Twin-screw wet granulation: a novel manufacturing approach for solidifying nanosuspensions

Abstract

Despite their widely recognized performance-related benefits, nanosuspensions (NSs) present major challenges, mainly due to their poor stability during storage. Their transformation into solid dosage forms can overcome this limitation, but usually requires energy- and time-intensive manufacturing methods. In this context, we assessed a twin-screw wet granulation (TSWG) process, based on a dry binder approach, combined with fluid-bed drying (FBD) as a novel and scalable semi-continuous strategy for transforming NSs into solid orally administered dosage forms. Future optimization of the TSWG temperature may enable drying within the process stream, allowing the transition toward a fully continuous manufacturing approach. A DoE considering soluble (lactose, LAC; mannitol MAN) and insoluble (hydrated colloidal silicon dioxide, SYL; pregelatinized maize starch, PGS) fillers in different ratios was employed, using a model cinnarizine (CN)-containing NS as the wetting liquid and powder blends comprising a fixed combination of disintegrant, lubricant and glidant. The granules attained were checked for key quality attributes (e.g. physio-technological properties, nanocrystal redispersibility, release performance) and further evaluated as intermediates for tablet production. Overall, this strategy turned out effective in speeding up the identification of optimal formulations. Specifically, those containing lower amounts of SYL, irrespective of the paired soluble filler, yielded to granules with the most desirable characteristics in terms of CN load, porosity, redispersibility and compaction behavior. Conversely, analogous formulations containing PGS exhibited suboptimal compressibility and CN content, while MAN emerged as a more effective soluble filler. Finally, the nanoscale size of the drug, which was successfully preserved during processing, showed improved dissolution rate and transepithelial permeability in model Caco-2 cells.

Introduction

Over the past years, the continuous manufacturing (CM) approach has garnered significant interest in the pharmaceutical field [[1], [2], [3], [4]]. Under this framework, several unit operations involved in the production of a specific dosage form (e.g. blending, granulation, drying, milling, dosing, tableting) are integrated into a single, streamlined process. By leveraging process analytical technologies, it also enables real-time monitoring of the downstream manufacturing chain, supporting continuous optimization [[5], [6], [7]]. Due to these peculiar characteristics, CM allows overcoming the current limitations of the batch-wise manufacturing, such as unexpected inconsistency among batches, which are ruled out in a delayed manner with respect to the time of manufacturing, risk of contamination, and relatively long process times [[8], [9], [10], [11]]. In this respect, CM leads to substantial cost and time savings, facilitating shorter production cycles, reducing the number of processing steps, and minimizing energy consumption as well as waste, increasing the overall manufacturing efficiency while enhancing product consistency and reproducibility, which are critical for maintaining high-quality standards. The latter aspects are especially relevant today, as the pharmaceutical industry increasingly prioritizes sustainability and leaner manufacturing approaches. Its inherent flexibility in scaling either up or down allows for a more adaptable manufacturing process, which can quickly respond to changes in market demands, even including the new ones associated with personalized medicine. In a wider perspective, all these features make CM an interesting tool in the field of medicinal products, and its application potential deserves to be further explored [7,12,13].

Within the CM paradigm, twin-screw wet granulation (TSWG) stands out as a versatile, reliable, cost- and time-efficient method for producing solid oral dosage forms [14,15]. Indeed, it offers several advantages, including flexibility in formulation (i.e. type and amount of excipients), equipment design (i.e. screw elements and barrel configuration), and processing parameters (i.e. screw speed, feed rate) [16]. Moreover, TSWG supports both small- and large-scale production by simply adjusting the processing time and/or throughput, without the need to change the equipment in use. Finally, it enables robust in-line process controls, enhancing consistency and ensuring reliable product quality [[17], [18], [19], [20], [21], [22], [23], [24]].

Based on the addition of a granulation liquid to a powder stream, TSWG represents an advantageous alternative to freeze- and spray-drying for multi-particulate production. Depending on the process temperature control, it can be applied as a standalone single-step drying process or combined with a subsequent continuous fluid-bed drying (FBD) step. By way of example, the prolonged time required by spray-granulation methods not only increases production costs but can also lead to instability constraints, particularly when dealing with highly heat-sensitive materials, such as biopharmaceuticals, and with thermodynamically unstable systems, like nanosuspensions (NSs) [20,[25], [26], [27], [28]]. NSs are submicron-sized, colloidal, heterogeneous aqueous dispersions containing poorly soluble active pharmaceutical ingredients (APIs), with particle sizes ranging from 1 to 1000 nm [[29], [30], [31]]. Overall, they are characterized by an increased specific surface area (SSA) of the drug which can led to i) improved saturation solubility [32], ii) a faster dissolution rate as described by the Noyes-Whitney equation [32,33], and iii) enhanced mucoadhesive properties, which may prolong the residence time in the gastrointestinal tract, thus providing more time for the active molecule to completely dissolve [[34], [35], [36], [37]].

However, all these features, which could in principle improve drug bioavailability, are accompanied by major challenges, mainly related to the physical-chemical instability of the water-based nature of NSs. In fact, as the surface area increases, Gibbs free energy rises, leading to a thermodynamically unstable system sensitive to sedimentation, aggregation, solid-state transformation, and crystal growth phenomena. As a result, dimensional changes of the API nanoparticles may occur, worsening their dissolution performance and, ultimately, bioavailability [[38], [39], [40], [41], [42]]. In this respect, transforming NSs into more convenient solid products by downstream processes, taking advantage of appropriate drying methods, was described as an interesting strategy to address the above-mentioned challenges. Indeed, this approach not only enhances NS stability and ease of handling but also contributes to improve compliance from the patients’ perspective, as solid dosage forms remain the preferred route for drug administration [43,44]. Based on the aspects discussed above, this study preliminary evaluates the feasibility of TSWG for transforming a case-study NS into multiparticulate systems (i.e. granules) intended for oral administration. As an initial approach, TSWG was combined with a subsequent FBD step, resulting in a semi-continuous manufacturing process rather than a fully integrated continuous operation. However, further optimization of the barrel temperature during TSWG could promote in-line solvent evaporation and enable direct drying within the process stream itself, thereby allowing the transition toward a fully continuous manufacturing approach while reducing or potentially eliminating the need for an off-line drying step.

In this work, the TSWG process relied on i) a NS containing cinnarizine (CN) as a model drug, and ii) on the use of a dry binder, overcoming possible issues related to further addition of a binding solution. CN was selected as a model Biopharmaceutics Classification System (BCS) class II compound, a category comprising the majority of newly developed chemical entities [45]. Due to its very low aqueous solubility and pH-dependent dissolution behavior, CN represents a suitable benchmark for evaluating dissolution enhancement strategies based on nanonization [46,47]. In addition, its favorable safety profile simplify handling at relatively high concentrations during formulation development without raising major safety concerns for operators [[48], [49], [50], [51]]. Taken together these features make CN an interesting model drug for the purpose of this work. For guiding the experiments, a 23 full-factorial design was applied to investigate the formulation parameters (i.e. amount and type of fillers intended as carriers forming the powder bulk) and to evaluate robustness of the tested mixtures towards the addition of high amounts of water, as necessarily entailed by the use of a NS as the starting material. During the work, major efforts were dedicated to verifying that the transformation process did not change the particle size of drug, given its impact on CN dissolution rate and, therefore, on final in vivo performance.

Continue reading here

Materials

EXP: sodium starch glycolate (EXPLOTAB® CLV; JRS PHARMA, Rosenberg, Germany); A200: colloidal anhydrous silica (Aerosil 200; Evonik, Essen, Germany); PVP K-30: polyvinylpyrrolidone (Plasdone K30; Ashland, Hamburg, Germany); SSF: sodium stearyl fumarate (PRUV®; JRS Pharma, Rosenberg, Germany); LAC: spray-dried mixture of crystalline and amorphous lactose (Sheffield™ Spray Dried Fast Flo® 316; Kerry Group, Tralee, Ireland); MAN: spray-dried mannitol (PEARLITOL 200SD; Roquette, Lestrem, France).

Erasmo Ragucci, Victoria Pauli, Florence Desvignes, Marco Uboldi, Lorenza d’Adduzio, Carmen Lammi, Alice Melocchi, Mauro Serratoni, Lucia Zema, Twin-screw wet granulation: a novel manufacturing approach for solidifying nanosuspensions, Journal of Drug Delivery Science and Technology, Volume 124, 2026, 108597, ISSN 1773-2247, https://doi.org/10.1016/j.jddst.2026.108597.