Mohamed A. Sharaf

Norfloxacin is a synthetic antibacterial fluoroquinolone. It is related to nalidixic acid, but its relative potency has been increased by a fluorine atom and a piperazine moiety.

. reviewed the role of fluoroquinolones, particularly ciprofloxacin, norfloxacin, ofloxacin and lomefloxacin, to treat various eye infections.

Batch-to-batch variation in the raw material properties and variation between lots from different suppliers can lead to processing difficulties and variability in the properties of the finished product. Such variability may be because of a change in raw material properties arising from modification to the raw material manufacturing process.

  Changes in raw material may occur during the early drug development stage, or when a supplier identifies a cheaper route to prepare the raw material. Apart from polymorphism and solvate formation, there are few reports on interbatch variation in active ingredients, and the effects of this variation on the subsequent product properties and performance. More subtle variability in materials can occur, resulting in problems for formulators. Subtle process changes may have marked effects on active ingredients, as indicated by studies performed on ibuprofen.

  Mechanical property changes in ibuprofen compacts could be produced simply by alteration in the crystallization rate of raw material. 

Batch-to-batch variability in the particle size distribution and particle shape of the drug raw material can result in problems during compression. It has been shown that the variability in particle size of raw materials affects their compaction properties.

  Granulation techniques are expected to partly overcome batch-to-batch variability in particle size distribution and the particle shape of the raw material, but this does not rule out problems during compression. Furthermore, variation in drug release once disintegration of granules is complete may be anticipated.

Although physicochemical preformulation screening is practised universally within the pharmaceutical industry, physicomechanical screening is applied to a lesser extent and often only where a problem exists. For example, a physicomechanical quality control test may be introduced during the early development of a formulation to avoid processing or quality problems, such as flow tests for direct compression formulations and surface area tests for drugs where the dissolution rate may be a problem. 

The aim of the present work is to develop norfloxacin tablet formulations by either slugging of RM1 or pregranulation of the noncompressible RM2 with nonaqueous fluid. This will minimize water sorption encountered through wet granulation of RM2 during preparation of the commercial F4 tablets. Two types of commercial norfloxacin raw material will be investigated, a coarse and a fine noncompressible raw material. A third granular form will be developed from the fine commercial drug powder RM2 and further formulated into tablets. Both the physicochemical and physicomechanical characterization of the three materials will be performed. The norfloxacin tablets prepared in this study will be coated to mask the bitter taste. Evaluation will include assessing physical and chemical stability in comparison with tablets prepared by wet granulation, shortly after production and during storage for 12 months under different storage conditions. 

Table 1 Norfloxacin raw material characteristics.			

			 Norfloxacin from two different suppliers was used: coarse (RM1 [Merck AG, Germany]); fine (RM2 [Siegfried AG, Switzerland]) 

 PVP K-25 (ISP, Switzerland) as a wet granulation binder 

 Aerosil 200 fumed silica (Degussa AG, Germany) as a powder flow aid 

 Avicel PH102 microcrystalline cellulose (Lehmann & Voss & Co., Germany) and lactose monohydrate (DMV Campina BV, Holland) as fillers 

 talc powder (Tardy, France) and magnesium stearate (Union Deriva, Spain) as lubricants 

 Ac-Di-Sol croscarmellose sodium (FMC International, Ireland) as a disintegrant 

 starch (Cerestar, Belgium) paste (1%) as a wet binder 

 Eudragit E-100 polymeric methacrylate (Rohm Pharma GmbH, Germany) and Methocel E5 LV hydroxypropyl methylcellulose (Colorcon Ltd, UK) as coating agents 

 isopropyl alcohol as solvent for coating polymers, methanol as a mobile phase and 1-hexanesulfonic acid sodium salt (BDH Chemicals Ltd, UK) as ion-pairing agent 

 monobasic potassium phosphate, glacial acetic acid (El-Nasr Pharmaceuticals Co., Egypt) and sodium hydroxide (Kirsch, Germany) as acetate buffer components 

 ethyl alcohol (El-Nasr Pharmaceuticals Co.) as solvent for PVP 

 ethylene diamine analogue of norfloxacin, a gift from Merck Sharp & Dohme (Rhahway, NJ, USA) as a degradate of norfloxacin. 

Granulated raw material (RM3) was prepared in a Torrmat (Type FH-6; Drias, Germany) machine by kneading RM2 with a 2% w/v alcoholic solution of PVP K-25, followed by drying in a hot air oven at 60 °C for 5 min. The particle size of the wet granules was then reduced by passing through an oscillating granulator (Type F.G.S.; Erweka, Germany) fitted with a 1 mm sieve. 

Table 2 Composition of norfloxacin tablet formulations.		

				All three norfloxacin raw materials (RM1, RM2 and RM3) were evaluated using relevant physicochemical and physicomechanical tests (Table 1). 			

				Materials were ground with Nujol mull and placed between two potassium bromide disks, and their infrared spectra were recorded using spectrophotometer Model 1430 (Perkin Elmer, USA).			

Differential scanning calorimetry (DSC) was performed on 8–10 mg samples that were heated at a rate of 10°C/min between 20–280°C using a Mettler TA 4000 thermal analysis system (Mettler Instrument Corp., Hightstown, NJ, USA). Aluminium pans and lids were used for all samples. Instrument calibration was performed periodically using indium as a standard.  

Moisture content of the raw materials was determined by the Karl Fischer method as described in the USP 25.

Moisture uptake was determined by placing 2.0 g sample of each raw material in open, previously weighed petri dish. Petri dishes were then put into a desiccator containing a saturated solution of sodium chloride in purified water (with excess salt) to give a relative humidity of about 75%.

  The desiccators were stored at two different temperatures 25 ±1 °C and 40 ±1 °C. These conditions were considered representative of storage in temperate and tropical regions. Petri dishes were then removed from the two desiccators at predetermined time intervals (7, 14, 30, 45, 60 and 90 days) and rapidly weighed. The weight gain, representing the amount of moisture absorbed, and the percentage moisture gain were calculated and plotted against time. Monitoring the weight gain was continued until there was no further change in weight. 

Figure 1 SEM of norfloxacin raw materials; (a) RM1 and (b) RM2.			

Drug release testing was performed on 0.4 g samples of raw materials in a USP Apparatus II paddles (Pharma Test PTWS III, Germany) employing 750 mL of acetate buffer pH 4, at 37 °C and 50 rpm. 5 mL dissolution media samples, replaced with fresh medium, were withdrawn at a predetermined time, filtered, diluted and assayed spectrophotometerically at 313 nm.

  All dissolution experiments were run in duplicates. 

The compactability of the raw materials was investigated on a single punch, noninstrumented tablet machine Type AR400 (Erweka GmbH, Germany). 0.6 g of norfloxacin powder were compressed into tablets employing 11 mm concave punches. Punches and dies were lubricated by direct application of a film of magnesium stearate powder. Three different arbitrary compression forces were applied, designated as low, medium and high. 

Figure 2 Particle size distribution of tested norfloxacin raw materials.			

Powder particle size was determined using laser diffraction (LD) analyses. Samples were dispersed in water using 1% w/v Tween 80 as a wetting agent. An ultrasonic probe was applied to the suspension for varying time periods up to a maximum of 1 min. At various time intervals, samples were pumped through the flow cell of the LD analyser Sald-1100 (Shimadzu, Japan) for sizing. 

Figure 3 Moisture uptake of norfloxacin raw materials at 75% RH at (a) 25 Â°C and (b) 40 Â°C.			

			Scanning electron microscopy (SEM) was performed on RM1 and RM2 samples using SEM JSM–5300 (Jeol, Japan).			

Powder flow was determined using angle of repose and Carr's compressibility index.

The four tablet formulations (567 mg target weight) used in this study are shown in Table 2. The compositions of the three developed tablets were kept as close as possible to the commercial F4 tablets to allow reliable comparison of all formulations. Formulations F1 and F2 were prepared by slugging using the same tablet machine described above and 25 mm punches. The breaking force of the slugs range was 26–33 KN. The obtained slugs were crushed in an oscillating granulator Type FGS (Erweka, Germany) fitted with 1 mm sieve, mixed with other additives in a double-cone mixer Type DKM (Erweka) and finally compressed. F3 tablets were prepared by direct compression after mixing of all ingredients for 10 min followed by another 5 min after adding the lubricants in a double-cone mixer. F4 tablets were prepared by wet granulation (WG) of norfloxacin RM2 and other ingredients (except lubricants) with starch paste as a binder. WG was performed in a Torrmat kneader and the mass was subsequently passed through a 2.5 mm sieve and dried in a hot air oven at 60 °C for 6 h. Fumed silica, talc and magnesium stearate were added to dry granules and mixed for 5 min in the double-cone mixer. All tablets were prepared using 11 mm concave punches at the arbitrary set medium compression force. 

Figure 4 Effect of storage at 40 Â°C and 75% RH on breaking force (KN) of uncoated (F1âF3) and coated (F1âF4) norfloxacin tablet formulations. 			

The tablets were film coated in a coating pan (class - E; Manesty, UK) using a 5% solution of either HPMC or Eudragit E-100 in isopropyl alcohol.  

			The breaking force of the compacts was determined on six tablets from each batch using a hardness tester (PTB 3H, Pharma Test, Germany).			

Friability testing was performed on 10 weighed tablets using a Pharma Test machine (Type TAD, Erweka GmbH, Germany) at a fixed speed (25 rpm) for 15 min. The friability testing procedure described above is the same adopted by the manufacturer of the commercial F4 tablets and is applied in this study to enable satisfactory comparison with the experimental formulations (F1–F3). 

Disintegration testing was performed on six tablets (Pharma Test) according to the specifications of USP 25 disintegration test for plain (non-enteric) coated tablets using water maintained at 37±2 °C.

Dissolution studies were performed according to USP 25 monograph for norfloxacin tablets. 

Assay of drug content was conducted on 20 powdered tablets using 1M sodium hydroxide solution. The absorbance of a standard and test solutions were measured at 335 nm against a blank.

Figure 5 Effect of storage at 25 Â°C and 40 Â° C and 75% relative humidity (RH) and uncontrolled humidity (Un) on disintegration time of F4 norfloxacin tablets.			

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Although physicochemical preformulation screening is practised universally within the pharmaceutical industry, physicomechanical screening is applied to a lesser extent and often only where a problem exists.

Mohamed A. Sharaf

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Effect of raw materials on the formulation of norfloxacin tablets