(T0930-09-60) Poloxamers in Continuous Melt Granulation: Dual Role as a Binder and a Solubilizer

Purpose: Poloxamers are amphiphilic, non-ionic triblock copolymers with solubilizing and thermoplastic binding properties, ideal for melt granulation. Their low melting points (~50–60 °C) enable binder functionality without solvents. This study explores Poloxamers’ dual role—enhancing solubility and promoting granulation—for developing simplified, robust formulations of poorly water-soluble drugs through a solvent-free thermal agglomeration process.

Methods: Solubility studies were conducted using the shake flask method for four poorly soluble drugs: Nifedipine, Danazol, Naproxen, and Fenofibrate. Each drug was added in excess to water and 10% w/w aqueous solutions of Kolliphor® P 188, P 338, and P 407 (BASF Corp., USA), and stirred at 37 ± 1 °C for 72 hours. Samples were filtered (0.45 μm), diluted in methanol, and analyzed via UV spectroscopy (UV5, Mettler Toledo, USA). For melt granulation, Naproxen and P 407 were blended in 10:1, 2:1, and 1:1 ratios using an acoustic mixer (LabRAM I) at 70 ACC for 15 minutes. Granulation was performed using a twin-screw granulator (Pharma 11, Thermo Fisher Scientific) at 3 g/min. The screw design included one kneading zone (6th segment) and mixing elements to reduce lumping. Barrel zones 3–6 were heated to 60 °C, with segments 7–8 cooled to 35 °C and 25 °C to prevent agglomeration. Granules were sieved (#20) and milled (Fitzpatrick Co-mill). Characterization included bulk/tapped density (USP < 616 >), DSC (TA DSC 25), and XRD (Rigaku Smartlab, 2θ = 7–50°). In vitro dissolution (n=3) of granules equivalent to 250 mg Naproxen in pH 4.5 buffer was monitored using fiber optic probes (Rainbow, PION Inc.) in USP-II apparatus.

Results: Irrespective of the drug molecule, at a constant concentration, solubility followed the order: P 407 > > > P 338 > P 188 (Figure 1a). This trend can be attributed to key properties such as critical micelle concentration (CMC) and the hydrodynamic radii of the hydrophobic PPO core of the micelle, derived from the structural composition of various Poloxamer grades. In general, for a fixed PPO block, a higher EO content leads to less aggregation, smaller core size, and a more hydrophilic character. For instance, comparing Poloxamer 188 and 338, although they possess similar EO/PO ratios, the higher molecular weight of Poloxamer 338 indicates a larger hydrophobic domain, enabling accommodation of more drug molecules. This supports a higher concentration gradient for drug solubilization, and higher solubility in Poloxamer 338 as compared to Poloxamer 188. The graph (Figure 1b) below illustrates the fold increase in drug solubility achieved using different grades of Poloxamers. Notably, a remarkable enhancement in solubility was observed for Fenofibrate, showing approximately a 2250-fold increase in the presence of Poloxamer P 407 and an ~800-fold increase with Poloxamer 338. This pronounced enhancement can be attributed to the drug’s higher hydrophobicity, as reflected by its Log P value of 5.2, compared to other drugs in the study with Log P values ranging between 2.2 and 3.8. The stronger interaction of this highly hydrophobic drug with the hydrophobic micellar polypropylene oxide (PPO) core likely facilitates enhanced solubilization. Melt granulation produced robust granules, with higher Poloxamer 407 content requiring multiple milling cycles due to stronger binding and increased granule strength. Bulk density increased with rising P 407 levels: 0.41 vs. 0.18 g/mL (10:1), 0.44 vs. 0.22 g/mL (2:1), and 0.47 vs. 0.31 g/mL (1:1). DSC showed melting point depression, suggesting improved miscibility, while XRD confirmed Naproxen's crystallinity. Dissolution improved significantly at 2:1 and 1:1 ratios, indicating enhanced solubilization by P 407.

Conclusion: This study highlights the multifaceted functionality of Poloxamers, particularly P 407, in enhancing drug solubility and improving granule properties through melt granulation. Among the different grades, P 407 demonstrated superior solubilizing capacity, driven by its low critical micelle concentration and larger hydrophobic PPO core. In the context of melt granulation, increasing P 407 content significantly improved granule strength, as indicated by higher resistance to milling and increased bulk density. Thermal analysis revealed the melting point depression of Naproxen with increasing P 407, reflecting improved miscibility; however, XRD confirmed the retention of crystallinity. Despite this, formulations with higher P 407 ratios (1:1 and 2:1) exhibited markedly enhanced dissolution profiles compared to pure Naproxen and the 10:1 formulation. Overall, Poloxamer 407 proved to be an effective binder and solubilizer, offering a robust strategy for improving the performance of poorly soluble, hydrophobic drugs in melt granulation systems.

Figure 1(a)- left. Solubility of poorly soluble drugs in different Poloxamer measured at 37° C; Figure 1 (b)-right: Fold increase in the solubility compared to its solubility in water

Figure 2.. In-vitro release profile of Nap: P 407 (n=3) granules in various ratios as compared to pure Naproxen (left) in pH 4.5 acetate buffer, 500 mL, USP-II,: DSC thermograms (right)