All4Nutra
Abstract
Background: Modification of commercially available medicine, e.g. splitting or dissolving of tablets or pharmacy compounding, is current clinical practice when desired oral dosage forms are unavailable. These practices are defined as conventional pharmacy compounding techniques and are used to produce medicines that are not commercially available. 3D printing is an automated compounding technique that allows pharmacists to personalize oral dosage forms. This study aimed to compare the quality of 3D printing hydrocortisone tablets with conventional pharmacy compounded formulations. Secondary and tertiary aims were to assess manufacturing costs of 3D printed tablets and to explore whether modifying the hydrocortisone drug release profile is possible using 3D printing.
Methods: Semi-solid extrusion (SSE) 3D printing was used to produce immediate release and sustained release hydrocortisone tablets. Conventional compounded hydrocortisone formulations were used as comparators, including pharmacy compounded capsules, split tablets, and commercially available tablets dissolved in syringes.
Results: Immediate and sustained release hydrocortisone tablets were printed successfully. The acceptance values (AVs) of 3D printed tablets, tablet dissolved-in-syringe and one batch of pharmacy compounded capsules were ≤ 15. The AVs of the other 2 pharmacy compounded capsules and split tablets were > 15 and did not comply with content uniformity requirements. Personalization of 3D printed tablets was possible with a dose range of 0.5 – 10.0 mg. Costs of 3D printed tablets were <€ 3.00 per tablet for both release profiles.
Conclusion: SSE 3D printing leads to higher quality hydrocortisone tablets compared to conventional pharmacy compounding methods at acceptable manufacturing costs. 3D printing further allows for modification of hydrocortisone release profiles, which is not possible using conventional manufacturing methods. The low dose minitablets are especially suitable for pediatric indications requiring a personalized hydrocortisone dose.
Introduction
There is a high unmet need for personalized medication, especially in the pediatric population and in rare diseases. Commercial products do not always meet unique patients’ needs. Modifying existing medicines to obtain necessary dosages is common practice for pediatric indications, due to a lack of availability of specific dosages (Heitman et al., 2019; J Saito et al., 2020; Fadda et al., 2024). Conventional methods of personalizing medicines are manual and involve the modification of existing dosage forms, or compounding of capsules. Modification is defined by the manipulation of marketed medicines, which are split, crushed or dissolved before oral administration (Rautamo et al., 2020). This includes orally administering medication off-label that is intended for intravenous use, due to non-availability of oral dosage forms (Rautamo et al., 2020). Modifying existing dosage forms is associated with decreased product quality, operator and patient-safety risks. Crushing an existing dose may for instance lower the dose due to drug loss during preparation. Crushing may also change drug dissolution and increase the risk of toxicity (Taylor and Glass, 2018). Studies that investigated tablet splitting report different outcomes. Some studies report that weight and content variation are minimal, depending on the splitting method (Chaudhri et al., 2022; Habib et al., 2014; Olgac et al., 2021). Others report a high variation in drug dose, and poor compliance with pharmacopeial standards (Habib et al., 2014; Jude et al., 2018). Nevertheless, they all conclude that administering commercial dosage forms is always associated with higher quality compared to modified medication.
In terms of uniformity in content and mass, compounding of capsules may be a better alternative compared to modifying existing tablets. For pharmacy compounded capsules, some studies report high deviations in drug content between capsules, while others report a high quality (Bouwhuis et al., 2023; Markman et al., 2010). In one study, compounded hydrocortisone batches were analyzed and 21.4 % did not comply with compendial standards (Neumann et al., 2017). Due to their manual nature, conventional compounding and drug manipulation always bear the risk of quality changes in the final product. The associated risk greatly depends on the compounded drug substances. For example, variations in hydrocortisone content of compounded formulations can lead to severe clinical consequences and poor disease control in patients with adrenal insufficiency due to either hypocortisolism or hypercortisolism from overdose (Barillas et al., 2018; Al-Rayess et al., 2020). Fortunately, these are just individual case-studies where errors were made, and pharmacy compounding remains an essential tool to provide medicines to those in need when no commercial alternatives are available. Although pharmacists in The Netherlands do not need to comply with good manufacturing practice regulations, set for industrial scale manufacturing, there are strict regulations in place to assure quality of pharmacy compounded medicines. The Royal Dutch Pharmacy Association provides guidelines on validation and quality requirements for pharmacy compounded capsules. A risk-based, worst-case approach should for instance be maintained to validate the capsule filling method and use it to compound non-standardized formulations. Furthermore, validated analytical methods are used to ensure that the capsule filling method is suitable for compounding capsules. The content requirement for validation is 90 −110 % in relation to the declared amount, which is regulated by the Dutch Medicine Act (2025).
In recent years, 3D printing (3DP) has been extensively researched for the production of pharmacy compounded medicines (Tracy et al., 2023; Ayyoubi et al., 2021). 3DP is an automated compounding method and comprises different technologies. Extrusion based 3DP methods such as fused deposition modeling (FDM) and semi-solid extrusion (SSE) are among the most widely researched 3DP techniques in pharmaceutics (Wang et al., 2023). Not only the drug dose can be personalized with 3DP, but also the drug release, taste and shape of medicines can be tailored (Ayyoubi et al., 2021; Varghese et al., 2022; Ayyoubi et al., 2023). This is not possible with conventional compounding techniques, such as manual pharmacy compounding of capsules. One study investigated the viability of SSE for tablet production in a hospital setting using SSE 3DP and compared it with pharmacy compounded capsules (Levine et al., 2024). Here, the quality of SSE tablets was higher when compared to compounded capsules demonstrated by an average drug content of 4.8 ± 0.1 mg, whereas capsules had an average content of 5.1 ± 1.4 mg. The variation is higher in the capsule group, mainly attributed to one capsule with a drug content of 11.0 mg. Furthermore, interviews with pharmaceutical professionals reveal that they agreed unanimously that SSE makes it easier to produce a specific dose for patients that needs non-standard dosages. Another clinical study assessed the variation in plasma drug concentrations of 3D printed tablets versus compounded capsules (Goyanes et al., 2019). This study demonstrated lower variation in plasma concentrations of 3D printed isoleucine versus pharmacy compounded capsules. Nevertheless, the place of pharmaceutical 3DP in compounding personalized medicine is yet to be established.
The aim of this study is to compare the quality of split tablets, tablets dissolved in syringes, compounded capsules and tablets 3D printed via SSE. Hydrocortisone was selected as the study drug, as there is an unmet need for personalized hydrocortisone for patients with adrenal insufficiency, as described earlier (Ayyoubi et al., 2023). It is also a drug that is widely compounded, and described in case studies regarding compounding or modification errors (Neumann et al., 2017; Barillas et al., 2018; Al-Rayess et al., 2020; J Saito et al., 2020).
The secondary aim of this study was to gain insights into manufacturing costs of SSE medication. Until now, only one formal costing analysis has been performed for 3D medication using FDM (Ayyoubi et al., 2024). Manufacturing costs of 3D printed immediate release (IR) hydrocortisone tablets using SSE are unknown. Cost insights may aid the implementation of SSE 3DP in standard pharmaceutical practice of compounding magistral preparations. The tertiary aim was to explore whether modifying the hydrocortisone drug release profile is possible using SSE 3D printing. This was demonstrated earlier for FDM, but unknown impurities were formed due to high processing temperatures (Ayyoubi et al., 2024). SSE 3DP utilizes lower printing temperatures which might be a more feasible solution for a thermolabile drug such as hydrocortisone. Currently, it is not possible to compound modified drug release formulations, where the drug is slowly released for instance. Sustained release (SR), personalized, pharmacy compounded drugs would have a major clinical value in specific patient populations, such as in adrenal insufficiency (Ayyoubi et al., 2023).
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Materials
Micronized hydrocortisone (HC) and poloxamer 407 were purchased from Duchefa (Haarlem, The Netherlands). Lactose monohydrate (Sorbolac 400) was provided by Meggle (Wasserburg am Inn, Germany). Kollidon SR was provided by BASF (Ludwigshafen am Rhein, Germany).
Ayyoubi S, Holst AJ, Maduro JE, Van der Kuy PHM, Van Ee RJ, Van de Velde D, Valkenburg B, Hennep C, Quodbach J, Ruijgrok EJ, Benchmarking pharmaceutical quality and manufacturing costs of 3D printing against conventional compounding methods for personalization of medicine, European Journal of Pharmaceutical Sciences, Volume 212, 2025, 107180, ISSN 0928-0987, https://doi.org/10.1016/j.ejps.2025.107180.
Read also our introduction article on 3D Printing here:
