Fluidized bed granulation of a poorly soluble API with phospholipids to increase solubility

This poster has been presented at the  15th World Meeting on Pharmaceutics, Biopharmaceutics and Pharmaceutical Technology  which took place in Prague, Czech Republic.

Fluidized bed granulation of a poorly soluble API with phospholipids to increase solubility

INTRODUCTION

More and more active ingredients are considered to be poorly soluble.

• Challenge in the pharmaceutical industry (1, 2)
• Especially compounds that fall into the BCS Class II are relevant, they represent the majority of pipeline substances (3). Class II compounds exhibit low solubility and high permeability.
• Bioavailability of BCS class II compounds can be improved by increasing the dissolution rate.
• Wetting agents or surfactants can be used to improve the aqueous solubility and dissolution rates of poorly soluble drugs.
• This project aimed to investigate a method to improve the solubility of the BCS class II compound Naproxen (NAP).
• Two phospholipids (PL), PHOSPHOLIPON® 90 G (PLG) and PHOSPHOLIPON® 90 H (PLH), were investigated to improve the solubility and dissolution of NAP. A fluidized bed granulation method was developed to produce multiple formulations of granules. The suitability of the granules for tablet production as final dosage form was evaluated using both tablet compression and laser powder bed fusion (LPBF) 3D printing [Figure 1].

RESULTS AND DISCUSSION

Fluidized bed granulation

• The granules 3:1 NAP:PLG and 3:1 NAP:PLH achieved good flow properties with the corresponding Hausner ratios of 1.12 ± 0.043 and 1.15 ± 0.037.
• Narrow particle size distributions between 22 μm (d10) and 174 μm (d90) with d50-values between 65 and 83 μm were obtained [Figure 2].

Dissolution testing

• The raw NAP shows the slowest dissolution rate.
• All formulations of NAP containing PLs dissolve faster than raw NAP, especially in the range of 0 – 120 min [Figure 3].
• The fastest dissolution was observed for formulations containing a NAP:PL ratio of 99:1, independent of which PL was used.

Tablet properties

• It was possible to obtain tablets by applying tablet compaction and LPBF and with both phospholipid types, PLG and PLH.
• The compressed tablet properties varied depending on the type of phospholipid used.
• For the 3:1 NAP:PLG, no smooth surface is observed; artifacts from pronounced elastic recovery are visible in almost all tablets produced from this batch.
• The 3:1 NAP:PLH tablets, on the other hand, are very smooth and uniform [Figure 4].
• As expected, the 3D printed tablets are porous and uneven. There is no visible difference between the tablets, regardless of which granule batches were used.

Table 1 Quantitative formulation of granules

CONCLUSION

In this work, a fluidized bed granulation process for a poorly soluble API using phospholipids was successfully developed. The resulting granules showed good flowability. The in vitro dissolution profiles of the granules were analysed, and improved dissolution was achieved compared to the raw NAP. Two tableting techniques, compression and LPBF 3D printing, were tested, and tablet production was possible for both, leading to a potential final dosage form.

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Source: Annette Grave, Serafine Möri, Florian Engelsing, Richard Wibel, Peter Hölig, Julian Quodbach, Fluidized bed granulation of a poorly soluble API with phospholipids to increase solubility, Glatt, Lipoid, Utrecht University

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