3D printing of amorphous solid dispersions: A comparison of fused deposition modeling and drop-on-powder printing.

Nowadays, a high number of pipeline drugs are poorly soluble and require solubility enhancement by e.g., manufacturing of amorphous solid dispersion. Pharmaceutical 3D printing has great potential in producing amorphous solid oral dosage forms. However, 3D printing techniques differ greatly in terms of processing as well as tablet properties. In this study, an amorphous formulation, which had been printed via Fused Deposition Modeling and drop-on-powder printing, also known as binder jetting, was characterized in terms of solid-state properties and physical stability. Solid state assessment was performed by differential scanning calorimetry, powder X-ray diffraction and polarized microscopy. The supersaturation performance of the amorphous solid dispersion was assessed via non-sink dissolution. We further evaluated both 3D printing techniques regarding their processability as well as tablet uniformity in terms of dimension, mass and content. Challenges and limitations of each 3D printing technique were discussed. Both techniques are feasible for the production of amorphous formulations. Results indicated that Fused Deposition Modeling is better suited for production, as the recrystallization tendency was lower. Still, filament production and printing presented a major challenge. Drop-on-powder printing can be a viable alternative for the production of amorphous tablets, when a formulation is not printable by Fused Deposition Modeling.

Drop-on-powder 3D printing of amorphous high dose oral dosage forms: Process development, opportunities and printing limitations.

Drop-on-powder 3D printing is able to produce highly drug loaded solid oral dosage forms. However, this technique is mainly limited to well soluble drugs. The majority of pipeline compounds is poorly soluble, though, and requires solubility enhancement, e.g., via formation of amorphous solid dispersions. This study presents a detailed and systematic development approach for the production of tablets containing high amounts of a poorly soluble, amorphized drug via drop-on-powder 3D printing (also known as binder jetting). Amorphization of the compound was achieved via hot-melt extrusion using the exemplary system of the model compound ketoconazole and copovidone as matrix polymer at drug loadings of 20% and 40%. The milled extrudate was used as powder for printing and the influence of inks and different ink-to-powder ratios on recrystallization of ketoconazole was investigated in a material-saving small-scale screening. Crystallinity assessment was performed using differential scanning calorimetry and polarized light microscopy to identify even small traces of crystallinity. Printing of tablets showed that the performed small-scale screening was capable to identify printing parameters for the development of amorphous and mechanically stable tablets via drop-on-powder printing. A stability study demonstrated physically stable tablets over twelve weeks at accelerated storage conditions.

Determination of feed forces to improve process understanding of Fused Deposition Modeling 3D printing and to ensure mass conformity of printed solid oral dosage forms.

Fused Deposition Modeling is a suitable technique for the production of personalized solid oral dosage forms. For widespread application, it is necessary to be able to print a wide range of different formulations to address individual therapeutic needs. Due to the complexity of formulation composition (e.g., due to different compounds, excipients for enhancement of release and mechanical properties) and limited mechanical understanding, determination of suitable printing parameters is challenging. To address this challenge, we have developed a feed force tester using a Texture Analyser setup that mimics the actual printing process. Feed force data were compared to the mass of tablets printed from technical materials as well as pharmaceutical filaments containing ketoconazole at high drug loads of 20% and 40% and polyvinyl alcohol. By determining a feed force limit for the 3D printer from feed force data of several formulations printed, it was possible to specify the operable printing range, where printing is reproducible and printed mass corresponds the target mass. Based on these results, rational optimization of the printing process in terms of speed, time and temperature for different materials and formulations is possible.

Quality of FDM 3D Printed Medicines for Pediatrics: Considerations for Formulation Development, Filament Extrusion, Printing Process and Printer Design.

3d printing is capable of providing dose individualization for pediatric medicines and translating the precision medicine approach into practical application. In pediatrics, dose individualization and preparation of small dosage forms is a requirement for successful therapy, which is frequently not possible due to the lack of suitable dosage forms. For precision medicine, individual characteristics of patients are considered for the selection of the best possible API in the most suitable dose with the most effective release profile to improve therapeutic outcome. 3d printing is inherently suitable for manufacturing of individualized medicines with varying dosages, sizes, release profiles and drug combinations in small batch sizes, which cannot be manufactured with traditional technologies. However, understanding of critical quality attributes and process parameters still needs to be significantly improved for this new technology. To ensure health and safety of patients, cleaning and process validation needs to be established. Additionally, adequate analytical methods for the in-process control of intermediates, regarding their printability as well as control of the final 3d printed tablets considering any risk of this new technology will be required. The PolyPrint consortium is actively working on developing novel polymers for fused deposition modeling (FDM) 3d printing, filament formulation and manufacturing development as well as optimization of the printing process, and the design of a GMP-capable FDM 3d printer. In this manuscript, the consortium shares its views on quality aspects and measures for 3d printing from drug-loaded filaments, including formulation development, the printing process, and the printed dosage forms. Additionally, engineering approaches for quality assurance during the printing process and for the final dosage form will be presented together with considerations for a GMP-capable printer design.

Brittle polymers in Fused Deposition Modeling: An improved feeding approach to enable the printing of highly drug loaded filament.

Brittleness is often described as a restricting material property for the processability of filaments via Fused Deposition Modeling. Especially filaments produced from approved pharmaceutical polymers often tend to fracture between feeding gears, the commonly employed feeding mechanism. In order to enhance their mechanical properties, usually extensive formulation development is performed. This study presents a different strategy to enable the printing of brittle filaments without the use of additional excipients by adapting the feeding mechanism to piston feeding. The polymers Soluplus®, Kollidon® VA64 and Eudragit® E PO were used, which have been reported to be brittle. Ketoconazole was used as model compound at 40% drug load and the influence on the mechanical properties was investigated using the three-point flexural test. In order to gain a better understanding of the mechanism affecting brittleness, filaments were analyzed in terms of crystallinity and miscibility of the components using polarized microscopy, differential scanning calorimetry and X-ray diffraction. Printing was performed with the aim to obtain immediate release tablets. The addition of Ketoconazole resulted in filaments even more brittle than placebo filaments. Nevertheless, the adaption of the feeding mechanism enabled the successful manufacturing of uniform tablets from all formulations.

Is Breast Magnetic Resonance Imaging an Accurate Predictor of Nodal Status After Neoadjuvant Chemotherapy?

BACKGROUND: With increasing use of sentinel lymph node biopsy (SLNB) after neoadjuvant chemotherapy (NAC), preoperative imaging assessment of axillary lymph nodes (ALNs) has become more important in operative planning and patient counseling. We aimed to assess if MRI is an accurate predictor of the ALN status after NAC. METHODS: We used our institutional proprietary prospective database to review all patients with newly diagnosed breast cancer between August 2015 and March 2017 who received NAC, underwent post-NAC MRI, and axillary surgery. Imaging findings, axillary surgery, and histopathology results were analyzed. RESULTS: Of 114 patients receiving NAC, 50 underwent post-NAC MRI before surgery. The mean age was 46 y; 36% were triple-negative, 26% were triple-positive, 26% were ER-positive and HER2/neu-negative, and 12% were ER-negative and Her2/neu-positive. Post-NAC MRI ALN status was normal in 35 patients, of which 30 underwent SLNB and five went directly to axillary lymph node dissection (ALND). 26 of these 35 were negative for metastasis on final pathology resulting in a negative-predictive value of 74.3%. In 15 patients with an abnormal post-NAC MRI ALN status, eight went directly to ALND and seven underwent SLNB. Eight of these 15 were positive for metastasis on final pathology resulting in a positive predictive value of 53.3%. CONCLUSIONS: Assessment of axillary imaging findings on post-NAC MRI predicts the absence of nodal disease with higher accuracy than its presence but not with adequate accuracy as surrogate for surgical pathologic evaluation of ALNs. This information is valuable in both patient counseling and axillary surgical management after NAC.

Three-dimensional Automated Breast US: Facts and Artifacts.

As automated breast (AB) US becomes more integrated into the daily practice of breast imaging, the need to address the artifacts that interfere with AB US image interpretation is becoming more important. Learning methods to detect and subsequently resolve artifacts such as shadowing can enhance the reader's confidence and ability to differentiate artifacts and true abnormalities. Understanding the basic principles of AB US and its image acquisition process are key elements in resolving artifacts. Gaining familiarity with the common patterns of AB US artifacts and placing them into categories of technical, software, physiologic, and breast lesion-related causes can aid in image interpretation. Recognizing specific artifacts, such as dropout and lack of contact, and the ability to distinguish them from true abnormalities, such as surgical scars and suspicious lesions, can help minimize preventable false-positive interpretations. Applying methods to confirm shadowing as artifactual, including the use of a second view, additional planes, and software-related tools such as the rotational tool, can aid the radiologist in resolving artifacts and avoiding preventable recalls, potentially resulting in increased specificity. Presented is a methodical approach to recognizing AB US artifacts and their causes; analyzing shadowing, a challenging entity in the interpretation of AB US imaging studies; differentiating artifact from true abnormality; and reviewing characteristic patterns and basic techniques to resolve artifacts. The goal of this article is to enable the radiologist in applying these methods to help reduce preventable false-positive recommendations and increase efficiency in AB US image interpretation. Online supplemental material is available for this article. ©RSNA, 2019.