Correlating mechanical and rheological filament properties to processability and quality of 3D printed tablets using multiple linear regression.

Filament formulation for FDM is a challenging and time-consuming process. Several pharmaceutical polymers are not feedable on their own. Due to inadequate filament formulation, 3D printed tablets can also exhibit poor uniformity of tablet attributes. To better understand filament formulation process, 23 filaments were prepared with the polymer mixing approach. To yield processable filaments, brittle and pliable polymers were combined. A 20 % addition of a pliable polymer to a brittle one resulted in filament processability and vice versa. Predictive statistical models for filament processability and uniformity of tablet attributes were established based on the mechanical and rheological properties of filaments. 15 input variables were correlated to 9 responses, which represent filament processability and tablet properties, by using multiple linear regression approach. Filament stiffness, assessed by indentation, and its square term were the only variables that determined the filament's feedability. However, the resulting model is equipment-specific since different feeding mechanism exert different forces on the filaments. Additional models with good predictive power (R2pred > 0.50) were established for tablet width uniformity, drug release uniformity, tablet disintegration time uniformity and occurrence of disintegration, which are equipment-independent outputs. Therefore, the obtained model outcomes could be used in other research endeavours.

Development of Simvastatin-Loaded Particles Using Spray Drying Method for Ex Tempore Preparation of Cartridges for 2D Printing Technology.

In this work, a spray drying method was developed to produce drug/polymer (simvastatin/polycaprolactone) microparticles that have the potential to be used as a pre-formulation for ex tempore preparation of 2D printing cartridges. An experimental model was designed with the process parameters set to predict the smallest particle size required for successful 2D printing. Three different types of particles (lactose, nanocellulose/lactose, calcium silicate) were produced, and the average size of the dry particles varied depending on the sampling location (cyclone, collection vessel). The encapsulation efficiency of simvastatin was highest with nanocellulose/lactose from the collection vessel. The one-month stability of simvastatin in the particles showed low content, but the addition of ascorbic acid as an antioxidant increased the chemical stability of the drug. Interestingly, the addition of antioxidants decreased the stability of simvastatin in the calcium silicate particles from the collection vessel. Dispersion of the particles in three different propylene glycol and water mixtures (10/90, 50/50, and 90/10% (v/v)), representing a printable ink medium with three different viscosity and surface tension properties, showed that nanocellulose/lactose was the most suitable antiadhesive in terms of dispersed particle size (˂1 µm). After one month of storage, the dispersed particles remained in the same size range without undesirable particle agglomeration.

Influence of fused deposition modelling printing parameters on tablet disintegration times: a design of experiments study.

Despite the importance of process parameters in the printing of solid dosage forms using fused deposition modelling (FDM) technology, the field is still poorly explored. A design of experiment study was conducted to understand the complete set of process parameters of a custom developed FDM 3D printer and their influence on tablet disintegration time. Nine settings in the Simplify 3D printing process design software were evaluated with further experimental investigation conducted on the influence of infill percentage, infill pattern, nozzle diameter, and layer height. The percentage of infill was identified as the most impactful parameter, as increasing it parabolically affected the increase of disintegration time. Furthermore, a larger nozzle diameter prolonged tablet disintegration, since thicker extruded strands are generated through wider nozzles during the printing process. Three infill patterns were selected for in-depth analysis, demonstrating the clear importance of the geometry of the internal structure to resist mechanical stress during the disintegration test. Lastly, layer height did not influence the disintegration time. A statistical model with accurate fit (R 2 = 0.928) and predictability (Q 2 = 0.847) was created. In addition, only the infill pattern and layer height influenced both the uniformity of mass and uniformity of the disintegration time, which demonstrates the robustness of the printing process.

The Effect of Design and Size of the Fluid-Bed Equipment on the Particle Size-Dependent Trend of Particle Coating Thickness and Drug Prolonged-Release Profile.

The focus of the current work is to study and demonstrate the impact of the design, the scale, and settings of fluid-bed coating equipment on the differences in pellet coating thickness, which in case of prolonged-release pellets dictates the drug release. In the first set of coating experiments, the pellet cores were coated with the Tartrazine dye with the aim of estimating the coating equipment performance in terms of coating thickness distribution, assessed through color hue. In the second set, drug-layered pellets were film-coated with prolonged-release coating and dissolution profile tests were performed to estimate the thickness and uniformity of the coating thickness among differently sized pellets. In both study parts, film coating was performed at the laboratory and the pilot scale and essentially two types of distribution plate and different height adjustments of the draft tube were compared. The dye coating study proved to be extremely useful, as the results enable process correction and the optimal use of the process equipment in combination with the appropriate process parameters. Preferential film coating of larger drug-containing pellets was confirmed on the laboratory scale, while on the pilot scale, it was possible to achieve preferential coating of smaller pellets using rational alternatives of settings, which is desirable in terms of particle size-independent drug release profile of such prolonged-release dosage forms.

Comparison of the Robustness of Pellet Film Coating with and without In-Process Coating Thickness Evaluation.

The robustness of the pellet coating process with and without the use of an in-process coating thickness analyzer (PATVIS APA) was investigated. Pellets containing model drug were coated with a prolonged release film coating, using different process conditions. In the first set of experiments film coating was performed as process repetitions with unintentional variation of process parameters, and in the second set, controlled changes (inlet air humidity, gap between distribution plate and Wurster partition, starting pellet load) were made. Within the first set of experiments, the coating process endpoint was determined either via gravimetric consumption of coating dispersion or by means of in-line coating thickness monitoring. The release profiles of the pellets were analyzed and the density of coating calculated. Both methods of the process endpoint determination can be relatively robust in batch processing, if key factors influencing drug release profile are under control. PATVIS APA was shown to be a useful tool to better understand the coating process and can be helpful if coating process interruptions are encountered. Water content was shown to be the key factor influencing the drug profile, presumably by influencing the structure and thickness of the coating applied.

Influence of the Binder Jetting Process Parameters and Binder Liquid Composition on the Relevant Attributes of 3D-Printed Tablets.

Binder jetting has the potential to revolutionize the way we produce medicine. However, tablets produced by binder jetting technology can be quite fragile and hard to handle. In this study, the printing process and ink composition were examined to optimize the mechanical properties of tablets. A model formulation containing the ketoprofen drug was developed and used as a base for optimization. Firstly, important printing parameters were identified with a fractional factorial design. Saturation and layer height critically influenced selected tablet properties. Relevant process parameters were optimized for tablet mechanical strength by using the D-optimization DoE approach. The best mechanical properties were achieved when saturation was set to 1 and layer height to 150 µm. On the other hand, binder ink composition did not appear to impact tablet mechanical strength as much as process parameters did. Three ethanol-water mixtures were tested at three tablet strength levels and no definitive conclusions could be drawn. The binder jetting process can be wasteful, especially if the unbound powder cannot be reused. To determine the suitability of powder blend recycling, the ketoprofen content was measured for 27 subsequent batches of tablets. While the trendline did indicate a slight reduction in ketoprofen content, the powder blend reuse can nevertheless be employed.

Relative bioavailability enhancement of simvastatin via dry emulsion systems: Comparison of spray drying and fluid bed layering technology.

Comprehensive comparisons of similar lipid based drug delivery systems produced by different technologies are scarce. Spray drying and fluid bed layering technologies were compared with respect to the process and product characteristics of otherwise similar simvastatin loaded dry emulsion systems. Fluid bed layering provided higher process yield (83.3% vs 71.5%), encapsulation efficiency (80.0% vs 68.4%), relative one month product stability (93.8% vs 85.5%), larger and more circular particles (336 µm vs 56 µm) and lower median oil droplet size after product reconstitution in water (2.85 µm vs 4.27 µm), compared to spray drying. However, spray dried products exhibited higher drug content (22.2 mg/g vs 9.34 mg/g). An in-vivo pharmacokinetic study in rats was performed and a pharmacokinetic model was developed in order to compare the optimised simvastatin loaded dry emulsion systems, a simvastatin glyceride mimetic loaded in the dry emulsion and a simvastatin loaded SMEDDS with a reference physical mixture. Of the formulation tested, fluid bed layered pellets excelled and provided a 115% relative increase in bioavailability. Among the two technologies, fluid bed layering provided dry emulsion products with higher relative bioavailability and better product characteristics for further processing into final dosage forms.

The Potential of Macroporous Silica-Nanocrystalline Cellulose Combination for Formulating Dry Emulsion Systems with Improved Flow Properties: A DoE Study.

The objective of this study was to explore the possible use of a new combination of two excipients, i.e., nanocrystalline cellulose (NCC) and macroporous silica (MS), as matrix materials for the compounding of dry emulsion systems and the effects these two excipients have on the characteristics of dry emulsion powders produced by the spray drying process. A previously developed liquid O/W nanoemulsion, comprised of simvastatin, 1-oleoyl-rac-glycerol, Miglyol 812 and Tween 20, was employed. In order to comprehend the effects that these two matrix formers have on the spray drying process and on dry emulsion powder characteristics, alone and in combination, a DoE (Design of Experiment) approach was used. The physicochemical properties of dry emulsion samples were characterised by atomic force microscopy, scanning electron microscopy, mercury intrusion porosimetry, energy-dispersive X-ray spectroscopy and laser diffraction analysis. Additionally, total release and dissolution experiments were performed to assess drug release from multiple formulations. It was found that the macroporous silica matrix drastically improved flow properties of dry emulsion powders; however, it partially trapped the oil-drug mixture inside the pores and hindered complete release. NCC showed its potential to reduce oil entrapment in MS, but because of its rod-shaped particles deposited on the MS surface, powder flowability was deteriorated.

Assessment of Mini-Tablets Coating Uniformity as a Function of Fluid Bed Coater Inlet Conditions.

This study concerned the quality of mini-tablets' coating uniformity obtained by either the bottom spray chamber with a classical Wurster distributor (CW) or a swirl distributor (SW). Mini-tablets with a diameter of 2.0, 2.5, and 3.0 mm were coated with hypromellose using two different inlet air distributors as well as inlet airflow rates (130 and 156 m3/h). Tartrazine was used as a colorant in the coating layer and the coating uniformity was assessed by spectrophotometric analysis of solutions obtained after disintegration of the mini-tablets (n = 100). Higher uniformity of coating material distribution among the mini-tablets was observed in the case of SW distributor, even for the biggest mini-tablets (d = 3.0 mm), with an RSD no larger than 5.0%. Additionally, coating thickness was evaluated by colorimetric analysis (n = 1000), using a scanner method, and expressed as a hue value. A high correlation (R = 0.993) between inter-tablet variability of hue and UV-Vis results was obtained. Mini-tablets were successfully coated in a fluid bed system using both a classical Wurster distributor as well as a swirl generator. However, regardless of the mini-tablets' diameter, better film uniformity was achieved in the case of a distributor with a swirl generator.

Particle properties and drug metastable solubility of simvastatin containing PVP matrix particles prepared by electrospraying technique.

In this work the preparation of drug loaded polymeric nanoparticles using electrospraying method and their subsequent characterization is presented. Our purpose was to incorporate the drug with extremely low solubility and low oxidative stability into polyvinylpyrolidone nanoparticles in order to improve its solubility and preserve its chemical stability and hence evaluate the ability of the technology to stabilize such systems in nanoparticulate form. Through the initial screening and optimization of process parameters and polymer solution properties, we detected different morphologies of electrosprayed product particles, where the use of lower molecular weight polymer resulted in a higher process instability as well as in a broader particle size distribution. On the other hand, the solution containing polyvinylpyrolidone with higher molecular weight showed sensitivity to different flow rates and electric field changes, which again resulted in differing the particle size and morphology. The electrosprayed products, prepared by sufficient process stability and having adequately narrow size distribution span, showed lower initial simvastatin contents than theoretically expected, which indicated an oxidative drug degradation already during the electrospraying process. The addition of antioxidants improved simvastatin chemical stability in the particles, during the process itself as well as after accelerated stability study. With an addition of butylated hydroxyanisole antioxidant mixture into initial polymer solution more than 95% of the drug content was preserved after one month at accelerated conditions, whereas in formulations without antioxidants simvastatin content was less than 6%. Antioxidants addition however did not influence only simvastatin stability but also simvastatin solubility. Surprisingly, antioxidants addition did decrease drug solubility in buffers (pH=4 and pH=6.8) for more than a half without any solid state changes of simvastatin. Potential hydrophobic interaction between simvastatin and antioxidants are hindering the drug solubility in the respective buffer, despite drug being in amorphous state.

Preparation, Physicochemical Characterisation and DoE Optimisation of a Spray-Dried Dry Emulsion Platform for Delivery of a Poorly Soluble Drug, Simvastatin.

In the presented study, insight into the development and optimisation of the dry emulsion formulation and spray drying process is provided. The aim was to facilitate the dissolution of the poorly soluble, highly lipophilic drug, simvastatin, by forming spray-dried dry emulsion particles having adequate powder flow properties, while assuring sufficient drug content. Simvastatin and a mixture of caprylic, capric triglyceride and 1-oleoyl-rac-glycerol were employed as a model drug and solubilising oils, respectively. A matrix of the dry emulsions was composed at a fixed ratio mixture of mannitol and HPMC. Tween 20 was used in low amounts as the primary emulsion stabiliser. To facilitate process optimisation, a DoE surface response design was used to study the influence of formulation and process parameters on the particle size distribution, powder bulk properties, emulsion reconstitution ability, drug stability and process yield of spray-dried products. Two-fluid nozzle geometry was identified, studied and confirmed to be important for most product critical quality attributes. Models obtained after the study showed acceptable coefficients of determination and provided good insight in the relationship governing the process and product characteristics. Five model optimised products showed adequate process yield, suitable particle size distribution, good reconstitution ability and improved dissolution profile, when compared to a non-lipid-based tablet and the pure drug. However, the obtained dry emulsion powders exhibited poor flow character according to the Carr index. The optimised product was further analysed with NMR during lipolysis to gain insight into the species formed during digestion and the kinetics of their formation.

Analytical Challenges of Spray Pattern Method Development for Purposes of In Vitro Bioequivalence Testing in the Case of a Nasal Spray Product.

Background: A spray pattern (SP) test is one of the most challenging in vitro tests for nasal spray products (NSPs) associated with a high degree of variation. The total results variation observed in such studies should be in major part representative of product performance to assure high confidence when making conclusions based on obtained results. Analytical methods should be developed in a way to minimize variation contribution of random factors. A systematic statistical assessment of sources of variation is encouraged to be performed during any method development. Methods: This study includes the development of a product-shaking procedure, definition of in vivo relevant actuation parameters, and the development of a robust SP method considering NSP behavior. The final SP method is tested on different days and in different laboratories to evaluate the contribution of individual factors and interactions to the observed variance in SP using a gauge repeatability and reproducibility (GRR) model. Results: It was found that the time lag between consecutive actuations significantly influences the variability of the SP area, suggesting the importance of determining a recovery period. Factor analyst was not found to be important. Factor day was found to have the potential to impact results, mostly through interactions with other factors, suggesting that one should pay attention when performing any comparative studies within the same laboratory on different days. Significant differences were observed when the same product was tested in different laboratories. Conclusion: Key random factors, which significantly contribute to total variation, were identified using a GRR approach. By applying an appropriate control strategy over these factors, one can assure that assessed total variation can be representative of product performance. The same general approach is not only applicable to development of SP method for NSP but to all types of analytical testing as well.

A Novel Simulation-Based Approach for Comparing the Population Against Average Bioequivalence Statistical Test for the Evaluation of Nasal Spray Products on Spray Pattern and Droplet Size Distribution Parameters.

The aim of this work is to evaluate average bioequivalence (ABE) and population bioequivalence (PBE) statistical approaches so as to identify which approach is most suitable for in vitro bioequivalence (IVBE) testing of nasal spray products. For droplet size distribution (DSD) and spray pattern (SP), in vitro data were collected using a well-established nasal spray on the market (Nasonex®, manufactured by Merck Sharp & Dohme Limited). Simulations were performed using in vitro data to comparatively investigate ABE and PBE tests. For highly variable parameters such as SP area, this study clearly demonstrates that the level of agreement between ABE and PBE test conclusions is much smaller as compared with that of DSD Dv(50), which was found to have moderate variability. PBE approach dictates equivalence for both means and variances, and was found to handle both SP and DSD parameters with similar passing rates compared to the passing rates from the ABE approach. However, pronounced asymmetric behavior of PBE empirical power curves for highly variable SP area was observed. A modified PBE statistical approach is proposed for DSD span and Dv(50) in vitro parameters, where acceptance criteria would be based on comparison of reference/branded product to itself as part of "pre-IVBE study" via innovative statistical bootstrap simulations. Due to inherent high variability of the SP area parameter driving pronounced asymmetric behavior of PBE power curves, and due to unclear in vivo relevance for SP area and ovality, authors propose that SP parameters be used as development and quality control tools rather than for demonstration of IVBE.

In-Line Film Coating Thickness Estimation of Minitablets in a Fluid-Bed Coating Equipment.

Film coating thickness of minitablets was estimated in-line during coating in a fluid-bed equipment by means of visual imaging. An existing, commercially available image acquisition system was used for image acquisition, while dedicated image analysis and data analysis methods were developed for this purpose. The methods were first tested against simulated minitablet's images and after that examined on a laboratory-scale fluid-bed Wurster coating process. An observation window cleaning mechanism was developed for this purpose. Six batches of minitablets were coated in total, using two different dispersions, where for the second dispersion coating endpoint was determined based on the in-line measurement. Coating thickness estimates were calculated from the increasing size distributions of the minitablet's major and minor lengths, assessed from the acquired images. Information on both the minitablet's average band and average cap coating thicknesses was obtained. The in-line coating thickness estimates were compared to the coating thickness weight gain calculations and the optical microscope measurements as a reference method. Average band coating thickness estimate was found the most accurate in comparison to microscope measurements, with root mean square error of 1.30 µm. The window cleaning mechanism was crucial for the accuracy of the in-line measurements as was evident from the corresponding decrease of the root mean square error (9.52 µm, band coating thickness). The presented visual imaging approach exhibits accuracy of at least 2 µm and is not susceptible to coating formulation or color variations. It presents a promising alternative to other existing techniques for the in-line coating thickness estimation.

A redispersible dry emulsion system with simvastatin prepared via fluid bed layering as a means of dissolution enhancement of a lipophilic drug.

The purpose of the study was to develop a redispersible dry emulsion, containing a lipophilic, poorly water soluble model drug simvastatin, by employing fluid bed coating technology. The presented dry emulsion manufacturing approach produces pellets in a way, where a layer of the dry emulsion is applied to a neutral core. In the preliminary formulation development phase 1-oleoyl-rac-glycerol was chosen as the oily lipid phase, based on the high drug solubility and potential bioavailability enhancement capability. Mannitol, HPMC and Tween 20 were selected as the solid carriers and surfactant, respectively. The design of experiments, specifically the mixture design approach, was used to obtain the optimal formulation composition. The emulsion reconstitution ability and stability were the main responses, used as the decisive parameters for formulation optimisation. Optimised formulations showed narrow droplet size distribution upon reconstitution, high stability, suitable drug loading and enhanced dissolution profile, compared to a non-lipid based tablet and the pure drug. The scanning electron microscopy, Raman spectroscopy and image analysis disclosed a uniform morphology of the applied layer with separated droplets with simvastatin and uniform size distribution and a circular shape of coated pellets. The study represents the proof of concept of designing redispersible dry emulsions using a fluid bed layering approach.

Mechanics of Pharmaceutical Pellets-Constitutive Properties, Deformation, and Breakage Behavior.

To ensure robust manufacturing of unit-based oral solid dosage forms with minimal structural imperfections and high mechanical reliability across subsequent processing unit operations (e.g., withstanding mechanical stresses during coating, optional axial compression, handling, packaging, storage, and transport conditions), process design should include consideration of precise limits of accurate micro, macro, and bulk properties of the constituent pellets. This communication presents a comprehensive intricate database of micromechanical properties' and breakage probability distribution functions of pellets, illustrating the stiffening and strengthening effects of coatings and the softening and weakening effects of structural moisture. Further insights such as the (contact) history-dependent softening during decompression, strain hardening on repeated stressing, strength recovery by drying, and the fragmentation pattern by cracking are also presented. The contents herein are based on conveniently performable lab-scale diametrical compression measurements on model microcrystalline cellulose pellets-demonstrating feasibility of the approach and validity of the contribution.

Analysis of pellet coating uniformity using a computer scanner.

A fast method for pellet coating uniformity analysis, using a commercial computer scanner was developed. The analysis of the individual particle coating thicknesses was based on using a transparent orange colored coating layer deposited on white pellet cores. Besides the analysis of the coating thickness the information of pellet size and shape was obtained as well. Particle size dependent coating thickness and particle size independent coating variability was calculated by combining the information of coating thickness and pellet size. Decoupling coating thickness variation sources is unique to presented method. For each coating experiment around 10000 pellets were analyzed, giving results with a high statistical confidence. Proposed method was employed for the performance evaluation of classical Wurster and swirl enhanced Wurster coater operated at different gap settings and air flow rates.

Elucidation of Formulation and Delivery Device-Related Effects on In Vitro Performance of Nasal Spray with Implication to Rational Product Specification Identification.

BACKGROUND: The aim of this work is to use an experimental design approach to identify and study influential formulation and delivery device properties, which can be controlled by final product manufacturer, to establish design space, within which desired in vitro performance can be reached. METHODS: Combining three factors, viscosity of suspension, nozzle orifice diameter (OD), and shot weight (SW), at three levels resulted in D-optimal experimental design with 20 runs. Responses within this study were droplet size distribution (DSD) and spray pattern (SP) in vitro tests. In addition, the amount of mechanical work needed for actuation was integrated from force profiles and used as a response. Results were fit to quadratic model by regression, which allowed also for determination of second-order and interaction effects between factors. Models were further optimized by keeping significant terms only. Optimized models were used to create response surfaces and design space with confidence levels. RESULTS: Viscosity has a dominant effect on DSD and modest effect on SP, with lower viscosities related to generation of smaller DSD and larger SP. Orifice diameter was found to have the highest impact on SP, with larger diameter resulting in larger SP. This effect was additionally confirmed by results of Plume Geometry in vitro test. Shot weight factor exerts significant influence on all tested metrics. Work, however, did not vary greatly with suspension viscosity or orifice diameter. Shot weight is the most dominant factor for work and important for DSD having a positive effect on both responses. In the case of SP, its relationship with shot weight is described by second-order polynomial fit. Inspection of raw data revealed that density of droplets within SP area is different for different shot weights. CONCLUSION: Presented study elucidated an inherent relationship between factors and responses and established mathematical models (response surfaces) for predictive purposes to target specific in vitro performance of nasal sprays by appropriate specification of factors, taking into account control space with included risk and uncertainty analysis.

Evaluation of the tablets' surface flow velocities in pan coaters.

The tablet pan coating process involves various types of transverse tablet bed motions, ranging from rolling to cascading. To preserve satisfactory results in terms of coating quality after scale-up, understanding the dynamics of pan coating process should be achieved. The aim of this study was to establish a methodology of estimating translational surface velocities of the tablets in a pan coater and to assess their dependence on the drum's filling degree, the pan speed, the presence of baffles and the selected tablet properties in a dry bed system and during coating while varying the drum's filling degree and the pan speed. Experiments were conducted on the laboratory scale and on the pilot scale in side-vented pan coaters. Surface movement of biconvex two-layer tablets was assessed before, during and after the process of active coating. In order to determine the tablets' surface flow velocities, a high-speed video of the tablet surface flow was recorded via a borescope inserted into the coating drum and analysed via a cross-correlation algorithm. The obtained tablet velocity data were arranged in a linear fashion as a function of the coating drum's radius and frequency. Velocity data obtained during coating were close to those of dry tablets after coating. The filling degree had little influence on the tablet velocity profile in a coating drum with baffles but clearly affected it in a coating drum without baffles. In most but not all cases, tablets with a lower static angle of repose had tablet velocity profiles with lower slopes than tablets with higher inter-tablet friction. This particular tablet velocity response can be explained by case specific values of tablet bed's dynamic angle of repose.