Faculty of Pharmacy and Medical Sciences Al-Ahliyya Amman University FORMULATION OF LEVOFLOXACIN AS ORODISPERSIBLE TABLETS USING A READY-MADE BLEND OF EXCIPIENTS COMPARED WITH CLASSIC FORMULATION STRATEGIES ISRAA H. AL-ANI,Ph.D Faculty of Pharmacy and Medical Sciences Al-Ahliyya Amman University Jordan

INTRODUCTION Orodispersible tablets (ODTs) are defined as tablets that disperse or disintegrate in short time (upto 2minutes) in the mouth prior to being swallowed, which results in the rapid dissolution and absorption of the active pharmaceutical ingredients contained in these tablets, providing a rapid onset of action.

ODTs also provide specific advantages to pediatric and geriatric patient populations, which can sometimes experience difficulties in swallowing conventional tablets and capsules .

A variety of different processes have been developed for the production of ODTs, including freeze drying and molding, as well as several other more conventional methods, including dry and wet granulation processes and direct compression. The key challenges associated with the formulation of good ODTs include fast disintegration times, reasonably sized tablets, low moisture sensitivity and taste .

What are ready made excipients? The International Pharmaceutical Excipients Council (IPEC) defines excipients as "Substances, other than the API in finished dosage form, which have been appropriately evaluated for safety and are included in a drug delivery system to either aid the processing or to aid manufacture, protect, support, enhance stability, bioavailability or patient acceptability, assist in product identification, or enhance any other attributes of the overall safety and effectiveness of the drug delivery system during storage or use" .

Co-processing of excipients could lead to the formation of excipients with superior properties compared to the simple physical mixtures of their components. The main aim of co-processing is to obtain a product with added value related to the ratio of its functionality/price.

Development of co-processed directly compressible adjuvant starts with the selection of the excipients to be combined, their targeted proportion and the selection of preparation method to get optimized product with desired physico-chemical parameters, and it ends with minimizing avoidance with batch-to-batch variations. An excipient of reasonable price has to be combined with the optimal amount of a functional material in order to obtain an integrated product, with superior functionality to the simple mixture of components.

This synergistic effect should improve the quality of the tablet equally in all aspects ranging from hardness to dissolution and/or stability. Most important characteristics are the binding and blending properties of the co-processed excipients, which must be better than those of a physical mixture of the starting materials. Cost is another factor to be considered in the selection of co-processed product.

Major limitation of co-processed excipient mixture is that the ratio of the excipients in a mixture is fixed and in developing a new formulation, a fixed ratio of the excipients may not be an optimum choice for the API and the dose per tablet under development . Co-processed adjuvant lacks the official acceptance in pharmacopoeia. For this reason, a combination filler-binder will not be accepted by the pharmaceutical industry until it exhibits significant advantages in the tablet compaction when compared to the physical mixtures of the excipients.

Aim of the work The aim of this study was to compare the physical characteristics and dissolution properties of ODTs prepared using conventional methods with those prepared using a ready-made mixture of excipients (PROSOLV® ODT). These comparison experiments were conducted using levofloxacin as a model active pharmaceutical ingredient.

Experimental Part Levofloxacin: method of analysis and calibration curve (ICH guideline). Formulation of ODT. - preparation of the powder blends (weighing and mixing-using Cubic-mixer) Six formulas were prepared each contained 250 mg Levof. F1-F5 used physical mixture of Mannitol, disintegrants, Avicel, aspartam talc and Mg stearate. And F6 used the ready-made blend.

The target weight was 500 mg The target weight was 500 mg. Small scale of 500 tablets was prepared, then scaling up was achieved. - Evaluation of powder blend (particle size distribution, bulk density , tapped density, flowability and angle of repose and percentage comprisibility) Note: all tests followed USP requirements.

Table (1): The prepared formulas Ingredients F1 F2 F3 F4 F5 F6 Levofloxacin 250 CCS 25 35 SSG CP Aspartam 5 Talc 8 Mannitol 209 199 149 Avicel® 50 ® Mg Stearate 3 Total (mg) 500

Experimental Part “Particle size distribution (PSD) of a powder, or granular material, or particles dispersed in fluid, is a list of values or a mathematical function that defines the relative amounts of particles present, sorted according to size.” Samples were taken randomly from different levels of the vessel and were analyzed by laser diffraction method. (WJL-608 laser particle size analyzer) no further processes were done after mixing.

Experimental Part Direct compression of the powder blends. Evaluation of the tablets: - Weight Variation . - Hardness and Friability . - Content Uniformity . - Wetting time (paper and petri dish method) - In vitro disintegration time (petridish and disintegrator methods). * Dissolution test (USP NF 2013, type I apparatus)

Scaling up Three batches were prepared to evaluate feasibility and coast effectiveness of the work. They were prepared in Pharmaceuticals. 5 kg batch 20 kg batch 50 kg batch. The tablets resulted from 50 kg were also evaluated for the same parameters.

Results and Discussion Evaluation of the powder blend. 1- Particle size distribution : results showed superior PSD of the ready made blend. The average PS was smaller and showed higher uniformity foe F6 with the co-processed excipient.

Powder characteristics Table (2) Results of powder Evaluation Formula code F1 F2 F3 F4 F5 F6 Bulk Density (g/ml) 0.48 0.47 0.49 0.58 0.51 Tapped Density (g/ml) 0.55 0.54 0.56 0.66 Angle of Repose (degree) 28o 27o 30o 32o 31o 23o Percentage comprissibility 12.72 12.69 10.90 14.2 12.12 8.93 Hausner ratio 1.14 1.15 1.12 1.16 1.13 1.09

Table (3) Results of Evaluation of Tablets Formula code Weight variation Hardness kg/cm2 Friability (%) Wetting time (sec) In vitro DT (sec) Drug Content (%) F1 Pass 3.5±0.51 0.61±0.05 38±1.1 40±1.3 98±1.5 F2 3.6±0.62 0.60±0.06 48±1.5 45±2.1 99±2.0 F3 3.4±0.38 0.63±0.09 45±2.0 48±2.0 100±1.1 F4 3.5±0.44 0.55±0.09 29±1.8 32±1.2 101±0.98 F5 3.7±0.51 0.52±0.08 35±2.1 36±3.1 98±0.99 F6 3.2±0.08 0.40±0.01 30±1.5 31±1.3 99±0.5

Fig 1: Dissolution Profile of the six prepared formulas Drug Dissolution Fig 1: Dissolution Profile of the six prepared formulas

Dissolution of Drug Formula Code F1 F2 F3 F4 F5 F6 Percent drug dissolved T (5 min) 25±2.0 24±1.8 24±1.2 28±1.9 22±2.0 50±1.8 Higher dissolution rate was achieved in the first five minutes with F6 All evaluation results above were obtained from the 50-kg batch

Coast effect and advantages Preliminary Evaluation of coast: Time saving: average 3 hours/working day. Mixing time of F6 is about 1/3 of that of other formulas. Preparation and weighing average of 2 hr saving. Labour : 2 workers less for the major processes. Energy saving: around 3 hours working/batch. Materials coast: 30% less.

Conclusion Using ready-made excipients in formulation of levofloxacin ODT added an advantage over the physical mixture of excipients in characteristics of the result tablets and cost effect.

Acknowledgment All thanks to my University (Al-Ahliyya Amman University) for support of scientific research. And to the cooperating Pharmaceuticals in Jordan for their highly appreciated help in this work. Thanks are extended to my colleagues and students who inspire me all the time.

Thank you For your kind Attention! You are welcome in Jordan