Deaggregation of micronized insoluble drugs by incorporating mannitol form α.

Micronization is frequently employed to increase the dissolution of poorly soluble drugs, but it easily led to powder aggregation and difficult to mix well on the micro level with poor content uniformity and erratic dissolution behavior. Mannitol is the most commonly used pharmaceutical excipient, and its β form (β-mannitol) is commercially available and extensively investigated, whereas form α (α-mannitol) remain poorly understood. Here, this study demonstrated that α-mannitol could significantly eliminate aggregation phenomena of micronized drugs (i.e., lurasidone hydrochloride, indomethacin and ibuprofen) after general mixing, while β-mannitol could not. In addition, the drug dissolutions after mixing with α-mannitol were also significantly higher than that with β one. This stemmed from the different molecular orientation on their dominant crystal facets, resulting in greater number of unsaturated hydrogen bonds site (0.050 Å-2vs 0.042 Å-2) on α-mannitol's crystal facet {013}, leading to more positive charge and negative charge site and higher surface energy (64.42 mJ/m2vs 50.26mJ/m2). Subsequently, this increased the interaction between drug and α-mannitol, which is higher than interaction between drug itself, also higher than interaction between drug and β-mannitol, resulting in adhesion of drug powder on α-mannitol rather than cohesion into aggregates. Moreover, after 30 days of storage at 60 °C or 92.5 % relative humidity, the polymorphic purity of α-mannitol remained above 99 %, indicating good polymorphic stability during transportation and storage. This work illustrates that α-mannitol exhibited great potential to serve as a new pharmaceutical excipient in solid dosage forms. We believe that utilizing the benefits of polymorphism and mitigating their limitations will exert great potential for the development of functional pharmaceutical excipients.