Influence of homolog composition and hydration states of magnesium stearate on carrier-based dry powder formulations for inhalation

Abstract

Magnesium stearate (MgSt) has been used as a force control agent (FCA) to enhance the aerosol performance of carrier-based dry-powder inhalers (DPIs). MgSt is a mixture of magnesium salts of fatty acids—primarily stearic acid (SA) and palmitic acid (PA)—and the SA:PA ratio can vary depending on the natural source. In addition, different processing routes can yield variation in both chemical and solid form composition of commercial grade MgSt. This study investigated whether variations in fatty acid composition and hydration state (hydrate form) of MgSt affect the aerosol performance of carrier-based DPIs. Samples of MgSt with different SA/PA molar ratios and hydration states were obtained and micronized, then blended with coarse lactose (carrier) and tratinterol hydrochloride (TH), a new long-acting bronchodilator used as a model drug, to prepare DPI formulations (TH-DPIs). After physicochemical characterization, the aerosol performance of the TH-DPI formulations was assessed using a Next Generation Impactor (NGI). NGI results showed that the fine particle fraction (FPF) of TH-DPIs increased with increasing MgSt content, irrespective of fatty acid composition or hydration state. Changes in the SA/PA ratio had little effect on aerosol performance. In contrast, formulations containing trihydrate MgSt generally exhibited higher FPFs than those containing dihydrate or low-hydration MgSt. In conclusion, changes in the hydration state of MgSt exert a greater impact on DPI aerosol performance than variations in its fatty-acid composition.

Introduction

In recent years, dry powder inhaler (DPI) formulations are well established for the treatment of pulmonary diseases (Boer et al., 2017). Most of DPIs are composed of coarse lactose particles as carriers (> 50 μm) and micronized drug particles (< 5 μm), in which the carriers prevent the aggregation of drug particles, increase the powder bulk and improve the flowability (Ooi et al., 2011). However, some studies have shown that the excessive adhesion between the carrier particles and drug particles confines the separation of the drug from the carriers, which is the main factor leading to the low efficiency of drug delivery (Begat et al., 2004; Pilcer et al., 2012; Xian et al., 2000). To overcome this challenge, different methods have been attempted to reduce the strong interaction between micronized drug fine particles and the carriers, in which an addition of force control agent (FCA) in DPIs is considered to be an effective method (Peng et al., 2016). As one of the FCAs, magnesium stearate (MgSt) is well-known for the improvement of aerodynamic performance of carrier-based DPIs (Begat et al., 2005; Jetzer et al., 2017). It has been used in some Food and Drug Administration (FDA) approved DPI products, such as Foradil Certihaler® and Breo Ellipta® (1% in vilanterol dry powder) to improve the lung deposition efficiency of the active pharmaceutical ingredients. Our recent study also showed that MgSt is capable of improving lung deposition of tratinterol hydrochloride (TH), a new long-acting bronchodilator with strong β2 adrenoceptor stimulation activity by formulating them into carrier-based DPIs (Liu et al., 2022). That study also showed that, compared to MgSt as received, fine particle fraction (FPF) of TH could be improved further when it was formulated with micronized MgSt (Liu et al., 2022).

Even though there are many papers reporting the FCA role of MgSt (Guchardi et al., 2008; Lau et al., 2017; Peng et al., 2016; Zhou et al., 2012), the exact mechanisms behind improving aerosol performance of DPI by this excipient have not been fully understood. It is generally believed that MgSt can coat the surface of the coarse lactose particles as carriers upon the mixing process involved in the preparation of dry powders for inhalation. The lipophilic carbon chains of MgSt are aligned outward, which consequently reduces the strong binding of drug particles to the lactose carrier. As a result the fine drug particles can readily detach from the carrier and result in enhanced lung deposition during inhalation. However, there was no quantitative analysis of the modifying effect of MgSt. Moreover, MgSt is a mixture of magnesium salts of fatty acids — primarily stearic acid (SA) and palmitic acid (PA). These fatty acids are commonly found together in natural sources (like animal fats or vegetable oils), which are used in the industrial production of MgSt. Commercial MgSt often contains both magnesium stearate and magnesium palmitate. The SA/PA ratio depends on the source of the fatty acids and the manufacturing process and purification steps.

In addition, MgSt can possess multiple hydration states (hydrate forms): anhydrate, monohydrate, dihydrate and trihydrate (Delaney et al., 2017). MgSt can exist as dominantly single hydration state system, or contain multiple hydration states (Swaminathan and Kildsig, 2001). The impact of this variation has been thoroughly investigated for tablet manufacturing processes, as exemplified by Calahan et al. (Calahan et al., 2020). However, the studies on how different hydration states of MgSt affecting aerosol performance of DPIs are limited, although a recent study reported that the monohydrate form of magnesium stearate improved the DPI performance of arformoterol and budesonide more effectively than the anhydrate or dihydrate form (Jeong et al., 2025).

Interestingly, trihydrate form of MgSt was not included in the study. It should be noted that crystal structures of commercial MgSt hydrate forms have not yet been published, despite the efforts to characterize, e.g., the pure magnesium stearate hydrate forms(Herzberg et al., 2023).

Tratinterol hydrochloride (TH; 2-(3-chloro-4-amino-5-trifluoromethyl-phenyl)-2-tert-butanol·HCl) is a novel, long-acting β₂-adrenergic receptor agonist (LABA) that displays high receptor selectivity. A phase-III oral-dose trial showed TH to be as effective and well tolerated as procaterol hydrochloride tablets (Kong et al., 2021). Our previous work has additionally demonstrated the feasibility of formulating TH as a dry-powder inhaler (Liu et al., 2023).

This study aimed to investigate whether the variation in the SA/PA ratio and the hydration states including trihydrate form of MgSt would influence the aerosol performance of DPIs of TH, a new long-acting bronchodilator. To this end, we prepared various MgSt with different SA/PA ratios and hydration states prior to modifying coarse lactose particles with these MgSt. TH was used as a model drug to prepare carrier-based DPIs in this study. The effect of various MgSt on the aerosol performance of TH-DPIs was assessed using next generation pharmaceutical impactor.

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Materials

Coarse lactose (Lactohale® 206, α-lactose monohydrate,) was donated by DFE pharma. Tratinterol hydrochloride (TH) was supplied by Jinzhou Jiutai Co., Ltd, the micronized TH fine powders was described in our previous study (Liu et al., 2023). MgSt (SH-YM-M) was provided by Anhui Sunhere Pharmaceutical Excipients Co., Ltd. Stearic acid and palmitic acid (purity >97%) was obtained from Shanghai Macklin Biochemical Technology Co., Ltd. Sodium hydroxide, magnesium chloride hexahydrate, acetone and Tween 80 of chemical grade, and all other chemicals and solvents of HPLC grade were purchased from Shandong Yuwang Pharmaceutical Co., Ltd. #3 hydroxypropyl methyl cellulose (HPMC) capsule was a gift from Capsugel Co., Ltd. Purified water was obtained from Milli-Q water machine.

Tingting Liu, Wenwen Xu, Xiaoxiao Gao, Li Pan, Maosheng Cheng, Baoming Ning, Jukka Rantanen, Dongmei Cun, Mingshi Yang, Influence of homolog composition and hydration states of magnesium stearate on carrier-based dry powder formulations for inhalation, European Journal of Pharmaceutical Sciences, 2025, 107351, ISSN 0928-0987, https://doi.org/10.1016/j.ejps.2025.107351.

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