Category: Formulation and Quality
Purpose: Thanks to recent pediatric initiatives, there is an increasing need for taste masked drug products. Lipid Multi-Particulates (LMP) that are solid-phase lipid-based formulations could be an answer as they can be produced by many processes: thermoplastic pelletization, melt-spray congealing (MSC) or direct injection (DI) with a large selection of lipid-based materials. The latter two processes are of particular interest as they can produce LMPs without a solid-phase carrier, solvent, or any emulsifier for potential specific population benefit such as pediatrics and geriatrics. Indeed, both populations have specific needs like easy-to-swallow formulations, safe excipients, adaptable doses, and acceptable palatability. LMPs offer this flexibility as dosing solution. The current study proposes to explore the interplay of lipid material properties and process conditions (MSC and DI using a static mixer for continuous manufacturing) on the particulate properties and functionality of LMPs.
Methods: Lipid materials selected were hard fats (Suppocire® A and Gelucire® 43/01, Gattefossé, with melting temperature of 36°C and 44°C, respectively), a mixture of stearyl alcohol and poloxamer at 85/15% w/w (Crodacol™ S95, Croda; Kolliphor® P407, BASF with a melting temperature of 61°C), and glyceryl dibehenate (Compritol® 888 ATO, Gattefossé with a melting temperature of 71°C). Gelling agents selected were Carbomer Homopolymer Type A and Polycarbophil (Carbopol® 971P and Noveon® AA1, Lubrizol)
The MSC process consists in a melted lipid phase poured onto a rotating disc. Droplets are generated and crystallize in a cold air chamber. Process parameters explored were the temperature and speed of the rotating disk, and the lipid injection velocity.
The DI process consists in the injection of a melted lipid phase in a well characterized gel phase where the pore network generates and controls the size of the lipid droplets. Solid LMPs are formed after cooling of the suspension. Process parameters explored were the temperature of the lipid phase injection, the gelling agent type and concentration, and the ratio lipid/gel phases.
Gel and lipid properties were characterized by rheology, thermorheology, and DSC. The particulate properties of LMPs were characterized by optical macroscopy and particle size and shape distribution.
Results: LMPs particle size distribution and shape depend on the process selected. LMPs produced with the DI process exhibit higher circularity ( >0.9, Figure 1A) than those obtained by MSC where elongated spheres can be obtained when the lipid phase comprises plastic polymers (circularity ranging from 0.8 to 0.9, Figure 1B, C). The particle size distribution is also impacted by the choice of process, DI giving directly a rather narrow distribution (span < 1.5) whereas MSC can generate wider or even bimodal distribution especially for lipid phase with low plasticity. The main process parameter to control the size distribution of LMPs obtained by DI is the viscosity of the gel phase (Figure 2). For the MSC process the main process parameters are the rotating disk speed for controlling the LMPs size (Figure 3) and the lipid phase injection velocity for avoiding the formation of big agglomerates and favor high process yield (mean yield >90% for glyceryl dibehenate for example). Among lipid materials evaluated within this study, hard fats with a low melting temperature and a wide crystallization exotherm are well adapted for the DI process. This process is then chosen for target product profiles (TPP) such as immediate release or bioavailability enhancement. Conversely, MSC is amenable for other TPP like sustained drug release or taste masking where higher melting point lipid materials are needed.
Conclusion: This study demonstrates the critical process parameters for the DI and MSC processes and their impact on LMP properties. The main TPPs achievable with each process are conditioned by the properties of lipid materials needed to achieve LMPs with good particulate properties and high process yield.