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Formulation &invitro evaluation of clarithromycin floating microsponge

capsule

Research · March 2016

DOI: 10.13140/RG.2.2.29072.05128

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Kerbala journal of pharmaceutical sciences No (11) . 2016 (11 ) ‫ﻣﺠﻠﺔ ﻛﺮﺑﻼء ﻟﻠﻌﻠﻮﻡ ﺍﻟﺼﻴﺪﻻﻧﻴﺔ ﺍﻟﻌﺪﺩ‬
Formulation &invitro evaluation of clarithromycin floating
microsponge capsule
Jenan m. Mohsin al mosawi1, Alaa Abdul- Razzaq 2, Hasanain Shakir Mahmood3
1Department of Pharmaceutics, Collage of Pharmacy, University of Kerbala, Iraq, 2 Ministry of
health, Karbala health directorate, Al Husain Teaching Hospital, 3Department of Pharmaceutics,
Collage of Pharmacy, University of Kerbala.
ph.jenan @gmail.com

Keywords: Microsponges, clarithromycin, Quasi-emulsion solvent diffusion method.

Received (May) , Accepted (June).

ABSTRACT:
Objective: The aim of this study is to formulate microsponge of clarithromycin capsule
dosage form and evaluate the release profile in comparing with marketed clarithromycin
(Clamycin)
Methods: clarithromycin microsponge was prepared by quasi-emulsion solvent diffusion
method by using polymers Eudragite RL100 in organic solution as internal phase and
aqueous solution of polyvinyl alcohol as external phase. The compatibility of the drug
with formulated components was established by Fourier Transform Infra-Red (FTIR)
spectroscopy. The prepared microsponge powder was evaluated for angle of repose,
Carr's Index ,particle size, floating time production yield, drug loading efficiency of
microsponges and release profile in comparison with marketed drug.
Results: Formulation F4 with a ratio 8:1 drug to polymer, and 0.25% polyvinyl
pyrrolodine solution was the best formulation showing the highest degree of sustained
release that was 79.59% at the end of 12 hours with a floating time capsule 12 hr.
Eudragit RL 100 could control drug release in stomach.

‫ﺗﺤﻀﻴﺮ ﻭﺗﻘﻴﻢ ﻛﺒﺴﻮﻝ ﺍﻟﻜﻼﺭﺛﺮﻭﻣﺎﻳﺴﻴﻦ ﺍﻟﻤﺎﻳﻜﺮﻭ ﺍﺳﻔﻨﺠﻲ ﺍﻟﻌﺎﺋﻢ‬

‫ﺣﺴﻨﻴﻦ ﺷﺎﻛﺮ ﻣﺤﻤﻮﺩ‬3 , ‫ ﻋﻼء ﻋﺒﺪ ﺍﻟﺮﺯﺍﻕ ﻣﺤﻤﺪﺣﺴﻴﻦ‬2 ,‫ﺟﻨﺎﻥ ﻣﺤﻤﺪ ﻣﺤﺴﻦ‬
3, ‫ ﻭﺯﺍﺭﺓ ﺍﻟﺼﺤﺔ ﺩﺍﺋﺮﺓ ﺻﺤﺔ ﻛﺮﺑﻼء ﻣﺪﻳﻨﺔ ﺍﻻﻣﺎﻡ ﺍﻟﺤﺴﻴﻦ ﺍﻟﻄﺒﻴﺔ‬2،‫ ﻓﺮﻉ ﺍﻟﺼﻴﺪﻻﻧﻴﺎﺕ ﻛﻠﻴﺔ ﺍﻟﺼﻴﺪﻟﺔ ﺟﺎﻣﻌﺔ ﻛﺮﺑﻼء‬1
‫ﻓﺮﻉ ﺍﻟﺼﻴﺪﻻﻧﻴﺎﺕ ﻛﻠﻴﺔ ﺍﻟﺼﻴﺪﻟﺔ ﺟﺎﻣﻌﺔ ﻛﺮﺑﻼء‬
‫ ﻁﺮﻳﻘﺔ ﺍﻧﺘﺸﺎﺭ ﺍﻟﻤﺬﻳﺒﺎﺕ ﺍﻟﺸﺒﻪ ﻣﺴﺘﺤﻠﺒﻪ‬،‫ ﻛﻼﺭﺛﺮﻭﻣﺎﻳﺴﻴﻦ‬،‫ ﺍﻟﻤﺎﻳﻜﺮﻭ ﺍﺳﻔﻨﺠﻲ‬:‫ﻣﻔﺘﺎﺡ ﺍﻟﻜﻠﻤﺎﺕ‬

:‫ﺍﻟﺨﻼﺻﺔ‬
‫ﺍﻥ ﺍﻟﻬﺪﻑ ﻣﻦ ﻫﺬﺍ ﺍﻟﺪﺭﺍﺳﻪ ﻫﻮ ﺻﻴﺎﻏﻪ ﺍﻟﻜﻼﺭﺛﺮﻭﻣﺎﻳﺴﻦ ﺍﻟﻤﺎﻳﻜﺮﻭ ﺍﺳﻔﻨﺠﻲ ﺍﻟﻌﺎﺋﻢ ﻛﺸﻜﻞ ﻣﻦ ﺍﺷﻜﺎﻝ ﺍﻟﺠﺮﻉ ﺍﻟﺪﻭﺍﺋﻴﻪ ﻭﻫﻮ‬
‫ ﺗﻢ ﺗﺤﻀﻴﺮ ﺍﻟﻌﺪﻳﺪ ﻣﻦ ﺻﻴﻎ‬. ‫ﺍﻟﻜﺒﺴﻮﻝ ﻭﺗﻘﻴﻢ ﺍﻟﺘﺤﺮﺭ ﺍﻟﺪﻭﺍﺋﻲ ﻟﻪ ﻭﻣﻘﺎﺭﻧﺘﻪ ﻣﻊ ﺩﻭﺍء ﺍﻟﻜﻼﻣﻴﺴﻴﻦ ﺍﻟﻤﺘﻮﻓﺮ ﻓﻲ ﺍﻟﺴﻮﻕ‬
)‫ﺍﻟﻜﻼﺭﺛﺮﻭﻣﺎﻳﺴﻴﻦ ﺍﻟﻤﺎﻳﻜﺮﻭﺍﺳﻔﻨﺠﻲ ﺑﻄﺮﻳﻘﻪ ﺍﻧﺘﺸﺎﺭ ﺍﻟﻤﺬﻳﺐ ﻓﻲ ﺷﺒﻪ ﺍﻟﻤﺴﺘﺤﻠﺐ ﺑﻮﺍﺳﻄﺔ ﺍﺳﺘﻌﻤﺎﻝ ﺍﻟﻴﻮﺩﺭﺍﺟﻴﺖ ﺑﻮﻟﻴﻤﺮ‬
.‫( ﺍﻟﻤﺒﻄﺊ ﻟﻠﺘﺤﺮﺭ ﻓﻲ ﺍﻟﻤﺤﻠﻮﻝ ﺍﻟﻌﻀﻮﻱ ﻛﻮﺳﻂ ﺩﺍﺧﻠﻲ ﻭﻣﺤﻠﻮﻝ ﻣﺎﺋﻲ ﻣﻦ ﺍﻟﺒﻮﻟﻴﻔﻨﻴﻞ ﺍﻟﻜﺤﻮﻝ ﻛﻮﺳﻂ ﺧﺎﺭﺟﻲ‬RL100
‫ ﺣﺠﻢ ﺍﻟﺠﺰﻳﺌﺎﺕ ﻭﺗﺤﺮﺭ ﺍﻟﻤﺎﺩﻩ ﺍﻟﻔﻌﺎﻟﻪ ﻭ ﺗﻮﺍﻓﻖ ﺍﻟﺪﻭﺍء ﻣﻊ ﺑﺎﻗﻲ ﻣﻜﻮﻧﺎﺕ‬,‫ﺍﻟﻄﻔﻮ‬،‫ﺗﻢ ﺗﻘﻴﻴﻢ ﺍﻟﺘﺮﻛﻴﺒﺎﺕ ﻟﺨﺼﺎﺋﺺ ﺍﻟﺘﺪﻓﻖ‬
. FTIR ‫ﺍﻟﺘﺮﻛﻴﺒﺔ ﺑﻮﺍﺳﻄﻪ‬
0.25 ‫ ﻭﻣﺜﺒﺖ ﺑﺘﺮﻛﻴﺰ‬1:8 ‫ ﺍﻟﺘﻲ ﺣﻀﺮﺕ ﺑﺘﺮﻛﻴﺰ ﻧﺴﺒﻪ ﺍﻟﺪﻭﺍء ﺍﻟﻰ ﺍﻟﺒﻮﻟﻴﻤﺮ‬F4 ‫ﺍﻅﻬﺮﺕ ﺍﻟﻨﺘﺎﺋﺞ ﺍﻥ ﺍﻓﻀﻞ ﺻﻴﻐﻪ ﻫﻲ‬
.‫ﺳﺎﻋﺔ‬12 ‫ﻛﻤﺎ ﺍﻅﻬﺮﺕ ﺃﻓﻀﻞ ﺗﺪﻓﻖ ﻭﻁﻮﻓﺎﻥ ﻟﻜﻼﺭﺛﺮﻭﻣﺎﻳﺴﻴﻦ ﺍﻟﻤﺎﻳﻜﺮﻭ ﺍﺳﻔﻨﺠﻲ ﻟﻤﺪﻩ‬

1. INTRODUCTION:

Clarithromycin (CLR) is a macrolide antibiotic with a broad spectrum of activity. It is

be given for treatment of respiratory tract infections and skin and soft tissue infections.

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Kerbala journal of pharmaceutical sciences No (11) . 2016 (11 ) ‫ﻣﺠﻠﺔ ﻛﺮﺑﻼء ﻟﻠﻌﻠﻮﻡ ﺍﻟﺼﻴﺪﻻﻧﻴﺔ ﺍﻟﻌﺪﺩ‬
CLR may be given to eradicate H. pylori for treatment regimens of peptic ulcer diseases.
[1] CLR is rapidly absorbed from the gastrointestinal tract and undergoes first pass
metabolism. The bioavailability of the drug is about 55%. It is be given in a dose of 250
mg or 500 mg as tablets or suspension dosage forms. The terminal half-life of CLR is
reportedly about 3-4 hours. Thus, CLR has all the requisites of gastro retentive drug
delivery system. [2]
Eudragit polymers have an ability to resist the acid environment of stomach and retain
there for prolonged period. [3]
Hence, an attempt was be made to develop floating micros- pong of CLR using eudragit
polymers with an aim to retain the microsponges in the stomach for prolonged period.
Microsponges are highly cross linked patented, porous, polymeric microspheres that
acquire the flexibility to entrap a wide variety of active ingredients that are mostly used
for prolonged topical administration and recently for oral administration. They are tiny,
sponge like spherical particles that consist of a myriad of interconnecting voids within a
non-collapsible structure with a large porous surface. Moreover, they enhance stability,
reduce side effects and modify drug release. [4]
2. MATERIALS AND METHODS
Materials:
Clarithromycin (gifted by Samarra Drug Industries (SDI), Iraq), Evonik Degussa Ltd.,
India provided Eudragit RL 100 as gift sample. Clamycin ® provided by julphar
company, All other chemicals used were of analytical grade.

Methods
Clarithromycin floating microsponges were prepared by quasi- emulsion solvent
diffusion method. The internal phase was eudragit RS-100 dissolved in 10 ml mixture of
dichloromethane and ethanol (1:1) at room temperature. This was, followed by addition
of drug with sonication for 15min. The internal phase was then poured into polyvinyl
alcohol (PVA) solution in water, the external phase with stirring, and the microsponges
then washed and filtered, then dried at 40°C for 12 hours.
The composition of the prepared formulations are shown in table (1).

Table1: Composition of all the formulations (Batch F1 – Batch F7)

Formulation Drug: polymer ethanol:dichloro- PVA (%w/v) Water(ml)

cod ratio methane volume
F1 1:1 10 0.25 200
F2 2:1 10 0.25 200
F3 4:1 10 0.25 200
F4 8:1 10 0.25 200
F5 12:1 10 0.25 200
F6 2:1 10 0.5 200
F7 2:1 10 0.75 200

28
Kerbala journal of pharmaceutical sciences No (11) . 2016 (11 ) ‫ﻣﺠﻠﺔ ﻛﺮﺑﻼء ﻟﻠﻌﻠﻮﻡ ﺍﻟﺼﻴﺪﻻﻧﻴﺔ ﺍﻟﻌﺪﺩ‬
Microsponge Characterization:
Particle size analysis.
The particle size and size distribution of the prepared microsponges were determined by
using optical microscopy method .approximately 200- 300 microsponge were counted for
particle size using a calibrated optical microscope (Olympus Pvt. Ltd., India) .[5]
Drug-excipients compatibility studies
Fourier transform infrared (FTIR) spectroscopic
Drug-excipient interaction is one of the most important compatibility studies, FTIR study
used for this purpose on samples of pure clarithromycin and the blend powder of selected
formula. Spectra obtained by using (Shimadzu 8300, Japan) according to KBr disk
method. About 2-3 mg sample were mixed with dried IR grade potassium bromide
powder and the spectra were in between the wave number range of 4000-400 cm-1
Production yield and loading efficiency
Asample of microsponge which equivalent to 100 mg of CLR was dissolve in 100 ml of
0.1 N HCL. The absorbance was measured spectrophotometriclly at 275 nm. Then
Percentage yield can calculated using the equation (1) as following :
Production yield (PY) = (Final obtained mass of microsponge / initial mass of polymer
and drug) × 100. ---------eq. (1)
The drug loading efficiency of the microsponge can be computed using equation (2) as
following:
Loading Efficiency (LE %) = (Actual drug content / Theoretical drug content) × 100 ---
eq. (2). [6]
Determination the flowability of powder
A. Bulk density and tapped density.
Both loose bulk density (LBD) and Tapped bulk density were determined. Powder of
microsponge was taken in a 10ml measuring cylinder and initial volume was write and
tapped at height of 2.5cm at 2-second intervals until no further change in volume was
noted after tapping.
LBD and TBD calculated using the following formula.
LBD = Weight of the powder/volume of the packing
TBD= Weight of the powder/Tapped volume of the packing. [7]
B. Determination of carr's index:
The compressibility index of the powder determined by the Carr’s Compressibility index
as shown in equation (3)
Carr’s index (%) = (TBD-LBD) x100/TBD. --------- eq. (3). [8]

C. Determination of the angle of repose

Angle of repose was measured for the microsponge powder, to observe the flow
properties of powders. The Funnel method was used; the powder was allowed to pass
freely through a funnel and poured onto a horizontal plane, fixed base diameter, free of
vibration petri dish to form a cone. The funnel height was maintained at approximately 2-
4 cm from the tip of the powder pile in order to minimize the impact of the falling powder
on the tip of the cone.
The tan of angle of repose (θ) was calculated after measuring the height (H) of the cone
of the powder utilizing equation no. (4):
Tan Ө = h/r … equation (4)
The accepted limit of good flow properties is (20-30). [9]

29
Kerbala journal of pharmaceutical sciences No (11) . 2016 (11 ) ‫ﻣﺠﻠﺔ ﻛﺮﺑﻼء ﻟﻠﻌﻠﻮﻡ ﺍﻟﺼﻴﺪﻻﻧﻴﺔ ﺍﻟﻌﺪﺩ‬
Optimization of formulation parameters and process factors:
The effect of drug: polymer ratio, concentration of emulsifying agent and volume of
solvent was determined and show effect on particle size, production yield and drug
loading efficiency
In vitro buoyancy study:
Buoyancy test was determined by using USP type II apparatus at 50 rpm maintained at
37±0.5°C. The capsules were be placed in 900 ml jar containing 0.1N HCl as dissolution
medium. The time required the capsule to rise to the surface and float was determined as
floating lag time, while the time during which the capsules remained buoyant was the
floating time. [10]

In vitro dissolution studies:

The release rate of CLR from floating microsponge capsules (n=3) was determined
using USP dissolution test apparatus Type II (paddle method). The dissolution test was
carried out by using 900 ml of 0.1NHCl at 50 rpm. The temperature of the medium
maintained at 37±0.5ºC and the study carried out for 12 hrs. Samples of 5 ml were be
withdrawn at an interval of every hour; the withdrawn samples were replaced with fresh
dissolution medium. The samples filtered through Whatman filter paper, and then
analyzed spectrophotometrically at 275 nm. [11]

3. RESULTS AND DISCUSSION:

Evaluation of clarithromycin microsponge formulation:
The clarithromycin floating microsponge was prepared by quasi-emulsion solvent
diffusion method. This method found to be very easy, reproducible, rapid and avoid
solvent toxicity. [12]
The microsponges found to be uniform in size. Particle size of prepared microsponges
was in the range of 78.3 ± 12.5 µm to 39.4 ± 12.5µm (Table 2) the sizes of microsponges
affect the encapsulation efficiency and the release rate of the drug. It observed that as the
ratio of drug to polymer was increased, the particle size decreased. This could probably
be due to the fact that in high drug to polymer ratio, the amount of polymer available per
microsponge was comparatively less. Probably in high drug-polymer ratios, less polymer
amounts surround the drug were obtained which reduce the thickness of polymer wall and
microsponges with smaller size. [13]
The effect of concentration of PVA on size of microsponges was studies for optimized
formulation. The selected concentration of PVA was 0.25% (F2) since 0.5 % of PVA
(F6) the particle size increased from 60.3 ± 10.3 μm to77 ± 12.5 μm. Further increasing
the concentration to 0.75 % of PVA (F7) the particle size increased to 83.3± 15 μm.
The dispersion of the solution of the drug and polymer into droplets affected by the
concentration of PVA in the external phase. When the concentration of PVA increased,
the size of microsponges increased which may be explained to be due to the increased
viscosity wherein larger emulsion droplets formed resulting in larger microsponges.[14]
Fourier transform infrared (FTIR)
Fourier transform infrared (FTIR) spectral study was done to find out the chemical
stability or interaction of the excipients. In FTIR studies, the prominent peaks in the FTIR
spectrum of pure drug CLR (figure1) at 1730.18 for O-C=O stretching vibration in a
lactone ring, characteristic peaks of C=O stretching vibration from ketone group in a
lactone ring at 1691.03 cm−1 , 3468.85 for Tertiary –N stretching, which are the same as
the reported one. Hence, it can be concluded that there was no interaction between drug
and excipients, since similar peaks of specific functional groups were be obtained as
shown in figure (2). [1

30
Kerbala journal of pharmaceutical sciences No (11) . 2016 (11 ) ‫ﻣﺠﻠﺔ ﻛﺮﺑﻼء ﻟﻠﻌﻠﻮﻡ ﺍﻟﺼﻴﺪﻻﻧﻴﺔ ﺍﻟﻌﺪﺩ‬

Fig. 1: FTIR spectrum of pure clarithromycin

95
90
Transmittance [%]
85
80
75
70

3743.26

2978.00
2939.96

2376.83
2349.87
2311.99

1726.98
1691.34

1455.55

1377.48
1319.61
1278.01
1244.63
1167.64
1120.93
1086.92
1068.73
1050.18
1011.26
977.33
962.76
934.32
891.87
844.54
805.55
753.86
728.58
697.98
633.92
617.00

3500 3000 2500 2000 1500 1000

Wavenumber cm-1

Fig. 2: FTIR spectrum of clarithromycin microsponge

Production yield:
The production yield of the prepared microsponges of clarithromycin was in the range of
(53 % to 90.1 %). The loss of product may be due to the formation of some agglomerates
and polymer adherence to the container because of viscous nature of slurry.[16]
Drug loading efficiency:
Drug content in different formulations estimated by UV spectrophotometric method.
Loading of the drug depends on the successful molecular association of the drug with the
polymers. The drug loading efficiency of the microsponges found in the range of (37% to
91.1 %). The best drug encapsulation efficiency found for the formulation F4 and F5 with
the drug polymer ratio of 8:1 and 12:1 respectively. [17]

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Kerbala journal of pharmaceutical sciences No (11) . 2016 (11 ) ‫ﻣﺠﻠﺔ ﻛﺮﺑﻼء ﻟﻠﻌﻠﻮﻡ ﺍﻟﺼﻴﺪﻻﻧﻴﺔ ﺍﻟﻌﺪﺩ‬
Table 2: production yield, particle size and drug loading efficiency of
Prepared micros pong.
Formulation code Production Yield Particle size (μm) Drug loading
(%) efficiency (%)
F1 53 78.3 37
F2 68.5 69 64.2
F3 74 58 73.4
F4 88.2 50.2 90.3
F5 90.1 39.4 91.1

Determination of the angle of repose:

The results of angle of repose were shown in table (3) .the angle of repose were ranged
between 25.10 ±1.12 to 24.10 ± 2.12, which indicates good flow properties of powder.
[18]

Determination of carr's index:

The result of the carr’s index are show in table (3), its indicted that the carr’s index of all
the formulation were less than 20 from (14.347 ±0.25 to 12.90±0.12 ) which indicate
good flow properties and good compressibility.[19]
In vitro buoyancy study:
The in vitro floating test showed that the floating lag time observed in case of all
formulation was zero. After placing of the CLR capsules in 0.1N HCl acid, the capsules
did not reach even in the bulk of the floating medium and they showed to remain at the
surface. The capsules also showed a total floating time greater than 12 hours. These
results exhibited satisfactory floatable ability because of their low density and internal
voids. [20]

Table 3: Bulk density, tapped density, angle of repose and carr’s index % of
batches (f1 –f5).
Formlua Bulk density Tapped Angle of Carr’s index Flow
no. density repose % character
FI 0.462± 0.006 0.528 ± 0.008 24.02± 1.72 14.347± 0.25 Good
F2 0.472±0.0065 0.571±0.0102 25.34±1.15 12.32±0.99 Good
F3 0.512±0.007 0.527±0.0144 26.60±2.02 13.723±0.13 Good
F4 0.463±o.0113 0.583±0.0109 24.64±1.15 12.32±0.87 Good
F5 0.430±0.0061 0.517±0.0086 24.10±2.12 12.90±2.12 Good

In-vitro drug release studies:

In-vitro drug release studies were carried out in 0.1N HCl for 12 hours. The release
profiles obtained for the formulation (F4, F5 and marketed clarithromycin) shown in
Figure (3). It was observed that the drug release increases with increase in drug polymer
ratio. This may be due to the fact the polymer concentration was be kept constant for each
formulation while the concentration of drug molecules was increasing which results in
reduced thickness of polymer coat surrounding micro particles.
The in-vitro performance of CLR floating microsponge (F5) showed prolonged and
controlled release of CLR in predictable manner as the polymer concentration increases
the drug release from the floating microsponge decreases. This may be explained to be
due to the less water permeability of eudragit RL100 and increase in polymer thickness

32
Kerbala journal of pharmaceutical sciences No (11) . 2016 (11 ) ‫ﻣﺠﻠﺔ ﻛﺮﺑﻼء ﻟﻠﻌﻠﻮﻡ ﺍﻟﺼﻴﺪﻻﻧﻴﺔ ﺍﻟﻌﺪﺩ‬
will increase in diffusion and erosion pathways. Also it observed that there was
insignificant differences between marketed CLR (Clamycin ®) release and the other two
formulas (P<0.05) [21]

Fig. 3: The dissolution profile of formulas (F4, F5 and marketed drug

(Clamycin ®))at 37oC ± 0.5 oC in 0.1N HCl.

CONCLUSION:
Floating microsponges of clarithromycin successfully prepared by quasi-emulsion solvent
diffusion method using eudragit RL100. As the drug to polymer ratio was increased, the
percentage yield of clarithromycin floating microsponge was also increased. The average
particle size of clarithromycin floating microsponge has decreased with an increase in its
drug to polymer rati0.Buoyancy time more than 12 hr. Microsponge containing eudragit
RL100 in the ratio of 8:1 show high drug loading efficiency with particle size 50.2 μm. In-
vitro release studies showed that microsponges containing eudragit RL100 in formulation
F4 showed a good degree of sustained release. As the polymer, concentration increases
the amount of drug-released decreases.
Acknowledgement
Authors are thankful to Samarra Drug industries (SDI), Iraq for providing drug sample of
Clarithromycin.

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Li .,Stephen D. Hall,(2010) Physiologically Based Pharmacokinetic Model of
Mechanism-Based Inhibition of CYP3A by Clarithromycin , drug metabolism and
deposition; 38(2): 241-248.
[2] Bertam G.katzung, (2004) Basic and clinical pharmacology,.4thedithion, Appleton
and lange,USA,747-749.
[3] N.Sriram and R. Hima Bindu,(2013) Formulation and evaluation of glimepiride
microspheres, International Journal of pharmaceutical development and technology,
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