Formulation and Evaluation of oral reconstitutable Azithromycin Suspension for the treatment of Bacterial Infection

 

 

ABSTRACT:

Azithromycin is used for the treatment of bacterial infection, mainly used in middle ear infection, typhoid, sinusitis, bronchitis in urinary tract infection and venereal disease. The present study aimed to develop dry or oral reconstitutable suspension to minimize the solubility problem of the drug. It shows the adequate chemical stability of the drug during the shelf life and it avoids the problem of physical stability and solubility of drug. The study was carried out by preparing the dry powder or granules for oral reconstitutable suspension by using suspending agent sodium CMC and acacia on release profile of the drug. The prepared best formulation (F6) was selected depending on its physiochemical properties. The prepared oral reconstitutable suspension was evaluated for the rheological, viscosity, re-suspendibility and sedimentation volume. The formulation of acacia showed excellent sedimentation volume and good re-dispersibility as compared to other formulation. The study was found that the dry physical mixture method showed good stability of the drug.

 

 

 

INTRODUCTION:

Dry or oral reconstitutable suspension is commercial dry mixtures that require addition of water at the time of dispensing¹. The major consequence of the bitter taste is to restrict greatly the further development of oral preparations and clinical applications of these drugs². There are many physical and chemical considerations in the preparation and development of a suspension to satisfy its pharmaceutical requirements³. However, it differs chemically from erythromycin in that a methyl-substitution nitrogen atom is incorporated into the lactone ring⁴.

 

Azithromycin is an antibiotic useful for the treatment of a number of bacterial infections⁵. Thisincludes middleear infections, pneumonia and certain other intestinal infections⁶. It may also be used for a number of sexually transmitted infections including chlamydia and gonorrhea infections. Along with other medications, it may also be usedfor malaria^7-12.

 

MATERIALS AND METHODS:

Materials:

Azithromycin was received as a gift sample from Jubilant life science limited, suspending agents like Acacia, Sodium CMC and other excipients like tribasic sodium ortho phosphate, Disodium EDTA, sodium saccharin, methylparaben (M.P.) and propyl paraben (P.P.) purchased fromLobachemie Pvt Ltd, India.

 

 

 

 

METHOD OF PREPARATION:

Preparation of calibration curve of Azithromycin in 6.8 pH phosphate buffer:

Preparation of buffer solution:

6.8 pH phosphate buffer was prepared by mixing 250ml of 0.2M potassium dihydrogen phosphate along with 112ml of 0.2M NaOH, distilled water was added to adjust the volume and make up the volume to 1000ml.

 

Preparation of standard stock solution:

Standard drug solution of Azithromycin was prepared by dissolving 50mg pure drug in 50.00ml 6.8pH phosphate buffer. A concentration of 1000μg/ml was obtained from which desired concentration solutions were prepared.

 

Determination of λmax:

10μg/ml solution of Azithromycin was prepared and scanned in UV range 200-400nm and spectrum was obtained. The λmax was found to be 210nm.

 

Preparation of Calibration curve:

From the stock solution of Azithomycin, a series of dilutions ranging from 2-10 μg/ml were prepared. Absorbance of these solutions was measured at 210 nm wavelength and calibration curve was plotted between concentration and absorbance.

 

Standard calibration curve of Azithromycin:

Calibration curve of Azithromycin was prepared in 6.8pH phosphate buffer. In6.8 phosphate buffer the slope of the graph was found to be 0.066 and intercept with -0.012 with regression coefficient R² = 0.998

 

Formulation of azithromycin dry suspension:

Azithromycin aqueous suspension was prepared by physical mixture powder for reconstitution (as dry powder).

 

Dry powder method for suspension preparation:

Take azithromycin drug and excipients in a separate petridish and gradually mix the all excipients with the drug. Then passed it through sieve no.100 to obtained a fine powder.

 

Table no.1: Composition of azithromycin dry suspension

 

Evaluation:

Bulk Density:

The predetermined or pre weighed mass of the powder blend volume was measured for determination of bulk density

 

Bulk Density (Db) = (M) / (Vo)

Where,

M =Weight of the powder blend

Vo = Apparent volume of the powder blend^13-15

 

Tapped Density:

The measuring cylinder which contains a powder sample was mechanically tapped. The initial volumewas observed before tapping, the cylinder was mechanically tapped and volume readings were taken until little further volume change was observed.

 

Tapped density (Dt) = (M) / (Vf)

where,

M = weight of the powder blend.

Vf = Final volume of the powder blend¹⁶

 

Carr’s Index or Compressibility Index:

The Carr’s Index or Compressibilty Index was calculated by the formula

 

I = Dt -Db / Dt ×100%

Where,

Db = Bulk density,

Dt = Tapped density.¹⁷

 

Angle of Repose (θ):

The angle of repose of powder blend was determined by using employing fixed funnel method

 

Tan θ= H/R,

Where,

H = height of the heap,

R = radius of the heap¹⁸

 

Sedimentation behaviour:

Redispersibility:

The redispersibility was determined by number of strokes to redisperse the formed sediment at thestorage of the formulations (not more than 100 strokes=Redispersibility).

Sedimentation volume measurement:

50 ml of each suspension was diluted with distilled water to a volume of 100 ml in a stopper graduated cylinder. The suspensions were shaken vigorously to ensure uniformity and then left undisturbed. The sedimentation volume was measured every 4 hours for a period of 48 hours.¹⁹

 

In vitro release study:

The in vitro release profile of the dry or reconstituted suspension was determined by using USP type II dissolution apparatus (Electrolab TDT- 08L).5 ml sample of suspension was added into the dissolution medium 0.1N HCl (500 ml) maintained at 37°C. Then a sample of dissolution medium was withdrawn at different time intervals (5, 10, 15, 20, 25, 30 minutes) through a pipette fitted with a filter paper. The same fresh dissolution medium was added to the jar each time to replace with drawn samples. Each sample was suitably diluted and assayed UV spectrophotometry at 210nm for azithromycin content.

 

RESULT AND DISCUSSION:

Table no.2-Evaluation data on flow properties of reconstitutable oral Suspension

Formulation	Angle of Repose	Bulk Density (g/cm3)	Tap Density (g/cm3)	Carr’s index
F1	14.1	0.25	0.37	7.5
F2	14.5	0.25	0.31	7.8
F3	14.2	0.26	0.30	6.5
F4	13.9	0.27	0.31	8.5
F5	15.1	0.28	0.32	7.5
F6	14.5	0.25	0.32	7.6

 

Table No.3- Evaluation Of Reconstitutable Oral Suspension

Formulation	Redispersibility (No. of strokes)	Sedimentation volume	% drug release
F1	7	0.38	65.1
F2	8	0.43	69.3
F3	8	0.39	82.4
F4	7	0.40	84.1
F5	5	0.41	85.69
F6	6	0.43	98.5

 

Table 4: Comparative invitro dissolution study of different formulations of Azithromycin oral reconstitutable suspension

Time (min.)	F1	F2	F3	F4	F5	F6
0	0	0	0	0	0	0
20	5.23	6.15	8.4	12.3	13.73	17.2
40	20.1	19.4	19.9	30.1	28.97	33.5
60	35.24	35.9	42.4	39.2	49.6	54.2
80	48	45.12	59.7	52.9	60.39	65.7
100	55.1	57.4	70.6	72.6	72.53	80.4
120	65.1	69.3	82.4	84.1	85.69	98.5

 

 

Figure 1:- Comparative study in vitro dissolution profile ofdifferent formulation of Azithromycin oral reconstitutable suspense

 

DISCUSSION:

In the present work oral reconstitutable suspension were prepared by physical dry mixture technique using azithromycin containing various proportions of Acacia and Sodium CMC. All formulations showed excellent flow properties. Formulation with acacia showed excellent sedimentation volume and in vitro dissolution. In the given concentrations of the suspending agents Acacia shows excellent suspending properties after reconstitution at the same time, in the given concentration, Sodium CMC show excellent flow properties. The formulation F6 was found to be best on basis of sedimentation volume andin vitro drug release. Formulation F6 was having best sedimentation volume and resuspendibility therefore it easily redisperse when shaking. In comparision to this formulation F5 showed a good redispersibility.

 

Among all the formulations formulation F6 was found to have better release profile when compared with to others. This formulation showed good dissolution profile to control the drug release respectively.

 

The study helped to evaluate a wide range and concentrations of suspending agents as anti- caking agents for optimization of oral reconstitutable suspension.

 

CONCLUSION:

The study of Azithromycin dry or oral reconsitutable suspension was prepared by using different suspending agent such as Acacia and Sodium CMC. The formulation f6 was found to be best on the basis of different post formulation study. In formulation f6 acacia is used as a suspending agent. In present study the formulation containing Acacia (F6) showed better sedimentation volume as compared to other formulations. Also show better drug release profile for Azithromycin. Here in we report of Azithromycin. This study was to explore the development of suspension using suspending agent which enhance its stability during storage or preservation of dosage form.

 

ACKNOWLEDGMENT:

Authors want to acknowledge the facilities provided by the Rungta College of Pharmaceutical Sciences and Research, Kohka, Kurud Road, Bhilai, Chhattisgarh, India. The authors also wants to acknowledge Chhattisgarh Council of Science and Technology (CGCOST) for providing financial assistance under mini research project (MRP) vide letter no. 1124/CCOST/MRP/2015; Dated: September 4, 2015 and 1115/CCOST/MRP/2015; Dated: September 4, 2015.

 

REFERENCE:

1.       Saba H. Jaber,ZainabT.Salih and HibaM. Salmo, Formulation of Azithromycin Suspension as an Oral Dosage Form, Iraqi J Pharm Sci, Vol.21(1) 2012.

2.       Hitendra S Mahajan*1, Vilas S Jadhav2, Formulation and Evaluation of Mouth Dissolving Tablets of Azithromycin Dihydrate and Chloroquine by Melt Granulation, International Journal of PharmTech ResearchCODEN (USA): IJPRIF, ISSN : 0974-4304, Vol.6, No.5, pp 1616-1623, Sept-Oct 2014

3.       Jain D.K., Darwhekar G.N., and Choudhary N. Formulation and Evaluation of Reconstitutable Oral Suspension of AmbroxolHCl and Azithromycin, International Journal of PharmTech Research CODEN (USA): IJPRI , ISSN : 0974-4304 Vol. 3, No.2, pp 741-746, April-June 2011

4.       Harshada Sanjay Akre, Dharmendra R. Mundhada, ShyamalaBhaskaran, SohailAsghar and GopalSatishkumar Gandhi, Dry Suspension Formulation of Taste Masked Antibiotic Drug for Pediatric Use, Journal of Applied Pharmaceutical Science 02 (07); 2012: 166-171, ISSN: 2231-3354

5.       Kuchekar, B. S., Atul, B.C., Mahajan, H.S.: Mouth dissolving tablets: A novel drug delivery system. Pharma Times. 2003,35,7-9.

6.       Alexander A., Ajazuddin,Khan J., Saraf S., Saraf S. Polyethylene glycol (PEG)–Poly(N-isopropylacrylamide) (PNIPAAm) based thermosensitive injectable hydrogels for biomedical applications. European Journal of Pharmaceutics and Biopharmaceutics 2014; 88 (3): 575-85.

7.       Ashawat M. S, Saraf S., Saraf S .Preparation and characterization of herbal creams for improvement of skin viscoelastic properties. International Journal of Cosmetic Science 2008; 30 (3): 183-93.

8.       Vyas A, Saraf S., Saraf S, Encapsulation of cyclodextrincomplexed simvastatin in chitosan nanocarriers: A novel technique for oral delivery. J InclPhenomMacrocyclChem 2010; 66 (3-4): 251-59. English.

9.       Singh D., Singh M., Saraf S.,Dixit V.K., Saraf S., Optimization and Characterization of Gentamicin Loaded Chitosan Microspheres for Effective Wound Healing. Indian J Pharm Educ Res 2010; 44 (2): 171-182.

10.     Alexander A, Ajazuddin, Patel R.J., Saraf S., Saraf S. Recent expansion of pharmaceutical nanotechnologies and targeting strategies in the field of phytopharmaceuticals for the delivery of herbal extracts and bioactives. Journal of Controlled Release 2016; 241:110-124.

11.     Alexander A., Ajazuddin, Khan J., Saraf S., Saraf S. Understanding the role of poloxamer 407 based thermoreversible in situ gelling hydrogel for delivery of PEGylated melphalan conjugate. Current Drug Delivery 2016; 13 (4): 621-630

12.     Jeswani G, AlexanderA., Saraf S., Saraf S, Qureshi A, Ajazuddin. Recent approaches for reducing hemolytic activity of chemotherapeutic agents. Journal of Controlled Release 2015; 211:10-21.

13.     Alexander A., Saraf S., Saraf S. A comparative study of chitosan and poloxamer based thermosensitive hydrogel for the delivery of PEGylated melphalan conjugates. Drug Development and Industrial Pharmacy 2015;41(12):1954-61

14.     Alexander A., Ajazuddin, Khan J., Saraf S., Saraf S. Poly(ethylene glycol)–poly(lactic-co-glycolic acid) based thermosensitive injectable hydrogels for biomedical applications. Journal of Controlled Release 2013; 172 (3): 715-29

15.     Ajazuddin, Alexander A, Khan J,GiriT.K.,Tripathi D.K., Saraf S., Saraf S. Advancement in stimuli triggered in situ gelling delivery for local and systemic route. Expert Opinion on Drug Delivery 2012; 9 (12): 1573-92.

16.     Alexander A,Dwivedi S., Ajazuddin, Giri T.K., Saraf S., Saraf S., Tripathi D.K. Approaches for breaking the barriers of drug permeation through transdermal drug delivery. Journal of Controlled Release 2012; 164 (1): 26-40.

17.     Ajazuddin, Saraf S., Applications of novel drug delivery system for herbal formulations. Fitoterapia 2010; 81 (7): 680-89.

18.     Dewangan K,Nagori K, Sharma M,Singh A,Chandrakar S,Sahu V. D,Sharma G, Gupta S, Solanki H,Majumdar M, Tripathi D.K., Alexander A, Ajazuddin. Formulation, evaluation and release studies of Indomethacin Suppositories, Research J. Pharm. and Tech, July 2016, 9(7), 1-3.

19.     Chandrakar S,Nagori K, Sharma M, Gupta S, Solanki H, Dewangan K, Sharma G, Sahu V. D, , Majumdar M, Tripathi D.K., Alexander A, Ajazuddin. Formulation and Evaluation of Floating tablet of Metronidazole for eradication of Helicobacter pylori, Research J. Pharm. and Tech., July 2016, 9(7), 1-5.

 

 

 

 

 

 

Accepted on 24.10.2017          © RJPT All right reserved

Research J. Pharm. and Tech 2018; 11(4):1351-1354.