KBr) using Fourier Transform Infrared spectrophotometer. A base line correction

was made using dried potassium bromide and the spectra of the pure drug, polymer and the

formulation mixture were recorded on FT-IR (BRUKER, Japan). The data are represented in

figure 1 & 2.

Fig.1 FT-IR spectrum of pure drug Levodropropizine




Fig. 2 FT-IR spectrum of Levodropropizine controlled release matrix tablet.

Calculation:

Pharmaceutical Analysis of the Total Dose Calculation for Controlled Release

Levodropropizine Matrix Tablets:

Initial Dose (DI) = Css.Vd.1/F (as Css = FX0/Ke.Vd.T) therefore DI = Xo/Ke.T

Initial Dose DI = 1*180/0.3465*24, DI = 21.645 mg, [Ke = 0.693/ t1/2; t1/2 = 2 hrs]

X0 = Actual amount of drug which has to be controlled, Ke = Elimination rate constant,

T = Time taken in hrs to controlled the drug release (24hrs).

Maintainance Dose (DM) = KS.T, Desired rate of drug release (Ks) = DI.Ke

Ks = 21.645*0.3465 = 7.49

Maintenance Dose DM = 7.49 *19 = 142.31mg (Here time taken to maintain drug release

controlledly, as Css of the drug was not mentioned)

Total Dose = DM + Corrected dose.

Corrected Dose = DI – Ks.tp [Time of peak action (tp =1hr)]

=21.645-7.5*1 = 14.145mg

Total dose = 142.31+14.14 = 156.45mg (Rounded off to around150)




Preparation of Matrix Tablets:

Controlled release tablets of Levodropropizine were formulated by the wet granulation method

using polymer HPMC of different grades like K4M, K15M, K100M and by keeping at drug to

polymer ratios of 1:0.5, 1:0.75, 1:1, 1:1.5, 1:2 for each grade as shown in table 1.

Levodropropizine, polymer HPMC (K4M, K15M, K100M), MCC were accurately weighed and

mixed thoroughly in a mortar, PVP in alcohol (5%) solution was added drop wise until suitable

mass of granulation is obtained. The coherent mass was passed through sieve # 20. The granules

were dried in conventional hot air oven at 45°C. Drying of the granules was stopped when the

sample taken from the oven reached a loss on drying (LOD) value of 0.5 to 1.5 %, as measured

by a moisture balance at 105°C. The dried granules were sized through 40/60mesh, lubricated

with magnesium stearate (3% w/w) and purified talc (3 %w/w) and then compressed using 16

station rotary tablet compression machine (Cadmach Machinery Ltd., Ahmedabad, India) using

12 mm round flat faced punches The tablets were off white, round and flat. The hardness of the

tablets was kept constant. Total 15 formulations were prepared and coded them from F1 to F15.

Table1: Formulation of 600 mg tablet containing Levodropropizine

FORMUL-

ATION

DRUG

(mg)

K4M

(mg)

K15M

(mg)

K100M

(mg)

MCC

(mg)

TALC

(mg)

Mg

Str

(mg)

PVP

/Alc

TOTAL

(mg)

F1 150 75 - - 339 18 18 QS 600

F2 150 112.5 - - 301.5 18 18 QS 600

F3 150 150 - - 264 18 18 QS 600

F4 150 225 - - 189 18 18 QS 600

F5 150 300 - - 114 18 18 QS 600

F6 150 - 75 - 339 18 18 QS 600

F7 150 - 112.5 - 301.5 18 18 QS 600

F8 150 - 150 - 264 18 18 QS 600

F9 150 - 225 - 189 18 18 QS 600

F10 150 - 300 - 114 18 18 QS 600

F11 150 - - 75 339 18 18 QS 600

F12 150 - - 112.5 301.5 18 18 QS 600

F13 150 - - 150 264 18 18 QS 600

F14 150 - - 225 189 18 18 QS 600

F15 150 - - 300 114 18 18 QS 600




EVALUATIONS

Evaluation of Levodropropizine granules

The flow properties of granules (before compression) were characterized in terms of ranges of

angle of repose (21.58±0.15-25.64±0.21), tapped density (0.335±0.03 - 0.581±0.03), bulk

density (0.304±0.02-0.553±0.09), Carr’s index (11.25±0.03-15.33±0.04) and Hausner ratio

(0.86±0.014-1.176±0.016). All the evaluation parameters were found to be within the limits.

Physical characterization of fabricated tablets

Two tablets from each formulation were randomly selected and organoleptic properties such as

colour, odour, taste, and shape were evaluated. Thickness and diameter of ten tablets were

measured using screw guage ( in range of 0.380-0.396 cm). The quality control tests for the

tablets, such as hardness, friability, weight variation etc. were determined using reported

procedure. The tablet crushing strength was tested by using Mansanto hardness tester and

maintained in b/w 7-7.5 Kg/cm3 for all batches. Friability was determined by Roche® friabilator

(Toshiba Pvt. Ltd., Mumbai, India), was rotated for 4 min at 25 rpm. After dedusting, the total

remaining mass of the tablets was recorded and the percent friability was calculated and was

found to be <1% (in b/w 0.456-0.731). Weight variation was determined by weighing 20 tablets

individually, the individual weights were compared with the average weights for determination

of weight variation and the limits were meeting standard I.P values >250 ( limit <10%) [5, 6].

Physical characters observed for various batches were given in table 2.

Content uniformity

Standard preparation

An accurately weighed amount of pure Levodropropizine (100 mg) transferred into 100 mL

volumetric flask. It was dissolved in little amount of methanol and made up to volume with pH

6.8 phosphate buffer and absorbance was measured at 237 nm.

Sample preparation

Five tablets were weighed individually then placed in a mortar and powdered with a pestle. An

amount of powdered Levodropropizine (100 mg) was extracted in buffer. The solution was




filtered through 0.45µm membrane and absorbance was measured at 237 nm after suitable

dilution. The amount of Levodropropizine present in tablets can be calculated using the below

formula and values were represented in table 2

At/As x Sw/100 x 100/St x Av

Where, At = Absorbance of sample preparation, As = Absorbance of Standard preparation, Sw =

weight at Levodropropizine working standard (mg), St = weight of Levodropropizine tablet(mg),

Av = Average weight of tablet (mg).

Table 2: Physical evaluations of matrix tablets of levodropropizine.

Formulation

code

Weight

variation

Hardness

(kg/cm2)

Thickness

(cm)

%Friability

Content

Uniformity

(%)

F1 598.95±2.999 7.2±0.288 0.390±0.005 0.731±0.070 97.8±0.034

F2 599.95±3.15 7.5±0.223 0.390±0.004 0.66±0.093 98.3±0.013

F3 599.2±3.12 7.1±0.223 0.389±0.003 0.506±0.045 98.6±0.053

F4 599.35±4.04 7.2±0.273 0.380±0.002 0.536±0.121 98.0±0.024

F5 598.76±4.33 7.4±0.223 0.393±0.001 0.493±0.184 97.7±0.032

F6 597.75±3.47 7.3±0.273 0.391±0.002 0.063±0.192 98.2±0.032

F7 599.25±3.611 7±0.273 0.399±0.005 0.575±0.147 99.4±0.021

F8 600±2.489 7.5±0.273 0.392±0.004 0.62±0.119 98.6±0.029

F9 598.95±4.48 7.4±0.223 0.388±0.003 0.631±0.168 99.1±0.032

F10 596±3.98 7.3±0.273 0.389±0.002 0.523±0.223 99.5±0.025

F11 601±4.992 7.2±0.273 0.382±0.001 0.629±0.112 99.8±0.032

F12 597.8±3.79 7.4±0.223 0.391±0.005 0.645±0.123 98.8±0.032

F13 598.2±2.18 7.5±0.273 0.396±0.006 0.784±0.212 98.6±0.053

F14 600±1.852 7±0.223 0.391±0.002 0.456±0.234 97.7±0.043

F15 597.35±2.24 7.5±0.273 0.392±0.001 0.475±0.345 98.2±0.032

All the values are expressed as a mean + SD., n = 3




In vitro dissolution studies:

The in-vitro release of Levodropropizine from the controlled release tablet was studied in 1000

mL of 0.1N HCl for first 2hrs and then 900 mL of phosphate buffer pH 6.8 as dissolution

medium for rest of hrs till 24 hrs using a USP type II dissolution apparatus (paddle assembly) at

50 rpm and 37oC± 0.5

oC. 5ml of the sample was withdrawn at every hour. Samples were

collected periodically (1, 2, 3, 4, 5, 6, 7, 8, 12, 23 & 24 hrs) and replaced with fresh dissolution

medium, then, the samples were analyzed using spectrophotometer at 237 nm. Drug content was

determined by UV-visible spectrophotometer at 237 nm. Dissolution studies were performed 3

times for a period of 24 hrs and the mean values were taken. Cumulative percentage of drug

release was calculated. Dissolution graphs of all 15 formulations were shown in the figures 1, 2,

3.

Kinetic mechanism of Drug Release

Kinetic mechanism of drug release was evaluated mathematically by Zero-order, First-

order, Higuchi & Korsmayer-Peppas equations for all the formulations [7, 8, 9, 10] and it was

given in the table 3. Kinetic profile data of optimized formulation F3 was shown in the table 4

and individual kinetic graphs in figures 4,5,6,7.

Determination of swelling index of optimized formulation

Swelling index was measured using USP type 2 apparatus which it is consists of 900 ml of pH

6.8 phosphate buffer till 24hrs at a regular periodical intervals tablet was withdrawn from the

medium excess water should strip off and weighed. Percentage swelling index was measured [6].

Values were shown in table 5 and figure 8.

Stability studies

Stability studies were carried out for optimized formulation F3. The tablets were packed in

aluminium foil placed in air tight container and kept at 40ºC/ 75 % RH in stability chamber for 3

months at the interval of 30 days the tablets were withdrawn and evaluated for physical

properties, in-vitro drug release. From the data, the formulation was found to be stable under the

conditions mentioned before since there was no significant change in the percentage amount of




drug content (table 6). Thus, it was found that the controlled release tablets of Levodropropizine

(F3) were stable under the stability storage conditions for 3 months [11].

Table 3: Drug release kinetics of Levodropropizine F1-F15

Formulation

code

Coefficient of determination ( R2 )

Zero order First

order Higuchi

Korsmeyer

peppas n value

F1 0.903 0.949 0.987 0.969 0.550

F2 0.624 0.965 0.900 0.934 0.392

F3 0.827 0.977 0.981 0.990 0.410

F4 0.834 0.957 0.965 0.966 0.367

F5 0.880 0.968 0.978 0.967 0.376

F6 0.841 0.957 0.976 0.965 0.568

F7 0.924 0.971 0.989 0.986 0.564

F8 0.768 0.925 0.954 0.985 0.340

F9 0.824 0.943 0.979 0.993 0.363

F10 0.869 0.970 0.988 0.981 0.387

F11 0.791 0.940 0.961 0.946 0.499

F12 0.816 0.962 0.967 0.965 0.391

F13 0.862 0.964 0.977 0.974 0.385

F14 0.912 0.979 0.989 0.979 0.432

F15 0.932 0.971 0.978 0.971 0.458

All the values are expressed as a mean + SD., n = 3

Fig.3 In- vitro drug release of F1-F5 Fig.4 In- vitro drug release of F6-F10




Fig.5 In- vitro drug release of F11-F15

Table 4 Release kinetics of optimized formulation F3

Formulation

code

Coefficient of determination ( R2)

Zero

order

First

order Higuchi

Korsmeyer

peppas n value

F3 0.827 0.977 0.981 0.990 0.410

Fig.6 Zero order release profile Fig. 7 First order release profile

Fig.8 Higuchi profile Fig.9 Peppas model




Table5 : % Swelling index

Fig.10 swelling index graph

Table.6 Stability study for the optimized formulation F3 drug release estimation.

Time(hrs)

Cumulative percentage drug release

Before After 1 month After 2months

After 3months

1 27.5± 0.173 27.2 ± 0.754 27.18 ± 0.802 27.35 ± 0.577

2 32.45 ± 0.409 32.52 ± 1.322 32.34 ± 1.422 32.59 ± 0.518

3 40.1 ± 0.076 39.92 ± 0.655 40.7 ± 0.251 40.12 ± 0.763

4 45.47 ± 0.286 45.72 ± 0.68 44.97 ± 1 45.86 ± 0.346

5 49.93 ± 0.121 50.01 ± 1 49.98 ± 0.3 50.25 ± 0.808

6 54.45 ± 0.309 54.48 ± 0.665 53.86 ± 0.115 54.63 ± 0.577

7 58.6 ± 0.208 59.4 ± 0.529 58.8 ± 0.763 59 ± 1

8 64.02 ± 0.02 64.18 ± 0.763 65 ± 1 64.65 ± 0.4

12 76.88 ± 0.064 76.9 ± 1.708 77.1 ± 2.254 77.31 ± 0.472

23 90.93 ± 0.757 90.95 ± 0.901 91.2 ± 1.311 90.8 ± 0.854

24 95.5 ± 0.307 95.71 ± 0.709 95.88 ± 0.785 95.43 ± 0.871

All values represent mean ± standard deviation (SD), n=3

Time(hrs) % Swelling index

0 0

1 22.34

2 49.86

3 65.89

4 79.85

5 85.5

6 94.3

8 90.2

12 86.5

24 80.54




Fig.11 Bar diagram showing the drug release study of optimized formulation (F3) till 8hrs.

RESULTS AND DISCUSSION

The preformulation studies shows that Levodropropizine possesses all requisite qualities required for

controlled drug delivery system using different viscosity grades of HPMC (K4M, K15M and K100M) by

wet granulation technique. Microcrystalline cellulose (20-90%) was used as diluent, talc (3%) as glidant,

magnesium stearate (3%) as lubricant, PVP K90 in alc. (5%) as binder. The FT-IR spectra obtained

indicated no change in chemical identity of the drug and polymers. All the prepared tablets were found to

be good without chipping, capping and sticking. The drug content was uniform (97.7 to 99.8%) and all

pre, post compression parameters well within the accepted limits. The drug: polymer ratio, viscosity

grades of HPMC were found to influence the release of drug from the prepared CR tablets.The amount of

drug released for a particular drug polymer ratio was found to be in the order of

K4M > K15M > K100M.

All the developed formulations were undergone for the in-viro dissolution studies. F1 formulation can’t

withstand for more time and release of 100% seen at the end of 8th hr, as the polymer ratio was (0.5%)

less. F2 formulation withstood till 12 hrs and release the drug was 100% at the 12th hr. F3 formulation

showed the drug release of 95.5% at the end of 24 hrs with (1:1) drug-polymer ratio. In case of F4, F5

formulations extended up to 24 hrs, with the drug release of 88.73% and 83.4% respectively. F6 and F7

withstand for 12 hrs and showed 100% drug release at the end of 12 hrs. F8, F9, F10 formulations

showed the drug release of 84.1%, 80%, 74.08% respectively and withstand till 24 hrs. F11 formulation

withstand till 8 hrs due to the less concentration of polymer (1:0.5) of drug-polymer ratio used in the

formulation. Remaining four formulations F12, F13, F14, and F15 extended up to 24 hrs and percentage

release of the drug showed was 84.83%, 80%, 75.4%, and 71.5% respectively.




Among all the formulations F3 was found to be optimized formulation and release 95.5% drug at the end

of 24 hrs. Drug release data was best explained by first order equation, as the plot showed the highest

linearity (R2=0.977), followed by Korsmeyer Peppas model (R

2=0.990) so it was chosen as the optimized

formulation because it showed more linearity among all the formulations. As indicated by the value of R2

the release kinetics was best explained by first order kinetics and to determine the mechanism of drug

release pattern the in vitro dissolution data was fitted into Higuchi and Korsmeyer Peppas equation and

the value of release exponent (n) for the optimized formulation F3 was 0.410 (R2=0.990) indicating the

drug release follows fickian diffusion.

Optimized batch of CR tablet of Levodropropizine (F3) was further subjected for short term stability

studies and found to be stable for 90 days. From the stability studies, it is clear that the formulation was

stable for ninety days and the FTIR spectra obtained indicated no change in chemical identity of the drug.

CONCLUSION

Results of present research work demonstrate that the different grades of hydrophilic polymers were

successfully employed for formulation of Levodropropizine controlled release tablets. The controlled

release formulation of Levodropropizine have introduced into the drug therapy with a purpose to reduce

the number of single doses during the day, and to decrease the fluctuations of serum in view to obtain

better therapeutic efficacy and diminished toxicity. Among all formulations F3 batch tablets prepared

using HPMC K4M as polymer and drug in equimolar ratio (1:1) along with 52.8% MCC as diluent was

extended the drug release till 24hrs. The drug release from F3 formulation was found to follow first- order

kinetics. It was also found linear in Peppas plot. Thus the phenomenon of drug release showed that the

release of optimized formulation F3 is controlled by diffusion as n=0.410.

ACKNOWLEDGEMENT

The authors are sincerely thankful to Vaagdevi college of pharmacy (Warangal, India) institution and

management for providing infrastructure facilities to carry out this research work.

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