World Journal of Pharmaceutical Research

Madhusudan et al. World Journal of Pharmaceutical Research

SJIF Impact Factor 5.045

Volume 4, Issue 4, 646-659. Research Article ISSN 2277– 7105

FORMULATION AND EVALUATION OF LEVODROPROPIZINE

LOZENGES

Srikanth Parepalli, Madhusudan Rao Y* and Shravan Kumar. Y

Department of Pharmaceutics, Vaagdevi College of Pharmacy, Warangal, Telangana State

India.

ABSTRACT
Article Received on
29 Jan 2015, In the present investigation Levodropropizine was formulated as high
Revised on 24 Feb 2015, boiled sugar hard candies to provide slow release of medicament for
Accepted on 22 March 2015
the treatment of bronchial cancer induced cough and cough due to
other reasons. The local acting mechanism of levodropropizine makes
*Correspondence for
it more suitable to formulate as lozenges. . The hard candy lozenges
Author
were formulated using sugar as a base and the usage of corn syrup in
Madhusudan Rao Y.
Department of the formulation made the lozenges transparent and smooth which
Pharmaceutics, Vaagdevi helped in improving the elegancy of formulation. Formulations of hard
College of Pharmacy, candies were subjected to physico-chemical as well as in-vitro drug
Warangal, Telangana
release. Among all the formulation of among all the formulation of
State India.
hard candy lozenges FL13, FL14 and FT15 had shown in-vitro drug
release of 99.1%, 98.2% and 95.5% at the end of 20 min.
KEYWORDS: Hard candy lozenges; corn syrup; transparent; cough.

INTRODUCTION
Lozenges are the flavored medicated dosage forms intended to be sucked and held in the
mouth or pharynx containing one or more medicaments usually in the sweetened base. They
dissolve slowly in the mouth and so release the drug dissolved in the saliva. The drugs having
a large dose can be easily administered formulating as lozenges. Local Anesthetics,
Antimicrobials, Antibiotics, vitamins, Decongestants, Analgesics if the active ingredient is
heat labile, it may be made into lozenge preparation by compression. The granulation is
prepared in a manner similar to that used for any compressed tablet with Cough suppressants,
Nicotine like substances for smoking cessation.

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Coughis a forceful expulsion of air from the lungs. It isnormally a protective reflex for
removing foreign bodies,environmental irritants, or accumulated secretions fromthe
respiratory tract. The cough reflex involves centraland peripheral mechanisms. Centrally, the
cough centerin the medulla oblongata receives stimuli and initiates thereflex response (deep
inspiration, closed glottis, buildupof pressure within the lungs, and forceful exhalation).
Peripherally,cough receptors in the pharynx, larynx, trachea,or lungs may be stimulated by
air, dryness ofmucous membranes, or excessive secretions.

Figure. No 1 Mechanism of cough

Levodropropizine is an antitussive and its Brand names are Antux, Arlicough, Bronal,
Mechanism of action : LDP is a peripherally acting agent inhibiting the afferent pathways.
That mediates the generation of the cough reflex. Its mechanism of Action is mainly
peripheral at the trachea-bronchial level, although it is also associated to some anti-allergic
and anti bronchospastic activity. (1 ; Mellillo G et al ., 1988) It is very effective in the dry
cough caused in Bronchial Cancer even which can not cured by chemotherapy.

MATERIALS AND METHODOLOGY

Levodropropizine (ANTUX,) Gift sample from Euro Drugs, Hyd., Polymers are Gift sample
from Hetero Drugs, Hyd. Aspartame Gift sample from AIZANT Drugs, Hyd. Mannitol,
Sugar, liquid Glucose Dextrose, Flavors and Colours are from local chemical supplers.

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METHOD OF PREPARATION FOR LEVODROPIZINE TROCHES

Preparation of Levodropropizine Hard Candy Lozenges (Nagoba et al., 2011; Shojaei et
al., 1998; Jelvehgari Mitra et al., 2006) Preparation of Candy Lozenges: Required quantity of
sugar syrup was prepared mixing sugar and water and heated to 1100C then liquid glucose
was poured into the sugar syrup and heated to 160 0C. Drug and Flavors were added when the
temperature was brought to 40-50 °C. Now this semisolid mass was poured into pre-
lubricated moulds and subjected to cooling. Then the hard candy lozenges were taken out
from the moulds and packed in aluminum foil pouches. Levodropropizine gives a bitter taste
so in order to mask the bitter taste of LDP formulation includes aspartame and flavours.

2a DEXTROSE 2b CORN SYRUP

In figure 2a dextrose was used to prevent crystallization of sugar

In figure 2b corn syrup was used to prevent crystallization of sugar
Figures. 2 prepared lozenges

EVALUATION OF THE DEVELOPED FORMULATIONS

Characterization of Lozenges. (Purushotham Rao et al., 2011; Rawlins et al,.1995)
The prepared Levodropropizine Lozenges were studied for their physicochemical properties
like weight variation, hardness, thickness, friability and drug content. (Lachmann et al., 1991;
Bankar and Rhodes 2008).

Weight variation test

Twenty tablets were taken and their weight was determined individually and collectively on a
digital weighing balance. The average weight of one tablet was determined from the
collective weight. The weight variation test would be a satisfactory method of determining
the drug content uniformity. The percent deviation was calculated using the following
formula.
% Deviation = (Individual weight – Average weight / Average weight) × 100

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Lozenge hardness
Hardness of lozenge is defined as the force applied across the diameter of the tablet in order
to break the tablet. The resistance of the tablet to chipping, abrasion or breakage under
condition of storage transformation and handling before usage depends on its hardness. For
each formulation, the hardness of 6 tablets was determined using Monsanto hardness tester
and the average was calculated and presented with standard deviation.

Lozenge thickness
The Thickness and diameter of the Lozenges from production run is carefully controlled.
Thickness can vary with no change in weight due to air entrapment during pouring into
moulds and lack of reproducibility during pouring. Hence this parameter is essential for
consumer acceptance, Lozenge uniformity and packaging. The thickness and diameter of the
lozenges were determined using Digital vernier calipers. Ten lozenges from each formulation
were used and average values were calculated. The average thickness for lozenges were
calculated and presented with standard deviation.

Determination of drug content

Twenty lozenges were finely powdered; quantities of the powder equivalent to 60 mg of LDP
(Drug) were accurately weighed, transferred to a 100 ml volumetric flask containing 50 ml of
6.8 Phosphate buffer and allowed to stand for 30min with intermittent sonication to ensure
complete solubility of the drug. The mixture was made up to volume with distilled water.The
solution was suitably diluted and the absorption was determined by UV-Visible
spectrophotometer at λmax 237nm. The drug concentration was calculated from the standard
curve.
In vitro drug release studies Dissolution conditions
 Apparatus : USP I apparatus
 Dissolution medium : 250ml of pH 6.8 Phosphate buffer
 Temperature : 37±0.50 C
 Rotating speed of the paddle : 50 rpm
 Sample time intervals : 5, 10,15,20,25,30 minutes
 Detection : UV-VIS spectrophotometer at λmax 237nm
The samples were withdrawn at predetermined time points, diluted appropriately and were
analyzed spectrophotometrically at 237 nm. The cumulative percentage release and standard
deviation were calculated and the results are presented in the table.

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Release kinetics
Data of In vitro release was fit into different equations to explain the release kinetics of
Levodropropizine Lozenges and Troches. The kinetic equations used were zero–order and
first order equations.

Drug-Excipients Compatibility study

Levodropropizine (drug) was mixed with all excipients, used in the formulation in different
ratios and subjected to FTIR/Physical observation.

Drug-Excipients Compatibility study by physical observation

LDP (DRUG) was mixed in different proportions with all excipients which were used in the
formulation, in different ratios and kept at 40oC/75%RH conditions for two months. The
physical properties (Colour change) were monitored regularly. The change in colour of any
mixture was considered as incompatibility and the excipients blend was discarded from
study.

FT-IR
A Fourier Transform- Infra Red spectrophotometer (FTIR Spectrum BX series 2.19 version)
equipped with spectrumv2.19 software was used to study the non-thermal analysis of drug-
excipients (binary mixture of drug: excipients 1:1 ratio) compatibility. The spectrum for each
sample was recorded over the 450 - 4000 cm-1 spectral region with a resolution of 4 cm-1.

Standard graph of Levodropropizine

Standard graph of Levodropropizine at max at 237nm
Standard stock solution of pure drug containing 100 mg of LDP/100mL were prepared using
different buffer solutions like 6.8 pH phosphate buffer The working standards were obtained
by dilution of the stock solution in corresponding buffers. The standard curves for
Levodropropizine were prepared in concentration range of 4-24µg/mL at the selected wave
length 237 nm. Their absorptivity values were used to determine the linearity. Solution were
scanned and Beer Lamberts law limit was obeyed in concentration range of 4, 8, 12, 16, 20,
24 µg/mL.

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Table.No.1Standard graph of Levodropropizine at 237 nm in 6.8 phosphate Buffer.

Concentration
S.No Absorbance
(µg/mL)
1 4 0.157
2 8 0.311
3 12 0.449
4 16 0.593
5 20 0.745
6 24 0.890

Figure. No. 3: Standard graph of Levodropropizine in phosphate buffer pH 6.8

Formulation of Lozenges of lozenges were shown in Table.No.2

Formulati FL FL FL FL FL FL FL FL FL FL1 FL FL FL1 FL FL
on Code 1 2 3 4 5 6 7 8 9 0 11 12 3 14 15
Drug (mg) 60 60 60 60 60 60 60 60 60 60 60 60 60 60 60
Sugar(mg) 235 220 207 219 219 217 219 219 217 219 219 217 219 219 217
0 5 5 7.5 0 5 7.5 0 5 7.5 0 5 7.5 0 5
Liquid 370 500 620 500 500 500 500 500 500 500 500 500 500 500 500
Glucose
HPMC K - - - 0.25 0.5 1% - - - - - - - - -
200 % %
HPMC K - - - - - - 0.25 0.5 1% - - - - - -
4M % %
HPMC K - - - - - - - - - 0.25 0.5 1% - - -
15M % %
XANTHA - - - - - - - - - - - - 0.25 0.5 1%
N GUM % %
Citric Acid 60 60 60 60 60 60 60 60 60 60 60 60 60 60 60
Sodium 30 30 30 30 30 30 30 30 30 30 30 30 30 30 30
Citrate
Aspartame 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100
Color qs qs qs qs qs qs qs qs qs qs qs Qs qs qs qs
Flavor qs qs qs qs qs qs qs qs qs qs qs Qs qs qs qs
Total weight 3000mg

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RESULTS
Evaluation of Levodropropizine Lozenges prepared with varying concentration of different
polymers were shown in Table. No.3 In all formulation, tablet weight and thickness were
with in mean ± 7.5% and mean ± 5 % respectively. The weight variation in all the
formulations were found to be, 2999.9 ± 2.2mg to 3000.6 ± 2.7 mg which was in
pharamacoepial limits. The thickness varies between 7.28 to7.42 mm. Hardness of all the
tablets was maintained 10.39±0.29 to 11.17±0.66 Assay was performed and percent drug
content of all the lozenges were found to be between 98.48 ± 1.60 and 99.43 ± 2.06 of
levodropropizine, which was with in the acceptable limits.
Table.No.3 Evaluation of Levodropropizine Lozenges prepared with varying
concentration of different polymers;

Formulation Weightb (mg) Hardnessa (kg/cm2) Thicknessa (mm) Drugb Content(%)

FL1 3000.6±2.7 10.25±0.51 7.38±0.05 99.16±1.71
FL2 2999.3±2.65 10.3±0.46 7.31±0.04 98.8±1.65
FL3 3000.7±3.6 10.82±0.41 7.42±0.03 99.26±1.82
FL4 2999.6±2.3 10.78±0.63 7.28±0.06 98.87±1.95
FL5 3000.2±2.3 11.07±0.47 7.35±0.05 99.43±2.06
FL6 2999.8±1.97 10.8±0.92 7.33±0.04 98.8±1.48
FL7 2999.4±1.56 10.41±0.46 7.35±0.04 99.27±1.42
FL8 2999.9±2.2 11.03±0.70 7.33±0.06 99.2±1.8
FL9 2999.7±2.5 10.51±0.49 7.31±0.05 99.15±1.58
FL10 3000.5±1.58 10.4±0.52 7.41±0.06 98.59±1.66
FL11 2999.3±2.1 10.39±0.29 7.28±0.07 98.85±1.79
FL12 2999.6±2.8 11.17±0.66 7.32±0.05 99±1.84
FL1`3 2999.6±2.7 10.47±0.39 7.35±0.04 98.48±1.60
FL14 2999.9±2.5 10.77±0.58 7.37±0.05 99.13±1.77
FL15 3000.2±1.86 10.91±0.52 7.36±0.06 98.48±1.60
a-Results are mean of 10 observations ± SD
b-Results are mean of 20 observations ± SD

Table.4: Cumulative percent of levodropropizine released from lozenges containing

varying concentration of different polymer

CUMULATIVE % DRUG RELEASE OF LOZENGES

Time(min) FL1 FL2 FL3 FL4 FL5 FL6
0 0 0 0 0 0 0
5 61±0.53 63±0.24 65.1±0.86 40.2±0.44 39.9±0.7 40.4±0.66
10 86.2±0.6 84.2±0.61 83.8±0.45 64.1±0.49 63.7±0.2 62.8±0.32
15 98.2±0.24 98.7±0.53 99.4±0.28 83.2±0.62 81.9±0.53 79.3±0.70
20 92.7±0.57 89.2±0.18 87.8±0.66
*Results are mean of 4 observations ± SD

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Table. No 5. Cumulative percent of levodropropizine released from lozenges containing

varying concentration of different polymer:

CUMULATIVE % DRUG RELEASE OF LOZENGES

Time(min) FL7 FL8 FL9 FL10 FL11 FL12
0 0 0 0 0 0 0
5 38±0.32 36.23±0.44 33.7±0.57 39.5±0.44 39.1±0.21 37.6±0.57
10 64.9±0.20 64±0.54 64.4±0.73 65.2±0.36 64.6±0.28 64±0.32
15 81.1±0.79 79.9±0.43 77±0.44 78.6±0.32 78.4±0.31 76±0.63
20 91.9±0.44 89.9±0.63 84.7±0.54 89.6±0.32 87.7±0.3 81.9±0.64

Table.No.6: Cumulative percent of levodropropizine released from lozenges. Containing

varying concentration of different polymer:

Cumulative % Drug Release Of Lozenges

Time(min) FL13 FL14 FL15
0 0 0 0
5 415±0.48 41.1±0.82 41.3±0.74
10 65.6±0.24 66.2±0.74 63.9±0.57
15 82±0.72 83±0.85 81.1±0.78
20 99.1±0.0.58 98.2±0.65 95.5±0.48

Figure. No.4: Graphical representation of cumulative percent of Levodropropizine

released from Lozenges formulation FL1-FL3

Formulation FL1,FL2 and FL3 with out polymer have recorded the drug release of 98.2%,
98.7% and 99.4% at the end of 15 min. this formulation contain varying concentration of corn
syrup.

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Figure.No.5: Graphical representation of cumulative percent of Levodropropizine

released from Lozenges formulations FL4-FL6

Formulation FL4 ,FL5 and FL6 containing varying concentration of HPMC K 200 recorded
the drug release of 92.7%, 89.2% and 87.8% at the end of 20 min.

Figure.No.6 Graphical representation of cumulative percent of Levodropropizine

released from Lozenges formulation FL7-FL9

Formulation FL7, FL8 and FT9 containg HPMC K 4M as a polymer of varying

concentration have recorded the drug release of 91.8% ,88.9% and 84.7% at the end of 20
min.

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Figure. No 7: Graphical representation of cumulative percent of Levodropropizine

released from Lozenges formulations FL9-FL12

Formulations FL10, FL11 and FL12 containing HPMC K 15 M as polymer of different

concentration have shown the drug release of 89.6%, 87.7% and 81.9% at the end of 20 min.

Figure.No.8: Graphical representation of cumulative percent Levodropropizine

released from Lozenges formulations FL13-FL15

Formulation FL13, FL14 and FT15 containing varying concentration of Xanthan gum have
shown in vitro drug release of 99.1%, 98.2% and 95.5% at the end of 20 min.

Release kinetics and correlation coefficients of lozenges shown inTable.No.7

Mathematical models (Release Kinetics)

Formulation code Zero order First order
2
R R2
FL1`3 0.9552 0.8246
FL14 0.9220 0.9963
FL15 0.9334 0.9929

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Levodropropizine

LDP+XANTHAN GUM

OPTIMIZED FORMULATION OF LOZENGES.

Figure.No9. FTIR SPECTRUM

Table.No.8. The Fourier transform infrared spectroscopy studies were carried out for
pure drug along with drug and excipients combination. The results summarized below.
PEAK OF FUNCTIONAL GROUPS {WAVE LENGTH(cm-1)}
C-H C-H C=C
IR O-H Stretching C-N
Stretching Bending Stretching
Spectra (Free Hydroxyl) Stretching
(alkane) (aromatic)
LDP(Drug) 2817 3655 1051 765 1593
Sugar+LDP 2816 3655 1050 765 1593
Xanthan+LDP 2890 3655 1029 765 1598
Lg+LDP 2815 3655 1012 765 1548
Lozenges 2817 3655 1051 765 1548

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The above peaks are considered as characteristic peaks of Levodropropizine. These peaks
that not affected and prominently observed in IR spectra of drug and excipients. This
indicates there is no interaction between drug and excipients.

DISCUSSION
The suggested ratio of the sugar to corn syrup is 60:40 for attaing transparency and
smoothness. This is due to prevention of sugar crystallization by corn syrup. (Lachman et al.,
1989).

But in the present investigation sufficient transparency was attained with the use of the 13%,
18% and 20%. This suggests that even at low concentration of corn syrup has ability to retain
the capacity to prevent crystallization of sugar.

This difference in the concentration of corn syrup to attain the smoothness and transparency
may be due type of apparatus used in the cooking process as follows.
20% - Open kettle
30 % - Batch vacuum cookers
35 % - Semi-continuous
40% - Continuous-cookers.

The difference in the requirement of corn syrup is due to increasing amountof mechanical
action or turbulence to which the candy is subjected after cooking.
 More the agitation, more the requirement of corn syrup
 Other mechanism to control the crystallization are:

High Molecular weight sugar in the corn syrup

Low cooking temperatures
Minimum mixing during cooking
Dextrose is used instead of corn syrup (Purushotham Rao.K et al., 2011).Use of 40% dextrose
instead of corn syrup affected the transparency. Dextrose failed to retard crystallization of the
sugar. Even use of gelatin which was transparent when heated with water (forms transparent
soft gel like consistency) also failed to attain the transparency alone as well as combination
with corn syrup. Use of honey instead of corn syrup resulted in the transparent lozenges but
was sticky and not satisfactory. The formulation developed using honey was very sticky due

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to the hygroscopic nature of honey. The obtained transparency with honey is due to its ability
to retard crystallization. (Raymond C Rowe et al., 2006.)

Problem with Developed Formulation

Developed formulation failed to prevent stickiness of lozenges though it was dusted with
sugar powder or talc and they are stored in double wrapped aluminum foil after formulation
of lozenges. Moreover dusting process affected the transparency.

CONCLUSION
Patient compliance is one of the important aspect for administration of drugs especially those
which are bitter in taste. For patient compliance attractive taste masking formulations are the
need of the hour. In the present study levodropropizine sweetened tablet lozenges and hard
candy lozenges were designed for the effective treatment of bronchial cancer induced cough
and cough due to other reasons.

Among all the Formulation of Lozenges FL13, FL14 and FT15 containing varying
concentration of Xanthan gum have shown in vitro drug release of 99.1%, 98.2% and 95.5%
at the end of 20 min the long lasting release of the drug from the formulation containing
xanthan gum.

All the formulations of Hard Candy Lozenges were subjected various evaluations and the
values obtained are within acceptable range.or any formulation, drug excipients interactions
plays an important role and hence the formulations were subjected to infrared spectral
analysis, it was observed that the drug peaks were undisturbed revealing the compatibility
drug.

ACKNOWLEDGEMENTS
The authors are very thankful to Vaagdevi College of pharmacy (Faculty & Management)
for providing facilities to carry out this research work.

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