Category: Formulation and Quality
Purpose: Amongst all commercially available pediatric drug products, antibiotics are the majority1. However, their intense bitter taste and after taste are a challenge with respect to children acceptability and thus compliance and therapeutic success. Dry syrup formulations are widely accepted dosage forms for pediatric use because of their ease of reconstitution and administration as well as their dose flexibility2. The aim of the present study was to formulate bitter taste masked antibiotic azithromycin dihydrate as dry syrup with EUDRAGIT® E PO using common manufacturing techniques and equipment.
Methods: Azithromycin dihydrate granules were prepared in a rapid mixer granulator (impeller 100 rpm, 5 min; chopper 200 rpm, 2 min). The binder solution of partially neutralized EUDRAGIT® E PO (solid content 30% w/w) was prepared by dissolving EUDRAGIT® E PO (Evonik Industries AG) with sodium lauryl sulfate and stearic acid in purified water while stirring for 1 hour3. The granules were dried on trays at 47°C till LOD (Sartorius) was not more than 2.5% at 60°C. These granules were sized between 175 µm to 250 µm and then mixed with extragranular excipients (Table 1) in a double cone blender (12 rpm, 10 mins). All excipients used were within the IIG limits. Single doses of this blend equivalent to azithromycin 100 mg were packed in HDPE bottles and reconstituted with purified water to 5 mL final volume. Dissolution, viscosity, deliverable volume and microbiological test were performed on the reconstituted syrup using the USP methods. Unconstituted formulations were studied for morphology (SEM; Thermo Fisher) and assay. Sensory evaluation of the reconstituted syrup with respect to bitter taste, after taste masking and mouth feel was done with the help of taste panel study. 1 mL of reconstituted formulation was kept onto tongue for 30 seconds and spat out.
Results: Bitter taste of Azithromycin was found to be completely masked in the dry syrup; and there was no bitter after taste either. The mouth feel was also very good. EUDRAGIT® E PO has wrapped the granules lightly enough to hold the bitter taste for 30 seconds in saliva. The pH of the reconstituted formulation (9.9 – 10.1) was maintained above the pKa of Azithromycin (8.7) by adding magnesium oxide. It is assumed that this reduced the escape of the drug particles in the vehicle which further contributed to reconstitution stability. Near-spherical appearance of the granules (Figure 1) and sufficient viscosity (0.48 Pas) further minimized any gritty sensation during consumption of the syrup. Drug dissolution from the syrup in the USP media on the day of reconstitution and 7 days later was found to be comparable indicating reconstitution stability (Figure 2). The assay of 90% to 110% indicates adequacy of mixing and dose uniformity. Deliverable volume of the reconstituted formulation was found to be not less than 100%. Hence, it can be concluded that the declared volume was available for administration and formulation viscosity was adequate. Microbiological testing performed on the reconstituted formulation on the day of reconstitution and after 7 days of reconstitution showed total aerobic microbial count, total combined yeast and mold count and pathogens below acceptable pharmacopoeial limits, indicating adequate microbial stability during storage without addition of preservative.
Conclusion: Taste masked azithromycin dihydrate dry syrup for pediatric use was successfully developed using EUDRAGIT® E PO. Such development involved use of aqueous wet granulation manufacturing technique, common equipment and well-established excipients.
Viraj Kulthe– Evonik Industries, Mumbai, Maharashtra, India
Priyanka Haksar– Mumbai, Maharashtra, India
Shraddha Joshi– Director, Formulation Development Orals, Evonik India Pvt Ltd, Mumbai, Maharashtra, India
Smitha Shetty– Head of Analytical Development, Evonik Industries, Mumbai, Maharashtra, India
Shrikant Patil– Mumbai, Maharashtra, India
Firouz Asgarzadeh– Director of Technical Marketing, Evonik Corporation, Piscataway, New Jersey
Dr. Viraj Kulthe– Assistant Manager, Evonik India Pvt Ltd, Mumbai, India, India