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
Journal of Research in Biology
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
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
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).
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
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
dichloromethane (immiscible with water).
When an ammonia-water solution 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
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
(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 peaks (1728 cm-1,1610 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
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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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 Needle shape crystals |
1% Tween 80 |
R.T. 50-20° C |
Whole amount |
Needle shape crystals Needle shape crystals with clumps |
2% Tween 80 |
R.T. 50-20° C |
Whole amount |
Irregular agglomerates with needle Irregular crystals with needle |
5% Tween 80 |
R.T. 50-20° C |
Whole amount |
Clumps with needle crystals Clumps with needle crystals |
1% Span 60 |
R.T. 50-20° C |
Whole amount |
Agglomerate surrounded by needles Agglomerate surrounded by needles |
2% Span 60 |
R.T. 50-20° C |
Whole amount |
Good agglomerated with little surrounding needle crystals Good agglomerated with too little surrounding needle crystals |
5% Span 60 |
R.T. 50-20° C |
Whole amount |
Clumps with very viscous solution Clumps |
1% PEG 6000 |
R.T. 50-20° C |
Whole amount |
Needle shape crystals Needle shape crystals |
2% PEG 6000 |
R.T. 50-20° C |
Whole amount |
Agglomerate with little needles Good agglomerated needle crystals |
5% PEG 6000 |
R.T. 50-20° C |
Whole amount |
Clumps with needle crystals Clumps with needle crystals |
1% CMC |
R.T. 50-20° C |
Whole amount |
Totally needle crystals Needle crystals with clumps |
2% CMC |
R.T. 50-20° C |
Whole amount |
More needle crystals & viscous soln. Clumps |
5% CMC |
R.T. 50-20° C |
Whole amount |
Clumps Clumps |
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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 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 needles 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. |
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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 |
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1410 Journal of Research in Biology (2014) 4(5): 1405-1416
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 |
Journal of Research in Biology (2014) 4(5): 1405-14163 1410
Muthukumar and Rodriguez, 2014
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
Muthukumar and Rodriguez 2014
1411 Journal of Research in Biology (2014) 4(5): 1405-1416
Figure 2 IR Spectra of Lomefloxacin- Spherical
Journal of Research in Biology (2014) 4(5): 1405-1416 1412
Muthukumar and Rodriguez, 2014
Muthukumar and Rodriguez 2014
1413 Journal of Research in Biology (2014) 4(5): 1405-1416
Journal of Research in Biology (2014) 4(5): 1405-1416 1414
Muthukumar and Rodriguez, 2014
Muthukumar and Rodriguez, 2014
1415 Journal of Research in Biology (2014) 4(5): 1405-1416
Muthukumar and Rodriguez, 2014
Journal of Research in Biology (2014) 4(5): 1405-1416
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