α-Lactose monohydrate – new insights into physicochemical response to temperature and humidity exposure

Abstract

Environmental relative humidity (RH) and temperature (T) are known to be promoters of physicochemical changes in pharmaceutical grade lactose, either in controlled (supervised conditioning), or uncontrolled (during transit and repository storage) scenarios. Comprehensive knowledge of this excipient’s material characteristics prior to its use in formulation development is therefore a fundamental requirement. In this work, two kinetic processes are identified and characterized, namely crystallization and relaxation. The former is driven mainly by recrystallization of amorphous surface regions and may lead to particle aggregation and apparent growth, while the latter is explained by long-term structural reorganization and smoothing of particle surfaces. By quantitatively determining changes in amorphicity, particle size distribution, specific surface area, crystal structure and thermal properties, a two-step fitting kinetic model is proposed which captures experimental trends. The results show that while the crystallization component and initial relaxation is mainly driven by relative humidity, the long-term relaxation, which has a continuous impact on specific surface area, is less dependent on temperature and humidity and is only partially related to changes in amorphicity and apparent particle size.

Introduction

Lactose (α-monohydrate) is a key ingredient in pharmaceutical formulation, used mainly in solid dosage forms such as tablets, capsules and dry powders for inhalation, due to its safe toxicological profile, high biocompatibility and commercial availability (Pilcer and Amighi, 2010); (Dominici, et al., 2022). Regarding the field of dry powders for inhalation, an area where only few pharmaceutical excipients are approved, lactose is without comparison the main excipient material, and one used in a range of particle sizes, from coarse particles providing flowability to the powders, to very fine micronized particles. Inhalation formulations are either produced as soft spherical agglomerates or, more commonly, as adhesive mixtures (formerly called “ordered mixtures”) (Hersey, 1975); (Hoppentocht et al., 2014). The soft agglomerates normally consist of a mixture of micron-sized active pharmaceutical ingredient (API) and micron-sized lactose. In adhesive mixtures the main components are the lactose carrier particles and the micronized API; the API content is thus limited by the carrier’s surface capacity to bind the active substance.

Additionally, micron-sized lactose particles (termed “fines”) are frequently added to customize the formulation’s performance, thus resulting in a tertiary system: lactose carrier particles (D50 = 50–200  µm), lactose fines (D50 < 10  µm) and micron-sized API. To produce such pharmaceutical adhesive mixture formulations, fine tuning of the formulation properties is of utmost importance and is achieved by carefully selecting and processing the three components in adequate ratios to enable efficient and reproducible delivery to the lungs.

The routes for production of adhesive mixtures for inhalation have been scrutinized elsewhere (Whittier, 1944); (Pilcer et al., 2012). Still, prior to the actual mixing process, it is important to have a complete understanding of excipient materials to make educated selections, as their inherent characteristics will undoubtedly affect their interactions with the API. In this context, both intrinsic and induced characteristics of the lactose excipients (in combination with the formulation process) are critical to ensure that a well-performing and robust pharmaceutical formulation can be obtained. Characteristics such as particle size distribution, surface roughness and shape, as well as the intrinsic particle forces present, i.e. Van der Waals’, electrostatic and capillary forces (Dickhoff et al., 2006); (Thalberg, Sep. 2024) can all affect formulation performance. Excipients which are not physically inert but vary over time may induce changes in API dispersibility and eventually product performance. It has been shown that lactose inhalation mixtures exhibit changes in specific surface area (SSA) when exposed to different humidity conditions (Watling et al., May 2010). Similarly, several authors (e.g. (Kawashima et al., 1998) have reported the impact on drug delivery efficiency that arises from varying the SSA of carrier lactose. Additionally, the presence of lactose fines was documented to have a positive impact on the drug delivery efficacy (Zeng et al., 1998); (Zeng et al., 2001).

Although some of the excipients’ characteristics will be provided as part of the material specifications, these are not comprehensive. Even more important, not all characteristics remain unchanged over time, especially when exposed to varying transient and repository humidity (RH) and temperature (T) conditions. Similarly, ancillary processes in the production of lactose fines grades such as jet mill micronization can introduce amorphous surface regions during the fragmentation process (Briggner et al., 1994). To counteract such effects, additional steps are often undertaken to neutralize or reduce the high surface energy of the newly created amorphous surfaces via active recrystallization (Larsson, 2007) (Briggner et al., 1994). Such active recrystallization processes (normally termed “conditioning”) of partly amorphous particles will inevitably change the nature of the material by inducing a substantial decrease in SSA and consequently changing the interaction between excipient and API particles. All these factors will have a significant impact on formulation behavior and powder performance and must be addressed, understood and acknowledged prior to mixing.

In parallel to the crystallization process of amorphous surface regions, there is an additional component that exerts a continuous long-term impact on the SSA. This process appears to take place at elevated RHs, as previously studied in lactose blends (Watling et al., May 2010). The nature behind this mechanism is not fully understood, but it has been suggested that part of the explanation lies within a ‘healing’ process of crystal defects including the transformation of small fractions of anhydrate β-form into the α-form (Portnoy and Barbano, 2021), and the removal of ‘high energy sites’. Such changes have also been hypothesized to be due to dissolution-precipitation of narrow pores or interstices (and/or very small particles or surface asperities) due to the Kelvin effect and may even lead to formation of solid bridges (Watling et al., May 2010). The term “relaxation” is here used to describe these long-term processes.

The aforementioned crystallization and relaxation processes can often be inadvertently introduced, e.g. by exposure to varying humidity and temperature during transportation or secondary processing i.e., storage or handling. Hence, the combination of uncontrolled crystallization and relaxation events may result in the evolution of unexpected phenomena for pharmaceutical manufacturers and developers, including triboelectric charging (“statics”), caking due to bridge formation, and gradual changes in SSA. These effects will undoubtedly introduce variability in powder performance and give rise to production quality and stability issues.

The purpose of the present study is to provide a holistic analysis of two types of inhalation grade lactose, one lactose fines grade and one lactose carrier grade, with special emphasis on the physicochemical changes that arise as a result of environmental exposure and storage. Instead of targeting crystallization and relaxation separately, their combined effect on lactose excipients is investigated. Additionally, traces of β-anhydrate, and phase transformations between different crystal forms arising from environmental exposure are also investigated.

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Materials

Two freshly manufactured grades of lactose were used, which hereby are referred to as lactose fines (LF) and lactose carrier (LC) qualities. (Note the terms “fines” or “carrier”, and their respective acronyms will be used interchangeably.).

Andrea Sanchez-Valencia, Johanna Husman-Piirainen, Päivi Kokkonen, Annika Merikivi, Antti Toppari, Kyrre Thalberg, Bert van Veen, Lars-Erik Briggner, α-Lactose monohydrate – new insights into physicochemical response to temperature and humidity exposure, International Journal of Pharmaceutics, 2026, 126710, ISSN 0378-5173, https://doi.org/10.1016/j.ijpharm.2026.126710.

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