Needles to Spheres: Evaluation of inkjet printing as a particle shape enhancement tool

Active pharmaceutical ingredients (APIs) often reveal shapes challenging to process, e.g. acicular structures, and exhibit reduced bioavailability induced by slow dissolution rate. Leveraging the API particles’ surface and bulk properties offers an attractive pathway to circumvent these challenges. Inkjet printing is an attractive processing technique able to tackle these limitations already in initial stages when little material is available, while particle properties are maintained over the entire production scale. Additionally, it is applicable to a wide range of formulations and offers the possibility of co-processing with a variety of excipients to improve the API’s bioavailability. This study addresses the optimization of particle shapes for processability enhancement and demonstrates the successful application of inkjet printing to engineer spherical lacosamide particles, which are usually highly acicular. By optimizing the ink formulation, adapting the substrate-liquid interface and tailoring the heat transfer to the particle, spherical particles in the vicinity of 100 µm, with improved flow properties compared to the bulk material, were produced. Furthermore, the particle size was tailored reproducibly by adjusting the deposited ink volume per cycle and the number of printing cycles. Therefore, the present study shows a novel, reliable, scalable and economical strategy to overcome challenging particle morphologies by co-processing an API with suitable excipients.

Introduction

The reasons for the challenging development of novel pharmaceutical formulations are manifold. First, new chemical entities are often classified as class II or class IV in the biopharmaceutical classification system, indicating that their solubility is the limiting factor in terms of bioavailability. Therefore, it is of vital importance to improve the dissolution behavior to assure the desired biological response at the site of action in the human body [1], [2], [3]. Second, novel entities often exhibit challenging shapes (e.g. acicular structures) [4], [5], [6], [7], leading to process instabilities due to poor flow properties. Third, conventionally employed processes can negatively influence the solid state of the active pharmaceutical ingredient (API), particularly the polymorphic form and the stability of the processed compound [8], [9], [10], which implies a high risk for any new drug development. Hence, new processes that accelerate the development of new drugs are required.

According to Paul et al. [11], solutions need to be found to move from the traditional drug development process to a “quick win, fast fail” approach. This should be done by reducing the number of candidates to the most promising ones in the early stages of the development process, ideally before the first human dose (FHD). This reduces the financial investment tremendously, as costs are shifted toward the early stages, where less material is needed [11]. To successfully employ this approach, processes are needed that already achieve functionality with very low amounts of material, are scalable with consistent quality, and offer product flexibility and co-processing capabilities. Inkjet printing could prove to be a process that is able to meet all those requirements.

There are several ways to achieve droplet generation via inkjet printing: application of pressure for continuous inkjet (CIJ) processes as well as thermal and piezoelectric actuation of the ink for drop on demand (DOD) ejection. While CIJ ejects droplets continuously and is mainly used for marking and coding of products, DOD systems eject drops individually due to a pressure pulse. This pressure pulse is created via rapid heating and thus evaporation of ink in thermal DOD systems or via a piezoelectric pulse (via excitation of a piezo crystal in an electric field). Most emerging applications nowadays use the piezoelectric approach, as it offers a large flexibility and does not need high thermal stability of the used ink [12]. Industrially available cartridges consist of up to a few hundred nozzles per printhead, each individually addressable to produce droplets with a high size uniformity between 1 and 100 pl, depending on the diameter of the nozzle orifice [12], [13], [14]. Depending on the used system, already small ink volumes of around 1 ml are sufficient for initial studies. In a nutshell, inkjet printing is a versatile process, easily scaled-up via parallelization that has been proven to be well suited to process various APIs [15], [16], [17], [18], [19], be it for personalized medications [16], [19], [20], [21], [22], [23], [24], [25], [26], ranging from nanosuspensions [27], [28], [29] to biological compounds [30], [31], [32].

Additionally, the applicability for amorphous solid dispersions and self-emulsifying systems has been investigated [33], along with control possibilities [34], suitable analytical methods [35] and smart dosage forms [36]. Recent studies from our group demonstrated the feasibility of processing APIs in solution and monitoring the applied dose via hyperspectral imaging [37], the deposition of poorly soluble APIs (i.e. itraconazole) as nanosuspension on contact lenses as a novel ophthalmic delivery technique [28] and the applicability of using inkjet printing as a particle engineering tool with an excipient (i.e. Mannitol) [38]. Since the development of this workflow was successful, the mitigation toward a pharmaceutically relevant API for particle engineering purposes was a logical next step, as presented in this study. So far, inkjet printing seems to be one of the few techniques suitable for the development of future drugs, as it allows both the formation of particles of uniform size [38] and increased bioavailability through different formulation strategies. However, this potential has not yet been proven for any pharmaceutical drug, since the particle formation implies an in-depth understanding of the complex interplay between instationary process conditions (e.g. the deposited volume, contact angle, evaporation enthalpy, substrate temperature, and ambient air conditions) and material properties (solid content within the ink, heat of crystallization, viscosity, density, surface tension).

Therefore, the present study aims at closing this gap by evaluating the applicability of inkjet printing for API particle shape engineering. Lacosamide, an anti-epileptic compound with a pronounced needle shape, was inkjet-printed for the first time. Lacosamide is considered a BCS class I drug, thus shows a high permeability and has a minimum, pH dependent solubility of 20 mg/ml at 25 °C. Its log P (octanol/water) is around 0.25 and it does not exhibit a pKa-value between pH 1.5 and 12 [39]. To this end, the present study aimed at tailoring particle shape rather than bioavailability enhancement. Lacosamide has four known polymorphic and one amorphous form, where only two polymorphic forms (modification I and II) are reported to occur during production [39]. Recently, additionally-two more polymorphic forms were found at low temperatures [40]. To result in spherical particles, not only the stability of various ink formulations and their interactions with distinct substrates were optimized, but also poly(ethylene glycol) (PEG) with different mean molecular weight was added to the ink formulation to increase viscosity and particle compactness. After adapting the pulse shape and printing strategy, spherical particles, which were analyzed in terms of shape, solid state and size, were produced.

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Manuel Zettl, Christina Winter, Jérôme Mantanus, Eftychios Hadjittofis, Sandrine Rome, Gerd Leitinger, Wen-Kai Hsiao, Eva Roblegg, Joana T. Pinto, Martin Spoerk, Needles to Spheres: Evaluation of inkjet printing as a particle shape enhancement tool, European Journal of Pharmaceutics and Biopharmaceutics, Volume 184, 2023, Pages 92-102, ISSN 0939-6411, https://doi.org/10.1016/j.ejpb.2023.01.016.