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INTERNATIONAL JOURNAL OF PHARMACEUTICS Volume 642, 25 July 2023, 123072 https://doi.org/10.1016/j.ijpharm.2023.123072Get rights and content ABSTRACT Hydrocortisone (HC) is the preferred drug

in children with congenital adrenal hyperplasia due to its lower potency as well as fewer reports of side effects. Fused deposition modelling (FDM) 3D printing holds the potential to

produce low-cost personalised doses for children at the point of care. However, the compatibility of the thermal process to produce immediate-release bespoke tablets for this thermally

labile active is yet to be established. This work aims to develop immediate-release HC tablets using FDM 3D printing and assess drug contents as a critical quality attribute (CQA) using a

compact, low-cost near-infrared (NIR) spectroscopy as a process analytical technology (PAT). The FDM 3D printing temperature (140 °C) and drug concentration in the filament (10%-15% w/w)

were critical parameters to meet the compendial criteria for drug contents and impurities. Using a compact low-cost NIR spectral device over a wavelength of 900–1700 nm, the drug contents of

3D printed tablets were assessed. Partial least squares (PLS) regression was used to develop individual calibration models to detect HC content in 3D printed tablets of lower drug contents,

small caplet design, and relatively complex formula. The models demonstrated the ability to predict HC concentrations over a wide concentration range (0–15% w/w), which was confirmed by

HPLC as a reference method. Ultimately, the capability of the NIR model had preceding dose verification performance on HC tablets, with linearity (R2 = 0.981) and accuracy (RMSECV = 0.46%).

In the future, the integration of 3DP technology with non-destructive PAT techniques will accelerate the adoption of on-demand, individualised dosing in a clinical setting. GRAPHICAL

ABSTRACT INTRODUCTION Congenital adrenal hyperplasia (CAH) is an inherited disorder in children associated with low levels of cortisol hormones release from adrenal glands. In cortisol

replacement therapy, hydrocortisone (HC) has been the preferred drug in children. In most cases, a daily dose is accurately calculated based on body surface area (often 8 mg/m2), ideally in

four divided doses (Claahsen - van der Grinten et al., 2022). However, oral HC formulations are most often available as 10 mg tablets. Therefore, in practice, a nurse or carer will often

achieve an adequate dose of 2.5 mg per dose by manually splitting a 10-mg tablet into quarters. However, over half of quartered HC 10 mg tablets showed to be outside of the ± 10% of the

United States Pharmacopoeia (USP) content criterion (Madathilethu et al., 2018). The use of 3D printing (3DP) holds the promise of enabling a digital pharmacy revolution and for the

point-of-care manufacture of medicines (Araújo et al., 2019). This is due to the several advantages that 3DP technologies offer, including relatively low-cost and the ease to use. 3D

printers also have minimal space requirements, which facilitates the possibility of on-site manufacturing of medicines within a hospital or community pharmacy (Reich, 2005). This can involve

a digital prescription being sent to a 3D printer following a clinical and accuracy check by a clinician and a pharmacist. Serving as a compact manufacturing station, a 3D printer can

manufacture medicine for a specific therapeutic requirement by adjusting the design of doage form (Awad et al., 2018). The challenge of carrying out quality control of these products arises

partially from the requirement of a relatively large proportion of the product to be performed (Trenfield et al., 2018). In addition, the conventional methods of quality control (QC) require

a high level of skill and training to operate the instrumentation, which are generally expensive, including both start-up and running costs (Xiang et al., 2009). Considering the time needed

for product preparation, and the time required to perform analysis and data evaluation, these processes are collectively time-consuming. To achieve real-time batch release in a

point-of-care setting for 3D printed products, the ideal solution may come from the use of a non-destructive, non-invasive, and rapid analytical technique (Vakili et al., 2017). Currently,

dose verification of solid oral dosage forms is often accomplished using high-performance liquid chromatography (HPLC) or ultra-violet (UV) spectroscopy. Both methods require the destruction

of the dosage forms for the recovery of a drug in a liquid solution. Further research is required into considerations of how 3D printers can be scaled up to manufacture larger batches and

to shorten batch production time (Pandey et al., 2020). Process analytical technology (PAT) includes the use of near-infrared (NIR), laser-induced breakdown, and Raman spectroscopy to

provide a rapid analytical methodology to perform in-line and online analyses during the manufacturing process (Green et al., 2005, Luypaert et al., 2007, Pandey et al., 2020). NIR

spectroscopy has been used to monitor many QC attributes including moisture content, the particle size of granules, crystallinity, uniformity during powder blending, lubricant uniformity

during lubrication, tablet hardness during tabletting, film thickness during film coating and tablet content uniformity (De Beer et al., 2011, Knop and Kleinebudde, 2013, Lee et al., 2011,

Schaefer et al., 2014, Wahl et al., 2014). NIR spectroscopy is often most favoured as it is non-destructive, easy to operate, low cost, rapid and being of minimal to no sample preparation

requirements (Reich, 2005). It has been applied to the tabletting manufacturing process, integrating the device into the tablet feed frame, enabling the scanning of the tablets as they are

being produced (Wahl et al., 2014)(Chavez et al., 2015). However, the physical characteristics of 3D printed tablets can be potentially different from coated tablets, mainly the surface

smoothness. This can potentially contribute to variations in the NIR spectra (Tabasi et al., 2008). A portable NIR device was recently developed to accurately quantify the drug contents of

the tablets which were manufactured using selective laser sintering (SLS) 3D printing technology (Trenfield et al., 2022). Furthermore, the miniaturisation of NIR devices in recent years has

popularised which has led to the development of low-cost and portable hand-held NIR devices. Their effectiveness as a dose verification technique has been studied (Yan and Siesler, 2018),

and has also been compared to standard, benchtop NIR spectroscopes (Zontov et al., 2016). However, applying this approach for fused deposition modelling (FDM) 3D printing is yet to be

investigated. Fused deposition modelling (FDM) 3D printing has been heavily researched for the development of 3D printed tablets of immediate, extended, and delayed release (Patel et al.,

2021). Being low-cost and of minimal production site requirements, this technology offers an advantage for small-batch manufacturing. Several studies have highlighted the impact of two

thermal processes: hotmelt extrusion (HME) for filament preparation and FDM 3D printing on the stability of thermally labile products (Hoffmann et al., 2022, Kempin et al., 2018, Sadia et

al., 2018a, Sadia et al., 2018b). In addition, HC has been reported to be prone to oxidation under elevated temperatures (Zhang et al., 2016). Hence, for developing a 3D printing technology

to dispense accurate HC dosing, it is of vital importance to develop a manufacturing process that maintains stability through these thermal processes. In this project, we aim to assess the

impact of HME and 3D printing on the degradation of HC to produce immediate-release tablets. The impact of the processing temperature was assessed by monitoring the impurity profile across

all stages of manufacturing. We have also investigated the use of a low-cost, compact NIR spectroscope to develop a model that can accurately assess the content measurement of HC within a

3D-printed tablet. SECTION SNIPPETS MATERIALS Pharmaceutical-grade HC was acquired from Kemprotec Limited (UK). Titanium dioxide (TiO2) was obtained from Special Ingredients (UK). Talc

(Luzenac Pharma M) was donated by Imerys (Paris, France). Eudragit EPO was contributed by Evonik Industries (Darmstadt, Germany), and sodium stearyl fumarate (PRUV) by JRS Pharma (Germany).

Triethyl citrate (TEC) FCC grade was purchased from Sigma-Aldrich (Missouri, USA). Acetonitrile (HPLC gradient grade) was supplied from Merck Sigma-Aldrich (UK). PREPARATION OF HC-LOADED

METHACRYLATE-BASED FILAMENTS The HC DEVELOPMENT AND THERMAL ANALYSIS OF FILAMENT AND 3D PRINTED TABLETS TGA thermograph indicated that no weight loss was established for HC, talc, titanium

dioxide, and Eudragit EPO <180 °C (Fig. 1A). Whilst sodium stearyl fumarate and TEC underwent a significant weight loss for temperatures > 100 °C and > 150 °C, respectively. In

addition, HC showed a steady thermal degradation starting from > 180 °C (DiNunzio et al., 2010). The degradation of HC was also noted during the thermal extrusion of HC-containing films

and could be attributed to the drug degradation CONCLUSION This research provides a proof-of-concept for manufacturing immediate-release HC tablets for precise dose titration for children

with CAH. The FDM 3D printer produced caplets of bespoke doses of the thermal-labile product. Both 3D printing temperature and drug concentration of the polymer appeared to be critical to

meet the pharmacopeial limits for drug contents and impurities. While increasing drug concentration favoured drug recovery and purity outcomes, excessive drug loading yielded FDM 3D CREDIT

AUTHORSHIP CONTRIBUTION STATEMENT TZUYI L. YANG: Investigation, Methodology, Writing – original draft. MELPOMENI STOGIANNARI: Investigation, Methodology. SYLWIA JANECZKO: Investigation.

MARVA KHOSHAN: Investigation, Methodology. YUEYUAN LIN: Investigation, Methodology. ABDULLAH ISREB: Investigation. ROBER HABASHY: Writing – review & editing, Methodology. JOANNA

GIEBUŁTOWIC: Writing – review & editing. MATTHEW PEAK: Conceptualization. MOHAMED A. ALHNAN: Conceptualization, Supervision, Software, Writing – review & editing, DECLARATION OF

COMPETING INTEREST The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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(2016) View more references CITED BY (22) * DEVELOPING AN INNOVATIVE 3D PRINTING PLATFORM FOR PRODUCTION OF PERSONALISED MEDICINES IN A HOSPITAL FOR THE OPERA CLINICAL TRIAL 2024,

International Journal of Pharmaceutics Citation Excerpt : Manufacturing combination dosage forms of tamoxifen and either venlafaxine or duloxetine through conventional methods is impractical

due to both the release concerns and dose adjustments of each active pharmaceutical ingredient (API). Three-dimensional (3D) printing is a transformative technology capable of producing

bespoke medicines (printlets) with varying drug doses as well as products containing multiple APIs with different release requirements (Khaled, Burley et al. 2015, Keikhosravi, Mirdamadian

et al. 2020, Awad, Hollis et al. 2023, Tracy, Wu et al. 2023, Yang, Stogiannari et al. 2023, Patel, Raje et al. 2024). As such, 3D printing offers a possible solution for targeted tamoxifen

interventions such as differentiated doses and combination therapies to increase adherence among recovering breast cancer patients. Show abstract Breast cancer is the most frequently

diagnosed cancer in women worldwide, and non-adherence to adjuvant hormonotherapy can negatively impact cancer recurrence and relapse. Non-adherence is associated with side effects of

hormonotherapy. Pharmacological strategies to mitigate the side effects include coadministration of antidepressants, however patients remain non-adherent. The aim of this work was to develop

medicines containing both hormonotherapy, tamoxifen (20 mg), along with anti-depressants, either venlafaxine (37.5 or 75 mg) or duloxetine (30 or 60 mg), to assess the acceptability and

efficacy of this personalised approach for mitigating tamoxifen side effects in a clinical trial. A major criterion for the developed medicines was the production rate, specified at minimum

200 dosage units per hour to produce more than 40,000 units required for the clinical trial. A novel capsule filling approach enabled by the pharmaceutical 3D printer M3DIMAKER 2 was

developed for this purpose. Firstly, semi-solid extrusion 3D printing enabled the filling of tamoxifen pharma-ink prepared according to French compounding regulation, followed by filling of

commercial venlafaxine or duloxetine pellets enabled by the development of an innovative pellet dispensing printhead. The medicines were successfully developed and produced in the clinical

pharmacy department of the cancer hospital Gustave Roussy, located in Paris, France. The developed medicines satisfied quality and production rate requirements and were stable for storage up

to one year to cover the duration of the trial. This work demonstrates the feasibility of developing and producing combined tamoxifen medicines in a hospital setting through a

pharmaceutical 3D printer to enable a clinical trial with a high medicines production rate requirement. * ENSURING THE QUALITY OF 3D PRINTED MEDICINES: INTEGRATING A BALANCE INTO A

PHARMACEUTICAL PRINTER FOR IN-LINE UNIFORMITY OF MASS TESTING 2024, Journal of Drug Delivery Science and Technology Citation Excerpt : An in-line NIR system was investigated to perform

real-time drug content analysis of efavirenz-loaded printlets prepared using pharma-inks produced by a pharmaceutical company [26]. Portable NIR equipment has also been used as a PAT tool

for quantifying timolol maleate printed on contact lenses [48], amlodipine and lisinopril polyprintlets [52], caffeine printlets [49], and hydrocortisone printlets [53]. In addition, NIR

hyperspectral imaging (NIR-HSI) was used as a PAT tool to monitor and quantify the amount of metformin hydrochloride printed onto films [51]. Show abstract Semi-solid extrusion (SSE) 3D

printing has great potential to be integrated in a clinical setting, with the use of pre-filled and disposable pharma-ink syringes meeting regulatory good manufacturing practice (GMP)

requirements. Uniformity of mass testing is a critical quality attribute and is carried out by weighing a specific amount of dosage units in a single batch and finding the average mass to

evaluate any deviations. However, this test for small batches of 3D printed medicines may require weighing the entire manufactured batch. To overcome this limitation, an in-line analytical

balance was implemented inside a GMP pharmaceutical 3D printer, with a specialised software-controlled weighing system for the automated mass uniformity testing of the entire printed batch.

Three different dose batches (n = 28) of hydrocortisone pharma-ink were 3D printed and subjected to in-line mass uniformity testing. The developed software was capable of registering the

weights of all individual printlets and accurately detecting any deviations within the accepted limits. Only one printlet was outside the accepted weight range, a result of the first print

often being imperfect due to the semi-solid nature of the pharma-ink. The weight results were compared against an external analytical balance, and no significant differences were found. This

study is the first to integrate an analytical balance inside a pharmaceutical printer, automating the dosage form mass uniformity testing which can save time, labour, and resources, whilst

improving the quality control testing of 3D printed pharmaceuticals. * OPTIMIZING ENVIRONMENTAL SUSTAINABILITY IN PHARMACEUTICAL 3D PRINTING THROUGH MACHINE LEARNING 2023, International

Journal of Pharmaceutics Show abstract 3D Printing (3DP) of pharmaceuticals could drastically transform the manufacturing of medicines and facilitate the widespread availability of

personalised healthcare. However, with increasing awareness of the environmental damage of manufacturing, 3DP must be eco-friendly, especially when it comes to carbon emissions. This study

investigated the environmental effects of pharmaceutical 3DP. Using Design of Experiments (DoE) and Machine Learning (ML), we looked at energy use in pharmaceutical Fused Deposition Modeling

(FDM). From 136 experimental runs across four common dosage forms, we identified several key parameters that contributed to energy consumption, and consequently CO2 emission. These

parameters, identified by both DoE and ML, were the number of objects printed, build plate temperature, nozzle temperature, and layer height. Our analysis revealed that minimizing

trial-and-error by being more efficient in R&D and reducing the build plate temperature can significantly decrease CO2 emissions. Furthermore, we demonstrated that only the ML pipeline

could accurately predict CO2 emissions, suggesting ML could be a powerful tool in the development of more sustainable manufacturing processes. The models were validated experimentally on new

dosage forms of varying geometric complexities and were found to maintain high accuracy across all three dosage forms. The study underscores the potential of merging sustainability and

digitalization in the pharmaceutical sector, aligning with the principles of Industry 5.0. It highlights the comparable learning traits between DoE and ML, indicating a promising pathway for

wider adoption of ML in pharmaceutical manufacturing. Through focused efforts to reduce wasteful practices and optimize printing parameters, we can pave the way for a more environmentally

sustainable future in pharmaceutical 3DP. * DEVELOPMENT OF 3D PRINTED MINI-WAFFLE SHAPES CONTAINING HYDROCORTISONE FOR CHILDREN'S PERSONALIZED MEDICINE 2023, International Journal of

Pharmaceutics Citation Excerpt : For instance, Ayyoubi et al. developed 3D printed personalized sustained release cortisol for patients suffering of AS (Ayyoubi et al., 2023). Yang et al.

developed point-of-care tests to analyze printed forms containing HCT for children suffering of congenital adrenal hyperplasia (Yang et al., 2023). Many difficulties are encountered to

develop 3D printed solid oral forms intended for children, like colour acceptation, swallowability and dose accuracy (Strickley et al., 2008). Show abstract Hydrocortisone is mainly used in

the substitution treatment of adrenal insufficiency which results in a dysregulation of cortisol. Compounding of hydrocortisone capsules remains the only low-dose oral treatment suitable for

the pediatric population. However, capsules often show non-compliance in mass and content uniformity. Three-dimensional printing offers the prospect of practising personalized medicine for

vulnerable patients like children. The goal of this work is to develop low-dose solid oral forms containing hydrocortisone by hot-melt extrusion coupled with fused deposition modeling for

the pediatric population. Formulation, design and processes temperatures were optimized to produce printed forms with the desired characteristics. Red mini-waffle shapes containing drug

loads of 2, 5 and 8 mg were successfully printed. This new 3D design allow to release more than 80 % of the drug in 45 min indicating a conventional release like the one obtained with

capsules. Mass and content uniformity, hardness and friability tests complied with European Pharmacopeia specifications, despite the considerable challenge of the small dimensions of the

forms. This study demonstrates that FDM can be used to produce innovative pediatric-friendly printed shapes of an advanced pharmaceutical quality to practice personalize medicine. * 3D

PRINTING PROCESSES IN PRECISE DRUG DELIVERY FOR PERSONALIZED MEDICINE 2024, Biofabrication * PEDIATRIC FORMULATIONS DEVELOPED BY EXTRUSION-BASED 3D PRINTING: FROM PAST DISCOVERIES TO FUTURE

PROSPECTS 2024, Pharmaceutics View all citing articles on Scopus View full text © 2023 Elsevier B.V. All rights reserved.