Deaggregation of micronized insoluble drugs by incorporating mannitol form α

Abstract

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⁻² vs 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/m² vs 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.

Highlights

In comparison to mannitol form β, form α exhibited deaggregation function for micronized drug powders with increased mixing uniformity and improved dissolution rate.

The number of H-bond sites on the α-mannitol dominant facet {013} is higher than that of β-mannitol {002} facet, leading to more positive charge sites and negative charge sites, and higher surface free energy.

The interaction between drug and α-mannitol 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.

Introduction

Micronization is a frequently used pharmaceutical process to increase the surface area of drugs and hence improve the dissolution of poorly soluble drugs (Kawabata et al., 2011, Pinto et al. , 2012; Vogt et al., 2008). For dry powder inhalations, micronized drugs (2–5 μm) can increase drug deposition in the lungs, thereby enhancing the therapeutic efficacy for pulmonary diseases, such as chronic obstructive pulmonary disease (COPD), asthma, or cystic fibrosis (Spahn et al., 2022). However, decreasing particle size often results in increased Van der Waals’ interactions and electrostatic attraction between powder (Shah et al., 2017). This causes aggregation of powder, thereby compromising the increase in surface area gained by micronization, resulting in decreased dissolution rates (Saravanan et al., 2021; Heng et al., 2006) and reduced drug deposition in the lungs (Spahn et al., 2022). Additionally, powder aggregation can cause a decrease in flowability (Li et al., 2004), posing challenges in the manufacturing process (Olusanmi et al., 2014). There has been considerable interest in developing strategies for deaggregation of micronized drugs. One approach is surface modification, which involves incorporating inert groups onto the powder surface to reduce interparticle interactions, thereby facilitating deaggregation (Han et al., 2011, Qu et al., 2015). However, this method requires customized design based on the surface structure of individual drugs, making it a relatively complex process. On the other hand, mixing micronized drugs with appropriate excipients is a widely used strategy to prevent aggregation (Dudhat et al., 2023). Till now, most of the excipients reported are surfactants, which often lack adequate biocompatibility (Zhang et al., 2023). Therefore, there is a critical need to develop biocompatible pharmaceutical excipients to promote the deaggregation of micronized drugs.

In Inactive Ingredient Search for Approved Drug Products database (FDA, July 31, 2024), the oral max daily exposure of mannitol is 20.5 g, indicating its satisfactory biocompatibility. In this study, the aggregation phenomena of micronized drugs (i.e., ibuprofen (IBU), indomethacin (IMC), and lurasidone hydrochloride (LH)) were significantly improved with adding mannitol form α (α-mannitol) than adding mannitol form β (β-mannitol), and the content uniformity and dissolution rate of these drugs tablets were significantly increased. Nevertheless, in contrast to the extensively researched β-mannitol (De Pauw et al., 2022, Vanhoorne et al., 2020), α-mannitol has not been commercially available yet, and its potential pharmaceutical application is still in early stages. It would be systematically studied in this study, in order to establish the groundwork for the industrial application of this crystalline form of pharmaceutical excipient. In addition, a deep insight into the relationships between α-mannitol crystal structure and deaggregation functionality were provided from the macro and micro levels via surface free energy calculation and molecular simulation, respectively.

Materials

β-mannitol (Pearlitol® 25C) was obtained from Roquette (France). Lurasidone hydrochloride (LH, micronized, purity of 99.9 %) was kindly gifted by Changzhou Yinsheng Pharmaceutical Co., Ltd (Changzhou, China). Ibuprofen (IBU, purity of 99.9 %) was purchased from Shandong Xinhua Pharmaceutical Co., Ltd (Shandong, China). Indomethacin (IMC, purity of 99.9 %) was purchased from Shanghai Yuanye Biotechnology Co., Ltd (Shanghai, China).

Ke Zhang, Yan Miao, Huina Liu, Liqin Hu, Mi Tang, Yingran Duan, Yuan Gao, Shuai Qian, Jianjun Zhang, Yuanfeng Wei, Deaggregation of micronized insoluble drugs by incorporating mannitol form α, International Journal of Pharmaceutics, 2025, 125161, ISSN 0378-5173, https://doi.org/10.1016/j.ijpharm.2024.125161.