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Binder jetting (BJ) three-dimensional (3D) printing is becoming an established additive manufacturing technology for manufacturing of solid products for oral drug delivery. Similar to traditional solutions based on compaction of powder mixture, successful processing of BJ products requires control of bulk powder properties. In contrast to traditional compaction-based process, BJ 3D printing allows for flexible modifications on microstructure, material composition and dose in the printed pharmaceutical products. Currently, systematic strategies for selecting excipients and optimizing the printing process have not been fully established. To address this challenge, a summary of the published work and selected patent literature around BJ 3D printing to fabricate pharmaceutical solid products for oral administration purposes is presented. First, an overview of characteristics of printed products as a part of the product design and a description of the commonly used excipients and active pharmaceutical ingredients is given. The critical powder and ink properties, as well as physical geometries and inner structures of a final product, are discussed in term of the mechanisms that determine the formation of a printed solid product and finally the quality of this product. This review is also summarizing the technical features of printers, printheads, and the critical considerations for post-processing procedures. BJ 3D printing is one of the most promising additive manufacturing technologies for mass customization of pharmaceutical products.

Thermal methods are indispensable for the characterization of most materials. However, the existing methods require bulk amounts for analysis and give an averaged response of a material. This can be especially challenging in a biomedical setting, where only very limited amounts of material are initially available. Nano- and microelectromechanical systems (NEMS/MEMS) offer the possibility of conducting thermal analysis on small amounts of materials in the nano-microgram range, but cleanroom fabricated resonators are required. Here, we report the use of single drug and collagen particles as micro mechanical resonators, thereby eliminating the need for cleanroom fabrication. Furthermore, the proposed method reveals additional thermal transitions that are undetected by standard thermal methods and provide the possibility of understanding fundamental changes in the mechanical properties of the materials during thermal cycling. This method is applicable to a variety of different materials and opens the door to fundamental mechanistic insights., Eliminating the need for cleanroom fabrication for thermomechanical characterization of organic samples in a biomedical setting remains a challenge. Here, the authors propose the use of a single drug and collagen particles as resonators, enabling direct measurements on a material during thermal cycling.

Asthma is a prevalent lung disorder that cause heavy burdens globally. Inhalation medicaments can relieve symptoms, improve lung function and, thus, the quality of life. However, it is well-documented that patients often do not get the prescribed dose out of an inhaler and the deposition of drug is suboptimal, due to incorrect handling of the device and wrong inhalation technique. This study aims to design and fabricate an acoustic dry powder inhaler (ADPI) for monitoring inhalation flow and related drug administration in order to evaluate whether the patient receives the complete dose out of the inhaler. The devices were fabricated using 3D printing and the impact of the acoustic element geometry and printing resolution on the acoustic signal was investigated. Commercial Foradil (formoterol fumarate) capsules were used to validate the availability of the ADPI for medication dose tracking. The acoustic signal was analysed with Partial-Least-Squares (PLS) regression. Indicate that specific acoustic signals could be generated at different air flow rates using a passive acoustic element with specific design features. This acoustic signal could be correlated with the PLS model to the air flow rate. A more distinct sound spectra could be acquired at higher printing resolution. The sound spectra from the ADPI with no capsule, a full capsule and an empty capsule are different which could be used for medication tracking. This study shows that it is possible to evaluate the medication quality of inhaled medicaments by monitoring the acoustic signal generated during the inhalation process.

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.

Many future drug products will be based on innovative manufacturing solutions, which will increase the need for a thorough understanding of the interplay between drug material properties and processability. In this study, hot melt extrusion of a drug-drug mixture with minimal amount of polymeric excipient was investigated. Using indomethacin-cimetidine as a model drug-drug system, processability of physical mixtures with and without 5% (w/w) of polyethylene oxide (PEO) were studied using Differential Scanning Calorimetry (DSC) and Small Amplitude Oscillatory Shear (SAOS) rheometry. Extrudates containing a co-amorphous glass solution were produced and the solid-state composition of these was studied with DSC. Rheological analysis indicated that the studied systems display viscosities higher than expected for small molecule melts and addition of PEO decreased the viscosity of the melt. Extrudates of indomethacin-cimetidine alone displayed amorphous-amorphous phase separation after 4 weeks of storage, whereas no phase separation was observed during the 16 week storage of the indomethacin-cimetidine extrudates containing 5% (w/w) PEO. Melt extrusion of co-amorphous extrudates with low amounts of polymer was found to be a feasible manufacturing technique. Addition of 5% (w/w) polymer reduced melt viscosity and prevented phase separation.

The purpose of this study was to investigate the applicability of Raman spectroscopy for visualization and quantification of inkjet-printed pharmaceuticals. Haloperidol was used as a model active pharmaceutical ingredient (API), and a printable ink base containing lactic acid and ethanol was developed. Inkjet printing technology was used to apply haloperidol ink onto three different substrates. Custom-made inorganic compacts and dry foam, as well as marketed paracetamol tablets were used as the substrates. Therapeutic personalized doses were printed by using one to ten printing rounds on the substrates. The haloperidol content in the finished dosage forms were determined by high-performance liquid chromatography (HPLC). The distribution of the haloperidol on the dosage forms were visualized using Raman chemical imaging combined with principal components analysis (PCA). Raman spectroscopy combined with modeling by partial least squares (PLS) regression was used for establishment of a quantitative model of the haloperidol content in the printed dosage forms. A good prediction of the haloperidol content was achieved for the inorganic compacts, while a slightly poorer prediction was observed for the paracetamol tablets. It was not possible to quantify haloperidol on the dry foam due to the low and varying density of the substrate. Raman spectroscopy is a useful tool for visualization and quality control of inkjet printed personalized medicine.

Mohammed Al-Sharabi's affiliation was incorrect at the time of publishing. The updated affiliation appears below.

The use of inkjet printing for pharmaceutical manufacturing is gaining interest for production of personalized dosage forms tailored to specific patients. As part of the manufacturing, it is imperative to ensure that the correct dose is printed. The aim of this study was to use inkjet printing for manufacturing of personalized dosage forms combined with the use of near-infrared (NIR) and Raman spectroscopy as complementary analytical techniques for active pharmaceutical ingredient (API) quantification of the inkjet-printed dosage forms. Three APIs, propranolol (0.5–4.1 mg), montelukast (2.1–12.1 mg), and haloperidol (0.6–4.1 mg) were inkjet printed in 1 cm2 areas on a porous substrate. The printed doses were non-destructively analyzed by transmission NIR and Raman spectroscopy (both transmission and backscatter). X-ray computed microtomography (μ-CT) analysis was undertaken for porosity measurements of the substrate. The API content was confirmed using high-performance liquid chromatography (HPLC), and the content in the dosage forms was modeled from the NIR and Raman spectra using partial least squares regression (PLS). HPLC analysis revealed a linear correlation of the number of layers printed to the API content. The resulting PLS models for both NIR and Raman had R2 values between 0.95 and 0.99. The best predictive model was obtained using NIR, followed by Raman spectroscopy. μ-CT revealed the substrate to be highly porous and optimal for inkjet printing. In conclusion, NIR and Raman spectroscopic techniques could be used complementary as fast API quantification tools for inkjet-printed medicines.

Printing technologies were recently introduced to the pharmaceutical field for manufacturing of drug delivery systems. Printing allows on demand manufacturing of flexible pharmaceutical doses in a personalized manner, which is critical for a successful and safe treatment of patient populations with specific needs, such as children and the elderly, and patients facing multimorbidity. Printing of pharmaceuticals as technique generates new demands on the quality control procedures. For example, rapid quality control is needed as the printing can be done on demand and at the point of care. This study evaluated the potential use of a handheld colorimetry device for quality control of printed doses of vitamin Bs on edible rice and sugar substrates. The structural features of the substrates with and without ink were also compared. A multicomponent ink formulation with vitamin B1, B2, B3, and B6 was developed. Doses (4 cm2) were prepared by applying 1–10 layers of yellow ink onto the white substrates using thermal inkjet technology. The colorimetric method was seen to be viable in detecting doses up to the 5th and 6th printed layers until color saturation of the yellow color parameter (b*) was observed on the substrates. Liquid chromatography mass spectrometry was used as a reference method for the colorimetry measurements plotted against the number of printed layers. It was concluded that colorimetry could be used as a quality control tool for detection of different doses. However, optimization of the color addition needs to be done to avoid color saturation within the planned dose interval.

Purpose A 3D printer was used to realise compartmental dosage forms containing multiple active pharmaceutical ingredient (API) formulations. This work demonstrates the microstructural characterisation of 3D printed solid dosage forms using X-ray computed microtomography (XμCT) and terahertz pulsed imaging (TPI). Methods Printing was performed with either polyvinyl alcohol (PVA) or polylactic acid (PLA). The structures were examined by XμCT and TPI. Liquid self-nanoemulsifying drug delivery system (SNEDDS) formulations containing saquinavir and halofantrine were incorporated into the 3D printed compartmentalised structures and in vitro drug release determined. Results A clear difference in terms of pore structure between PVA and PLA prints was observed by extracting the porosity (5.5% for PVA and 0.2% for PLA prints), pore length and pore volume from the XμCT data. The print resolution and accuracy was characterised by XμCT and TPI on the basis of the computer-aided design (CAD) models of the dosage form (compartmentalised PVA structures were 7.5 ± 0.75% larger than designed; n = 3). Conclusions The 3D printer can reproduce specific structures very accurately, whereas the 3D prints can deviate from the designed model. The microstructural information extracted by XμCT and TPI will assist to gain a better understanding about the performance of 3D printed dosage forms. Electronic supplementary material The online version of this article (doi:10.1007/s11095-016-2083-1) contains supplementary material, which is available to authorized users.

The purpose of this study was to modulate the release profiles of the model protein drug from spray dried poly(DL-lactic-co-glycolic acid) (PLGA) microparticles by incorporating hyaluronic acid (HA) in the formulation. Bovine serum albumin (BSA)-loaded PLGA microparticles with or without HA were prepared using a spray dryer equipped with a 3-fluid nozzle. The effects of HA on the surface tension and the rheological behavior of the inner feed solution were investigated. The physicochemical properties of the resulting microparticles were characterized using scanning electron microscopy (SEM), laser diffraction (LD), confocal laser scanning microscopy (CLSM) and X-ray photoelectron spectroscopy (XPS). Circular dischoism (CD) was used to characterize conformational integrity of BSA released from the microparticles. Spherical microparticles with D50 of 5–10 μm were obtained. Addition of HA in inner feed solutions increased the feed viscosity, but with no influence on the surface tension. All inner feed solutions showed non-Newtonian shear thinning behavior and the rheological properties were not time dependent. The CLSM and XPS analyses suggested a core-shell like structure of the microparticles when HA was incorporated. The release profiles of BSA were extended and the initial burst releases were suppressed with an increase in HA in the microparticle formulations. In addition, HA seemed to protect BSA from degradation upon the spray-drying process. The present work demonstrates the potential of HA to modulate protein release profile from PLGA microparticle formulations produced via spray drying using 3-fluid nozzle.

Most dissolution testing systems rely on analyzing samples taken remotely from the dissolving sample surface at different time points with poor time resolution and therefore provide relatively unresolved temporally and spatially information on the dissolution process. In this study, a flexible numerical model was combined with a novel UV imaging system, allowing monitoring of the dissolution process with sub second time resolution. The dissolution process was monitored by both effluent collection and UV imaging of compacts of paracetamol. A finite element model (FEM) was used to characterize the UV imaging system. A finite element model of the UV imaging system was successfully built. The dissolution of paracetamol was studied by UV imaging and by analysis of the effluent. The dissolution rates obtained from the collected effluent were in good agreement with the numerical model. The numerical model allowed an assessment of the ability of the UV imager to measure dissolution—time profiles. The simulation was able to extend the experimental results to conditions not easily obtained experimentally. Combining FEM,experimental dissolution data and UV imaging provided experimental validation of the FEM model as well as a detailed description of the dissolution process.

It is imperative to understand the particle formation mechanisms when designing advanced nano/microparticulate drug delivery systems. We investigated how the solvent power and volatility influence the texture and surface chemistry of celecoxib-loaded poly (lactic-co-glycolic acid) (PLGA) microparticles prepared by spray-drying.Binary mixtures of acetone and methanol at different molar ratios were applied to dissolve celecoxib and PLGA prior to spray-drying. The resulting microparticles were characterized with respect to morphology, texture, surface chemistry, solid state properties and drug release profile. The evaporation profiles of the feed solutions were investigated using thermogravimetric analysis (TGA).Spherical PLGA microparticles were obtained, irrespectively of the solvent composition. The particle size and surface chemistry were highly dependent on the solvent power of the feed solution. An obvious burst release was observed for the microparticles prepared by the feed solutions with the highest amount of poor solvent for PLGA. TGA analysis revealed distinct drying kinetics for the binary mixtures.The particle formation process is mainly governed by the PLGA precipitation rate, which is solvent-dependent, and the migration rate of celecoxib molecules during drying. The texture and surface chemistry of the spray-dried PLGA microparticles can therefore be tailored by adjusting the solvent composition.

To investigate the heating-induced dehydration and melting behavior of the trihydrate phase of the calcium salt of atorvastatin.Multivariate curve resolution (MCR) was used to decompose a variable-temperature synchrotron X-ray powder diffraction (VT-XRPD) data matrix into diffraction patterns and concentration profiles of pure drug phases.By means of the MCR-estimated diffraction patterns and concentration profiles, the trihydrate phase of the drug salt was found to dehydrate sequentially into two partially dehydrated hydrate structures upon heating from 25 to 110°C, with no associated breakage of the original crystal lattice. During heating from 110 to 140°C, the remaining water was lost from the solid drug salt, which instantly collapsed into a liquid crystalline phase. An isotropic melt was formed above 155°C. Thermogravimetric analysis, hot-stage polarized light microscopy, and hot-stage Raman spectroscopy combined with principal component analysis (PCA) was shown to provide consistent results.This study demonstrates that MCR combined with VT-XRPD is a powerful tool for rapid interpretation of complex dehydration behavior of drug hydrates, and it is also the first report on a liquid crystalline phase of the calcium salt of atorvastatin.

To investigate anti-solvent crystallization and growth mechanism of nitrendipine spherical crystals in an aqueous solution containing polymeric additives. Size and shape of crystals were investigated using laser diffractometry, optical microscopy and scanning electron microscopy (SEM). Crystalline form was determined by X-ray powder diffractometer (XRPD). During crystal growth, morphological changes at different time points were observed using SEM. Morphology of nitrendipine crystals was affected by polymers and temperature. Monodispersed micro-spherical crystals were obtained when polyvinyl alcohol (PVA) and PEG 200 were present in crystallization medium at 2°C. During crystallization, large number of amorphous nanoparticles was first observed, followed by aggregation into a core for spherical crystals. Once crystalline state was achieved, rapid growth on core surface was observed with amorphous particles acting as a reservoir allowing formation of star-like particles with needle-like subunits. Spherical crystals were formed by filling the gap between needle-like distinct crystalline units of star-like templates with molecules from dissolved amorphous particles. Monodispersed nitrendipine spherical crystals were obtained using carefully controlled conditions. A mechanism for the nitrendipine spherical crystal growth is suggested. These findings provide a new insight into spherulitic crystallization of active pharmaceutical ingredients.

To investigate solid state transformations of drug substances during compaction using grazing incidence X-ray diffraction (GIXD). The solid forms of three model drugs–theophylline (TP), nitrofurantoin (NF) and amlodipine besylate (AMB)–were compacted at different pressures (from 100 to 1000 MPa); prepared tablets were measured using GIXD. After the initial measurements of freshly compacted tablets, tablets were subjected to suitable recrystallization treatment, and analogous measurements were performed. Solid forms of TP, NF and AMB showed partial amorphization as well as crystal disordering during compaction; the extent of these effects generally increased as a function of pressure. The changes were most pronounced at the outer surface region. The different solid forms showed difference in the formation of amorphicity/crystal disordering. Dehydration due to compaction was observed for the TP monohydrate, whereas hydrates of NF and AMB were stable towards dehydration. With GIXD measurements, it was possible to probe the solid form composition at the different depths of the tablet surfaces and to obtain depth-dependent information on the compaction-induced amorphization, crystal disordering and dehydration.

Water can be incorporated into crystalline lattice of organic molecules in several ways and thus forms systems with different molecular packing characteristics. This review outlines a general classification of hydrates and explains why it is of high relevance for pharmaceutical researchers to investigate water of crystallization and hydrate systems. The different manufacturing steps related to the final drug product are also briefly discussed with an emphasis on the role of water and possible solid-state transformations related to hydrates. Application of spectroscopic techniques in characterizing water of crystallization and the effect of water on the drug and formulation stability are presented. Moreover, the role of water on the in vitro drug dissolution behavior is reviewed where an example is shown to illustrate the recent development on correlating solid state of the drug, for instance, hydrate formation, to the dissolution profile of the product, to achieve a better understanding of the dissolution process.

The purpose of this study was to investigate the usability of poly(N-isopropyl acrylamide) (PNIPAM) as an additive for crystallization of a model drug, nitrofurantoin (NF), and utilizing the thermoresponsivity of the polymer to enable control of the viscosity during the crystallization process. Crystallization of NF in the presence of PNIPAM resulted in dendritic crystal growth and the originally observed growth of needle-shaped crystals was prohibited. The effect of acetone, a cosolvent used for the crystallization, on thermosensitivity of PNIPAM was studied and the properties of atactic PNIPAM and triblock PNIPAM polymers containing atactic and isotactic rich blocks were compared. The investigated PNIPAMs were all soluble in the acetone–water mixtures leading to phase separation at lower temperatures with increasing acetone content, up to approximately 50 vol% (0.20 mol fraction). At higher acetone contents no phase separation was observed on heating. The presence of acetone altered the viscosity of the solutions prior to the phase separation depending on the polymer architecture. The PNIPAM polymers induced smaller and potentially more easily processable crystals, however, the viscosity increase in the presence of acetone occurred only 1–3 °C prior to phase separation complicating the practical use of this approach.

The purpose of this study was to evaluate the change of surface roughness and the development of the film during the film coating process using laser profilometer roughness measurements, SEM imaging, and energy dispersive X-ray (EDX) analysis. Surface roughness and texture changes developing during the process of film coating tablets were studied by noncontact laser profilometry and scanning electron microscopy (SEM). An EDX analysis was used to monitor the magnesium stearate and titanium dioxide of the tablets. The tablet cores were film coated with aqueous hydroxypropyl methylcellulose, and the film coating was performed using an instrumented pilot-scale side-vented drum coater. The SEM images of the film-coated tablets showed that within the first 30 minutes, the surface of the tablet cores was completely covered with a thin film. The magnesium signal that was monitored by SEM-EDX disappeared after ~15 to 30 minutes, indicating that the tablet surface was homogeneously covered with film coating. The surface roughness started to increase from the beginning of the coating process, and the increase in the roughness broke off after 30 minutes of spraying. The results clearly showed that the surface roughness of the tablets increased until the film coating covered the whole surface area of the tablets, corresponding to a coating time period of 15 to 30 minutes (from the beginning of the spraying phase). Thereafter, the film only became thicker. The methods used in this study were applicable in the visualization of the changes caused by the film coating on the tablet surfaces.

The aim of this research was to describe the thermal behavior of beta-sitosterol crystals in oil-suspensions with a focus on the role of water during heating. The suspensions were prepared by recrystallization in order to achieve a microcrystalline particle size. The structural changes together with the mechanical properties of the suspensions during heating were studied by using variable temperature X-ray powder diffractometry (VT-XRPD), differential scanning calorimetry (DSC), and dynamic mechanical analysis (DMA). Hydrated beta-sitosterol crystals in an oil-suspension dehydrated, despite the composition of the suspensions, at low temperatures. At high beta-sitosterol concentration, the monohydrate crystal form changed partially to a hemihydrated form, and when only a small amount of water was initially incorporated, the hemihydrate crystal form dehydrated to a mostly anhydrate crystal form. The released water, which was immiscible in the surrounding oil, caused the recrystallization of hydrated beta-sitosterol during cooling. This procedure indicated a reversible dehydration process. Structural and thermal analysis of beta-sitosterol crystals in suspensions, together with mechanical analysis made it possible to understand various physical changes during heating.

An instrumentation and automation system for a side-vented pan coater with a novel air-flow rate measurement system for monitoring the film-coating process of tablets was designed and tested. The instrumented coating system was tested and validated by film-coating over 20 pilot-scale batches of tablets with aqueous-based hydroxypropyl methylcellulose (HPMC). Thirteen different process parameters were continuously measured and monitored, and the most significant ones were logged for analysis. Laser profilometry was used to measure the surface roughness of the coated tablets. The instrumentation system provided comprehensive and quantitative information on the process parameters monitored. The measured process parameters and the responses of the film-coated tablet batches showed that the coating process is reproducible. The inlet air-flow rate influenced the coating process and the subsequent quality of the coated tablets. Increasing the inlet flow rate accelerated the drying of the tablet surface. At high inlet flow rate, obvious film-coating defects (ie, unacceptable surface roughness of the coated tablets) were observed and the loss of coating material increased. The instrumented and automated pan-coating system described, including historical data storage capability and a novel air-flow measurement system, is a useful tool for controlling and characterizing the tablet film-coating process. Monitoring of critical process parameters increases the overall coating process efficiency and predictability.

Purpose. The aim was to follow hydrate formation of two structurally related drugs, theophylline and caffeine, during wet granulation using fast and nondestructive spectroscopic methods. Methods. Anhydrous theophylline and caffeine were granulated with purified water. Charge-coupled device (CCD) Raman spectroscopy was compared with near-infrared spectroscopy (NIR) in following hydrate formation of drugs during wet granulation (off-line). To perform an at-line process analysis, the effect of water addition was monitored by NIR spectroscopy and principal components analysis (PCA). The changes in the crystal arrangements were verified by using X-ray powder diffraction (XRPD). Results. Hydrate formation of theophylline and caffeine could be followed by CCD Raman spectroscopy. The NIR and Raman spectroscopic results were consistent with each other. NIR revealed the state of water, and Raman spectroscopy gave information related to the drug molecule itself. The XRPD confirmed the spectroscopic results. PCA with three principal components explained 99.9 of the spectral variation in the second derivative NIR spectra. Conclusions. Both CCD Raman and NIR spectroscopic methods can be applied to monitoring of hydrate formation processes. However, NIR is more suitable for monitoring solid-water interactions.

1 system for fluidized bed granulator automation with in-line multichannel near infrared (NIR) moisture measurement and a unique air flow rate measurement design was assembled, and the information gained was investigated. The multivariate process data collected was analyzed using principal component analysis (PCA). The test materials (theophylline and microcrystalline cellulose) were granulated and the calibration behavior of the multichannel NIR set-up was evaluated against full Fourier Transform (FT) NIR spectra. Accurate and reliable process air flow rate measurement proved critical in controlling the granulation process. The process data describing the state of the process was projected in two dimensions, and the information from various trend charts was outlined simultaneously. The absorbence of test material at correction wavelengths (NIR region) and the nature of material-water interactions affected the detected in-line NIR water signal. This resulted in different calibration models for the test materials. Development of process analytical methods together with new data visualization algorithms creates new tools for in-process control of the fluidized bed granulation.