(T1430-12-78) Preliminary Study of How Capsule Materials Influence the Physical Stability of Dried Powder Inhalers

Purpose: Capsule-based dry powder inhalers (DPI) are a convenient option for delivering therapeutics directly to the lungs.¹ Commonly, pharmaceutical capsules are fabricated from gelatin or hydroxypropyl methylcellulose (HPMC). In this work, we aimed to evaluate the effect of capsule composition on the solid-state stability of encapsulated powders. For this purpose, we used lactose prepared by spray drying to determine changes in their solid state after different storage conditions. Lactose is a commonly employed excipient for inhaled powders and has four known polymorphs.^2,3

Methods: Lactose powders were prepared using a Büchi Mini Spray Dryer B-290 (Flawil, Switzerland) with an inlet temperature set at 130°C and an aqueous lactose solution at 5% (w/v) atomized at a flow rate of 2.5mL/min. 30 mg of the dried lactose powder was encapsulated in gelatin or HPMC capsules (ACGcaps^TM ), and the powder in capsules was stored in closed glass vials at 75% relative humidity and 40°C for one week. Separately, dynamic vapor sorption (DVS, Surface Measurement Systems Ltd., London, UK) was used to evaluate the humidity-dependent mass increase of capsules, spray-dried lactose, and Respitose ®SV003 (DFE Pharma, Goch, Germany). The samples were analyzed using wide-angle x-ray scattering (WAXS) to determine changes in their solid state using a SAXSLab instrument (WAXSLab, Northampton, MA, USA) equipped with a PILATUS3 R 300 K detector (DECTRIS Ltd., Philadelphia, PA, USA). Additionally, the particle size distribution of spray-dried lactose, freshly prepared and after 6 months of storage, was characterized using a HELOS-R laser diffraction tester attached to the RODOS dry powder disperser (Sympatec GmbH, Clausthal-Zellerfeld, Germany). RODOS was loaded with 3 mg of powder (n = 3) and operated at a dispersion primary pressure of 2 bar.

Results: The DVS results of the capsule shells showed that gelatin more rapidly absorbed moisture, increasing its weight by ̴30%, with an abrupt increment in the range of 75-90% RH (Figure 1a). In the case of HPMC capsules, there was a total increase in weight ( ̴21%) at 90% RH. These differences are likely be related to the amino acid composition of gelatin which has a higher tendency to form hydrogen bonds with water than HPMC moieties.⁴ Regarding Respitose ®SV003, there was a minimal increase in weight ( ̴0.4%) because of the presence of the monohydrate form of lactose, as confirmed by WAXS (Figure 2.). On the other hand, spray-dried lactose showed a 13% weight increase at 90% RH, retaining a 5.5% weight increase at the end of the cycle. This is because the spray-dried lactose was an amorphous material (with small traces of crystallinity), which may be converted into the monohydrate form. To further understand these weight differences during DVS, encapsulated samples were stored at 75% RH and 40° C (accelerated stability conditions) for 1 week. Then, WAXS showed changes in crystallinity and polymorphic forms. Spray-dried lactose encapsulated in both HPMC and gelatin capsules, recrystallized into lactose monohydrate from the amorphous state. Additionally, some peaks corresponding to the β-lactose form were also detected. There were minimal changes observed in the gelatin capsules loaded with Respitose ®SV003; it maintained its monohydrate form. However, some traces of the β-lactose form were detected. Interestingly, HPMC capsules loaded with Respitose ®SV003 showed a noticeably different peak pattern, being a mixture of β-lactose (peaks at 19.2, 25.6, 28.0, and 31.8° 2θ) and the monohydrate form. On the contrary, the spray-dried samples that were stored in vials under vacuum remained amorphous after 6 months. But, there was an increase in their particle size by 5-fold (d90: 3.65µm to 21.13 µm) during storage.

Conclusion: During the different storage conditions, crystallization and polymorphic changes were observed in the different capsule/lactose combinations by WAXS, which is a technique with higher sensitivity than traditional X-ray powder diffraction. Even when spray-dried lactose remained amorphous, it is necessary to determine its particle size distribution and changes in aerosolization. Further experiments will focus on how capsule polymer affects the physical stability of encapsulated powders for inhalation.

References: 1. Buttini, F., Quarta, E., Allegrini, C. & Lavorini, F. Understanding the Importance of Capsules in Dry Powder Inhalers. Pharmaceutics 13, 1936 (2021).
2. Ke, W.-R., Chang, R. Y. K., Kwok, P. C. L., Chen, D. & Chan, H.-K. Spray drying lactose from organic solvent suspensions for aerosol delivery to the lungs. Int. J. Pharm. 591, 119984 (2020).
3. Rowe, R. C., Sheskey, P. J. & Quinn, M. E. Handbook of pharmaceutical excipients. (2009).
4. Yang, N. et al. Moisture sorption and desorption properties of gelatin, HPMC and pullulan hard capsules. Int. J. Biol. Macromol. 159, 659–666 (2020).

Figure 1. (a) DVS Isotherms plot of HPMC and gelatin capsule shells. (b) DVS Isotherms plots of spray-dried lactose and SV003 lactose. (c) Close-up of the SV003 lactose DVS Isotherm.

Figure 2. (a) WAXS of encapsulated SV003 lactose after storage at 75% RH and 40°C. (b) WAXS of encapsulated spray-dried lactose after storage at 75% RH and 40°C. Peak pattern of SV003 lactose and spray-dried (SD) lactose as reference.

Table 1. Particle size distribution of spray-dried lactose before and after six months of storage. The samples were maintained under vacuum and at room temperature.