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Der Pharmacia Lettre, 2016, 8 (13):59-66

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ISSN 0975-5071
USA CODEN: DPLEB4

Formulation and Evaluation of Taste mask of Poorly soluble drug

Roxithromycin by Solid Dispersion
Abhishek Kumar Singh*1, Darekar A B1 and Saudagar R. B.2
1
Department of Pharmaceutics, R. G. Sapkal College of Pharmacy, Anjaneri, Nashik-422213,
Maharashtra, India.
2
Department of Pharmaceutical Chemistry, R.G. Sapkal College of Pharmacy, Anjaneri, Nashik-
422213, Maharashtra, India.

ABSTRACT

The objective of the present work is to mask the intensely bitter taste of Roxithromycin and to formulate an FDT of
the taste-masked drug by incorporation of Excipients in the tablets. Method of Roxithromycin was prepared by
solvent evaporation method using methanol as solvent for pH-sensitive polymer: act as the encapsulating medium.
The Mixture of Roxithromycin with PEG 6000 indicates highest increase in solubility with 3.7-folds Roxithromycin
and PEG 6000 (1:2SD) were selected as optimized combinations for Roxithromycin. The optimized combinations
was formulated into Fast dissolving tablet. The optimized combinations were subjected to FT-IR and while
dissolution, and accelerated stability studies were performed on their formulations. The physical properties were
evaluated with regard to yield, drug content, flow properties, particle size, in vitro drug release and taste. The
average size of microspheres was found to be satisfactory in terms of the size and size distribution. The FDTs
prepared by direct compression method and evaluated for hardness, thickness, weight variation, friability,
disintegration time, drug content, wetting time, in vitro disintegration, in vitro drug release and stability. Result and
discussion simulated salivary fluid (pH 6.8) and sufficient flow properties was shown in the drug: polymer ratio.

Key Words: Taste Masking, Roxithromycin, Fast dissolving tablet, superdisintegrants.

INTRODUCTION

Orally administered drugs completely absorbed only when they show fair solubility in gastric medium and such
drugs shows good bioavailability. In recent times more than 40 % NCEs (New Chemical Entities) developed in
Pharmaceutical Industry are practically insoluble in water. These poorly water soluble drugs are allied with slow
drug absorption leading to inadequate and variable bioavailability and gastrointestinal mucosal toxicity. [1,2]

Taste and its physiology

Phsiysiologically, taste is a sensory response resulting from a chemical stimulation of taste buds on the tongue . The
sense of taste is conducted to the brain by a process called taste transduction. Human have around 10,000 taste buds
which appear in fetus at about three months.

The poor solubility of drug substances in water and their low dissolution rate in the aqueous gastro-intestinal fluids
often lead to insufficient bioavailability. According to the equation of Noyes and Whitney, this may be achieved by
an increase in the surface area of the drug which is accessible for the dissolution medium of the stomach. The
gelation was takes place after the orally administered solution reached the stomach by complexing the calcium with
sodium. [2]

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MATERIALS AND METHODS

Materials
Roxithromycin was obtained from Symbiosis pharmaceutical, H.P, Sodium CMC, Aspartame, MCC,PEG 600,all
are of analytical grade.

Methods
Determination of maximum absorbance (λ max)
Stock solutions (100µg/ml) of Roxithromycin were prepared in methanol. These Solutions were diluted with
methanol to obtain suitable concentrations of each. The UV spectrums were recorded in the range 200-450 nm by
using UV-Visible double beam spectrophotometer (Shimadzu 2450). The wavelength of maximum absorption (λ
max) was determined [7].

Differential Scanning Calorimetry study of Roxithromycin

DSC analysis was performed using Shimadzu-Thermal Analyzer DSC 60 on 2-5mg samples. Sample was heated in
an open nitrogen pan at a rate of 10°C/min conducted over a temperature range of 116 to 125°C for Roxithromycin
under nitrogen flow of 2 bar pressure.

Formulation of Solid Dispersion:

The solid dispersion was prepared by using PEG6000 as a hydrophilic carrier.
Different drug and polymer ratios were employed in different ratios & SD’s were prepared by Solvent evaporation
method.

Solvent Evaporation (SE) method:

Solid dispersions were prepared using a SE method. Drug & polymers (PEG 6000)were dissolved in methanol in
different ratio & the solution were made homogeneous by continuous stirring and solvent was evaporated by
subjecting the solution with constant stirring at 70 to 80°C till complete evaporation of solvent. The obtained SD’s
were dried and subsequently pulverized by triturating in pestle-mortar and screened through 60 mesh sieve.

Method of Preparation of Powder Blend

Roxithromycin : PEG 6000 and other inactive ingredients along with varying % of sodium starch glycolate,
Croscarmellose sodium, Crospovidone at three concentration levels. Formulations coded as F1 to F9 respectively. In
the first step, active and inactive ingredients weighed accurately and were screened through a 60-mesh sieve. The
complex (Roxithromycin:PEG 6000) and super disintegrants were blended first in mortar and pestle then the
remaining ingredients are added in that and blended for 20 min. Finally the blend is passed through mesh #40 and
used for evaluation of flow characteristic. Formula for Fast Dissolving tablet of Roxithromycin.
Table 1 : Formula for fast dissolving tablet of Roxithromycin

Ingredients Formulation code

Quantity(mg) F1 F2 F3 F4 F5 F6 F7 F8 F9
Roxithromycin 250 250 250 250 250 250 250 250 250
equivalent to 150mg
Crospovidone 8 8 8 10 10 10 12 12 12
Sodium Starch glcolate 8 10 12 8 10 12 8 10 12
Mannitol 80 75 75 75 80 75 75 75 70
Magnesium 2 2 2 2 2 2 2 2 2
stearate
Micro Crystalline q.s q.s q.s q.s q.s q.s q.s q.s q.s
Cellulose
Total Weight (mg.) 350 350 350 350 350 350 350 350 350

Post-compression Evaluation of Fast Dissolving tablet

Thickness
The thickness of tablet is important for uniformity of tablet size. The thickness of the tablets was determined using a
Vernier Calliper. Three tablets were used.

Hardness
The hardness of three tablets was checked using the Monsanto hardness tester (LAB- HOSP)

Drug content (Assay)

Twenty tablets were weighed individually and powdered. The powder equivalent to 10 mg of Roxithromycin was
weighed and dissolved in 6.8 pH buffer. The volume was made to 100 ml with 6.8 pH buffer. From this stock

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solution, 10 µg/ml dilutions were prepared. The drug contents of the resulting solution were calculated from UV
absorbance at 205.[5]

Friability
Friability is the measure of tablet strength. In this test number of tablets subjected to combined effect of shock
abrasion by utilising a plastic chamber which revolves at a speed of 25rpm, dropping the tablets at a distance of 6
inches in each revolution. A sample of pre-weighed tablets was placed in Roche Friability tester This was then
operated for 100 revolutions. The tablets then dedusted and reweighed. Permitted friability limit is 1.0%. Tablets
were then weighed and friability values were determined.

W1 - W2
Friability = X 100
W1
Where,
W1 = weight of the tablets before test,
W2 = weight of the tablets after test.

Weight Variation
Twenty tablets were weighed individually. Average weight was calculated from the total weight of all tablets. The
individual weights were compared with the average weight. The percentage difference in the weight variation
should be within the acceptable limits (7.5%). The Percent deviation was calculated using the following formula.
[6]

% Deviation = Individual weight – Average weight x 100

Average weight
Table 2 : Standard Values of Weight Variation

Sr. No. Average weight of tablets (mg) Maximum percent deviation allowed (%)
1 80 or less 10
2 More than 80 but less than 250 7.5
3 More than 250 5

Wetting Time
A piece of tissue paper folded double was placed in a petri dish containing 6ml of water. The tablet was placed on
the paper and the time for complete wetting of the tablet was measured in seconds. The method was slightly
modified by maintaining water at 370 C. A method was used to measure wetting time and capillarity of the FDT.

Water Absorption Ratio

A piece of tissue paper folded twice was placed in small Petri dish (7.5cm) containing 7ml water. A tablet was put
on the tissue paper and allows wetting completely. The wetted tablet was then weighed. The water absorption ratio
R was determined using following equation.

Wa – Wb
R = X 100
Wa
Where;
Wa = weight of a tablet after absorption
Wb = weight of a table before absorption

Disintegration Time Study

The in-vitro disintegration studies were carried out using Tablet Disintegration Test Apparatus. One tablet was
placed in each of the six tubes of the basket assembly and disk was added to each tube.

In- vitro Drug Release Study

The test is designed to determine compliance with the dissolution requirement for solid dosage forms administered
orally.

Apparatus: 2 (Paddle)
Medium: 900 ml of 0.07 N HCL.
Speed: 55 rpm.

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Times: 1, 5, 7, 9, 10, 13 and 15min.

Temperature: 370c.
One Tablet was placed in jar containing 900ml of 0.07N HCl. At different time interval specified (1, 3, 5, 7, 9, 11,
13 and 15 min) 10 ml of aliquots were withdraw then filtered through whatman filter paper no.52. Cumulative
percentage of labelled amount of drug released was calculated. The drug release was compared with positive control
(Placebo for Roxithromycin).[11]

Stability Studies
The optimized formulation was wrapped in aluminum foil and subjected to 40 ±2°C temperature and 75±5% RH in
oven for the period of Six months. The formulation was analyzed for hardness, drug content, Disintegration time,
and dissolution.

Packaging material: The tablets were wrapped in aluminum foils.

Sampling points: The optimized formulations were subjected to stability for a period of Three months. The samples
were withdrawn at the end of Six months.

RESULTS AND DISCUSSION

Preformulation Study

Table 3: Results Of Organoleptic Properties Of Roxithromycin

Drug Properties Observed Result

Appearance Crystalline powder
Roxithromycin Colour White
Odour Odourless

Ultraviolet Spectroscopy
Determination of absorbance maximum (λ max )

Figure 1: λ max of Roxithromycin in Methanol

Wavelength of maximum absorption was found to be 205 nm for Roxithromycin in methanol. The drug content of
formulation was determined at the same wavelength in methanol.

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calibration curve of Roxithromycin in methanol

0.6
0.4

Absorban
0.2 y = 0.0094x + 0.0796 R² = 0.9786
0

01020 30 40 50 60
conc(ppm)

Fig 2 :Calibration Curve of Roxithromycin in methanol

Solubility Study of Roxithromycin

TABLE 4: Solubility Profile Roxithromycin

Sr. no. Solvent

1 Methanol
2 Phosphate buffer pH 6.8
3 Phosphate buffer pH 6.0

Compatibility study
FTIR
Major functional groups present in Roxithromycin show characteristic peaks in IR spectrum. shows peaks observed
at different wave numbers and the functional group associated with these peaks. The major peaks were identical to
functional group of Roxithromycin. Hence, the purity of sample was confirmed.

Fig 3: FT-IR. Spectrum of Roxithromycin

Fig 4: FT-IR study of Drug+Crosspovidone+excipient mixture

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The presence of absorption bands corresponding to the functional groups N-H Streching pri, sec amine 3377cm -1, O-
H Streching carboxylic acid 3299 cm -1, C=C Streching alkenes 1664 cm -1, C-C stretching aromatics 1410 cm -1, C-N
Streching aromatic amine1332 cm-1, C-O Streching carboxylic acid 1165 cm-1,present in the structure of
Roxithromycin and the absence of any well-defined unaccountable peaks is a confirmation of the purity of the drug
sample. From above spectrum, it was found that Roxithromycin is compatible mixture of all excipient.

Phase Solubility Study

The prepared SD’s were subjected for solubility study to evaluate the effect of different carriers on the aqueous
solubility of RXM and results of solubility analysis The aqueous solubility of RXM was found to be 0.0832 mg/ml.
The aqueous solubility of a drug, less than 0.1 mg/ml often present dissolution limitation to absorption. From the
result of phase solubility analysis it can be clearly established that the carriers like PEG 6000 and are having very
good solubility enhancing property.
TABLE 5: Summary of Roxithromycin PEG 6000 Phase Solubility Studies

Cyclodextrin/ medium Phase Stability constant M-1 Increased solubility Complexation Efficiency
solubility diagram St / So
PEG 6000 in AL 162.5 3.72 0.042
distilled water

X-Ray diffraction
The X-ray diffraction pattern Mixtures prepared by Solid dispersion

Figure 5: XRD of Solid dispersion (1:2)

From the Fig X-ray diffracometry (XRD) spectra Drug. The x-ray diffractogram of Roxithromycin has sharp
peaks at diffraction angles (2θ) 12.26-, 15.88-, 19.88-, 22.08-, and 23.92- showing a typical crystalline
pattern. However, all major characteristic crystalline peaks appear in the diffractogram of both physical mixtures
and solid dispersion system.[12]

Differential scanning calorimetry

Figure 6 : DSC study of Roxithromycin

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The DSC curve of Roxithromycin profiles a sharp endothermic peak at 123°C corresponding to its melting, which
confirm the purity of the drug. The drug do not undergoes decomposition following its melting.

150
F1
100 F2 F3 F4

%
50

0
F5
013579 11 13 15
F6
time(min)

Figure 7: Dissolution profile of fast dissolving tablets of Roxithromycin

Percent drug release data expressed Indicate In-Vitro release study was shown 98.7% release of Roxithromycin
through F6 formulation in 15 minutes. Formulation F6 showed less disintegration time and percent cumulative drug
release 98.7% so it was declared as an optimized formulation and was subjected for further evaluation and stability
studies.
TABLE 6: Evaluation Parameters Of F6 Optimized Batch

Sr. No. Parameters Results*

1 Weight variation (mg) 98.30 ±1.90
2 Thickness (mm) 3.8 ± 0.05
3 Hardness (kg/cm2) 2.17 ± 0.28
4 Friability (%) 0.72 ± 0.05
5 Wetting time (sec) 67.66 ± 3.51
6 Disintegration time (sec) 61.66 ± 2.51
7 Uniformity of content (%) 98.46 ± 1
8 Water absorption ratio(%) 58.28 ± 6.26

150
100
% cumulative

50
Drug

0 5 10 15 20
Time(min)

Figure 8: Graphical presentation of dissolution profile of optimized batch

TABLE 7: Parameters Studied Of [F6] Formulation Before And After Stability Study

Parameters Before stability study After stability study

Colour White White
Thickness (mm) 3.87 ± 0.05 3.67 ±0.20
Hardness (kg/cm2) 2.17 ± 0.28 2.67 ± 0.28
Content uniformity (%) 98.46 ± 1 97.66 ± 1.15
Weight variation(mg) 99.73 ± 1.90 99.73 ± 1.90
friability (%) 0.72 ± 0.05 0.74±0.5
Disintegration time (sec.) 61.66 ± 2.51 62.33 ± 2.08
Wetting time (sec.) 68± 2 66.67 ± 1.52
Water absorption ratio (%) 58.27 ± 6.26 57.54 ± 6.21

Stability Study
The accelerated stability study was carried out on optimized formulation F6. The tablets were wrapped in aluminium
foil and stored at 40 ± 20C &75 ± 5 % RH for a six months. After three months samples were withdrawn and tested

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for physical parameters, thickness, hardness, percent friability, content uniformity, disintegration time, wetting time,
Water absorption ratio (%) and in-vitro drug release studies.[8]
TABLE 8: Dissolution Study Of Formulation [F6] Before And After Stability Study.

Time (min) % Cumulative Drug release

Before S.S. After S.S.
1 27.67 ± 1.53 28.43 ± 1.14
3 72.53 ± 10.28 56.34 ± 1.05
5 85.54±12.70 72.22 ± 2.89
7 90.46±9.93 76.72±1.56
9 92.84±8.16 84.67 ±1.22
11 94.87±6.62 96.43 ± 0.11
13 99.57±3.14 98.11 ± 0.67
15 101.38 ±2.48 100.21 ±2.03

CONCLUSION

Roxithromycin slightly soluble in water. According to the biopharmaceutical classification, it comes under Class IV
and its poor aqueous solubility and dissolution is rate-limiting step in the absorption of poorly water soluble drug.
Oral bioavailability of Roxithromycin can be improved by using the Solid dispersion technique. The prepared
combinations were characterized by FT-IR, DSC, XRD, dissolution study.

Based on the results of saturation solubility studies The Mixture of Roxithromycin with PEG 6000 indicates highest
increase in solubility with 3.7-folds Roxithromycin and PEG 6000 (1:2SD) were selected as optimized combinations
for Roxithromycin. The optimized combinations was formulated into Fast dissolving tablet. The optimized
combinations were subjected to FT-IR and while dissolution, and accelerated stability studies were performed on
their formulations.

REFERENCES

[1] Jaime SA, Rainer HMA, Jan PM. European Journal of Pharmaceutical Sciences: Science Direct. 2013;
49(4):565-577.
[2] Revision of Monograph on Tablets. Final text for addition to The International Pharmacopoeia. World Health
Organisation, 2011.
[3] Sharma D, Kumar D, Singh M, Singh G, Rathore M. Journal of Drug Delivery & Therapeutics. 2012; 2(3):74-
86.
[4] Chotaliya B , Chakraborty S. International Journal of PharmTech Research. 2012; 4(4):1712-1720.
[5] Hadiya DP, Sanjay LD, Haresh MK. Inventi Impact: Pharm Tech.2011; (3):213-216.
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[7] Wagh MP, Yewale PC, Zate SU, Kothawade PI. International Journal of Pharmacy and Pharmaceutical
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[8] Paul Y, Tyagi S, Singh B. International Journal of Pharma and Bio Sciences. 2011; 2(2):20-30.
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[11] Sharma S, Lewis L.. International journal of pharmacy and pharmaceutical sciences. 2010; 2(2):6-13.
[12] Sikandar MK, Malviya R, Sharma PK. European journal of biological sciences. 2011; 3(3):67-71.
[13] Sharma D, Kumar D, Singh M, Singh G, Rathore MS. International research journal of pharmacy. 2012;
3(4):108-116.
[14] Snehalatha, shivakumar B, Verma S. American journal of pharmtech research. 2012; 2(3):156-164.
[15] Zelalem A, Vibha P, Lokesh K, Arvind K. Bansal. Trends in Pharmaceutical Taste Masking Technologies: A
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