The Stability of Ceftriaxone Sodium in vials using different Diluents

 

Mohammad Haroun

 

ABSTRACT:

Ceftriaxone sodium is an important antibiotic used for intravenous or intramuscular administration. The aim of this study was to evaluate the stability of  ceftriaxone sodium in vials that dissolved in different types of diluents when stored in different degrees of temperature and different concentrations. Six diluents were used, lidocaine 1%, lidocaine 2%, dextrose 5%, Nacl 0.9%, mixture serum, sterile water used for injection.The solutions of ceftriaxone sodium in sterile water and dextrose 5% (100mg/ml)showed the most stability for 3 days when stored at 25°C, and for 10 dayswhen stored at 4°C, whereas solutions in lidocaine 2% showed the lowest stability for 8 hours at 25°C, and 8days at 4°C.The concentration of the resulted solution has an important effect on the stability such as, the stability of ceftriaxone sodium in lidocaine 1%with concentration (100mg/ml) showed stability for 9 days when stored at 4°C, whereas for 3 days with concentration (250mg/ml).

 

 

 

INTRODUCTION:

Ceftriaxone sodium is a sterile, semisynthetic broad-spectrum cephalosporin antibiotic forintravenous or intramuscular administration.Chemically, is (6R,  7R)-3[(acetyl-oxy)methyl]-7-[[2Z)-2amino-4-thiazolyl) (methoxy-amino)-acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-ene-2carboxylic  acid (figure1). Ceftriaxone sodium is a white to yellowish-orange crystalline powder which is readilysoluble in water, sparingly soluble in methanoland very slightly soluble in ethanol [1-2].

 

 

Figure 1: Chemical structure of ceftriaxonesodium

 

Like other beta-lactam drugs, ceftriaxone exerts antibacterial activity by binding to and inhibiting the action of certain bacterial cell wall synthetic enzymes, namely the penicillin binding proteins. This results in the interruption of cell wall (peptidoglycan) biosynthesis, which can lead to bacterial cell lysis and death.  It is used in the treatment of a lot of diseases such aslower respiratory tract infections, acute bacterial otitis media, skin and skin structure infections, complicated and uncomplicated urinary tract infections, pelvic inflammatory disease, bacterial septicemia, bone and joint infections, and meningitis [3-10].

 

The degradation of ceftriaxone sodium in different solutions occurs by opening of β- lactam ringwith pseudo first order rate constants [11].

 

The aim of this study is to investigate the stability of  ceftriaxone sodium in vials that dissolved in various solutions used for intramuscular or intravenous administration when stored in different degrees of temperature and different concentrations.

 

MATERIALS AND METHODS:

Pure powder of ceftriaxone sodium, commercial syrian ceftriaxone sodium vials that have the strength of 1g (the same brand, batch number and expiration date), lidocaine  solutions (1%) and (2%),dextrosehuman serum (5%), Naclhuman serum (0.9%), mixture human serum (5% dextrose+0.9% Nacl), sterile water used for injection, analytical balance that is accurate to 0.1 mgMettler Toledo Aj150 (Mettler Toledo, Inc., Columbus, Ohio), spectrophotometer (uvs-2800, labomed, Inc.).

 

Calibration curves of ceftriaxone sodium using spectrophotometer at 258 nm:

A standard curveswere created for ceftriaxone sodium, using pure drug powder diluted to 5 known concentrations using different types of solution (in lidocaine 1% range between 1.5 and 5.5µg/ml), (in lidocaine2% range between 1.2 and 5.8 µg/ml),(in dextrose 5% range between 1and 5 µg/ml),(in Nacl 0.9% range between 1.4and 5.2 µg/ml), (in mixture serum range between 1and 5µg/ml), (in sterile water range between 1.5and 5.5µg/ml).These standard curves were established to verify accurate analysis of the drug.

 

Evaluation of the stability:

Each two vials (1g) were solved usingthe same diluent. This operation was repeated with others diluents,then each resulted solution was diluted inorder to have the obtained concentration is shown in table(1).Each solution for the same diluent was stored at 4°C and 25°C for different periods.

 

Table 1. conditions of the study

The used diluents	Concentration (mg/ml)	Storage conditions
		4°C	25°C
lidocaine 1%	100	10 days	24 hour
lidocaine 1%	250	10days	24 hour
lidocaine 2%	100	10days	24 hour
dextrose 5%	100	10 days	3 days
dextrose 5%	250	10days	24 hour
Nacl 0.9%	250	10 days	24 hour
mixture serum	100	10 days	24 hour
sterile water used for injection	100	10 days	3 days

 

during the stored period, a sample of each solution was token and diluted . The samples of each solution were assayed ceftriaxone sodium concentration using spectrophotometer at 258 nm. The drug content was quantified by calculating the concentrations from the absorbance readings obtained through UV analysis.

 

Several measures were calculated in order to assess the amount in drug content. The measured drug content expressed as a percent of label claim was calculated for each vial.a solution of ceftriaxone sodium remains stable when the content of each vial doesn’t decreaseless than 90% (loss less 10%).

 

RESULTS AND DISSICUISON:

Calibration curves of ceftriaxone sodium using spectrophotometer at 258 nm:

A linear relationship between the absorbance and the concentration of ceftriaxone sodium in different diluents at 258 nmis shown in table(2).

 

Table 2. calibration curves of ceftriaxone sodium

The used solvent	Concentration range(µg/ml)	The regression equation	The correlation coefficients (r)
lidocaine 1%	1.1 – 5.5	y=0.1386x+0.0948	0.9906
lidocaine 2%	1.2 - 5.8	y=0.1262x+0.0708	0.996
dextrose 5%	1 – 5	y=0.1505x+0.0738	0.9967
Nacl 0.9%	1.4 - 5.2	y=0.1564x+0.0257	0.9939
mixture serum	1 – 5	y=0.1494x+0.0676	0.9976
sterile water used for injection	1.5 - 5.5	y=0.1407x+0.0647	0.9974

 

Evaluation of the stability:

A- in lidocaine 1%

The results obtained from the assessment of the percentage content of ceftriaxone sodium inlidocaine (1%) solutions with concentrations (100 mg/ml and 250mg/ml) stored at 25°C showed that the Percent of content(%) decrease less than 90% after 8 hours of the storage, so we can say that the solutions of ceftriaxone sodium are stable in lidocaine 1% for 8 hours after dilution (table 3), whereassolutions of ceftriaxone sodium in lidocaine(1%) stored at 4°C showed more stability for 9 days for concentration (100 mg/ml) and 3days for concentration (250mg/ml) (table 4).

 

Table 3.assay of ceftriaxone sodium in lidocaine (1%) with concentrations (100 mg/ml and 250mg/ml) stored at 25°C

Assay time	Content (mg)		Percent of  content (%)
	Concentration=100 mg/ml	Concentration=250mg/ml	Concentration=100 mg/ml	Concentration= 250mg/ml
Dilution moment	99.8	249.2	100	100
After 2 hours	97.4	243.1	97.60	97.55
After 4 hours	95.5	235.8	95.69	94.62
After 6 hours	93.4	230.8	93.59	92.62
After 8 hours	90.8	224.3	90.98	90.01
After 24 hours	75.9	195.8	61.62	78.57

 

Table 4. assay of ceftriaxone sodium in lidocaine (1%) with concentrations (100 mg/ml and 250mg/ml) stored at 4°C

Assay time	Content (mg)		Percent of  content(%)
	Concentration= 100 mg/ml	Concentration= 250mg/ml	Concentration= 100 mg/ml	Concentration= 250mg/ml
Dilution moment	99.7	249.5	100	100
After 1 day	98.6	241.3	98.90	96.71
After 2 days	98.2	235.8	98.50	94.51
After 3days	96.9	225.3	97.19	90.30
After 4 days	96.1	215.8	96.39	86.49
After 7days	93.9	209.8	94.18	84.09
After 8 days	91.8	201.8	92.08	80.88
After 9 days	90.3	187.3	90.57	75.07
After 10days	87.4	173.3	87.66	69.46

 

 

B-in lidocaine (2%):

The results obtained from the assessment of the percentage content of ceftriaxone sodium in lidocaine(2%) solutions with concentrations (100 mg/ml) stored at 25°C showed that the Percent of  content(%) decrease less than 90% after 8 hours of the storage, so we can say that the solutions of ceftriaxone sodium are stable in lidocaine2% for 8 hours after dilution (table 5), whereas solutions of ceftriaxone sodium in lidocaine(2%) stored at 4°C showed more stability for 8 days with concentration (100 mg/ml) (table 6).

 

Table 5. assay of ceftriaxone sodium in lidocaine (2%) with concentration (100 mg/ml) stored at 25°C

Assay time	Content (mg)	Percent of  content(%)
Dilution moment	99.7	100
After 2 hours	96.4	96.69
After 4 hours	94.1	94.38
After 6 hours	92.7	92.98
After 8 hours	90.1	90.37
After 24 hours	70.2	70.41

 

Table 6. assay of ceftriaxone sodium in lidocaine (2%) with concentration (100 mg/ml( stored at 4°C:

Assay time	Content (mg)	Percent of content(%)
Dilution moment	99.6	100
After 1 day	98.6	99
After 2 days	97.2	97.59
After 3days	95.8	96.18
After 4 days	94.5	94.88
After 7days	92.1	92.47
After 8 days	90.2	90.56
After 9 days	89.1	89.46
After 10days	85.6	85.94

 

C- in dextrose 5%:

The results obtained from evaluation the percentage content of ceftriaxone sodium in dextrose(5%) solutions stored at 25°C showed that the Percent of  content(%) decrease less than 90% after 24 hours for concentration (250 mg/ml) and after 3 days for concentration (100mg/ml), so we can say that the solutions of ceftriaxone sodiumwith concentration (100mg/m) are stable in dextrose(5%) more than those with concentration (250mg/ml)(table 7), whereas solutions of ceftriaxone sodium in dextrose (5%) stored at 4°C showed more stability for 10 days for concentration (100 mg/ml) and 3days for concentration (250mg/ml) (table 8).

 

Table 7.assay of ceftriaxone sodium in dextrose (5%) with concentrations (100 mg/ml and 250mg/ml) stored at 25°C

Assay time	Content (mg)		Percent of  content(%)
	Concentration= 100 mg/ml	Concentration= 250mg/ml	Concentration= 100 mg/ml	Concentration= 250mg/ml
Dilution moment	99.6	249.5	100	100
After 2 hours	99.1	247.6	99.50	99.24
After 4 hours	98.8	243.1	99.20	97.43
After 6 hours	98.1	239.8	98.49	96.11
After 8 hours	97.4	235.4	97.79	94.35
After 24 hours	95.7	223.1	96.08	90.06
After 2 days	92.4	190.8	92.77	76.47
After 3 days	89.9	170.5	90.26	68.34

 

Table 8.  assay of ceftriaxone sodium in dextrose (5%) with concentrations (100 mg/ml and 250mg/ml) stored at 4°C

Assay time	Content (mg)		Percent of  content(%)
	Concentration= 100 mg/ml	Concentration= 250mg/ml	Concentration= 100 mg/ml	Concentration= 250mg/ml
Dilution moment	99.8	249.3	100.00	100.00
After 1 day	99.1	239.5	99.30	96.07
After 2 days	98.5	236.8	98.70	94.97
After 3days	97.3	228.5	97.49	91.66
After 4 days	95.6	215.5	95.79	86.44
After 7days	94.3	204.3	94.49	81.93
After 8 days	93.7	199.0	93.89	79.82
After 9 days	91.5	193.8	91.68	77.72
After 10days	90.1	164.5	90.28	65.98

 

Table 9. assay of ceftriaxone sodium in Nacl 0.9%(250mg/ml) and in mixture serum(100mg/ml): stored at 25°C

Assay time	Content (mg)		Percent of  content(%)
	Nacl 0.9% ( 250mg/ml)	Mixture serum (100mg/ml)	Nacl 0.9% ( 250mg/ml)	Mixture serum (100mg/ml)
Dilution moment	249.7	99.7	100	100
After 2 hours	239.5	96.1	96.02	96.39
After 4 hours	235.7	93.8	94.41	94.08
After 6 hours	233	92.9	93.31	93.18
After 8 hours	225.8	90.4	90.41	90.67
After 24 hours	173.4	70.1	69.58	70.31

 

Table 10. assay of ceftriaxone sodium in Nacl 0.9%(250mg/ml) and in mixture serum(100mg/ml) stored at 4°C

Assay time	Content (mg)		Percent of  content(%)
	Nacl 0.9%( 250mg/ml)	Mixture serum (100mg/ml)	Nacl 0.9%( 250mg/ml)	Mixture serum (100mg/ml)
Dilution moment	249.5	99.8	100	100
After 1 day	237.5	97.1	95.19	97.29
After 2 days	233.8	93.8	93.71	93.99
After 3days	225.3	90.5	90.30	90.68
After 4 days	215.5	85.6	86.37	85.77
After 7days	200.9	80.1	80.52	80.26
After 8 days	194.8	74.8	78.08	74.95
After 9 days	190.6	70.1	76.39	70.24
After 10days	170.5	60.8	68.34	60.92

 

 

D- inNacl0.9% and mixture serum:

The results obtained from evaluation the percentage content of ceftriaxone sodium in Nacl 0.9% and in mixture serum stored at 25°C showed that the Percent of content(%) decrease less than 90% after 8 hours for concentration (250 mg/ml)inNacl 0.9% and for concentration (100mg/ml) in mixture serum(table 9), whereas solutions of ceftriaxone sodium in Nacl 0.9% and in mixture serum stored at 4°C showed more stability for 3 days for the studied concentrations (table 10).

 

E-in sterile water used for injection:

The results obtained from the assessment of the percentage content of ceftriaxone sodium in sterile water with concentration (100 mg/ml) stored at 25°C showed that the Percent of  content(%) decrease less than 90% after 3 days of the storage, so we can say that the solutions of ceftriaxone sodium are stable in sterile water for 3days after dilution (table 11), whereas solutions of ceftriaxone sodium in sterile water stored at 4°C showed more stability for 10 days with concentration (100 mg/ml) (table 12).

Table 11. assay of ceftriaxone sodium in sterile water with concentrations (100 mg/ml) stored at 25°C

Assay time	Content (mg)	Percent of  content(%)
Dilution moment	99.6	100
After 2 hours	99.5	99.90
After 4 hours	99	99.40
After 6 hours	98.6	99.00
After 8 hours	98.1	98.49
After 24 hours	95.6	95.98
After 2 days	93.4	93.78
After 3 days	90.2	90.56

 

Table 12.  assay of ceftriaxone sodium in sterile water with concentration (100 mg/ml) stored at 4°C

Assay time	Content (mg)	Percent of  content(%)
Dilution moment	99.7	100
After 1 day	99.1	99.40
After 2 days	98.6	98.90
After 3days	97.8	98.09
After 4 days	96.9	97.19
After 7days	94.5	94.78
After 8 days	93.7	93.98
After 9 days	92.3	92.58
After 10days	90.1	90.37

 

The obtained results suggest best stability for ceftriaxone sodium in dextrose solution (pH=6) and in sterile water used for injection (pH=6.5), and less stability in Nacl0.9% and mixture serum (pH=7.5). The least stability was in lidocaine 1% (pH=8) and lidocaine 2% (pH =8.5).These results agree with other studies  that show more stability of ceftriaxone sodium in acidic conditions and less stability in basic conditions [12-14].

Also thisstudy agree with other studies that noticed the stability of ceftriaxone sodium reconstituted in solution is influenced by two factors:

 

a- type of fluid used in dissolve and dilution: ceftriaxone sodium can be dissolve in various diluents and many studies indicate that  is stable for a period ranging from few hours to10 days[15-16].

 

b- storage temperature: a lot of studies indicate that ceftriaxone sodium is stable for long period in solution when stored at 4°C than in solutions stored at temperature not exceeding 25°C[16-18].

 

CONCLUSION:

All in all, there is an important effect of temperature on the stability of solutions of ceftriaxone sodium, so all solutions that stored at 4°C showed more stability than those stored  at 25°C. The two important factor was the type of used diluent, so solutions of ceftriaxone sodium in sterile water and dextrose5%( for concentration 100 mg/100ml) were the most stable for 3 days at25°C and for 10 days at 4°C, and the solution in lidocaine 1% wasstable more than that in lidocaine 2%. Wealso noticed the important effect of concentration of the resulted solutions, so the stability of ceftriaxone sodium in solution that have the concentration of 100mg/ml were more than solutions with concentration 250mg/ml, such as in dextrose5% and lidocaine1%.

 

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Accepted on 24.11.2016           © RJPT All right reserved

Research J. Pharm. and Tech 2018; 11(6): 2163-2167.