(M1330-07-45) Formulation of Rapidly Dissolving Amorphous Solid Dispersion of Posaconazole, an Extremely Water-Insoluble Basic Drug via Hot-Melt Extrusion by Applying Acid-Base Supersolubilization Principle

Purpose: Posaconazole (PCZ) is a weakly basic drug with the reported pKa values of 3.6 and 4.6 and extremely low aqueous solubility of less than 0.3 µg/mL in the intestinal pH range of 5.5 to 7.5. Merck corporation has marketed it in the form of oral suspension, oral delayed-release tablet, and injection with the trade name of Noxafil^® to combat invasive fungal infections in immunocompromised patients. However, due to its poor solubility, posaconazole has been reported to exhibit a slow dissolution rate and variable bioavailability. This presentation details the results of a study where the aqueous solubility of posaconazole was increased by interacting with malic acid (MA) using a technique known as acid-base supersolubilization. The interaction between posaconazole and malic acid was then applied to develop an amorphous solid dispersion (ASD) with rapid drug dissolution rate and potentially higher bioavailability.

Methods: The posaconazole solubility in water was evaluated using solutions containing increasing concentration of malic acid by dissolving weigh amounts of malic acid per g of water. Excess amounts of API was then added, and the suspensions with excess amounts of drug were then shaken for 24h. The suspensions were then filtered and the dissolved drug concentration was measured by HPLC. In a second study, PCZ: MA mixtures at a 1:2 w/w ratio were prepared by mixing dry powders in a mortar and pestle, and the samples were heated at 5 ℃/min to observe a reduction in melting point due to the miscibility of PCZ with malic acid. Thermogravimetry analysis (TGA) at the rate of 10 ℃/min was conducted to confirm the thermal stability of the API and excipients. Then, to evaluate processing conditions, melt viscosity of physical mixtures namely, neat polymer, polymer-drug (90:10% w/w) and polymer-acid-surfactant-drug (50:20:20:10% w/w) were investigated to optimize the HME processing conditions. The polymer and surfactant employed in this study were Affinisol HPMC-15LV and poloxamer-407, respectively. The temperature sweep analysis for melt viscosity determination was performed from 100 ℃ to 190 ℃ at 5 ℃/min with a constant angular frequency of 0.1 rad/s. The angular frequency analysis ranged from 0.1 to 100 rad/s, at a constant temperature of 140 ℃. ASDs were prepared by Thermo Fisher Scientific Process 11 hot-melt extruder, where processing conditions were optimized, and extrudates were prepared using a suitable extrusion temperatures and the extrusion rate of 100 RPM. The extrudates were milled, and their solid-state properties were evaluated using differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD). Finally, an in-vitro dissolution test was performed using USP Apparatus II at 37 °C and 75 RPM using 100 mg drug equivalent and 250 mL of 0.01N HCl (pH 2) for 2h. Following dissolution at pH 2, the pH was adjusted to 6.8 and the dissolution was continued for additional 2h.

Results: Initially, it was confirmed that PCZ exhibited a solubility as high as106 mg per gram of malic acid solution. Using hot-stage microscopy, we confirmed that PCZ exhibited a melting point of 167 ℃; however, in presences of malic acid (1:2 w/w ratio), the physical mixtures melt at a temperature of 130 ℃. Then, the thermal stability of PCZ and several other excipients was confirmed via TGA analysis. Subsequently, using a rheometer, we confirmed that PCZ did not plasticize neat HPMC or decrease its melt-viscosity when used alone. However, the addition of malic acid and Poloxamer 407, caused a substantial decrease in melt-viscosity, allowing the physical mixture to be processed at temperatures as low as 140 °C. After the optimization of the processing parameters, a formulation comprising 10% PCZ, 15% Aeroperl-300, 20% malic acid, 20% Poloxamer-407, and 50% HPMC was developed via HME. Furthermore, using DSC and PXRD analysis, the amorphous nature of the prepared formulation was confirmed. Then, via in-vitro dissolution testing we confirmed that our prepared formulation containing 100 mg of PCZ exhibited complete drug release in presences of 250 mL of 0.01N HCl whereas the formulation precipitated as small micron sized particles ( < 5 µm) at pH 6.8 which remained dispersed throughout the dissolution media. Furthermore, the precipitated samples were collected, dried and analyzed using DSC to confirm that the precipitates were crystalline in nature and exhibited a melting point of 160 ℃. Therefore, by employing the ABS concept, we effectively synthesized ASDs that substantially improved the dissolution profile of posaconazole under gastric pH conditions.

Conclusion: By employing malic acid as supersolubilizing agent, we successfully reduced the melting temperature of PCZ to 130 ℃, and developed ASDs via HME using the ABS principle that considerably improved the dissolution profile of PCZ.

Acknowledgements: The author would like to thank St. John's University for financial support.



Figure 2: subfigure A represents temperature sweep analysis and subfigure B represents angular frequency analysis of 1-Neat HPMC-15LV, 2-HPMC-PCZ (90:10% w/w) and 3-HPMC-MA-P407-PCZ (50:20:20:10% w/w). The temperature sweep analysis was performed from 190 oC to 100 oC using a constant angular frequency of 0.1 rad/s and oscillation strain of 0.5%. The angular frequency analysis was performed using a constant temperature of 140 ℃ using angular frequency from 0.1 to 100 rad/s. Each data point is an average of 3 determinations.


Figure 3: Dissolution profile of (1 black line) neat PCZ, (2 red line) HPMC-PCZ [90:10% w/w], (3 blue line) HPMC-P407-MA-PCZ [50:20:20:10% w/w], (4-green line) aeroperl-300-P407-MA-PCZ [50:20:20:10 w/w], (5-purple line) HPMC-aeroperl-300-P407-MA-PCZ passed through 1.0 micron filter [35:15:20:20:10% w/w] and (6-yellow line) HPMC-aeroperl-300-P407-MA-PCZ passed through 5.0 micron filter [35:15:20:20:10% w/w]. Each formulation contains 100 mg of PCZ equivalent in 250 mL of dissolution media at 37 oC. The dissolution testing was conducted for 2 h at pH 2 (0.01N HCl) after which the pH was adjusted to 6.8 using Na3PO4.12H2O and dissolution testing was continued for another 2 h. The aliquots were filtered through 1.0 μm and 5.0 μm PTFE syringe filters before HPLC analysis.