1, December 2013 59
P.Palanisamy1
K.Gowdhaman1
B.Jaykar1
R.Margret Chandira1
B.S.Venkateswarlu1
A.Pasupathi1
Abstract
The present investigation is undertaken with an aim to formulation and evaluation of Film
coated tablet of Azithromycin dehydrate. The drug powders were subjected to
Preformulation studies. The Preformulation characteristics are within the
Pharmacopeial specifications. The drugs and excipients compatibility were carried out
by FT-IR studies. The spectra showed that there was no interaction between them. The
drugs and excipients compatibility were carried out by HPLC method and by physical
observation showed that there was no interaction between them. For Azithromycin
dihydrate FC tablets direct granulation was method of choice. Optimization was done
and it was found that release profile was found to be best with super-disintegrant i.e.
Polyvinyl Pyrrolidine and croscarmellose sodium. Film coating of Protectab HP-1
Sunset yellow Lake IPA coating 3 %w/w was done on Azithromycin dihydrate tablets as
to avoid in low humidity condition and geometric mixing is applied to avoid content
uniformity and segregation. Results found that release profile of batch no.ADF9
matches with Innovator product. The Percentage cumulative drug release of batch. No.
ADF9 was found at 45 Minutes 102.98%.
Introduction
The convenient oral drug delivery has been known for decades is the most widely utilized route
of administration among all the routes. It remains the preferred route of administration in the discovery
and development of new drug candidates. The popularity of oral route is attributed to patient
acceptance, ease of administration, accurate dosing, cost effective manufacturing methods and generally
improve the shelf life of the product(1). Immediate release tablets are designed to disintegrate and release
the drug in absence of any controlling features such as coating or other formulation techniques.
1
Department of Pharmaceutics, Yercaud Main Road, Salem-636 008, Vinayaka Missions College of
Pharmacy, Vinayaka Missions University, Salem, Tamil Nadu.
Despite a rising interest in controlled-release drug delivery systems, the most common tablets
are those intended to be swallowed whole, disintegrating and releasing their medicaments rapidly in the
gastrointestinal tract. A Disintegrant is a substance in a tablet formulation that enables the tablet to
break up into smaller fragments upon contact with gastrointestinal fluids. Such a rapid rupture of the
tablet matrix increases the surface area of the tablet particles, Thereby increasing the rate of absorption
of the active ingredient and producing the desired therapeutic action (2). The proper choice of
Disintegrant and its consistency of performance are critical to formulation development of immediate
release tablets. In the past, starch was one of the most widely used, Inexpensive, and effective tablet
disintegrants. A high concentration of starch is required to bring about effective disintegration.
Scientists search for disintegrating agents with efficient disintegrating properties at relatively
low concentrations has led to the development of some new compounds with excellent disintegrating
properties is called superdisintegrant. In the present work Azithromycin Dihydrate was chosen as a
model drug. Azithromycin dihydrate is macrolide antibiotic. It is widely used in the treatment of upper
and lower respiratory tract infection, prevention of disseminated Mycobacterium Avium Complex
(MAC) infection in patients with advanced human immunodeficiency virus (HIV) infections &
uncomplicated skin and skin structure infections like Folliculitis, Cellulitis, Erysipelas. Although it is
commonly used drug but the major problem is its bitterness. Oral administration constitutes the
preferred route for administering Azithromycin dihydrate. Due to the decline in the elderly patients
complain that it is difficult for them to take some currently used dosage form such as tablets and
capsules. For this reason the tablets that can rapidly disintegrated. These disintegrating tablet by direct
compression method using Polyvinyl Pyrrolidine and croscarmellose sodium as a super-disintegrant (3-5).
Ingredient Ratio
Azithromycin dihydrate 1
Azithromycin dihydrate : Starch 1:1
Azithromycin dihydrate :Lactose DCL -15 1:1
Azithromycin dihydrate : Dibasic Calcium Phosphate 1:1
Azithromycin dihydrate : MCCP 1:1
Azithromycin dihydrate : Polyvinyl Pyrrolidine 1:1
Azithromycin dihydrate : Croscarmellose Sodium 1:1
Azithromycin dihydrate : Sodium lauryl sulphate 1:1
Azithromycin dihydrate : Talc 1:1
Azithromycin dihydrate : Magnesium stearate 1:0.5
Azithromycin dihydrate : Aerosil 1:0.5
Azithromycin dihydrate : Sunset Yellow Lake
Azithromycin dihydrate : Protectab HP 1:0.5
Azithromycin dihydrate : All excipients 1:1
Tablet Manufacturing
INGREDIENTS ADF1 ADF2 ADF3 ADF4 ADF5 ADF6 ADF7 ADF8 ADF9
Azithromycin 583.33 583.33 583.33 583.33 583.33 583.33 583.33 583.33 583.33
dehydrate
Starch 95.58 80.58 65.58 50.58 95.58 80.58 65.58 50.58 50.58
Lactose DCL 15 75 90 105 120 - - - - 60
Dibasic Calcium - - - - 75 90 105 120 60
Phosphate
Microcrystalline 93.5 88.5 83.5 78.5 93.5 88.5 83.5 78.5 78.5
Cellulose Powder
Polyvinyl 30 35 40 45 - - - - 15
Pyrrolidine
Croscarmellose - - - - 30 35 40 45 30
Sodium
Sodium lauryl 6.07 6.07 6.07 6.07 6.07 6.07 6.07 6.07 6.07
sulphate
Talc 5 6 7 8 5 6 7 8 8
Magnesium 11 10 9 8 11 10 9 8 8
stearate
Aerosil 4 4 4 4 4 4 4 4 4
TOTAL 903.34mg/ Tablet
WEIGHT
Ingredients Quantity(mg)
Ingredients For One tablet
Sunset Yellow Lake 0.05
Protectab HP 1.8
Polysorbate 80 0.8
Purified Water Qs
Table No: 4 Optimized Parameters for Film Coating for Azithromycin dihydrate FC Tablets
b) Tablet Dimensions:
Thickness and diameter were measured using calibrated Vernier calipers. Five tablets of each
formulation were picked randomly and thickness and diameter was measured individually.
The results are shown in Table. No: 10-11.
c) Thickness:
The thickness of the tablets was determined by Vernier calipers. Five tablets from each batch
were used and the average values were calculated. The results are shown in Table. No: 10-11.
d) Hardness:
Hardness indicates the ability of a tablet to withstand mechanical shocks while handling. The
hardness of the tablets was determined using Monsanto hardness tester. It is expressed in kg/cm2. Five
tablets were randomly picked and hardness of the tablets was determined. The results are shown in
Table. No: 10-11.
e) Friability test:
The friability of tablets was determined by using Roche friabilator. It is expressed in percentage
(%). Twenty tablets were initially weighed (Wt) and transferred into friabilator. The friabilator was
operated at 25 rpm for 4 minutes or run up to 100revolutions. The tablets were weighed again (WF).
The % friability was then calculated by-
W (initial)-W (final)
%F = ___________________100
W (initial)
The results are shown in Table. No: 10-11.
f) Disintegration test:
The disintegration time for immediate release layer was determined using the disintegration
apparatus. One tablet was placed in each of six tubes placed in a beaker containing 1000 ml of purified
water maintained at 37 20 C and the apparatus was operated. The time taken for the tablets to
disintegrate and pass through the mesh was noted.
The results are shown in Table. No: 10-11.
Dissolution Technique
Drug is a water insoluble API. 7.4 pH phosphate buffer is taken as dissolution media, which
is listed on OGD website.
Following method was adopted to check dissolution profile.
The results are shown in Table. No: 12-13 & Figure. no: 4-5.
Stability Study(14-16) :
Tablets of the final batch were packed in High-Density Polyethylene Containers (HDPE,
60CC) and were subjected to accelerated stability studies.
(40020C/755%RH 1, 2 & 3 Months)
The effects of temperature and humidity with time on the physical and chemical characteristics of the
tablet were evaluated for assessing the stability of the prepared formulation. After each time period, the
samples were tested for Appearance, Dissolution, Assay and Impurities.
The results are shown in Table. No: 15-16.
*MeanSD n=3
2000
1500
1000
500
0
0 50 100 150 200 250
Concentration in PPM
Ft-Ir Spectroscopy:
The result of FT-IR study for Azithromycin Dihydrate and their excipients are shown in Figure.
No:
Figure No: 2 Azithromycin Dihydrate Pure
*MeanSD (n=6)
*MeanSD (n=6)
The physical parameters of drug as well as blends concluded that these were considerably good
to formulate the tablet using direct compression technique.
Table No: 10 Evaluation of Azithromycin Dihydrate Core-Tablets
Batch Weight variation Diameter Thickness Hardness Friability Disintegratio
No (mm)** (mm)* (mm)* (kg/cm2 )* (%)* n Time*
ADF1 9025.5 8.390.02 6.820.03 4.510.21 0.25 2 mts 23 sec
ADF2 9014.8 8.280.01 6.930.04 4.520.20 0.31 2 mts 33 sec
ADF3 9024.9 8.390.03 6.890.04 4.500.14 0.28 3 mts 33 sec
ADF4 9024.7 8.470.02 6.950.05 4.510.13 0.32 3 mts 55 sec
ADF5 9015.2 8.380.03 6.960.04 4.530.12 0.34 2 mts 32 sec
ADF6 9024.8 8.390.02 6.880.05 4.520.11 0.33 2 mts 31 sec
ADF7 9024.9 8.490.01 6.950.06 4.510.15 0.35 3 mts 12 sec
ADF8 9035.1 8.590.01 6.870.09 4.520.15 0.32 3 mts 45 sec
ADF9 9035.2 8.390.01 6.930.05 4.530.15 0.31 4 mts 10 sec
*MeanSD (n=6
100 ADF1
80 ADF2
ADF3
60
ADF4
40
ADF5
20
ADF6
0
0 10 20 30 40 50 ADF7
ADF8
Times in Minutes
*MeanSD (n=6)
Figure No: 5 Dissolution Profile of the Azithromycin dihydrate FC Tablets ADF1-ADF9 with
Innovator Tablet
100
80
60
40 ADF9
20 INNOVATOR
0
0 10 20 30 40 50
Times in Minutes
Azithromycin dihydrate
Content Mean SD RSD
Uniformity 101.56 1.7 1.7
*MeanSD (n=6)
*MeanSD (n=6) & *Mean=Not less than 75% ; **Mean = Not less than 80%
Stability Studies
Table No: 15 Stability Studies Data of the Azithromycin Dihydrate Optimized Formulations
(ADF9)
Parameters Initial 1st Month 2nd Month 3rd Month
RT 40C RT 40C RT 40C
Weight variation (mm)** 9065. 9065. 9055. 9054. 9054. 9054.8 9065.
4 1 3 9 7 4
Diameter (mm)* 8.590. 8.590. 8.580. 8.590. 8.580. 8.590. 8.580.
02 01 02 01 02 01 01
Thickness (mm)* 6.980. 6.980. 6.970. 6.970. 6.970. 6.980. 6.970.
07 08 07 07 06 07 06
Hardness (kg/cm2)* 4.590. 4.590. 4.580. 4.580. 4.570. 4.580. 4.570.
17 17 16 17 16 17 16
Disintegration Time* 6 mts 6 mts 6 mts 6 mts 6 mts 6 mts 17 6 mts
22 sec 20 sec 12 sec 20 sec 07 sec sec 03 sec
*MeanSD (n=6) **MeanSD(n=20)
Table No: 16 Stability Studies Data of the Assay & Dissolution Study of Azithromycin dihydrate
Optimized Formulations (ADF9)
Discussion: Assay*Mean=Not less than 75% ; Dissolution**Mean = Not less than 80%.
The results indicated that the, optimized formulated tablets were within the Pharmacopeial
specifications.
Acknowledgements:
Authors are thankful to Prof (Dr.).B.Jaykar, Principal Vinayaka Missions College of Pharmacy,
Salem, Tamil nadu and providing all the facilities for this research project.
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