Systematic investigation of thermal process parameters on the morphology of spray-freeze-dried powders

Abstract

Findings

Mannitol displayed pronounced process-dependent polymorphism, which is driven by annealing and temperature during sublimation. Lactose and trehalose remained amorphous throughout. Annealing above Tg’ promoted viscous flow within the vitrified matrices, producing partial particle fusion and reduced mechanical stability. Variations in recrystallization and Ostwald ripening during annealing systematically altered surface area and pore architecture. This connects annealing to sintering mechanisms, electrical conductivity and mechanical stability of micrometre sized spheres. Across all conditions, SFD consistently yielded spherical, low-density particles, yet the interplay of vitrification and phase transitions generated distinct microstructural outcomes

Introduction

Spray-freeze drying (SFD) is an emerging technique that enables the direct production of free-flowing, low-density powders from solution-based formulations. In contrast to conventional freeze-drying, where a liquid is frozen on trays or in vials, SFD involves atomizing the formulation into a cryogenic liquid or gas, followed by vacuum drying of the frozen droplets. This results in highly porous, spherical particles with large surface areas and favourable handling properties [1], which are characteristics particularly relevant in view of innovative pharmaceutical dosage forms for pulmonary, nasal, or oral solid drug formulations [2], [3], [4], [5], food processing [6], [7] and material science [8]. We propose that SFD can be regarded as a microscale freeze-casting process, in which ice templating within each droplet governs the formations of internal architecture and solid-state transitions. For this, it is essential to understand how freeze casting process parameters influence critical powder attributes, particularly morphology, density, specific surface area (SSA), and mechanical integrity [9].

In classical freeze casting, controlled nucleation allows ice crystal size to be tuned by initiating freezing at carefully chosen nucleation temperatures, yielding predictable pore structures besides shorter drying times [10]. In SFD into cool gases, droplets are frozen in free fall under dynamic conditions, where simultaneous nucleation control is not feasible, because droplets differ in size, undergo recoalescence and collision, and experience distinct cooling histories [11], [12]. As a result of droplet-wise, stochastic nucleation, the ice crystal framework in spray-freeze-drying may exhibit greater inter-particle variability than in bulk freeze-drying (FD), even when intra-particle structures are well defined [9], [13].

To preserve the spherical geometry of the resulting particles during SFD into cool gas, nucleation and complete freezing of the droplets must occur during free fall, before contacting reaching the collection surface at the bottom of the spray-freezing chamber, where the frozen droplets are collected. The set terminal temperatures in SFD into cold gas processes are therefore deeper compared to FD samples, with typical cryogen temperatures between 213 and 77 K (−60 and − 197 °C, [14]. Combined with small droplet volumes, cooling rates for SFD were proposed to reach up to 8.9 × 106 and 1.1 × 105 K/s for isopentane and liquid nitrogen, respectively [15], [16]. At such high rates, solidification below the glass transition of water (138 K, [17]) becomes possible, effectively vitrifying the matrix. In multi-component systems, the glass transition temperature (Tg) is expected to be elevated relative to pure water, consistent with the Gordon-Taylor model, due to the higher Tg values of the excipients. Solidifying below the Tg would kinetically trap the excipients in a rigid, metastable glassy matrix, with possibly unfavourable mechanical stability after drying if no subsequent devitrification is initiated.

Next to the exceptional behaviour of water as a solute, the matrix of the resulting product is governed by the glass transition temperature of the maximally freeze-concentrated matrix. If the excipients vitrify during solidification, these temperatures dictate whether the system behaves as a rigid glass or a mobile phase capable of rearrangement. Annealing can enable ice crystal growth (via Ostwald ripening) and further facilitate ice-solute separation. It has been proposed that vitrified water residues can be formed during the freezing process and that an annealing step would support the completion of the freeze-concentration process for subsequent freeze-drying [18]. Annealing has also been shown to improve drying kinetics in FD by creating larger, more open pores [10], and to increase the homogeneity of ice crystal size across fast-freezing cakes [19], [20], but also tends to reduce SSA [21].

In SFD, it could furthermore affect mechanical properties, by promoting the thickening of the solid framework, at the cost of the total number of structures (e.g. lamellae). Annealing could therefore be a suitable step in a SFD process, by allowing the water crystals to reorganize to a more homogeneous crystal framework across the powder particles. This would be especially relevant for complex excipients like mannitol, which is known to crystallize into multiple polymorphs, including α, β, and δ forms, and solvatomorphs, including hemihydrate and hydrate, depending on processing history. The occurrence of specific polymorphs can be influenced by the degree of molecular mobility during annealing, the presence of impurities, and the rate of water removal during drying. When crystallization occurs at sub-zero temperatures, mannitol has been reported to follow the Ostwald’s rule of stages, with metastable polymorphs forming first, and subsequent transition into the more stable forms [22]. Annealing has furthermore been reported to favour the reorganization of amorphous mannitol into thermodynamically more stable β and hemihydrate forms in the frozen solution [22], [23], as has recently been shown to be translatable to SFD [24], where longer annealing times (5 h, −50 °C) favoured the formation of the β polymorph, although their setup did not investigate different annealing temperatures and drying conditions..

In addition, high yields of β-mannitol formation have also been reported in SFD studies conducted without an explicit annealing step [25], [26]. These observations suggest that, beyond freezing temperature and annealing conditions, other stages of the process may contribute to polymorphic transitions. Collectively, these findings highlight the importance of considering SFD not as a single phase transition, but as a sequence of distinct yet interrelated transformations: the initial kinetically driven freezing of the solution (i), the subsequent thermodynamic reorganization of the water-solute system during annealing in accordance with temperature-dependent stability maxima (ii), and the progressive removal of water during drying (iii), which further shifts phase equilibria and may induce additional kinetically driven transitions.

An additional, so far unexplored, aspect is the restructuring of ice crystals and amorphous excipient during annealing, which may promote partial fusion at contact points between neighbouring particles, potentially leading to sintering. This has been observed in neighbouring comets and investigated in micrometre-sized pure ice particles [27], but not in icy spheres containing a solute. Since molecular mobility is not limited to water molecules, this could lead to the formation of powder aggregates, which could be potentially disadvantageous regarding various properties, such as limited handling properties.

Next to excipient type, freezing temperature, and annealing conditions, drying under vacuum at low shelf temperatures can help preserve the frozen morphology, maintaining lamellar frameworks and high SSA, but may prolong drying time. In contrast, higher drying temperatures accelerate sublimation but can promote pore collapse, facilitate late-stage crystallization, or again, induce partial fusion of neighbouring particles. Differences in drying temperature and pressure therefore directly modulate final powder morphology, SSA, and mechanical stability, interacting with prior annealing and excipient-specific behaviour.

This study focuses on how the thermal history of spray-frozen droplets shapes their internal architecture and solid-state properties. By controlling freezing, annealing relative to the glass transition, and drying, we investigate how ice growth, vitrification, and polymorphic transitions can be modulated to control properties of freeze casted powders.

A mechanistic understanding of the interplay of excipient properties with the spray-freeze drying processes enables the translation of porous architectures that are traditionally achievable only in bulk freeze-cast materials, into tunable, droplet-derived microstructures produced by SFD, opening new avenues for the design of low-density, high-surface-area porous materials.

To investigate these thermal history effects systematically, three pharmaceutically relevant excipients were selected: Mannitol was chosen as a common freeze-drying matrix with complex polymorphic behaviour, influencing particle morphology and mechanical stability [28]. Lactose was included for its FDA approval and widespread use in respiratory formulations, for SFD is increasingly utilized for pulmonary applications [26], [29], [30], [31], [32]. Trehalose was selected as its use in stabilizing amorphous structures and preserving surface area, as well as its common use in the preservation of biologicals [33], [34].

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Materials

Mannitol (Pearlitol® SD 200, Roquette, Lestrem, France), lactose monohydrate (FlowLac® 90, Meggle, Wasserburg am Inn, Germany), and D-trehalose dihydrate (Apollo Scientific, Manchester, United Kingdom) were obtained in pharmaceutical grade (EP/USP). Demineralized water (≤ 2 μS/cm) was used throughout.

Annika Rautenberg, José Ignacio Vázquez-Olvera, Paul Bühlbecker, Alf Lamprecht, Systematic investigation of thermal process parameters on the morphology of spray-freeze-dried powders, Journal of Colloid and Interface Science, 2026, 140304, ISSN 0021-9797, https://doi.org/10.1016/j.jcis.2026.140304.

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