(T1330-08-47) Effect of Particle Size and Distribution on the Dissolution Profile of Fenofibrate Capsules

Purpose: Approximately 50-70% of new drug compounds fall into class II of the Biopharmaceutics Classification System (BCS) with high permeability but low solubility which can result in poor bioavailability[1]. Reduction in particle size increases the surface area of the particulates which can improve the solubility. Particle size distribution impacts dose uniformity in solid dosage forms; a narrow particle size distribution is beneficial particularly for poorly soluble compounds. The purpose of this investigation is to determine the effect of particle size on the rate of dissolution, using HPLC as an analytical method to quantify the dissolution profile and evaluate the most effective method to reduce particle size and distribution.

Methods: Fenofibrate was sourced from two different suppliers with each batch having different physical appearances to investigate the difference in particle size between manufacturers. Particle size was manipulated by hand grinding and ball milling. Both raw batches of fenofibrate were dry ball milled using Retsch Mixer Mill MM 400 for 30 minutes at a frequency of 15Hz. Batch 2 was also hand ground with a pestle and mortar until a fine powder was formed since the particulates had a larger visible appearance.Hypromellose (HPMC) capsules were filled with 134 mg of fenofibrate in its raw form, ball milled and hand ground states to perform dissolution testing. The dissolution conditions outlined in USP Monograph for fenofibrate capsules Test 1 were optimised for this study[2]. High-performance liquid chromatography (HPLC) was used to quantify fenofibrate concentration of dissolution samples. Particle size and distribution were determined using laser light diffraction by a Malvern Mastersizer 2000 with a Hydro S unit and optical microscopy.

Results: Batch 1 of fenofibrate in its raw, unmanipulated form appeared as a fluffy, fine white powder whilst batch 2 of fenofibrate in its raw, unmanipulated form had a more crystalline white powder appearance. Ball milling of fenofibrate batch 1 had minimal impact on the particle size but slightly reduced the particle size distribution. The impact of this manipulation is detectable in the dissolution profiles. By contrast, ball milling of batch 2 greatly reduced the particle size of batch 2. Hand grinding of batch 2 resulted in the smallest weighted mean particle size of 396.065 μm but also gave the largest particle size distribution (Figure 1). The particle size distribution of raw batch 2 is very narrow, demonstrated in Table 1. This distribution is increased by reduction of particle size by ball milling and hand grinding, with hand grinding giving the largest particle size distribution. The hand grinding action is different to the action of ball milling which is repetitive and can result in more uniform particle sizes and shapes. The rate of dissolution is seen to increase as the particle size decreases in the dissolution profiles (Figure 2). Good agreement is seen between the particle size analysis and the dissolution profiles.

Conclusion: This study demonstrates that decreased particle size results in an increase in dissolution rate. The particle size distribution has shown to have a significant impact on the rate of dissolution. In formulation preparation of fenofibrate capsules, this is an important consideration as a wide particle size distribution could result in poor dosing uniformity, due to varying adsorption rates. Increasing the surface area of particle size by grinding/milling allows for decreased particle size and a change to particle size distribution which depends on the properties and weight of the material. The most effective of these two techniques is inconclusive as ball milling results in a more uniform particle size whilst hand grinding gave the smallest particle size measurement.

References: [1] Nikolakakis, I. and Partheniadis, I., 2017. Self-Emulsifying Granules and Pellets: Composition and Formation Mechanisms for Instant or Controlled Release. Pharmaceutics, 9(4), p.50.
[2] United States Pharmacopeia. Fenofibrate Capsules. USP-NF 26. Rockville, MD; 01 May 2019

Figure 1: Particle size distribution measured by laser diffraction for A) raw fenofibrate batch 1, B) fenofibrate batch 1 after balling milling for 30 minutes at a frequency of 15Hz, C) raw fenofibrate batch 2, D) fenofibrate batch 2 after ball milling for 30 minutes at a frequency of 15Hz and E) fenofibrate batch 2 after hand grinding.



Figure 2: Dissolution profiles of raw fenofibrate batch 1, fenofibrate batch 1 after balling milling for 30 minutes at a frequency of 15Hz, raw fenofibrate batch 2, fenofibrate batch 2 after ball milling for 30 minutes at a frequency of 15Hz and fenofibrate batch 2 after hand grinding.



Table 1: Summary of particle size measurements obtain by laser diffraction using the Malvern Mastersizer 2000 for all batches of fenofibrate prepared.