Semi-solid extrusion (SSE) 3D printing offers a versatile platform for preparing personalised pharmaceutical dosage forms. We investigated the applicability of the three different grades of poloxamers combined with polyethylene oxide (PEO) in pharmaceutical SSE 3D printing. The binary mixtures of poloxamers (F68, F87, and F108) and PEO at a ratio of 55:45 (w/w) were used in preparing the aqueous gels for SSE 3D printing. Acetylsalicylic acid (ASA) was used as a model drug in the concentrations 5%, 7%, and 9% (w/w). The physicochemical properties, printability, geometric accuracy, structural fidelity, and in-vitro drug-release behaviour of SSE 3D-printed 4 × 4 grids and axially perforated tablets were studied. We found that poloxamer F108 as a co-printed carrier polymer (with PEO) formed high-viscosity gels, which were feasible for SSE 3D-printing. The poloxamer F68- and F87-based gel formulations in turn showed reduced print fidelity. FTIR spectroscopy analysis confirmed compatibility between ASA, PEO, and all three poloxamers studied. The SSE 3D-printed grid preparations exhibited immediate-release behaviour with an initial burst release of the drug (ASA), followed by a diffusion- and erosion-controlled drug release in vitro. The release rates decreased in order of poloxamer grade: F87 > F68 > F108. Overall, poloxamer grade F108 was the most feasible carrier polymer to be combined with PEO for the SSE 3D printing of ASA-loaded dosage forms. The present poloxamer and PEO co-printed formulations provide an alternative printing platform for aqueous-based SSE 3D printing of immediate-release oral drug preparations applicable in personalized medicine or compounding settings.

Context: Quercetin oral delivery is limited by low aqueous solubility, chemical instability, and poor bioavailability. Semi-solid extrusion (SSE) three-dimensional (3D) printing may provide a flexible approach for preparing individualized oral dosage forms for quercetin. Aims: To develop and evaluate the feasibility of novel quercetin-loaded aqueous polyethylene oxide (PEO)-poloxamer gel inks for SSE 3D printing, and to investigate the physicochemical characteristics and in vitro performance of the resulting 3D-printed systems evaluated as candidates for oral formulation development. Methods: Six aqueous-ethanolic gel formulations containing quercetin dihydrate, PEO, and either Tween 80, Eumulgin® SMO 20, Pluronic® F-68, Pluronic® F-108, or Pluronic® F-87 were prepared. Gel viscosity, microscopic appearance, Fourier transform infrared (FTIR) spectral homogeneity, printability, scaffold mass, surface area, quercetin content, and in vitro dissolution were evaluated. Quercetin was quantified by high-performance liquid chromatography (HPLC) and ultraviolet (UV) spectrophotometry. Results: All formulations were printable, although quercetin crystals were detected microscopically in all gels. The addition of Tween 80 or poloxamers reduced viscosity and improved macroscopic homogeneity compared with the PEO-only formulation. Printed scaffolds showed uniform appearance and acceptable mass variation. Quercetin content in dried scaffolds was generally close to theoretical values. Poloxamer-containing formulations accelerated quercetin release. The Pluronic® F-68 formulation released approximately 95% of quercetin within 60 min, whereas the PEO-only formulation released approximately 51%. Conclusions: This proof-of-concept study demonstrated that PEO-based gels containing Tween 80 or Pluronic® F-68 may represent suitable candidates for further development of SSE 3D printing of quercetin oral dosage forms. Further analytical validation, biorelevant dissolution, stability, and bioavailability studies are required.

Background: Automated semi-solid extrusion (SSE) material deposition is a promising new technology for preparing personalized medicines for different patient groups and veterinary applications. The technology enables the preparation of custom-made oral elastic gel tablets of active pharmaceutical ingredient (API) by using a semi-solid polymeric printing ink. Methods: An automated SSE material deposition method was used for generating chewable gel tablets loaded with propranolol hydrochloride (-HCl) at three different API content levels (3.0 mg, 4.0 mg, 5.0 mg). The physical appearance, surface morphology, dimensions, mass and mass variation, process-derived solid-state changes, mechanical properties, and in-vitro drug release of the gel tablets were studied. Results: The inclusion of API (1% w/w) in the semi-solid CuraBlendTM printing mixture decreased viscosity and increased fluidity, thus promoting the spreading of the mixture on the printed (material deposition) bed and the printing performance of the gel tablets. The printed gel tablets were elastic, soft, jelly-like, chewable preparations. The mechanical properties of the gel tablets were dependent on the printing ink composition (i.e., with or without propranolol HCl). The maximum load for the final deformation of the CuraBlend™-API (3.0 mg) gel tablets was very uniform, ranging from 73 N to 80 N. The in-vitro dissolution test showed that more than 85% of the drug load was released within 15–20 min, thus verifying the immediate-release behavior of these drug preparations. Conclusions: Automated SSE material deposition as a modified 3D printing method is a feasible technology for preparing customized oral chewable gel tablets of propranolol HCl.

This study presents the development of personalized, immediate-release furosemide tablets for pediatric use using semi-solid extrusion (SSE) 3D printing integrated with compounding system solution (CSS) technology. Dose personalization and real-time quality assurance were implemented using near-infrared (NIR) spectroscopy with partial least squares (PLS) modeling, supported by Fourier-transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), and surface characterization via scanning white light interferometry (SWLI). Furosemide formulations (1 % and 2 % w/w) were prepared using a gel-based excipient and printed in doses from 2 to 10 mg. The NIR-based PLS model exhibited strong predictive accuracy (R² = 0.91; RMSEC = 3.37 %), enabling effective, non-destructive blend uniformity monitoring. All formulations met European Pharmacopoeia requirements for drug content (85.0-115.0 %) and content uniformity (AV < 15). Dissolution testing confirmed rapid release profiles, with >85 % release for all freshly prepared tablets. After six months, the 2 % formulation retained adequate performance (88.5 %), while the 1 % formulation showed a moderate decline (76.3 %). FTIR and XRD analyses revealed no significant drug-excipient interactions, and the crystalline structure of furosemide remained intact throughout storage. SWLI demonstrated surface morphology variations between formulations, revealing that excipient and surfactant levels influenced microtopography and potentially drug release kinetics. The integration of SSE 3D printing with spectroscopic and imaging tools offers a robust, reproducible, and patient-centric platform for personalized pediatric drug manufacturing. This approach supports the transition toward automated, non-sterile compounding with real-time control, improved dose precision, and enhanced product quality-addressing long-standing gaps in pediatric pharmaceutical care.

The exploration of three-dimensional (3D) printing inspired technologies in pharmaceutical compounding reveals a promising frontier in personalized medicine manufacture. This study focuses on the development of clopidogrel bisulphate tablets, with doses ranging from 2 mg to 20 mg per tablet, suitable for pediatric use. The study explored a semi-solid extrusion-based deposition technology already being used in compounding pharmacies across several European locations. The investigation explored various properties of two formulations of 1 % and 2 % clopidogrel gel tablets, with a specific focus on mass variation, drug content uniformity, in vitro drug release profiles, disintegration time, and stability. The mean weights of the smallest printed 200 mg tablets with 1 % and 2 % clopidogrel concentrations were 199.1 f 4.6 mg and 201.0 f 3.2 mg, respectively. For the largest printed 500 mg tablets with 1 % and 2 % concentrations, the mean weights were 499.3 f 7.7 mg and 501.7 f 6.5 mg, respectively. The mean clopidogrel content uniformity for 1 % clopidogrel 200 mg and 500 mg tablets were 102.0 f 1.8 %and 96.6 f 2.6 %, respectively, and for 2 % clopidogrel 200 mg and 500 mg were 102.6 f 3.9 % and 101.2 f 1.6 %, respectively, well within the acceptable acceptance value (AV) range of 3 to 12. Both 1 % and 2 % formulations of clopidogrel tablets exhibited rapid drug release, meeting the USP pharmacopeial target of 85 % release in 15 min. All tablet sizes formulated at 1 % and 2 % concentrations met specified disintegration specifications. The stability assessment over three months revealed consistent pH values and assay results within target specifications for both clopidogrel formulations (93.5 % for 1 % formulation and 93.6 % for 2 % formulation). At three months, Xray Diffraction (XRD) and Fourier Transform Infrared Spectroscopy (FTIR) results demonstrated stability in clopidogrel tablets. In conclusion, a comprehensive evaluation of our developed clopidogrel tablets demonstrate their suitability for clinical use in an extemporaneous setting using the presented semi-solid extrusion-based automation technology.

Background/Objectives: An automated extrusion-based material deposition is a contemporary and rapid method for pharmaceutical dose-dispensing and preparing (printing) individualized solid dosage forms. The aim of this study was to investigate and gain knowledge of the feasibility of automated extrusion-based material deposition technology in preparing customized prednisolone (PRD)-loaded gel tablets for veterinary applications (primarily for dogs and cats). Methods: The PRD loads of the extrusion-based deposited gel tablets were 0.5% and 1.0%, and the target weights of tablets were 0.250 g, 0.500 g, and 1.000 g. The effects of the material deposition processes on the physical solid state, in vitro dissolution, and the physicochemical stability of PRD gel tablets were investigated. Results: The small-sized gel tablets presented a uniform round shape with an exceptionally smooth outer surface texture. The actual average weight of the tablets (n = 10) was very close to the target weight, showing the precision of the process. We found that PRD was in a pseudopolymorphic sesquihydrate form (instead of an initial PRD crystalline form II) in the gel tablets. In all the immediate-release gel tablets studied, more than 70% of the drug load was released within 30 min. The soft texture and dimensions of gel tablets affected the dissolution behaviour in vitro, suggesting the need for further development and standardization of a dissolution test method for such gel tablets. A short-term storage stability study revealed that the content of PRD did not decrease within 3 months. Conclusions: Automated extrusion-based material deposition is a feasible method for the rapid preparation of gel tablets intended for veterinary applications. In addition, the present technology and gel tablets could be used in pediatric and personalized medicine where precise dosing is crucial.

Pharmacy compounding, the art and science of preparing customized medications to meet individual patient needs, is on the verge of transformation. Traditional methods of compounding often involve manual and time-consuming processes, presenting challenges in terms of consistency, dosage accuracy, quality control, contamination, and scalability. However, the emergence of cutting-edge technologies has paved a way for a new era for pharmacy compounding, promising to redefine the way medications are prepared and delivered as pharmacy-tailored personalized medicines. In this multi-site study, more than 30 hospitals and community pharmacies from eight countries in Europe utilized a novel automated dosing approach inspired by 3D printing for the compounding of non-sterile propranolol hydrochloride tablets. CuraBlend® excipient base, a GMP-manufactured excipient base (pharma-ink) intended for automated compounding applications, was used. A standardized study protocol to test the automated dosing of tablets with variable weights was performed in all participating pharmacies in four different iterative phases. Integrated quality control was performed with an in-process scale and NIR spectroscopy supported by HPLC content uniformity measurements. In total, 6088 propranolol tablets were produced at different locations during this study. It was shown that the dosing accuracy of the process increased from about 90% to 100% from Phase 1 to Phase 4 by making improvements to the formulation and the hardware solutions. The results indicate that through this automated and quality controlled compounding approach, extemporaneous pharmacy manufacturing can take a giant leap forward towards automation and digital manufacture of dosage forms in hospital pharmacies and compounding pharmacies.

Modern 3D printing technologies hold great promises for the manufacture of customized (“tailor-made”) medicines and personalized drug delivery systems (Seoane-Viaño et al., 2021; Vaz and Kumar, 2021). It is well known that a conventional “one-size-fits-all” concept is not suitable for all patient groups, and therefore pharmaceutical 3D-printing technologies are expected to make a revolutionary contribution to the new approach of personalized medicine. Oral conventional dosage forms (i.e., tablets, capsules and granules) are still the most widely used pharmaceutical preparations in both in human and veterinary drug treatments. Such drug preparations are manufactured by means of established manufacturing technologies and excipients widely used in the pharmaceutical industry. Within past 10-15 years, however, a number of promising 3D printing technologies have been introduced for pharmaceutical applications. Semi-solid extrusion (SSE) 3D printing is one interesting method for pharmaceutical polymer-based printing applications due to its simplicity, a low operating temperature and suitability for preparing high drug-loaded preparations (Sjöholm et al., 2020). Propranolol is a beta blocker used in the treatment of diseases such as high blood pressure, heart arrhythmias, performance anxiety and essential tremors. To date, only a few 3D-printed oral drug delivery systems for propranolol have been reported in the state-of-the-art literature. The aim of the present study was to develop a novel customized 3D-printed oral solid drug preparation for propranolol, and to investigate the physical solid-state properties and performance (dissolution in vitro) of such 3D-printed systems. A SSE 3D printing was used as a printing method for generating such drug preparations.

The current established manufacturing processes in the pharmaceutical industry do not enable to produce tailor-made (personalized) drug products. Therefore, multisite pharmaceutical 3D-printing approaches have found uses in fabricating customized drug preparations for both human and veterinary drug therapy applications. To date, many 3D-printing technologies have been introduced for preparing such customized pharmaceuticals. These methods include (but are not limited to) e.g., binder jetting, VAT photopolymerization, powder bed fusion, material extrusion, direct energy deposition, and sheet lamination (Seoane-Viaño et al. 2021). Among these technologies, semi-solid extrusion (SSE) 3D printing has been found as a suitable method for preparing customized oral solid drug preparations due to its simplicity. For example, a SSE 3D printing enables to prepare multi-drug loaded tablets, orodispersible tablets, and feasible oral solid drug preparations for veterinary uses. In addition, SSE 3D printing is the method of choice for adjusting the organoleptic properties (color and taste) of oral drug preparations, thus increasing patient compliance. A SSE 3D printing technology has found uses in hospitals and pharmacies (Beer et al., 2021), and more recently also in veterinary drug treatments (Sjöholm et al., 2020). The aim of the present study was to design and prepare a novel immediate-release tablets for veterinary applications (pets) using a SSE 3D printing technology. The physicochemical and dissolution properties of the tablets were evaluated. Moreover, a short-term storage stability study (up to 3 months) was performed for the present 3D-printed preparations (printed tablets). Мaterials and methods

Prescription affordability is a key component of healthcare accessibility and a determinant of health outcomes. Prior studies indicate that up to 1 in 4 Americans report difficulty affording prescriptions.Objective(s): This study aims to identify factors associated with cost-based prescription refusal.We identified 17,869 study participants from the 2017 National Health Interview Survey who had been prescribed at least one medication in the past 12 months. The outcome was defined as inability to afford at least one prescription medication. Covariates included demographic data, medical history, and social attitudes. Logistic regression models were constructed to identify predictors of cost-based prescription refusal.Among 8223 study participants, 8.1% reported the inability to afford at least one prescription medication in the past 12 months. Twenty-seven covariates were correlated with prescription unaffordability, and 8 were selected by the LASSO: Income (Odds ratio (OR) 0.55), Concerned About Bills (OR 2.0), Emergency Department Visits past 12 months (OR 1.33), Dissatisfaction with Medical Care (OR 1.3), Seeking Insurance Through the Health Insurance Marketplace (OR 1.26), Feeling Sad Most of the Time (OR 1.24), History of Asthma (OR 1.26) and History of Diabetes (OR 1.24).Prescription unaffordability remains a significant public health problem and is more common among low-income individuals and patients with, chronic medical conditions.

The poor solubility in water is very often a problem for active pharmaceutical substances of plant origin. The formulation of such drugs as liposomal preparations enables to improve the bioavailability of these drugs. Berberine (BBR) is a quaternary isoquinoline alkaloid derived from many native plant species (Coptis spp., Berberis spp., Hydrastis canadensis etc.). BBR has been traditionally used for the treatment of different disorders including hyper-cholesterolemia and cardiovascular diseases [1,2]. BBR has a strong antimicrobial activity enabling the use of it as an anti-diarrheal, anti-protozoal, fungal, candida, yeast, and parasitic intestinal active ingredient [3]. In addition, BBR has shown an anti-inflammatory, anti-diabetic, lipid peroxidation, and neuroprotective activity [3,4]. Unfortunaterly, BBR is poorly soluble in water and has a low bioavailability (<10%) due to the induced activity of multidrug efflux transporter Pglycoprotein (P-gp) in the intestine itself [2]. Such limitations associated with a poor oral bioavailability of BBR could be overcome by nanoformulating BBR to liposomes. Pharmaceutical liposomes can be fabricated by ethanol-injection and thin-film hydration methods. The lamellarity, size, shape and ultra-structure of liposomes can be determined by using different advanced techniques, such as cryogenic electron microscopy (Cryo-EM), dynamic light scattering (DLS), size-exclusion chromatography (SEC), and atomic force microscopy (AFM) [5]. Confocal laser scanning microscopy (CLSM) has been also used for such imaging [6]. The aim of our study is to investigate ethanolinjection and film hydration methods for generating BBR-loaded liposomes and to study the structure, size, size distribution and entrapment efficiency of the liposomes. The liposomes are ultimately intended for the oral treatment of hypercholesterolemia.

Berberine (BBR) is a poorly water-soluble quaternary isoquinoline alkaloid of plant origin with potential uses in the drug therapy of hypercholesterolemia. To tackle the limitations associated with the oral therapeutic use of BBR (such as a first-pass metabolism and poor absorption), BBR-loaded liposomes were fabricated by ethanol-injection and thin-film hydration methods. The size and size distribution, polydispersity index (PDI), solid-state properties, entrapment efficiency (EE) and in vitro drug release of liposomes were investigated. The BBR-loaded liposomes prepared by ethanol-injection and thin-film hydration methods presented an average liposome size ranging from 50 nm to 244 nm and from 111 nm to 449 nm, respectively. The PDI values for the liposomes were less than 0.3, suggesting a narrow size distribution. The EE of liposomes ranged from 56% to 92%. Poorly water-soluble BBR was found to accumulate in the bi-layered phospholipid membrane of the liposomes prepared by the thin-film hydration method. The BBR-loaded liposomes generated by both nanofabrication methods presented extended drug release behavior in vitro. In conclusion, both ethanol-injection and thin-film hydration nanofabrication methods are feasible for generating BBR-loaded oral liposomes with a uniform size, high EE and modified drug release behavior in vitro.

We investigated and monitored in situ the wetting and dissolution properties of polymeric nanofibers and determined the solid-state of a drug during dissolution. Piroxicam (PRX) was used as a low-dose and poorly-soluble model drug, and hydroxypropyl methylcellulose (HPMC) and polydextrose (PD) were used as carrier polymers for electrospinning (ES). The initial-stage dissolution of the nanofibers was monitored in situ with three-dimensional white light microscopic interferometry (SWLI) and high-resolution optical microscopy. The physical solid-state characterization of nanofibers was performed with Raman spectroscopy, X-ray powder diffraction (XRPD), and scanning electron microscopy (SEM). We showed that PRX recrystallizes in a microcrystalline form immediately after wetting of nanofibers, which could lead to enhanced dissolution of drug. Initiation of crystal formation was detected by SWLI, indicating: (1) that PRX was partially released from the nanofibers, and (2) that the solid-state form of PRX changed from amorphous to crystalline. The amount, shape, and size of the PRX crystals depended on the carrier polymer used in the nanofibers and dissolution media (pH). In conclusion, the present nanofibers loaded with PRX exhibit a quasi-dynamic dissolution via recrystallization. SWLI enables a rapid, non-contacting, and non-destructive method for in situ monitoring the early-stage dissolution of nanofibers and regional mapping of crystalline changes (re-crystallization) during wetting. Such analysis is crucial because the wetting and dissolution of nanofibers can greatly influence the performance of nanofibrous drug delivery systems in pharmaceutical and biomedical applications.

The isolation and physical material properties of suberin fatty acids (SFAs) were investigated with special reference to their potential applications as novel pharmaceutical excipients. SFAs were isolated from outer birch bark (OBB) with a new extractive hydrolysis method. The present simplified isolation process resulted in a moderate batch yield and chemical purity of SFAs, but further development is needed for establishing batch-to-batch variation. Cryogenic milling was the method of choice for the particle size reduction of SFAs powder. The cryogenically milled SFAs powder exhibited a semicrystalline structure with apparent microcrystalline domains within an amorphous fatty acids matrix. The thermogravimetric analysis (TGA) of SFAs samples showed a good thermal stability up to 200 °C, followed by a progressive weight loss, reaching a plateau at about 95% volatilization at about 470 °C. The binary blends of SFAs and microcrystalline cellulose (MCC; Avicel PH 101) in a ratio of 25:75 (w/w) displayed good powder flow and tablet compression properties. The corresponding theophylline-containing tablets showed sustained or prolonged-release characteristics. The physicochemical and bulk powder properties of SFAs isolated from OBB are auspicious in terms of potential pharmaceutical excipient applications.

Suberin fatty acids (SFAs) isolated from outer birch bark were investigated as an antimicrobial agent and biomaterial in nanofibrous mats intended for wound treatment. Electrospinning (ES) was used in preparing the composite nonwoven nanomats containing chloramphenicol (CAM; as a primary antimicrobial drug), SFAs, and polyvinylpyrrolidone (as a carrier polymer for ES). The X-ray powder diffraction, differential scanning calorimetry, scanning electron microscopy, atomic force microscopy, and texture analysis were used for the physicochemical and mechanical characterization of the nanomats. ES produced nanofibrous mats with uniform structure and with an average fiber diameter ranging from 370 to 425 nm. Microcrystalline SFAs and crystalline CAM were found to undergo a solid-state transformation during ES processing. The ES process caused also the loss of CAM in the final nanofibers. In the texture analysis, the SFAs containing nanofibers exhibited significantly higher maximum detachment force to an isolated pig skin (p < 0.05) than that obtained with the reference nanofibers. CAM exists in an amorphous form in the nanofibers which needs to be taken into account in controlling the physical storage stability. In conclusion, homogeneous composite nanofibrous mats for wound healing can be electrospun from the ternary mixture(s) of CAM, SFAs, and polyvinylpyrrolidone.

Electrospinning was used as a novel technique for fabricating polymeric nanofibers of a serum cholesterol lowering and poorly water-soluble plant sterol, β-sitosterol. Chitosan was used as a stabilizer/carrier polymer. The mean diameters of nanofibers ranged from 150 nm to218 nm. β-sitosterol was in an amorphous form and homogeneously dispersed in the nanofibers. The β-sitosterol-loaded nanofibers were freely water-soluble and exhibited very short lag-time in releasing the plant sterol. The dissolution was associated with an immediate recrystallization of β-sitosterol in submicron level. In conclusion, electrospinning is a promising future technology for the formulation of poorly water-soluble plant sterols.

We showed that the addition of suberin fatty acids (SFAs) even at small concentrations significantly improves the water vapor barrier properties of hydroxypropyl methylcellulose (HPMC) films. SFAs were isolated from the outer birch bark using extractive hydrolysis. The effects of SFAs on the film formation of aqueous HPMC were investigated with free films plasticized with polyethylene glycol (PEG 400). Special attention was paid on the physical solid-state, moisture barrier and mechanical stress-strain properties of films intended for tablet film coatings. Topography and surface morphology, glass transition temperature (Tg), tensile strength, Young’s modulus, and water vapor permeation (WVP) of films were studied. The addition of SFAs lowered the Tg of films suggesting partial enhancement in film plasticization. The WVP of films decreased with increasing SFAs concentration up to 15% (calculated as a % w/w from a polymer weight). The WVP value for a non-suberized reference film and suberized film plasticized with PEG 400 was 2.13×10−6 and 0.69[×10−6g/(mm2×h)×mm/Pa], respectively. The addition of SFAs impaired the mechanical stress-strain properties of HPMC films by reducing the deformation capacity of film. In conclusion, the film properties and performance of aqueous HPMC can be modified by including SFAs in the films.