Modular design principle based on compartmental drug delivery systems.

The current manufacturing solutions for oral solid dosage forms are fundamentally based on technologies from the 19th century. This approach is well suited for mass production of one-size-fits-all products; however, it does not allow for a straight-forward personalization and mass customization of the pharmaceutical end-product. In order to provide better therapies to the patients, a need for innovative manufacturing concepts and product design principles has been rising. Additive manufacturing opens up a possibility for compartmentalization of drug products, including design of spatially separated multidrug and functional excipient compartments. This compartmentalized solution can be further expanded to modular design thinking. Modular design is referring to combination of building blocks containing a given amount of drug compound(s) and related functional excipients into a larger final product. Implementation of modular design principles is paving the way for implementing the emerging personalization potential within health sciences by designing compartmental and reactive product structures that can be manufactured based on the individual needs of each patient. This review will introduce the existing compartmentalized product design principles and discuss the integration of these into edible electronics allowing for innovative control of drug release.

Practical Acoustic Energy-Based Estimation of Inhalation Flow Rate for Asthma Monitoring.

The estimation of inhalation flow rate (IFR) using acoustic devices has recently received attention. While existing work often assumes that the microphone is placed at a fixed distance from the acoustic device, this assumption does not hold in real settings. This leads to poor estimation of the IFR since the received acoustic energy varies significantly with the distance. Despite the fact that the acoustic source is passive and only one microphone is used, we show in this paper that the distance can be estimated by exploiting the inhaler actuation sound, generated when releasing the medication. Indeed, this sound is used as a reference acoustic signal which is leveraged to estimate the distance in real settings. The resulting IFR estimation is shown to be highly accurate (R2 = 80.3%).

Image-Based Artificial Intelligence Methods for Product Control of Tablet Coating Quality.

Mimicking the human decision-making process is challenging. Especially, many process control situations during the manufacturing of pharmaceuticals are based on visual observations and related experience-based actions. The aim of the present work was to investigate the use of image analysis to classify the quality of coated tablets. Tablets with an increasing amount of coating solution were imaged by fast scanning using a conventional office scanner. A segmentation routine was implemented to the images, allowing the extraction of numeric image-based information from individual tablets. The image preprocessing was performed prior to utilization of four different classification techniques for the individual tablet images. The support vector machine (SVM) technique performed superior compared to a convolutional neural network (CNN) in relation to computational time, and this approach was also slightly better at classifying the tablets correctly. The fastest multivariate method was partial least squares (PLS) regression, but this method was hampered by the inferior classification accuracy of the tablets. Finally, it was possible to create a numerical threshold classification model with an accuracy comparable to the SVM approach, so it is evident that there exist multiple valid options for classifying coated tablets.

Manufacturing of hybrid drug delivery systems by utilizing the fused filament fabrication (FFF) technology.

The potential of fused filament fabrication (FFF) for the administration of active pharmaceutical compounds is a recent approach to develop complex and custom-made drug delivery systems (DDSs). However, the FFF technology is characterized by certain limitations, which are associated with the nature of the process, i.e., the required mechanical properties of the feedstock, as well as the thermal stability of the incorporated polymers, excipients and active compounds. Thus, hybrid DDSs have been recently introduced, to overcome these boundaries. The concept of these systems is defined by the effective coupling of FFF with conventional manufacturing technologies, as a novel pathway to expand the available pool of raw materials and pharmaceutical applications of FFF.

Fabrication of Mucoadhesive Buccal Films for Local Administration of Ketoprofen and Lidocaine Hydrochloride by Combining Fused Deposition Modeling and Inkjet Printing.

In the area of developing oromucosal drug delivery systems, mucoadhesive buccal films are the most promising formulations for either systemic or local drug delivery. The current study presents the fabrication of buccal films, by combining fused deposition modeling (FDM) and inkjet printing. Hydroxypropyl methylcellulose-based films were fabricated via FDM, containing the non-steroidal anti-inflammatory drug ketoprofen. Unidirectional release properties were achieved, by incorporating an ethyl cellulose-based backing layer. The local anesthetic lidocaine hydrochloride, combined with the permeation enhancer l-menthol, was deposited onto the film by inkjet printing. Physicochemical analysis showed alterations in the characteristics of the films, and the mucoadhesive and mechanical properties were effectively modified, due to the ink deposition on the substrates. The in vitro release data of the active pharmaceutical compounds, as well as the permeation profiles across ex vivo porcine buccal mucosa and filter-grown TR146 cells of human buccal origin, were associated with the presence of the permeation enhancer and the backing layer. The lack of any toxicity of the fabricated films was demonstrated by the MTT viability assay. This proof-of-concept study provides an alternative formulation approach of mucoadhesive buccal films, intended for the treatment of local oromucosal diseases or systemic drug delivery.

Expedited Investigation of Powder Caking Aided by Rapid 3D Prototyping of Testing Devices.

Powder caking can dramatically affect powder handling and downstream production processes. Understanding the key factors that contribute to bulk powder caking is crucial. This article introduces the Hirschberg caking device (HCD), which is a 3D-printed device allowing for parallel testing of powder caking in a cylindrical geometry. In the HCD setup, the powder sample is stored in controlled conditions in the sample holder. On removal of the sample holder, the caked powder will remain in the shape determined by the sample geometry while the remaining powder will fall down. Caking indices can be calculated based on image analysis and weight measurement. The results obtained for the caking of lactose monohydrate with the HCD were in good agreement with the results obtained by a ring shear tester. In addition, a strain tester was used to measure the strength of the formed cakes. Using this approach, critical storage conditions and the required concentration of a given anticaking agent (talc) for lactose monohydrate could be identified. This work demonstrates the potential of rapid prototyping in powder characterization by introducing a fast and affordable approach for exploring and trouble-shooting powder caking.

Unidirectional drug release from 3D printed mucoadhesive buccal films using FDM technology: In vitro and ex vivo evaluation.

Oromucosal delivery of active pharmaceutical ingredients provides an attractive alternative route of administration, due to avoidance of the first pass effect and improved patient compliance. In the current work, fused deposition modelling (FDM) 3D printing was investigated as an additive manufacturing approach for poly(vinyl alcohol)-based mucoadhesive films, enabling unidirectional drug release. For this purpose, chitosan was incorporated as a permeation and mucoadhesion enhancer whereas ethylcellulose and commercial wafer sheets were evaluated as backing layers. The formulated films were initially assessed for structural integrity and dose uniformity. Solid-state characterization of the films, including thermal methods (DSC, TGA), diffraction (XRPD) and Raman spectroscopy, was implemented to characterize the physicochemical properties of the produced polymeric filaments and buccal films. The mechanical properties of the products were investigated by instrumented indentation and tensile tests. Evaluation of buccal films was assessed in vitro, to study the effect of backing-layer type on hydration capacity of the films, diffusion of the drug throughout the restricting layer and release profiles in simulated saliva. The ex vivo performance of the manufactured products, associated with the presence of chitosan, was investigated by textural analysis for mucoadhesion properties, whereas permeation studies and histological studies were performed across porcine buccal epithelium. The results demonstrated that FDM printing is a timesaving and versatile approach in the context of manufacturing multi-layered mucoadhesive buccal films, providing unidirectional release properties.

The Use of 3D Printed Molds to Cast Tablets with a Designed Disintegration Profile.

Development of new product design principles is crucial for obtaining pharmaceutical products with controlled functionality. Four different molds were designed using a computer-aided design (CAD) software and 3D printed with polylactic acid (PLA). A hydroxypropyl methylcellulose (HPMC) and polyethylene glycol (PEG)-based formulation containing indomethacin as the active pharmaceutical ingredient (API) was casted into the molds. Each mold produced a tablet that was designed to disintegrate into a defined number of sections (2, 4, and 6). This was achieved by incorporating break lines (regions that were significantly thinner than the remainder of the tablet) to control the disintegration process. Disintegration and drug release from these designed tablets was contrasted with a casted tablet without break lines. Disintegration studies confirmed that the casted tablets disintegrated according to their design. Drug-release studies meanwhile demonstrated that tablets with a greater number of sections released the API at a faster rate than those with fewer sections; for example, the 6-sectioned tablet released the API at twice the rate of the tablet without any break lines. It is expected that by using this concept, it would be possible to produce tablets with a designed disintegration profile, which could potentially allow the tailoring of the drug release.

Microfluidics-based self-assembly of peptide-loaded microgels: Effect of three dimensional (3D) printed micromixer design.

In an effort to contribute to research in scalable production systems for polymeric delivery systems loaded with antimicrobial peptides (AMPs), we here investigate effects of hydrodynamic flow conditions on microfluidic particle generation. For this purpose, rapid prototyping using 3D printing was applied to prepare micromixers with three different geometric designs, which were used to prepare Ca2+-cross-linked alginate microgels loaded with the AMP polymyxin B in a continuous process. Based on fluid dynamic simulations, the hydrodynamic flow patterns in the micromixers were designed to be either (i) turbulent with chaotic disruption, (ii) laminar with convective mixing, or (iii) convective with microvortex formation. The physicochemical properties of the microgels prepared with these micromixers were characterized by photon correlation spectroscopy, laser-Doppler micro-electrophoresis, small-angle x-ray scattering, and ellipsometry. The particle size and compactness were found to depend on the micromixer geometry: From such studies, particle size and compactness were found to depend on micromixer geometry, the smallest and most compact particles were obtained by preparation involving microvortex flows, while larger and more diffuse microgels were formed upon laminar mixing. Polymyxin B was found to be localized in the particle interior and to cause particle growth with increasing peptide loading. Ca2+-induced cross-linking of alginate, in turn, results in particle contraction. The peptide encapsulation efficiency was found to be higher than 80% for all investigated micromixer designs; the highest encapsulation efficiency observed for the smallest particles generated by microvortex-mediated self-assembly. Ellipsometry results for surface-immobilized microgels, as well as results on peptide encapsulation, demonstrated electrolyte-induced peptide release. Taken together, these findings demonstrate that rapid prototyping of microfluidics using 3D-printed micromixers offers promises for continuous manufacturing of AMP-loaded microgels. Although the micromixer combining turbulent flow and microvortexes was demonstrated to be the most efficient, all three micromixer designs were found to mediate self-assembly of small microgels displaying efficient peptide encapsulation. This demonstrates the robustness of employing 3D-printed micromixers for microfluidic assembly of AMP-loaded microgels during continuous production.

Using 3D Printing for Rapid Prototyping of Characterization Tools for Investigating Powder Blend Behavior.

There is an increasing need to provide more detailed insight into the behavior of particulate systems. The current powder characterization tools are developed empirically and in many cases, modification of existing equipment is difficult. More flexible tools are needed to provide understanding of complex powder behavior, such as mixing process and segregation phenomenon. An approach based on the fast prototyping of new powder handling geometries and interfacing solutions for process analytical tools is reported. This study utilized 3D printing for rapid prototyping of customized geometries; overall goal was to assess mixing process of powder blends at small-scale with a combination of spectroscopic and mechanical monitoring. As part of the segregation evaluation studies, the flowability of three different paracetamol/filler-blends at different ratios was investigated, inter alia to define the percolation thresholds. Blends with a paracetamol wt% above the percolation threshold were subsequently investigated in relation to their segregation behavior. Rapid prototyping using 3D printing allowed designing two funnels with tailored flow behavior (funnel flow) of model formulations, which could be monitored with an in-line near-infrared (NIR) spectrometer. Calculating the root mean square (RMS) of the scores of the two first principal components of the NIR spectra visualized spectral variation as a function of process time. In a same setup, mechanical properties (basic flow energy) of the powder blend were monitored during blending. Rapid prototyping allowed for fast modification of powder testing geometries and easy interfacing with process analytical tools, opening new possibilities for more detailed powder characterization.

The effect of HPMC and MC as pore formers on the rheology of the implant microenvironment and the drug release in vitro.

Porous implants or implantable scaffolds used for tissue regeneration can encourage tissue growth inside the implant and provide extended drug release. Water-soluble polymers incorporated into a biodegradable or inert implant matrix may leach out upon contact with biological fluids and thereby gradually increasing the porosity of the implant and simultaneously release drug from the implant matrix. Different molecular weight grades of methylcellulose (MC) and hydroxypropyl methylcellulose (HPMC) were mixed with polylactide and extruded into model implants containing nitrofurantoin as a model drug. The effect of the leached pore formers on the implant porosity and the rheology of the implant microenvironment in vitro was investigated and it was shown that HPMC pore formers had the greatest effect on the surrounding viscosity, with higher drug release and pore forming ability as compared to the MC pore formers. The highest molecular weight HPMC led to the most significant increase in viscosity of the implant microenvironment, while the highest drug release was achieved with the lowest molecular weight HPMC. The data suggested that the microenvironmental rheology of the implant, both in the formed pores and in biological fluids in the immediate vicinity of the implant could be an important factor affecting the diffusion of the drug and other molecules in the implantation site.

Anti-tuberculosis drug combination for controlled oral delivery using 3D printed compartmental dosage forms: From drug product design to in vivo testing.

The design and production of an oral dual-compartmental dosage unit (dcDU) was examined in vitro and in vivo with the purpose of physically isolating and modulating the release profile of an anti-tuberculosis drug combination. Rifampicin (RIF) and isoniazid (ISO) are first line combination drugs for treatment of tuberculosis (TB) that negatively interact with each other upon simultaneous release in acidic environment. The dcDUs were designed in silico by computer aided design (CAD) and fabricated in two steps; first three-dimensional (3D) printing of the outer structure, followed by hot-melt extrusion (HME) of the drug-containing filaments. The structure of the fabricated dcDUs was visualized by scanning electron microscopy (SEM). The 3D printed compartmentalized shells were loaded with filaments containing active pharmaceutical ingredient (API) and selectively sealed to modulate drug dissolution. The drug release profile of the dcDUs was characterized by pH-transfer dissolution in vitro and pharmacokinetics studies in rats, and resulted in modified release of the APIs from the dcDUs as compared to the free filaments. Furthermore, the selective physical sealing of the compartments resulted in an effective retardation of the in vitro API release. The findings of this study support the development of controllable-by-design dcDU systems for combination therapies to enable efficient therapeutic translation of oral dosage forms.

Inhalable siRNA-loaded nano-embedded microparticles engineered using microfluidics and spray drying.

Medicines based on small interfering RNA (siRNA) are promising for the treatment of a number of lung diseases. However, efficient delivery systems and design of stable dosage forms are required for inhalation therapy, as well as cost-effective methods for manufacturing of the final product. In this study, a 3D-printed micromixer was used for preparation of siRNA-dendrimer nanocomplexes, which were subsequently processed into microparticle-based dry powders for inhalation using spray drying. By applying the disposable micromixer, nanocomplexes were prepared of an average hydrodynamic diameter comparable to that of nanocomplexes prepared by manual mixing, but with narrower size distribution and low batch-to-batch variation. The nanocomplexes were processed into nanoembedded microparticles using different saccharide excipients. Data showed that siRNA integrity and bioactivity are retained after processing, and nanocomplexes could be reconstituted from the dry powders. The amorphous saccharide excipients trehalose and inulin provided better stabilization than crystalline mannitol, and they enabled full reconstitution of the nanocomplexes. In particular, a binary mixture of trehalose and inulin showed optimal stabilization, and enhanced cellular uptake and gene silencing efficiency. This study demonstrates that inexpensive and scalable micromixers can be used to optimize the production of siRNA-dendrimer nanocomplexes, and they can be applied in combination with spray drying for the engineering of dry powder formulations suitable for delivery of siRNA to the therapeutic target site.

High-Throughput Fabrication of Nanocomplexes Using 3D-Printed Micromixers.

3D printing allows a rapid and inexpensive manufacturing of custom made and prototype devices. Micromixers are used for rapid and controlled production of nanoparticles intended for therapeutic delivery. In this study, we demonstrate the fabrication of micromixers using computational design and 3D printing, which enable a continuous and industrial scale production of nanocomplexes formed by electrostatic complexation, using the polymers poly(diallyldimethylammonium chloride) and poly(sodium 4-styrenesulfonate). Several parameters including polymer concentration, flow rate, and flow ratio were systematically varied and their effect on the properties of nanocomplexes was studied and compared with nanocomplexes prepared by bulk mixing. Particles fabricated using this cost effective device were equally small and homogenous but more consistent and controllable in size compared with those prepared manually via bulk mixing. Moreover, each micromixer could process more than 2 liters per hour with unaffected performance and the setup could easily be scaled-up by aligning several micromixers in parallel. This demonstrates that 3D printing can be used to prepare disposable high-throughput micromixers for production of therapeutic nanoparticles.

Modifying release characteristics from 3D printed drug-eluting products.

This work describes an approach to modify the release of active compound from a 3D printed model drug product geometry intended for flexible dosing and precision medication. The production of novel polylactic acid and hydroxypropyl methylcellulose based feed materials containing nitrofurantoin for 3D printing purposes is demonstrated. Nitrofurantoin, Metolose® and polylactic acid were successfully co-extruded with up to 40% Metolose® content, and subsequently 3D printed into model disk geometries (ø10mm, h=2mm). Thermal analysis with differential scanning calorimetry and solid phase identification with Raman spectroscopy showed that nitrofurantoin remained in its original solid form during both hot-melt extrusion and subsequent 3D printing. Rheological measurements of the different compositions showed that the flow properties were sensitive to the amount of undissolved particles present in the formulation. Release of nitrofurantoin from the disks was dependent on Metolose® loading, with higher accumulated release observed for higher Metolose® loads. This work shows the potential of custom-made, drug loaded feed materials for 3D printing of precision drug products with tailored drug release characteristics.

Anhydrate to hydrate solid-state transformations of carbamazepine and nitrofurantoin in biorelevant media studied in situ using time-resolved synchrotron X-ray diffraction.

Transformation of the solid-state form of a drug compound in the lumen of the gastrointestinal tract may alter the drug bioavailability and in extreme cases result in patient fatalities. The solution-mediated anhydrate-to-hydrate phase transformation was examined using an in vitro model with different biorelevant media, simulated fasted and fed state intestinal fluids containing bile salt and dioleoylphosphatidylcholine (DOPC) micelles, DOPC/sodium dodecyl sulfate (SDS) mixture, bile salt solution and water. Two anhydrate compounds (carbamazepine, CBZ and nitrofurantoin, NF) with different overall transformation time into hydrate form were used as model compounds. The transformations were monitored using direct structural information from time-resolved synchrotron X-ray diffraction. The kinetics of these transformations were estimated using multivariate data analysis (principal component analysis, PCA) and compared to those for nitrofurantoin (NF). The study showed that the solution-mediated phase transformation of CBZ anhydrate was remarkably faster in the DOPC/SDS medium compared to transformation in all the other aqueous dispersion media. The conversion time for CBZ anhydrate in water was shorter than for DOPC/SDS but still faster than the conversion seen in fed and fasted state micellar media. The conversion of CBZ anhydrate to hydrate was the slowest in the solution containing bile salt alone. In contrast, the solution-mediated phase transformations of NF did only show limited kinetic dependence on the dispersion media used, indicating the complexity of the nucleation process. Furthermore, when the CBZ and NF material was compacted into tablets the transformation times were remarkably slower. Results suggest that variations in the composition of the contents of the stomach/gut may affect the recrystallization kinetics, especially when investigating compounds with relatively fast overall transformation time, such as CBZ.

Three-dimensional printing of drug-eluting implants: preparation of an antimicrobial polylactide feedstock material.

The aim of the present work was to investigate the potential of three-dimensional (3D) printing as a manufacturing method for products intended for personalized treatments by exploring the production of novel polylactide-based feedstock materials for 3D printing purposes. Nitrofurantoin (NF) and hydroxyapatite (HA) were successfully mixed and extruded with up to 30% drug load with and without addition of 5% HA in polylactide strands, which were subsequently 3D-printed into model disc geometries (10 × 2 mm). X-ray powder diffraction analysis showed that NF maintained its anhydrate solid form during the processing. Release of NF from the disks was dependent on the drug loading in a concentration-dependent manner as a higher level of released drug was observed from disks with higher drug loads. Disks with 30% drug loading were able to prevent surface-associated and planktonic growth of Staphylococcus aureus over a period of 7 days. At 10% drug loading, the disks did not inhibit planktonic growth, but still inhibited surface-associated growth. Elemental analysis indicated the presence of microdomains of solid drug supporting the observed slow and partial drug release. This work demonstrates the potential of custom-made, drug-loaded feedstock materials for 3D printing of pharmaceutical products for controlled release.

Rheology as a tool for evaluation of melt processability of innovative dosage forms.

Future manufacturing of pharmaceuticals will involve innovative use of polymeric excipients. Hot melt extrusion (HME) is an already established manufacturing technique and several products based on HME are on the market. Additionally, processing based on, e.g., HME or three dimensional (3D) printing, will have an increasingly important role when designing products for flexible dosing, since dosage forms based on compacting of a given powder mixture do not enable manufacturing of optimal pharmaceutical products for personalized treatments. The melt processability of polymers and API-polymer mixtures is highly dependent on the rheological properties of these systems, and rheological measurements should be considered as a more central part of the material characterization tool box when selecting suitable candidates for melt processing by, e.g., HME or 3D printing. The polymer processing industry offers established platforms, methods, and models for rheological characterization, and they can often be readily applied in the field of pharmaceutical manufacturing. Thoroughly measured and calculated rheological parameters together with thermal and mechanical material data are needed for the process simulations which are also becoming increasingly important. The authors aim to give an overview to the basics of rheology and summarize examples of the studies where rheology has been utilized in setting up or evaluating extrusion processes. Furthermore, examples of different experimental set-ups available for rheological measurements are presented, discussing each of their typical application area, advantages and limitations.

Simultaneous UV imaging and raman spectroscopy for the measurement of solvent-mediated phase transformations during dissolution testing.

The current work reports the simultaneous use of UV imaging and Raman spectroscopy for detailed characterization of drug dissolution behavior including solid-state phase transformations during dissolution. The dissolution of drug substances from compacts of sodium naproxen in 0.1 HCl as well as theophylline anhydrate and monohydrate in water was studied utilizing a flow-through setup. The decreases in dissolution rates with time observed by UV imaging were associated with concomitant solid form changes detected by Raman spectroscopy. Sodium naproxen and theophylline anhydrate were observed to convert to the more stable forms (naproxen, and theophylline monohydrate) within approximately 5 min. Interestingly, the new approach revealed that three intermediate forms are involved in the dissolution process prior to the appearance of the neutral naproxen during dissolution in an acidic medium. The combination of UV imaging and Raman spectroscopy offers a detailed characterization of drug dissolution behavior in a time-effective and sample-sparing manner.

Application of spray-drying and electrospraying/electospinning for poorly water-soluble drugs: a particle engineering approach.

Solid dispersions have been widely studied as an attractive formulation strategy for the increasingly prevalent poorly water-soluble drug compounds, including herbal medicines, often leading to improvements in drug dissolution rate and bioavailability. However, several challenges are encountered with solid dispersions, for instance regarding their physical stability, and the full potential of these formulations has yet to be reached. Solid dispersions have mainly been used to produce immediate release systems using water-soluble polymers but an extended release system may provide equal or better performance due to enhancement in the pharmacokinetics and low variability in plasma concentration. Progress in processing technologies and particle engineering provides new opportunities to prepare particle-based solid dispersions with control of physical characteristics and tailored drug release kinetics. Spray-drying and electrospraying are both technologies that allow production and continuous manufacturing of particle-based amorphous solid dispersions in a single step process and electrospinning further allows the production of fiber based systems. This review presents the use of spray drying and electrospraying/electrospinning as techniques for preparing particle-based solid dispersions, describes the particle formation processes via numerical and experimental models and discusses particle engineering using these techniques. Examples are given on the applications of these techniques for preparing solid dispersions and the challenges associated with the techniques such as stability, preparation of final dosage form and scale-up are also discussed.