3D printing of dose-flexible crystalline solid dispersion tablets suitable for preclinical and first-in-human studies

Abstract

Traditional extemporaneous compounding methods of solid oral dosage forms required in early-stage studies are laborious, and the drug’s solid state may affect the biopharmaceutical performance of the medicine. Maintaining the intended drug form in all stages of drug product development is critical. In this study, we evaluated the potential of Semi-solid extrusion (SSE) 3D printing to maintain a crystalline solid dispersion and automate small-batch tablet production suitable for preclinical and first-in-human (FIH) studies using high-solubility acetaminophen and low-solubility celecoxib as model compounds. Two drug-loaded pharma-inks were developed for each drug, containing 0.22 % w/w and 23 % w/w acetaminophen, and 0.2 % w/w and 30 % w/w celecoxib, respectively. Dose-flexible tablets were printed by SSE 3D printing at room temperature, covering a wide range of acetaminophen doses (0.5 mg, 150 mg, and 250 mg), and celecoxib doses (0.5 mg, 100 mg, and 200 mg) from the low or high drug-loaded pharma-inks, respectively. In vitro drug release confirmed the immediate release properties of the tablets. X-ray diffraction and DSC of the tablets confirmed crystalline acetaminophen and celecoxib dispersions post-printing. This work demonstrates that SSE 3D printing technology can be employed as a straightforward and cost-effective method to rapidly manufacture small batches of dose-flexible oral solid dosage forms on demand, suitable for early-stage studies, while maintaining API crystallinity and providing flexible dosing.

Highlights

SSE 3D printing maintained acetaminophen and celecoxib crystalline states in solid dispersion oral solid dosage forms suitable for preclinical and first-in-human studies while automating the compounding preparation process.

SSE 3D printing at room temperature increased in vitro dissolution of a low solubility BCS Class II drug, celecoxib in a crystalline solid dispersion.

Flexible dosing from low and high acetaminophen and celecoxib loaded pharma-inks (mixture of drug and excipients) with a dose range between 0.5 mg to 250 mg.

Introduction

Traditionally, preclinical and first-in-human studies are performed using oral dosage forms to evaluate the safety, pharmacokinetics, and bioequivalence of the new drug product. The common oral dosage forms used in such studies include solutions, suspensions, powders, capsules, gavage, and tablets. The selection of the dosage form depends on the drug’s properties such as solid form, the desired physicochemical properties of the drug product and the study design.

Identifying and maintaining the active pharmaceutical ingredient’s (API) solid form in early preclinical studies, as well as maintaining this form through to product launch regardless of the formulation, has been recognized as an ideal situation for the pharmaceutical industry. Non-compliance to this has often led to significant program delays and additional costs associated with bioequivalence studies, new crystallization studies, or completely new formulation development. Thus, the relevance of a drug’s solid form in drug product development has been well established. To fully understand drug properties, attention has been paid to solid state nature of drug molecules and their relationship to the drug formulation. The solid form of the API can significantly affect the quality and consistency of the final dosage form for drug product development, especially solid oral dosage formulations.

In some specialized approaches, for instance, to increase solubility, bioavailability and/or to maintain the solid form of the drug, the drug is contained as a solid dispersion within a polymer matrix. Depending on the crystallinity of the drug within the polymer matrix, solid dispersions can be categorized as amorphous solid dispersions (ASDs) or crystalline solid dispersions (CSDs). The ASDs possess the advantage of better nonequilibrium solubility than their crystalline counterparts. This is mostly applicable to BCS Class II and IV drugs to enhance solubility. The amorphous form generated can then be administered as such or as part of another dosage form. On the other hand, CSDs are systems where the drug is dispersed as a crystalline matrix, typically using a carrier. The carriers are mostly crystalline polymers. These dispersions offer several benefits, particularly in pharmaceutical development. For instance, CSDs have enhanced thermodynamic stability than amorphous systems due to the lower energy state. The risk of recrystallization is also removed. Drugs in a crystalline dispersion are already in a stable phase, minimizing the likelihood of phase transitions during storage. Consequently, they are less prone to physical ageing or morphological changes compared to amorphous systems, ensuring consistent drug performance over time.

While crystalline forms of drugs are generally less soluble than amorphous forms, dispersing them in a crystalline matrix can still improve the dissolution rate by reducing particle size and increasing the surface area for dissolution. This can therefore enhance the bioavailability of poorly soluble drugs. Moreover, they can be engineered to control the rate of drug release, making them suitable for sustained or targeted delivery applications. Other benefits include flexibility in the polymer carrier choice, i.e., various crystalline carriers can be selected based on the desired properties, such as solubility, compatibility, and release profile, offering customization for specific drug delivery needs. Moreover, crystalline materials absorb less moisture than their amorphous counterparts, thus, CSDs with reduced hygroscopicity, offer greater stability in humid conditions. From the drug product development and manufacturing perspective, CSDs often require less stringent processing conditions, making them more scalable for industrial production.

For preclinical and phase I clinical studies, CSDs are typically prepared as oral solid dosage forms using traditional extemporaneous compounding methods such as wet granulation, direct compression, or dry granulation. These are complex, expensive, and time-consuming processes that require modernization. Pharmaceutical three-dimensional (3D) printing is a novel process that could be utilized to manufacture small batches of CSDs for preclinical and first-in-human studies, automating the process while retaining the rapid turn-around flexibility required for early-stage studies. Pharmaceutical 3D printing is a disruptive additive manufacturing process that creates customizable drug delivery systems in a layer-by-layer style to form 3D objects from computer-aided design (CAD) models. 3D printing allows for precise, rapid, automated and flexible fabrication of different types of dosage forms, with various shapes, drug release, and formulation composition options, as part of automated, rapid prototyping workflows, especially for solid dosage forms such as tablets tailored to individual patient needs. This minimizes waste by only using small amounts of excipients and drug to produce small batches on-demand, reducing lead times and enhancing supply chain efficiency, especially for hard-to-reach healthcare facilities.

Semi-solid extrusion (SSE) is a subclass of material extrusion 3D printing which extrudes and deposits semi-solids such as gels or pastes. This technique can be carried out at lower temperatures or even room temperature, meaning most drugs can be printed this way. It is also an affordable technique that is easy to learn and clean, making immediate implementation into compounding and drug development workflows easier. The preparation of drug loaded gels or pastes referred to as ‘pharma-ink’ is performed in a simple way that can be easily performed by pharmacists and technicians. The use of disposable and pre-filled syringes also meets the critical quality specifications required by regulatory authorities. Hence, ensuring good manufacturing practice (GMP) requirements in pharmaceutical production facilities.As a versatile technology, SSE 3D printing can be used to prepare a wide range of dosage forms, including chewable tablets, orodispersible films, implantable patches, and rectal suppositories. SSE 3D printing is already proven to be effective for specialized treatment regimens in clinical settings under compounding regulations. This includes cancer therapy by combining multiple drugs in a single regimen and for pediatric patients in which the doses were personalized based on the individual patient’s needs.

Moreover, a recent study demonstrates additional capabilities of SSE 3D printing, to auto-fill capsules alongside an integrated quality control system in a community pharmacy to auto-dispense personalized doses of minoxidil to patients.

The aim of this study was to assess the use of SSE 3D printing to manufacture small batches of 3D printed tablets (printlets) that retain their crystalline state in solid dispersions, using acetaminophen and celecoxib as representative crystalline APIs with high and low solubility respectively. Acetaminophen is a BCS Class III drug with high aqueous solubility used to alleviate mild to moderate pain.Celecoxib on the other hand, belongs to BCS Class II drugs whose oral bioavailability is largely governed by its low aqueous solubility.

The significance of this approach is to explore the potential of pharmaceutical 3D printing for point-of-care (PoC) manufacturing of medicines on demand. PoC or decentralised manufacturing in this context refers to the production of innovative, patient-specific medicines at or near the site of treatment to ensure safety and quality. Moreover, the study also serves as a proof-of-concept to adopt 3D printing at PoC to automate the extemporaneous compounding of oral solid dosage forms suitable for preclinical and first-in-human studies. Thus, making the SSE 3D printing at PoC a versatile and adaptable technology for pharmaceutical industries and Contract Development Manufacturing Organizations (CDMOs) during clinical trials to prepare small batches of personalised treatment on demand.

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Materials

The active pharmaceutical ingredients, acetaminophen (paracetamol) and celecoxib were supplied by Pfizer (USA). Mannitol was purchased from Sigma-Aldrich (Germany), maltodextrins (Glucidex® IT 19D) was provided by Roquette (France). Croscarmellose sodium (Ac-Di-Sol®) was obtained from Dupont Nutrition Biosciences (Netherlands). Sodium carboxymethylcellulose salt was purchased from Fisher Scientific (United Kingdom). Tween 80® was supplied by Croda Chocques, France, glacial acetic acid, analytical grade ≥99.7 % (Fisher Chemical, UK), ammonium acetate, analytical grade ≥98 %, (Sigma Aldrich, the Netherlands).

Khalid Garba-Mohammed, Carlos Bendicho-Lavilla, Anna Worsley, Anna Bonelli, Gary Haggan, Charlene Hughes, Kennis Kahler, Clarisse Lukuamusu, Lodia Mawissa, Katrien Reynaert, Janyce Rogers, Ayse Savas, Aifang Li, Zhaohui Lei, Joseph Middleton, Dana M. Gates, Patrick Daugherity, Martin Rowland, Abdul W. Basit, Alvaro Goyanes, 3D printing of dose-flexible crystalline solid dispersion tablets suitable for preclinical and first-in-human studies, Journal of Pharmaceutical Sciences, Volume 114, Issue 10, 2025, 103943, ISSN 0022-3549, https://doi.org/10.1016/j.xphs.2025.103943.