Hetvi Triboandas¹, Mariana Bezerra¹, Delphine Ach-Hubert², Bruno Leclercq² and Walkiria Schlindwein¹ 

¹De Montfort University, Leicester, LE1 9BH  

²Medelpharm, F-01700 Beynost, France 

Purpose 

In this study, tablet compaction of amorphous solid dispersions (ASDs) of Itraconazole (ITZ) in Kollidon^® VA64 (KVA64) produced using continuous hot melt extrusion (HME) was undertaken, using the Styl’One nano compaction simulator. ASDs improve the poor solubility of the BCS Class II drug, compared to its pure crystalline form, however this enhancement is impaired at the tablets stage due to the high dose (100 mg) requirement and high polymer content (70%), which lead to low tensile strength of the compacts and delayed disintegration due to polymer gelation. To overcome these challenges, preliminary formulation strategies and the addition of five inorganic salts were explored; sodium chloride (NaCl) potassium chloride (KCl), bicarbonate (KHCO₃), dihydrogen orthophosphate (KH₂PO₄) and bromide (KBr).   

Methods 

Preliminary formulation strategies involved exploring excipients suitable for compaction, disintegrant type and decreasing the ASD percentage below 50%. The optimised tablet formulation compacted contained 44.44% ASD (100 mg dose), 10% Avicel^®PH102, 27.6% Tablettose^®70, 7.5% Kollidon^®-CL-SF and 0.5% magnesium stearate and the five salts (KCl, NaCl, KH₂PO_4, KHCO₃ and KBr) at 10%. The critical quality attributes (CQAs), tensile strength above 1.7 MPa and disintegration time less than 15 minutes, were tested for tablets produced at 200 MPa. Dissolution was also conducted on a final formulation with one salt (KCl) and compared to tablets comprised of the crystalline ITZ (physical mixture) and also the ASD without KCl.  

Results 

It was found that increasing the disintegrant amount (4 to 7.5%) and decreasing the ASD proportion (83.3 to 44.4%), alone did not enable disintegration. By increasing the tablet weight to 750 mg, it was possible to accommodate for the addition of inorganic kosmotropic salts. These promoted and accelerated disintegration greatly. Tablets containing KCl, KH₂PO₄ and KBr achieved the desirable tensile strength (above 1.7 MPa) whilst providing a quick disintegration time (<7 minutes). The drug release of crystalline ITZ tablets (PM+KCl) at 30 minutes was very poor (7%), compared to the ASD tablets with KCl (100%) and without KCl (21%) (Figure 1).  

Conclusions 

Several formulation strategies were adopted to overcome low tensile strength and delayed disintegration of ITZ ASD tablets. By adjusting tablet weight to 750 mg, the polymer content decreased which minimised gelation effects, along with room to add more soluble excipients such as, KCl, NaCl, KH₂PO_4, KHCO₃ and KBr. It was found that KCl and KH₂PO₄ were suitable candidates as the desired CQAs were achieved. The salt-polymer interactions effects have possibly modified the structure of water by the presence of ions beyond their hydration shells​ which impacted the disintegration mechanism and therefore allowing disintegration and dissolution of ITZ ASD tablets.