(T0930-05-30) Formulation Development and Optimization of Fenofibrate Nanosuspension Coated Microcrystalline Cellulose Based Granules

Purpose: Fenofibrate is a BCS class II drug that is highly lipophilic (log P = 5.24) with an aqueous solubility of < 0.1mg/mL i.e., practically insoluble in water and high permeability, therefore it is poorly bioavailable in the physiological gastric condition and shows variable clinical effects such as non- steady absorption among patients. Nanosuspension is a scale-up feasible drug delivery system to enhance the solubility and dissolution rate of poorly water-soluble drugs. Development of a solid-dry dosage form from a liquid nanosuspension is always challenging. This study aims to develop a robust nanosuspension of fenofibrate using a top-down nano-milling technique and to prepare fenofibrate nanosuspension-coated granules.

Methods: The preparation of nanocrystalline fenofibrate suspension by a top-down approach using dual centrifugation wet media milling (batch size of 35 mL) with 0.8mm beads at a milling speed of 1000 rpm for 90 minutes at a milling temperature of -20º C (Figure 1). Different polymers (VA64, HPMC E5) and surfactants (SLS, TW80, TPGS, Dowfax) with 5% w/v drug loading were screened. The optimized fenofibrate nanosuspension with acceptable PDI and low particle size among the different batches were further sprayed onto different grade microcrystalline cellulose carriers i.e., PH102, KG1000, Prosolv for the development of coated granules using a sprinkling spray nozzle and a pan coating machine with operating parameters of 5 mL/ min spraying rate, exhaust temperature of 25 ± 1°C and air blower temperature of 45 ± 2°C on 35g of MCC carrier to form a coat of nanosuspension on the surface of the carrier and exhaust mediated drying of coated granules throughout the coating process. The coated granules were further allowed to cool down for 30mins and evaluated for drug content estimation after sieving from #20 mesh and retaining upon #40 mesh number sieve, followed by evaluation of flow properties of coated granules such as angle of repose, bulk density, tapped density, compressibility index, and Hausner ratio. Finally, the in vitro dissolution of characterized nanosuspension-coated granules in 500mL of pH 1.2, 0.1N hydrochloric acid solution at 37º C, 50 rpm for 2 hours with 0.72% w/v SLS to maintain sink condition.

Results: Initial individual polymeric screening suggested that the particle size nanosuspension with VA64, HPMC E5 is within the acceptable particle size ( < 300 nm) and PDI range, compared to other stabilizers. The formulated nanosuspension with a combination of VA64, E5 along with SLS, TPGS, and Dowfax confirmed that nanosuspension with a combination of (VA64: Dowfax), (VA64: SLS) showed desired particle size with acceptable PDI range (Figure 2a). The optimized nanosuspension with 5% w/v drug, 2.5% w/v of VA64 polymer, and 0.5% w/v of Dowfax surfactant was found to have a significant reduction of particle size and stability with the particle size of 239.9 nm and 0.212 PDI after 90 mins of nano milling (Figure 2b, 2c) which is comparable with scaled-up batches of the same composition having an average particle size of 245.4 nm (± 23.06) and PDI of 0.259 (± 0.1) (Figure 2d). The assay for NCG_PH102 found 98.3% (± 0.009) compared with NCG_Prosolv, 81.7% (± 0.015), and NCG_KG1000, 90% (± 0.009). The flowability of fenofibrate nanosuspension-coated granules was found to be excellent at 13.78 º for NCG_PH102 compared to others i.e., NCG_KG1000, 21.98 º and NCG_Prosolv, 19.92 º. The flow property suggested that NCG_PH102 has a free-flowing character with a 12.57 % compressibility index (CI) and Hausner ratio of 1.14, compared with NCG_Prosolv, (14.49% CI; 1.17 Hausner ratio) and NCG_KG1000, (16.92% CI; Hausner ratio of 1.20 fair flow) (Figure. 2e, 2f). Finally, the in-vitro dissolution study identified that ~92% of the drug from liquid nanosuspension was released within 5-10 minutes whereas NCG_PH102 and NCG_KG1000 showed the highest similar drug release (~88%) compared with NCG_Prosolv with ~70% release and pure drug with ~10% release within 2 hours continuously (Figure. 3).

Conclusion: The stable fenofibrate nanosuspension was successfully developed using VA64 and Dowfax with 5% w/v drug loading. The nanosuspension-coated granules have free flowability when coated on PH102 grade MCC. The in-vitro dissolution studies indicated that PH102 and KG1000 have enhanced, and similar release profiles compared to pure drug. Thus, an efficient alternative to freeze drying and spray drying method was developed for preparation of solid nanosuspension dosage form.


Figure. 1. Graphical abstract for preparation, mechanism, and characterization of fenofibrate nanosuspension-coated granules.


Figure. 2. (a) The particle size and PDI of Fenofibrate nanosuspension i.e., individual polymeric screening; (b) Process optimization of nano milling time of finalized composition i.e., VA64 (2.5 % w/v), DOW (0.5% w/v); (c) Particle size distribution of optimized fenofibrate nanosuspension after 90 mins of nano milling; (d) Average particle size and PDI of scaleup batches of nanosuspension; (e) Angle of repose, compressibility index of granules with different MCC grade carriers; (f) Tapped & bulk density, Hausner ratio of granules with different MCC grade carriers.


Figure. 3. In-vitro dissolution study of fenofibrate nanosuspension-coated granules at pH 1.2