Evaluation of spherical agglomerated crystals of Lomefloxacin by IR and optical microscopy by Journal of Research in Biology

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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

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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 18±2ºC

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 40ºC to avoid solubility

and dry place .

problems. This solution was poured into a mixture of

Three

factors

have

been

involved

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 18±1ºC 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 40°C

Remarks 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) 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

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

20°C), 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

used

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

11,

which

suitable

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

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

Raw

material

differed

form

Spherical

dichloromethane, under agitation, an emulsion was

agglomerated crystals by 2 to 5°C,

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 (ºC) 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

200

rpm

resulted

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

needle crystals (Table VIII).

temperature

(16

20ºC),

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 â&#x20AC;&#x201C; 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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Journal of Research in Biology (2014) 4(5): 1405-1416