Abstract
The particle size reduction of active pharmaceutical ingredients is an efficient method to overcome challenges associated with a poor aqueous solubility. With respect to stability and patient’s convenience, the corresponding nanosuspensions are often further processed to solid dosage forms. In this regard, the influence of several formulation parameters (i.e., type of carrier material, type and amount of additional polymeric drying excipient in the nanosuspension) on the redispersibility of naproxen nanoparticle-loaded granules produced in a fluidized bed process was investigated. The dissolution rate of the carrier material (i.e., sucrose, mannitol, or lactose) was identified as a relevant material property, with higher dissolution rates (sucrose > mannitol > lactose) resulting in better redispersibility of the products. Additionally, the redispersibility of the product granules was observed to improve with increasing amounts of polymeric drying excipient in the nanosuspension. The redispersibility was observed to qualitatively correlate with the degree of nanoparticle embedding on the surface of the corresponding granules. This embedding was assumed to be either caused by a partial dissolution and subsequent resolidification of the carrier surface dependent on the dissolution rate of the carrier material or by resolidification of the dissolved polymeric drying excipient upon drying. As the correlation between the redispersibility and the morphology of the corresponding granules was observed for all investigated formulation parameters, it may be assumed that the redispersibility of the nanoparticles is determined by their distance in the dried state.
Highlights
Novel potential drug candidates often exhibit a poor aqueous solubility [1,2]
The underlying benefit of this approach is believed to be mainly driven by the increase in dissolution rate, as the latter is directly proportional to the surface area of a compound according to the Noyes–Whitney/Nernst–Brunner equation [4,5,6]
While this offers the possibility to generate amorphous nanoparticles [7,8], downsides of this approach are that corresponding processes are often difficult to control, yield low active pharmaceutical ingredients (APIs) concentrations, and result in related products that are challenging regarding stability and disintegration of final dosage forms
Summary
Novel potential drug candidates often exhibit a poor aqueous solubility [1,2]. Due to the fact that this potentially compromises the bioavailability, several formulation options (e.g., salt formation, complexation with cyclodextrins, and amorphization) have been developed in order to overcome issues associated with poor aqueous solubility [3]. Ostwald ripening may occur, especially when nanosuspensions with broad particle size distributions are produced, as larger particles may grow at the expense of smaller ones These physical instabilities may result in an alteration of the particle size in the suspensions and in a deterioration of dissolution properties and bioavailability [18]. Available literature describes bead-coating/layering with API nanosuspensions [29,30,31] or the application of the corresponding suspensions as granulation liquids in fluidized granulation processes [32,33,34,35,36] Most of these studies focus on the general feasibility of applying API nanosuspensions in the corresponding processes by showing enhanced dissolution profiles for nanoparticle-loaded products compared to the coarse API particles [29,30,31,32,33,34,35,36]. The product performance (i.e., redispersibility) was related to the structure of the corresponding granules, enabling a better understanding of the application of API nanosuspensions in a fluidized granulation process
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