Journal of Research in Biology

ISSN No: Print: 2231 6280; Online: 2231- 6299

An International Scientific Research Journal

Original Research

Journal of Research in Biology

Evaluation of spherical agglomerated crystals of Lomefloxacin by IR and optical

microscopy
Authors:

ABSTRACT:

Institution:
1. Associate Professor,
Department of
Pharmaceutical
Biotechnology,
Chilkur Balaji College of
Pharmacy, Hyderabad.

The spherical crystallization technique was studied to improve the dissolution

rate and bioavailability of lomefloxacin which is used as an antibacterial agent for
Typhoid, Vaginal, GIT and ENT infection. In solvent change method, irregular shaped
agglomeration was observed. Neutralization method was performed to maintain the
form of spherical crystals. In ammonia diffusion method, best form of spherical
agglomerates with crystal form was obtained. Spherical agglomerated crystals of
lomefloxacin were evaluated by IR and optical microscopy. The results suggested that
the spherical crystal form of lomefloxacin shows greater dissolution rates and bio
availability.

Muthukumar N1 and
Harry Thomas Rodriguez A2

2. Antarcticaa College of
Pharmacy, Tamil Nadu
India.
Corresponding author:

Keywords:
Spherical crystallization, Lomefloxacin, IR and Optical microscopy

Muthukumar N

Web Address:
http://jresearchbiology.com/
documents/RA0463.pdf

Article Citation:
Muthukumar N and Harry Thomas Rodriguez A
Evaluation of spherical agglomerated crystals of Lomefloaxacin by IR and optical
microscopy.
Journal of Research in Biology (2014) 4(8):1405-1416
Dates:
Received: 12 Jul 2014

Accepted: 27 Jul 2014

Published: 13 Aug 2014

This article is governed by the Creative Commons Attribution License (http://creativecommons.org/

licenses/by/4.0), which gives permission for unrestricted use, non-commercial, distribution and
reproduction in all medium, provided the original work is properly cited.
Journal of Research in Biology
An International
Scientific Research Journal

1405-1416| JRB | 2014 | Vol 4 | No 5

www.jresearchbiology.com

Muthukumar and Rodriguez, 2014

INTRODUCTION

EXPERIMENTAL WORK
MATERIAL USED

The formulation and manufacture of solid oral

Following laboratory grade solvents were used

dosage forms have undergone rapid change and

Acetone, Dichloromethane, Strong ammonium

development over the last several decades. Direct

solution

compression technique facilitates processing without the

Lomefloxacin Helios Pharmaceutical Pvt. Ltd.

need for moisture and heat. In the direct tableting

The following Hydrocolloids were used,

method, the flow ability and compressibility of the bulk

Tween 80, Span 60, PEG 6000 and CMC

powder is increased in order to retain a steady supply of

INSTRUMENTS USED

powder mixture to the tableting machine. Besides the

efficiency of the manufacturing process is increased for

(30-32%

w/v),

Glacial

Acetic

Acid,

The crystalline structure characterization was

carried out using the following equipments:

better bioavailability of the drug by improving the

Infrared spectroscopy Shimadzu 8300 Model

solubility of the bulk drug powder (Szabone et al., 1998).

using KBr pellets, Melting point apparatus (Toshniwal),

To enhance the advantages of direct compressible drugs,

Optical Microscopy Olympus bX40 Model, Olympus

a new crystalline technique has been introduced. It can

Optical

transform crystals directly into a compacted spherical

Instruments, Mumbai.

Ltd.,

JAPAN,

Magnetic

Stirrer

Remi

form, which is found to have good flow ability,

compressibility, portability and also good solubility in

METHODS

some cases. Hence, it is a novel particle design

Solvent Change Method

technique, by which crystallization and agglomeration

DMSO is a highly polar solvent and it was used

can be carried out simultaneously in one step. The

to dissolve all selected fluoroquinolones. For non-

micromeristic properties of the particles vary greatly

solvent, different hydrocolloids namely Span 60, Tween

when compared to the fine crystalline materials.

80, PEG 6000 and CMC were selected and it was used in
1%, 2% and 5% concentration respectively. Each drug

The principle of agglomeration was initially

(500mg) solution was added either as both whole amount

applied to non-pharmaceutical materials such as coal and

and drop wise method into hydrocolloid solution with

minerals (Capes et al., 1984). The hydrophobic

constant stirring at 250 rpm to obtain compacted

properties of coals agglomerates with ease and separate

agglomerated crystals. In both the cases, temperature

from the ash constituents by applying virtually any mode

was maintained at room temperature and 182C

of agitation in the presence of sufficient hydrocarbons as

throughout the process (Capes and Sutherland, 1967).

bridging liquid. In the field of pharmacy, this method

Neutralization Method

does not mean any commercialization value in

size

enlargement process (Smith and Puddington, 1960).

The fluoroquinolones are zwitter ionic in nature

and thus it is only soluble in acidic or alkaline solutions.
So, it was thought that neutralization method might be

The spherical crystallization technique is utilized

suitable, in which the drug was dissolved in either acid or

for crystal modification. It also improves dissolution

strong ammonia solution. Then the drug solution was

rates and bioavailability of drugs. So, in the present

transferred into 2% hydrocolloid solutions of Span 60,

work, it was envisaged to prepare spherical crystals of

Tween 80, Peg 6000, and CMC with constant stirring at

lomefloxacin by using suitable technique.

250 rpm. The strong ammonia solution or acetic acid

1406

Journal of Research in Biology (2014) 4(5): 1405-1416

Muthukumar and Rodriguez, 2014

was added to neutralize acid base and crystallize out the

process; the solvent mixture (ammonia water, acetone

drug in the form of agglomerates (Kawashima and

and dichloromethane) was removed by vacuum filtration

Furukaw, 1981).

and the agglomerated crystals were washed with

Ammonia Diffusion Method

dichloromethane. Afterwards, they were dried under

The drug was dissolved in 20% w/v ammonia

vacuum in desiccators until dry and then kept in a dark

water and maintained at 40C to avoid solubility

and dry place .

problems. This solution was poured into a mixture of

Three

factors

have

been

involved

in

acetone and dichloromethane under agitation at 150-200

agglomerating method for Spherical crystallization.

rpm by using magnetic stirrer in 250 ml beaker. The

They are substances dissolution medium, physical

system was thermally controlled at 181C throughout

factors, such as agitation, temperature and chemical

Table (I) Selection of solvent to dissolve drug

Type of Solvent used (with
Amount of solvent need to dissolve
Drug)
500mg drug
Acetone (Lomefloxacin)
60ml at 40C

Remarks
Not Soluble at room temp

Methanol (Lomefloxacin)

75ml at 40C

Not Soluble at room temp

DMF (Lomefloxacin)

8.5ml at 80-90C

Not Soluble at room temp

DMSO (Lomefloxacin)

5ml at 80-90C

Not Soluble at room temp

Table (II) Lomefloxacin

Non solvent (100ml)
Distilled water
1% Tween 80
2% Tween 80
5% Tween 80
1% Span 60
2% Span 60
5% Span 60
1% PEG 6000
2% PEG 6000
5% PEG 6000
1% CMC
2% CMC
5% CMC

System
Temperature
R.T.
50-20 C
R.T.
50-20 C
R.T.
50-20 C
R.T.
50-20 C
R.T.
50-20 C
R.T.
50-20 C
R.T.
50-20 C
R.T.
50-20 C
R.T.
50-20 C
R.T.
50-20 C
R.T.
50-20 C
R.T.
50-20 C
R.T.
50-20 C

Mode of addition of drug

solution
Whole amount
Whole amount
Whole amount
Whole amount
Whole amount
Whole amount
Whole amount
Whole amount
Whole amount
Whole amount
Whole amount
Whole amount
Whole amount

Journal of Research in Biology (2014) 4(5): 1405-1416

Observation
Needle shape crystals
Needle shape crystals
Needle shape crystals
Needle shape crystals with clumps
Irregular agglomerates with needle
Irregular crystals with needle
Clumps with needle crystals
Clumps with needle crystals
Agglomerate surrounded by needles
Agglomerate surrounded by needles
Good agglomerated with little
surrounding needle crystals
Good agglomerated with too little
surrounding needle crystals
Clumps with very viscous solution
Clumps
Needle shape crystals
Needle shape crystals
Agglomerate with little needles
Good agglomerated needle crystals
Clumps with needle crystals
Clumps with needle crystals
Totally needle crystals
Needle crystals with clumps
More needle crystals & viscous soln.
Clumps
Clumps
Clumps
1407

Muthukumar and Rodriguez, 2014

Table (III) Lomefloxacin
Non solvent
(100ml)
Distilled water
1% Tween 80
2% Tween 80
5% Tween 80
1% Span 60
2% Span 60
5% Span 60
1% PEG 6000
2% PEG 6000
5% PEG 6000
1% CMC
2% CMC
5% CMC

System
Temperature
R.T.
50-20 C
R.T.
50-20 C
R.T.
50-20 C
R.T.
50-20 C
R.T.
50-20 C
R.T.
50-20 C
R.T.
50-20 C
R.T.
50-20 C
R.T.
50-20 C
R.T.
50-20 C
R.T.
50-20 C
R.T.
50-20 C
R.T.
50-20 C

Mode of addition
of drug solution
Drop wise
Drop wise
Drop wise
Drop wise
Drop wise
Drop wise
Drop wise
Drop wise
Drop wise
Drop wise
Drop wise
Drop wise
Drop wise

factors, such as solubility, raw material concentration,

Observation
Needle crystals
Needle crystals
Agglomerate with needles
Agglomerate with needles
Irregular and needle crystals
Irregular agglomerate with needles
Clumps with few needle Clumps
Agglomerate with needles
Agglomerate with few needles
Agglomerated with few needle Good
Spherical agglomerates with needle crystals
Clumps
Clumps
Needle shaped crystals
Agglomerates with needle
Irregular agglomerate with needles. Good
Spherical agglomerates with few needle
Clumps with more needle Clumps with needle
crystals
Needle crystals
Needle crystals with agglomerate
Needle crystals with agglomerate.
Agglomerates with needles Clumps
Clumps with very viscous soln. Clumps with
very viscous soln.

RESULT AND DISCUSSION

and solvent quantity. Fluoroquinolones are antibacterial

In solvent change method, when drug solution

agents, which are used to treat urinary tract infection,

was added to distilled water with different proportion of

ENT infection, Typhoid etc. They have zwitter ionic

hydrocolloid under controlled temperatures (RT and 50 -

molecular structures and are only soluble in acid or

20C), the stirring speed should be maintained at 250rpm

alkaline solutions. This is the reason why conventional

throughout the process. From the results, it has been

technique to prepare spherical agglomerates cannot be

observed that irregular shaped agglomeration was

employed (Kawashima et al., 1983).

formed (Sano et al., 1992).

In neutralization method, a known quantity of

Selection of Solvents

drug was dissolved in determined amount of either acidic

Fluoroquinolones are only soluble in acidic or

or alkaline solution. Then drug solution was neutralized

alkaline solutions, reaching a maximum solubility value

with basic or acidic solution in presence of 2%

of 12% w/v at pH 10.5. To obtain fluoroquinolones

hydrocolloids in order to get agglomerated crystals.

agglomerates using the SC technique, a proper solvent

Though the theory states that fluoroquinolones are

was selected.

Accordingly, 20% w/v ammonia water

zwitter ionic nature, this method can be suitable to give

was used because its pH is 11.0. The other solvents were

spherical crystals, but practically this method was

acetone and dichloromethane (Kawashima et al., 1982).

unsuitable to exist spherical agglomerates (Deshpande

et al., 1997).

1408

Journal of Research in Biology (2014) 4(5): 1405-1416

Muthukumar and Rodriguez, 2014

Table (IV): Lomefloxacin
Type of acid/base
used to dissolve
500 mg drug (ml)

Type of
Hydrocolloid
(conc.)

Hydrocarbons
Agitation
speed
(rpm)

Amount of base/
acid used

2% Tween 80

Observation

200 300

Agglomerates with
more needles
Agglomerates with
more needles

2% Span 60
5% Ammonia water
(1.5ml)

Acetic acid (0.2ml)

200 300

2% PEG 6000

Needle crystals
200 300

2% CMC

Needle crystals

2% Tween 80 2%
Span 60 2% PEG
6000 2% CMC

30% Ammonia
water (27ml)

200 300
200 300
200 300
200 300
200 300

Acetic acid (39ml)

Needle crystals
Needle crystals
Needle crystals
Needle crystals

Table (V): Lomefloxacin

Type of acid/base
used to dissolve
500 mg drug (ml)

Type of Hydrocolloid
(conc.)

Amount of base/
acid

Agitation speed
(rpm)

2% Tween 80

Observation

200 300

2% Span 60

More needles with

irregular crystals
Turbid colloidal
solution

200 300
5% Ammonia water
(1.5ml)

Acetic acid (0.3ml)

Needle crystals
2% PEG 6000

200 300

2% CMC

200 300
200 300
200 300
200 300
200 300

Needle crystals
30% Ammonia
water(4ml)

2% Tween 80 2%
Span 60 2% PEG 6000
2% CMC

Acetic acid (8.5ml)

Needle crystals
Needle crystals
Needle crystals
Needle crystals

To improve spherical crystallization of amphoteric drug

and Halogenated hydrocarbons were utilized as water

substances, a new technique developed by Kawashima

immiscible solvents.

et.al. (1994) was used. Fluoroquinolones are slightly

Spherical agglomeration mechanism using ADS

soluble in water and highly soluble in acidic or alkaline

Invasion of acetone into ammonia water droplets

solution. Various type of immiscible solvents was tried

Diffusion of ammonia in agglomerates to the outer

and it has been found that a mixture of partially

immiscible solvents like acetone, ammonia water and
dichloromethane

could

be

used

to

solvents
Agglomeration ending

perform

In this method, the drug was dissolved in

crystallization. In this method, ammonia water functions

20% w/v ammonia water solution. This solution was

as a as a liquid bridge as well as good solvent for

having

fluoroquinolones. Due to water miscible and poor

fluoroquinolones. The other selected solvents were

solvent property of acetone, drugs got precipitated by

acetone (in which drug is partially soluble) and

pH

11,

which

is

suitable

to

dissolved

solvent change without forming ammonium salt.

Journal of Research in Biology (2014) 4(5): 1405-1416

1409

Muthukumar and Rodriguez, 2014

Table (VI): Lomefloxacin
Type of acid/base
used to dissolve
500 mg drug (ml)
Acetic acid (0.1ml)

Type of
Hydrocolloid
(conc.)

Agitation
speed
(rpm)

Amount of base/
acid

2% Tween 80

Observation

200 300

Needles crystals

200 300

Turbid colloidal
solution

2% PEG 6000

200 300

Turbid colloidal
solution

2% CMC
2% Tween 80

200 300
200 300

Needle crystals
Agglo. with few
needle crystals
Agglo. with few
needle crystals
Needle crystals
Needle crystals

2% Span 60
5% Ammonia water
(1.5ml)

30% Ammonia
water(4ml)

2% Span 60

200 300

Acetic acid (6.5ml)

2% PEG 6000 2%
CMC

200 300
200 300

Table: Ammonia diffusion method

Table (VII)
Combination of non solvent and
partially miscible solvent

Observation

Chloroform : Acetone

Clumps with needle crystals

benzene : Acetone

Clumps with needle crystals

Dicholomethane : Acetone

Agglomerated

Table (VIII ): Lomefloxacin

Composition of Acetone :
Dichloromethane (ml)
40:20
45:15
50:10
46:14
47:13

Observation
Needle crystals with few agglomerates
Agglomerates with few needle crystals
Agglomerates with few needle crystals
Spherical agglomerates with few needles
Good spherical agglomerates

dichloromethane (immiscible with water).

When

an

ammo nia-water

et al., 1994).
solution

Spherical agglomerated crystals of different

fluoroquinolones was poured into a mixture of acetone

fluoroquinolones were evaluated by flowing methods.

and

M.P.

water

immiscible

solvent,

such

as

of

Raw

material

differed

form

Spherical

dichloromethane, under agitation, an emulsion was

agglomerated crystals by 2 to 5C,

formed. After that, a small amount of ammonia diffused

Comparison of IR and Optical Microscopy: It was

out of the droplets to the outer organic solvent due to

carried using Olympus BX40 model, Olympus Optical

invasion of acetone into ammonia-water droplets and its

LTd., JAPAN under 10X/0.25 Ph1 and 40X/0.45 Ph2. It

ability as bridging liquid became weaker. It is noticeable

also shows the formation of Spherical agglomerated

that small crystals are needed to achieve good

crystals.

compaction as well as greater crystal surface (Morishima

1410

Optimization of experimental parameters such as

Journal of Research in Biology (2014) 4(5): 1405-1416

Muthukumar and Rodriguez, 2014

Table (IX): Stirring Speed of System
Agitation Speed (rpm)
100 200

Observation
Spherical agglomerates

200 300

Irregular Spherical agglomerates

300 500

Completely irregular crystals

Table (X): Temperature of system

Temperature (C)
5 10

Observation
Clumps with needle crystals

R.T.

Mostly needle crystals

16 20

Spherical agglomerates

Table (XI) Mode of addition of bridging liquid

Table (XI) Mode of addition
of bridging liquid

Observation

Whole amount

Good Spherical agglomerates

Drop wise

Irregular Spherical agglomerates

concentration of bridging liquid, mode of agitation,

above

effect of temperature, agitation speed, etc., was carried

agglomerates and completely irregular crystals due to

out to get the maximum yield of spherically crystallized

high shear force. The shape of the agglomerates became

drugs.

more irregular and some adhere to the vessel wall at a

A best agglomeration was observed when

acetone

and

dichloromethane

was

taken

in

200

rpm

resulted

in

irregular

spherical

speed slower than 1000 rpm.

the

Temperature was also found as one of the

composition of 47:13 ml. Decreased concentration of it

influencing factor for agglomeration. At low temperature

resulted in no agglomerates or agglomerates with more

(5 - 10C), no agglomeration was found while at higher

needle crystals (Table VIII).

temperature

(16

20C),

very

good

spherical

Uniform spherical crystals were produced at

agglomeration were found. Their effects were only due

agitation speed of 100 200 rpm. The agitation speed

to the difference in solubility of drug in solvent systems

Figure 1. IR Spectra of Lomefloxacin Pure

Journal of Research in Biology (2014) 4(5): 1405-14163

1410

Muthukumar and Rodriguez 2014

Figure 2 IR Spectra of Lomefloxacin- Spherical

(Table X).

structural change. Presence of traces of solvent, bridging

Drop wise addition of bridging typical during

crystallization

resulted

into

irregular

spherical

liquid etc., are responsible for existence of other peaks in

the spectra.

agglomerates (Table XI). The I.R. spectra of pure drug

The slight frequency changes to IR spectra of

form and spherically crystallized forms were presented in

different forms of drug (pure and spherical) may be due

the figure 1 2.

to inter-molecular hydrogen bonding, reduced free

The presence of all prominent characterizing

p e a k s

( 1 7 2 8

c m - 1 , 1 6 1 0

cm-1, 1420 cm-1, 1184 cm-1 etc.) indicates no chemical

1411

moisture and change in crystalline structure of drug.

Optical Microscopy
It reveals that the crystals of candidate drug
Journal of Research in Biology (2014) 4(5): 1405-1416

Muthukumar and Rodriguez, 2014

obtained by ADS method show spherical agglomerates

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