Formulation and Evaluation of Ceftazidime Chewable Tablets

Antimicrobial agents are among the most commonly used and misused of all drugs. The inevitable consequence of the widespread use of antimicrobial agents has been the emergence of antibiotic-resistant pathogens, feeling an ever-increasing need for new drugs. The Cephalosporin antibiotics are useful and frequently prescribed antimicrobial agents that share a common structure and mechanism of action ¾ inhibition of synthesis of the bacterial peptidoglycan cell wall. The β-lactams also include the cephalosporin antibiotics. Cephalosporium acremonium, the first source of the cephalosporins, was isolated in 1948 by Brotzu from the sea near a sewer outlet off the Sardinian coast. by determining the Quality assurance parameters during manufacturing, which influence the dissolution behavior of the drug hence its bioavailability. The formulation and evaluation done after the survey of literature, it shows the better result rather than first and second class of cephalosporin as chewable tablets.


INTRODUCTION
Ceftazidime is a 3 rd generation broad spectrum β-Lactam cephalosporin class of antibiotic administered orally in pediatric and adult patients.To reduce the development of drug-resistant bacteria and maintain the effectiveness of Ceftazidime and other antibacterial drugs,The bactericidal action of cephalosporin is due to the inhibition of cell wall synthesis.It binds to one of the penicillin binding proteins (PBPs) which inhibit the final transpeptidation step of the peptidoglycan synthesis in the bacterial cell wall, thus inhibiting biosynthesis and arresting cell wall assembly resulting in bacterial cell death.The cephalosporins have molecular weights of 400-450.They are relatively stable to pH and temperature changes.Numerous patients express complexity in swallowing tablets and hard gelatin capsules, resulting in non-compliance and ineffective therapy.Current advances in novel drug delivery systems endeavor to enhance safety and efficacy of drug molecules by formulating a convenient dosage form for administration and to achieve better patient compliance.One such approach led to development of fast chewable tablets.Bacterial resistance to an antimicrobial agent is attributable to three general mechanisms: (1) The drug does not reach its target, (2) the drug is not active, or (3) the target is altered.

Cefepime (MAXIPIME)
Comparable to third-generation but more resistant to some βlactamases.

MATERIALS AND METHODOLOGY: 2.1 Visual Examination
A small quantity of Drug X powder was taken in butter paper and viewed in well-illuminated place for color observation.

Determination of absorption maxima (λmax) for analysis
For scanning the λmax of drug, standard solution was prepared.about 20 mg of pure drug was weighed and transferred to a 20 ml volumetric flask.10ml of methanol was added and sonicated to dissolve and made up to mark with methanol.Further diluted 1 ml of resulting solution to 50 ml with methanol, mixed well and filtered through 0.45 Nylon filter.Standard solution was UV scanned between 200-400 nm and absorption maximum was determined spectrophotometrically.Methanol solvent was used as blank 2.3 Particle size distribution analysis Particle size analysis of the micronized API was performed using Malvern Particle size analyser.

Procedure:
• 500 mg of sample was taken and sufficient amount of anhydrous methanol added to the titration vessel and titrated to the electromeric end point with KF reagent.

Propylene glycol Very soluble Methanol
Very Soluble Ethanol Soluble • Quickly added 0.5 g of test samples mixed and again titrated to the electromeric end point with KF reagent.• Water content was calculated by the following formula Calculation: Water (%m/m) =      W = weight of sample taken (mg) V = Volume of KF reagent consumed (ml) F = Water equivalent factor of KF Reagent (mg/ml) Water by KF was determined for Assay potency calculation 2.5 Flow property Determination Flow property parameters like bulk density, tapped density, Hausner ratio, Compressibility index were calculated for determining flow properties of the drug.

Apparent Density / Bulk Density
Bulk density or apparent density is defined as the ratio of mass of a powder to the bulk volume.The bulk density of a powder depends primarily on particle size distribution, particle shape, and the tendency of the particles to adhere to one another.

Method:
Weighed quantity of Drug X drug was weighed and transferred in graduated cylinder.Carefully leveling of the powder without compacting was done and unsettled apparent volume (V0) was noted.Then appearance bulk density in g/ml was calculated by the following formula: Bulk density = Weight of the API Bulk Volume 2.7 Tapped Density: Weighed quantity of drug was taken and transferred in graduated cylinder.The cylinder containing the sample was mechanically tapped by raising the cylinder and allowing it to drop under its own weight using mechanically tapped density tester that provides a fixed drop of 14 ±2 mm at a nominal rate of 300 drops per minute.Cylinder was tapped for 500 times initially and tapped volume (V1) was measured to the nearest graduated units, repeated tapping of additional 750 times was done and tapped volume (V2) was measured.Additional Repeated tapping was performed if the difference between the two successive volumes was less than 2% as per USP chapter <611>.

Compressibility index and Hausner Ratio:
The Compressibility Index and Hausner Ratio are measures of the propensity of a powder to be compressed.As such, they are measures of the relative importance of interparticulate interactions.In a free-flowing powder, such interactions are generally less significant, and the bulk and tapped densities will be closer in value.For poorer flowing materials, there are frequently greater inter-particle interactions, and a greater difference between the bulk and tapped densities will be observed.Hausner's Ratio indicate s the flow properties of the powder and is measured by the ratio of tapped density to bulk density.It is the ratio of tapped density and bulk density.Hausner found that this ratio was related to interparticle friction and, as such, could be used to predict powder flow properties.= 227.52mg Note: In F1, F2,F3,F4 API having (d0.9)=210.65 µm particle size was used.In F1, poor flow of blend from hopper was observed due to micronized nature of API and low particle size pearlitoli.ePearlitol200 SD.Therefore tablets were difficult to be compressed by this method.To overcome this problem, in F2, Pearlitol 500 DC andAerosil was used to improve flow property.

2: FORMULA FOR PREPARATION OF F2 AND F3 BY DIRECT COMPRESSION
In F2, Capping was observed due to absence of binder in formulation.To overcome this problem, HPC LH 21 was added as binder in formulation F3.Tablets were compressed and checked for friability but friability test for tablets failed due to which further compression not performed and tablets not given for dissolution.Therefore due to above a problem, Direct Compression method was not choosen and Roller Compaction method was selected for further formulations (F4-F9).= 223.99mg In F4, same particle size API was used as used in Formulations F1-F3.Tablets were -compressed.Dissolution of Tablets was performed in Official medium (pH 7.2 Phosphate Buffer).Dissolution was very slow.So in F5, API having particle size d(0.9)-11μm was used to check the effect of particle size on dissolution by keeping same concentration of all functional excipients (Disintegrant, Binder, Lubricant) and amount of API change due to assay potency was adjusted in diluent quantity.Tablets were compressed and dissolution of tablets was performed.As a result, dissolution was still very slow as compared to innovator but better than F4.So this optimised particle size API was selected for further formulation devlopment.As dissolution of F5 was very slow at both initial and end time points as compared to marketed drug formulation (Innovator) in the dissolution medium.To improve dissolution, In F6, quantity of crospovidone (Disintegrating agent) was increased in intragranular part.Dissolution increased at end time points but was slow in initial time points.Therefore in F7, quantity of crospovidone increased in extragranular part to increase dissolution at initial time points.Dissolution was improved.In F8, quantity of HPC LH 21 was decreased to decrease disintegration time of tablet and to further improve dissolution.As a result disintegration time was decreased and increase in dissolution was also observed.Hence dissolution profile of F8 was found to be very similar with that of innovator in official medium ( pH 7.2 Phosphate buffer).Hence F8 was optimised and selected as final formula for further batches.Formulation F9 was taken as scale up batch keeping same formula as that of F8.

Determination of absorption maxima (λmax) for analysis
The organic molecules in solution form, upon exposure light in the ultra-violet region of the spectrum, absorb light of particular wavelength depending on the type of electronic transition associated with the absorption.Ceftazidimesolution (20µg/ml) was scanned between 200-400 nm and absorption maximum was determined spectrophotometrically.From the curve, λmax for Ceftazidimewas found at 288 nm,

Standard curve of Ceftazidime (optimized particle sized API)
The standard plot was prepared by taking concentration on x-axis and the absorbance on y-axis.The calibration equation for straight line was obtained.

FORMULATION TESTING Direct Compression method
In F1-Poor flow of blend from hopper was observed due to micronized nature of API and low particle size pearlitoli.ePearlitol200 SD.Therefore tablets were difficult to be compressed by this method.To overcome this problem, in F2, Pearlitol 500 DC andAerosil was used to improve flow property.In F2-Capping was observed due to absence of binder in formulation.To overcome this problem, HPC LH 21 was added as binder in formulation F3.In F3-Tablets were compressed and checked for friability but friability test for tablets failed due to which further compression not performed and tablets not given for dissolution.Therefore due to above problems, Direct Compression method was not choosen and Roller Compaction method was selected for further formulations (F4-F9).
In F4 and F5, particle size optimisation and selection of particle size was done to check effect on dissolution.In F4, API having d(0.9)-210.60 µm particle size was used as used in F1 and F2.As in F5, API having particle size d(0.9)-11µm was used, dissolution was better than that of F4.Therefore for further formulation development this optimised particle size d(0.9)-11µm was selected for further formulation.
In F5, disintegrating agent crospovidone added in extragranular part increased dissolution at initial time points.
In F6, disintegrating agent crospovidone added in intragranular part increased dissolution at end time points.
In F7, disintegrating agent crospovidone added in extragranular part as compaired to F5 increased dissolution at initial time points.In F8, added amount of Hydroxypropyle cellulose (LH-21) decreased, decreased disintegration time and further increased dissolution.Dissolution profile of F8 tablets was found to be similar with innovator.
In F9, dissolution profile of tablets also found to be similar with innovator.Tablets were found to be stable as all the physical and chemical properties were found within limits mention in monograph.Hence Formulation, development, evaluation of stable and bioequivalent chewable tablet was attained.

CONCLUSION
The aim was to develop a stable chewable tablet of cephalosporins whose in-vitro dissolution profile is similar or to the nearby with that of marketed dosage form, so that a dosage form having same therapeutic efficacy at a low cost can be available in the market.As Drug X has poor dissolution property.Therefore dissolution was improved by using micronised API, binder, disintegrant in the formulation.Preformulation study was performed.In-vitro parameters of formulations were evaluated.As according to USFDA guideline, similarty factor (f2) value should be between 50-100 in official medium.Therefore Formulation F8 was selected as best formulation as its dissolution profile was found to be similar (On basis of similarty factor f2 value 66) with that of Innovator in official medium (pH 7.2 phosphate buffer medium).Tablets dissolution was performed.Dissolution profile of F8 tablets also was found to be similar with that of innovator.It was optimised and Scale up (F9).Dissolution profile of F9 tablets was also found to be similar in pH 7.2 phosphate buffer medium (Similarty factor f2 value 63).Stability studies of final batch F9 (after packing) were performed and the product was found stable.Thus objective of Formulation, development and evaluation of a stable and bioequivalent chewable tablet was attained.

REFERENCES:
1. Bruton L, Keith P, Blumenthal D, Buxton Z. Goodman Escherichia coli, Klebsiella, Proteus, Haemophilusinfluenzae, Moraxella catarrhalis.Not as active against gram-positive organisms as first-generation agents.Inferior activity against S. aureus compared to cefuroxime but with added activity against Bacteroidesfragilis and other Bacteroides Cefuroxime axetil (CEFTIN) aeruginosa e; Serratia; Neisseria gonorrhoeae; activity for S. aureus, Streptococcus pneumoniae, and Streptococcus pyogenes f comparable to first-generation agents.Activity against Bacteroides spp.inferior to that of cefoxitin and cefotetan.

Figure 2 -
Figure 2-Standard Curve of Drug

Figure 3 :
Figure 3: FTIR Spectrum of Ceftazidime Note: Optimization of particle size was done on basis of dissolution results of the formulation.4.3 FORMULATION TESTING Direct Compression methodIn F1-Poor flow of blend from hopper was observed due to micronized nature of API and low particle size pearlitoli.ePearlitol200 SD.Therefore tablets were difficult to be compressed by this method.To overcome this problem, in F2, Pearlitol 500 DC andAerosil was used to improve flow property.In F2-Capping was observed due to absence of binder in formulation.To overcome this problem, HPC LH 21 was added as binder in formulation F3.

Table : 1.1 Classification of Cephalosporin Category: Antibacterial Sub Category: Antibiotic FIGURE 1: CHEMICAL STRUCTURE OF DRUG Melting point: 240 0
C Appearance: yellowish-white crystalline powder Solubility:

TABLE 2 .1: HAUSNER'S RATIO Method:
The compressibility index and the Hausner ratio were calculated as follows: Where B.D. = Bulk density T.D. = Tapped density 3.0 FORMULATION DESIGN Formulae for Preparation of Chewable Tablets of Ceftazidime.In Formulation (F1,F2,F3), Direct Compression method was selected for tablet compression.