The role of intrinsic fines in the performance change of expired lactose carriers for DPI applications

Dry powder inhalation offers a well-established administration route for either local or systemic drug delivery. Lactose-based powder blends still build the basis of respiratory drug delivery, despite of numerous emerging formulation approaches. The amount of fine lactose excipients, either extrinsic or intrinsic, crucially influences the aerodynamic performance of the corresponding blend. This study highlights the role of intrinsic fines as a fundamental performance affecting parameter during storage and expiry of lactose carrier bulk. We showed that intrinsic fines play an inferior role after expiring compared to fresh batches. If strongly adhering or even merged fines regain their mobility and contribute to the dispersion (by removal and re-addition), it will significantly enhance drug delivery. Furthermore, we provide evidence for decreased mobility of intrinsic fines caused by humidity (e.g., during inappropriate storage) resulting in decreased powder fluidisation.

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About this article: Nicholas Bungert, Mirjam Kobler, Regina Scherließ, The role of intrinsic fines in the performance change of expired lactose carriers for DPI applications, European Journal of Pharmaceutics and Biopharmaceutics,
Volume 175, 2022, Pages 7-12, ISSN 0939-6411, https://doi.org/10.1016/j.ejpb.2022.04.006. (https://www.sciencedirect.com/science/article/pii/S0939641122000789)

Materials
The carrier material investigated in this study was a highly crystalline, inhalation grade lactose (InhaLac® 230, IH230, Meggle, Wasserburg, Germany). In the following sections, we refer to a fresh batch as a batch that was still ahead of its retest date (< 12 months) and stored in its commercial packaging (sealed aluminium bag) at non-monitored benchtop conditions. Furthermore, we used an expired batch of the same carrier quality, stored batch. “Expired” refers to InhaLac 230, which was stored outside of its commercial packaging (wide neck screw top drum) at non-monitored benchtop conditions (IH230 (ex)) for more than 36 months.

See the overview video of the Meggle Inhalac product range here:

https://www.pharmaexcipients.com/wp-content/uploads/2021/04/MEGGLE-Dry-Powder-Inhalation-InhaLac.mp4

Conclusion
In this study, we assessed the decreasing aerodynamic performance of expired lactose batches and attributed this behaviour to the availability of intrinsic fines. We were able to show that FPFs of old, expired batches did not change significantly after removing their intrinsic fines.

The shrinking role of intrinsic fines after expiry in powder fluidisation was confirmed in powder rheometric measurements. Furthermore, we were able to reproduce the powder characteristics of the IH230 (ex) batch by high RH storage. We hypothesised, fines began to fuse with the carrier particle in a humid environment, which prevents the respective fines from contributing to the powder dispersion [17].

This work highlights the need to control the storage conditions of excipients used in DPI applications. Even though it was possible to release strongly bound fines by means of high-pressure dry dispersion (e.g., in laser diffraction measurement), the expired batches still reached significantly lower FPFs than the fresh ones. Consequently, the intrinsic fines are not the only detrimental change after long-time storage. Nevertheless, our study emphasises the present risk of solely relying on well-established characterisation techniques such as PSD measurement in quality control or re-test analysis as this may show fines that, however, are not able to contribute to the aerodynamic performance. PSD measurements at more realistic dispersion pressures may be a promising approach in future studies and eventually to be implemented in quality control.

Additionally, this study provides further insights into the crucial role of fine excipient fractions in lactose for inhalation. Whether to work with qualities containing higher ratios of intrinsic fines, or to manually add micronised lactose to a quality without intrinsic fines, is multifactorial: Depending on regulatory requirements, device specifications and many more, formulation scientist will make their choice. Both strategies allow for a full exploitation of the beneficial effects of fine excipients. Nevertheless, we conclude from this study that both strategies may be vulnerable to humidity dependent performance loss. Thus, lactose carriers containing fine fractions should always be used as fresh as possible.