(M1430-09-59) Control of Particle Size, Distribution and Modality of a Rifapentine Solid Drug Nanoparticle Formulation through Modified Formulation Approaches

Purpose: The relationship between certain physicochemical properties of nanoparticle formulations and their pharmacological behaviour is not currently well understood. Particle size distribution (PSD), as well as the dispersity and modality of these distributions may influence release behaviour by altering packing mechanisms within an injectable depot. Modification of these parameters is usually achieved by modifying the formulation composition itself – therefore convoluting the pharmacological effects of these parameters with those related to the formulation composition. Here, we present methods of controlling particle size parameters of a rifapentine (RPT) solid drug nanoparticle (SDN) formulation via several formulation approaches without altering the formulation composition.

Methods: RPT (40 wt%) SDNs, stabilised by trehalose (37.45 wt%), Plasdone^TM C-15 (21.75 wt%), sodium bis(2-ethylhexyl) sulfosuccinate (AOT, 3.0 wt%), and sodium ascorbate (0.5 wt%) were prepared via nanoprecipitation spray drying (NP-SD). A solution of RPT/AOT in either methanol (control), acetone/ethanol (1:1 A:E), acetone/methanol (9:1 A:M) or butanone/ethanol (1:1) was added – with stirring – to an aqueous solution of the remaining excipients (trehalose/Plasdone^TM C-15/sodium ascorbate). The resulting suspension was spray dried under nitrogen to yield a dry SDN powder.  Analogous SDN formulations were prepared to identical solid mass compositions via wet milling (20 Hz, 180 mins, stainless steel milling media) and in-line mixing (25,000 RPM, 80 mins). Dry SDN powders were reconstituted in dH₂O to [RPT] = 1.0 mg mL^-1 and analysed via dynamic light scattering.

Results: Control of particle size was demonstrated by alteration of the solvent system from which RPT was precipitated. Methanolic NP-SD afforded nanoparticles with small, narrow PSDs (186 ± 4 nm, PDI = 0.07 ± 0.01). PSDs were shown to increase after precipitation from acetone-based solvent systems (1:1 A:E = 238 ± 2, PDI = 0.11 ± 0.04; 9:1 A:M = 275 ± 6 nm, PDI = 0.09 ± 0.02) A marked increase in D_z was observed for RPT SDNs prepared from 1:1 butanone/ethanol (626 ± 17 nm), with an associated increase in PDI (0.40 ± 0.02).  Blends of RPT SDNs with differing PSDs afforded dispersions with controllable particle size characteristics (Figure 1). Milling of RPT also generated SDNs with altered particle size distributions – producing a multimodal PSD with D_z = 308 ± 6 nm (PDI = 0.37 ± 0.06).

Conclusion: Herein we have demonstrated control over a range of identical RPT SDN formulations via formulation approach, generating formulations having differing particle size distributions while maintaining the exact control composition, providing scope for the investigation of the effects of these particle characteristics on pharmacokinetic release profiles in vivo.

Acknowledgements: This work was funded through the UK national hub for advanced long-acting therapeutics (HALo).

Particle size distributions of RFP SDNs nanoprecipitated from A) 100% MeOH and B) 1:1 butanone/ethanol measured by DLS at 1.0 mg/mL [RFP]

Z-average diameter (Dz, circles) and polydispersity index (PDI, triangles) RFP SDNs precipitated from A) 100% MeOH and B) 1:1 butanone/ethanol prepared as blends of differing ratios of A:B.