Evaluation of spherical agglomerated crystals of Lomefloxacin by IR and optical microscopy

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

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Evaluation of spherical agglomerated crystals of Lomefloxacin by IR and optical

microscopy

Keywords: Spherical crystallization, Lomefloxacin, IR and Optical microscopy

ABSTRACT:

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.

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

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www.jresearchbiology.com Journal of Research in Biology

An International

Scientific Research Journal

Authors:

Muthukumar N1 and

Harry Thomas Rodriguez A2

Institution:

1. Associate Professor,

Department of

Pharmaceutical

Biotechnology,

Chilkur Balaji College of

Pharmacy, Hyderabad.

2. Antarcticaa College of

Pharmacy, Tamil Nadu

India.

Corresponding author: Muthukumar N

Web Address: http://jresearchbiology.com/

documents/RA0463.pdf

Dates: Received: 12 Jul 2014 Accepted: 27 Jul 2014 Published: 13 Aug 2014

Journal of Research in Biology

An International Scientific Research Journal

Original Research

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

INTRODUCTION

The formulation and manufacture of solid oral

dosage forms have undergone rapid change and

development over the last several decades. Direct

compression technique facilitates processing without the

need for moisture and heat. In the direct tableting

method, the flow ability and compressibility of the bulk

powder is increased in order to retain a steady supply of

powder mixture to the tableting machine. Besides the

efficiency of the manufacturing process is increased for

better bioavailability of the drug by improving the

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

To enhance the advantages of direct compressible drugs,

a new crystalline technique has been introduced. It can

transform crystals directly into a compacted spherical

form, which is found to have good flow ability,

compressibility, portability and also good solubility in

some cases. Hence, it is a novel particle design

technique, by which crystallization and agglomeration

can be carried out simultaneously in one step. The

micromeristic properties of the particles vary greatly

when compared to the fine crystalline materials.

The principle of agglomeration was initially

applied to non-pharmaceutical materials such as coal and

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

properties of coals agglomerates with ease and separate

from the ash constituents by applying virtually any mode

of agitation in the presence of sufficient hydrocarbons as

bridging liquid. In the field of pharmacy, this method

does not mean any commercialization value in size

enlargement process (Smith and Puddington, 1960).

The spherical crystallization technique is utilized

for crystal modification. It also improves dissolution

rates and bioavailability of drugs. So, in the present

work, it was envisaged to prepare spherical crystals of

lomefloxacin by using suitable technique.

EXPERIMENTAL WORK

MATERIAL USED

Following laboratory grade solvents were used

Acetone, Dichloromethane, Strong ammonium

solution (30-32% w/v), Glacial Acetic Acid,

Lomefloxacin – Helios Pharmaceutical Pvt. Ltd.

The following Hydrocolloids were used,

Tween 80, Span 60, PEG 6000 and CMC

INSTRUMENTS USED

The crystalline structure characterization was

carried out using the following equipments:

Infrared spectroscopy – Shimadzu 8300 Model

using KBr pellets, Melting point apparatus (Toshniwal),

Optical Microscopy – Olympus bX40 Model, Olympus

Optical Ltd., JAPAN, Magnetic Stirrer - Remi

Instruments, Mumbai.

METHODS

Solvent Change Method

DMSO is a highly polar solvent and it was used

to dissolve all selected fluoroquinolones. For non-

solvent, different hydrocolloids namely Span 60, Tween

80, PEG 6000 and CMC were selected and it was used in

1%, 2% and 5% concentration respectively. Each drug

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

and drop wise method into hydrocolloid solution with

constant stirring at 250 rpm to obtain compacted

agglomerated crystals. In both the cases, temperature

was maintained at room temperature and 18±2ºC

throughout the process (Capes and Sutherland, 1967).

Neutralization Method

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

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

strong ammonia solution. Then the drug solution was

transferred into 2% hydrocolloid solutions of Span 60,

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

250 rpm. The strong ammonia solution or acetic acid

Muthukumar and Rodriguez, 2014

1406 Journal of Research in Biology (2014) 4(5): 1405-1416

was added to neutralize acid base and crystallize out the

drug in the form of agglomerates (Kawashima and

Furukaw, 1981).

Ammonia Diffusion Method

The drug was dissolved in 20% w/v ammonia

water and maintained at 40ºC to avoid solubility

problems. This solution was poured into a mixture of

acetone and dichloromethane under agitation at 150-200

rpm by using magnetic stirrer in 250 ml beaker. The

system was thermally controlled at 18±1ºC throughout

process; the solvent mixture (ammonia water, acetone

and dichloromethane) was removed by vacuum filtration

and the agglomerated crystals were washed with

dichloromethane. Afterwards, they were dried under

vacuum in desiccators until dry and then kept in a dark

and dry place .

Three factors have been involved in

agglomerating method for Spherical crystallization.

They are substances dissolution medium, physical

factors, such as agitation, temperature and chemical

Journal of Research in Biology (2014) 4(5): 1405-1416 1407


Table (I) Selection of solvent to dissolve drug

Type of Solvent used (with

Drug)

Amount of solvent need to dissolve

500mg drug Remarks

Acetone (Lomefloxacin) 60ml at 40°C Not Soluble at room temp

Methanol (Lomefloxacin) 75ml at 40°C Not Soluble at room temp

DMF (Lomefloxacin) 8.5ml at 80-90°C Not Soluble at room temp

DMSO (Lomefloxacin) 5ml at 80-90°C Not Soluble at room temp

Table – (II) Lomefloxacin

Non solvent (100ml) System

Temperature

Mode of addition of drug

solution Observation

Distilled water R.T.

50-20° C Whole amount

Needle shape crystals


1% Tween 80 R.T.



Needle shape crystals with clumps

2% Tween 80 R.T.


Irregular agglomerates with needle

Irregular crystals with needle

5% Tween 80 R.T.


Clumps with needle crystals


1% Span 60 R.T.


Agglomerate surrounded by needles

Agglomerate surrounded by needles

2% Span 60 R.T.


Good agglomerated with little

surrounding needle crystals

Good agglomerated with too little

surrounding needle crystals

5% Span 60 R.T.


Clumps with very viscous solution

Clumps

1% PEG 6000 R.T.




2% PEG 6000 R.T.


Agglomerate with little needles

Good agglomerated needle crystals

5% PEG 6000 R.T.




1% CMC R.T.


Totally needle crystals

Needle crystals with clumps

2% CMC R.T.


More needle crystals & viscous soln.

Clumps

5% CMC R.T.


Clumps

Clumps

factors, such as solubility, raw material concentration,

and solvent quantity. Fluoroquinolones are antibacterial

agents, which are used to treat urinary tract infection,

ENT infection, Typhoid etc. They have zwitter ionic

molecular structures and are only soluble in acid or

alkaline solutions. This is the reason why conventional

technique to prepare spherical agglomerates cannot be

employed (Kawashima et al., 1983).

Selection of Solvents

Fluoroquinolones are only soluble in acidic or

alkaline solutions, reaching a maximum solubility value

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

agglomerates using the SC technique, a proper solvent

was selected. Accordingly, 20% w/v ammonia water

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

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

RESULT AND DISCUSSION

In solvent change method, when drug solution

was added to distilled water with different proportion of

hydrocolloid under controlled temperatures (RT and 50 -

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

throughout the process. From the results, it has been

observed that irregular shaped agglomeration was

formed (Sano et al., 1992).

In neutralization method, a known quantity of

drug was dissolved in determined amount of either acidic

or alkaline solution. Then drug solution was neutralized

with basic or acidic solution in presence of 2%

hydrocolloids in order to get agglomerated crystals.

Though the theory states that fluoroquinolones are

zwitter ionic nature, this method can be suitable to give

spherical crystals, but practically this method was

unsuitable to exist spherical agglomerates (Deshpande

et al., 1997).



Table – (III) Lomefloxacin

Non solvent

(100ml)

System

Temperature

Mode of addition

of drug solution Observation

Distilled water R.T.

50-20° C Drop wise

Needle crystals

Needle crystals

1% Tween 80 R.T.

50-20° C Drop wise

Agglomerate with needles


2% Tween 80 R.T.

50-20° C Drop wise

Irregular and needle crystals

Irregular agglomerate with needles

5% Tween 80 R.T.

50-20° C Drop wise Clumps with few needle Clumps

1% Span 60 R.T.

50-20° C Drop wise


Agglomerate with few needles

2% Span 60 R.T.

50-20° C Drop wise

Agglomerated with few needle Good

Spherical agglomerates with needle crystals

5% Span 60 R.T.

50-20° C Drop wise

Clumps

Clumps

1% PEG 6000 R.T.

50-20° C Drop wise

Needle shaped crystals

Agglomerates with needle

2% PEG 6000 R.T.

50-20° C Drop wise

Irregular agglomerate with needles. Good

Spherical agglomerates with few needle

5% PEG 6000 R.T.

50-20° C Drop wise

Clumps with more needle Clumps with needle

crystals

1% CMC R.T.

50-20° C Drop wise

Needle crystals

Needle crystals with agglomerate

2% CMC R.T.

50-20° C Drop wise

Needle crystals with agglomerate.

Agglomerates with needles Clumps

5% CMC R.T.

50-20° C Drop wise

Clumps with very viscous soln. Clumps with

very viscous soln.

To improve spherical crystallization of amphoteric drug

substances, a new technique developed by Kawashima

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

soluble in water and highly soluble in acidic or alkaline

solution. Various type of immiscible solvents was tried

and it has been found that a mixture of partially

immiscible solvents like acetone, ammonia water and

dichloromethane could be used to perform

crystallization. In this method, ammonia water functions

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

fluoroquinolones. Due to water miscible and poor

solvent property of acetone, drugs got precipitated by

solvent change without forming ammonium salt.

Hydrocarbons

and Halogenated hydrocarbons were utilized as water

immiscible solvents.

Spherical agglomeration mechanism using ADS

Invasion of acetone into ammonia water droplets

Diffusion of ammonia in agglomerates to the outer

solvents

Agglomeration ending

In this method, the drug was dissolved in

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

having pH 11, which is suitable to dissolved

fluoroquinolones. The other selected solvents were

acetone (in which drug is partially soluble) and



Table – (IV): Lomefloxacin

Type of acid/base

used to dissolve

500 mg drug (ml)

Type of

Hydrocolloid

(conc.)

Amount of base/

acid used

Agitation

speed

(rpm)

Observation

Acetic acid (0.2ml)

2% Tween 80

2% Span 60

2% PEG 6000

2% CMC

5% Ammonia water

(1.5ml)

200 – 300

200 – 300

200 – 300

200 – 300

Agglomerates with

more needles

Agglomerates with

more needles

Needle crystals

Needle crystals

30% Ammonia

water (27ml)

2% Tween 80 2%

Span 60 2% PEG

6000 2% CMC

Acetic acid (39ml)

200 – 300

200 – 300

200 – 300

200 – 300

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) Observation

Acetic acid (0.3ml)

2% Tween 80

2% Span 60

2% PEG 6000

2% CMC

5% Ammonia water

(1.5ml)

200 – 300

200 – 300

200 – 300

200 – 300

More needles with

irregular crystals

Turbid colloidal

solution

Needle crystals

Needle crystals

30% Ammonia

water(4ml)

2% Tween 80 2%

Span 60 2% PEG 6000

2% CMC

Acetic acid (8.5ml)

200 – 300

200 – 300

200 – 300

200 – 300

Needle crystals

Needle crystals

Needle crystals

Needle crystals

dichloromethane (immiscible with water).

W hen an a m mo nia -wa te r so lu t io n

fluoroquinolones was poured into a mixture of acetone

and a water immiscible solvent, such as

dichloromethane, under agitation, an emulsion was

formed. After that, a small amount of ammonia diffused

out of the droplets to the outer organic solvent due to

invasion of acetone into ammonia-water droplets and its

ability as bridging liquid became weaker. It is noticeable

that small crystals are needed to achieve good

compaction as well as greater crystal surface (Morishima

et al., 1994).

Spherical agglomerated crystals of different

fluoroquinolones were evaluated by flowing methods.

M.P. of Raw material differed form Spherical

agglomerated crystals by 2 to 5°C,

Comparison of IR and Optical Microscopy: It was

carried using Olympus BX40 model, Olympus Optical

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

also shows the formation of Spherical agglomerated

crystals.

Optimization of experimental parameters such as



Table – (VI): Lomefloxacin

Type of acid/base

used to dissolve

500 mg drug (ml)

Type of

Hydrocolloid

(conc.)

Amount of base/

acid

Agitation

speed

(rpm)

Observation

Acetic acid (0.1ml)

2% Tween 80

2% Span 60

2% PEG 6000

2% CMC

5% Ammonia water

(1.5ml)

200 – 300

200 – 300

200 – 300

200 – 300

Needles crystals

Turbid colloidal

solution

Turbid colloidal

solution

Needle crystals

30% Ammonia

water(4ml)

2% Tween 80

2% Span 60

2% PEG 6000 2%

CMC

Acetic acid (6.5ml)

200 – 300

200 – 300

200 – 300

200 – 300

Agglo. with few

needle crystals

Agglo. with few

needle crystals

Needle crystals

Needle crystals

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) Observation

40:20 Needle crystals with few agglomerates

45:15 Agglomerates with few needle crystals

50:10 Agglomerates with few needle crystals

46:14 Spherical agglomerates with few needles

47:13 Good spherical agglomerates

concentration of bridging liquid, mode of agitation,

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

out to get the maximum yield of spherically crystallized

drugs.

A best agglomeration was observed when

acetone and dichloromethane was taken in the

composition of 47:13 ml. Decreased concentration of it

resulted in no agglomerates or agglomerates with more

needle crystals (Table VIII).

Uniform spherical crystals were produced at

agitation speed of 100 – 200 rpm. The agitation speed

above 200 rpm resulted in irregular spherical

agglomerates and completely irregular crystals due to

high shear force. The shape of the agglomerates became

more irregular and some adhere to the vessel wall at a

speed slower than 1000 rpm.

Temperature was also found as one of the

influencing factor for agglomeration. At low temperature

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

temperature (16 - 20ºC), very good spherical

agglomeration were found. Their effects were only due

to the difference in solubility of drug in solvent systems



Agitation Speed (rpm) Observation

100 – 200 Spherical agglomerates

200 – 300 Irregular Spherical agglomerates

300 – 500 Completely irregular crystals

Table (IX): Stirring Speed of System

Table – (X): Temperature of system

Temperature (ºC) Observation

5 – 10 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

Figure 1. IR Spectra of Lomefloxacin – Pure

(Table X).

Drop wise addition of bridging typical during

crystallization resulted into irregular spherical

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

form and spherically crystallized forms were presented in

the figure 1 – 2.

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

structural change. Presence of traces of solvent, bridging

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

the spectra.

The slight frequency changes to IR spectra of

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

to inter-molecular hydrogen bonding, reduced free

moisture and change in crystalline structure of drug.

Optical Microscopy

It reveals that the crystals of candidate drug

Muthukumar and Rodriguez 2014


Figure 2 IR Spectra of Lomefloxacin- Spherical

obtained by ADS method show spherical agglomerates

and it is reported in Fig- 3 and 4. It indicates that the

spherical crystallizations technique offer the loose

agglomeration of crystallized form of drug which will

get converted into spherical nature which is responsible

for better flow characteristics if undergo formulation

studies (Kawashima et al., 1989).

CONCLUSION

The aim of our study was to improve dissolution

rate and bio availability of lomefloxacin by spherical

crystallization technique. Neutralization method was

performed to maintain the form of spherical crystals, in

order to overcome irregular shaped agglomerates found

in solvent change method. We observed the best form of

spherical agglomerates in ammonia diffusion method.

The spherical agglomerated crystals of lomefloxacin was

subjected to IR and optical microscopy. The results

suggested that the spherical crystal form of lomefloxacin

showed greater dissolution rates and bioavailability.

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