Itraconazoin Case Study

2.3 Amorphous forms, solid dispersions and cocrystals.
Stable crystal forms of drugs pose problem in solubilization due to higher lattice energy. So, in regards to solubility, disordered amorphous forms provide distinct advantage over crystal forms. Hence, changing the solid state characteristics of pharmaceutical API renders the molecule more water soluble. But, excess of enthalpy, entropy and free energy of amorphous forms make them prone to crystallization leading to the formation of stable crystals43.Along with these stability issues, other factors like complicated manufacturing process have resulted in reduced generic competition for already approved amorphous products. However, improving stability of amorphous forms can look up for their use in pharmaceutical formulations44. Ceftin, a formulation containing amorphous form of Cefuroxime axetil (practically insoluble in water) was launched by GlaxoSmithKline.
At neutral pH, Itraconazole has a negligible solubility of 1ng/mL52.For preparing solid dipersions of Itraconazole, spray layering technology was used in which organic solution of drug and Hydroxylpropyl methylcellulose (HPMC) was sprayed over sugar beads to form thin film consisting of molecularly dispersed drug and polymer. This amorphous formulation reported enhanced bioavailability than that of crystalline Itraconazole. Apart from spray layering, Itraconazole solid dispersions were also prepared using hot melt extrusion with varying polymers such as HPMC, Eudragit E100 and Eudragit E100 and Polyvinyl pyrrolidone(PVP) mixture. In vitro studies revealed a faster dissolution of SDs containing Eudragit E100 in comparison to HPMC and Sporanox52. In contrast to it, clinical studies revealed a similarity between SDs containing HPMC and Sporanox, which can be attributed to the solubilization and stabilization effects of HPMC in physiological (in vivo)