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.

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.

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.

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.

Assessment of critical material attributes of polyethylene oxide for formulation of prolonged-release tablets.

Physicochemical evaluation of polyethylene oxide (PEO) polymers with various molecular weights was performed at molecular (polymeric dispersion) and bulk level (powders, polymeric films, and tablets) with the aim of specifying polymer critical material attributes with the main contribution to drug release from prolonged-release tablets (PRTs). For this purpose, grades of PEO with low, medium, and high viscosity were used for formulating PRTs with a good soluble drug substance (dose solubility volume 15 ml). The results revealed a good correlation (r2=0.88) between in vivo data (pharmacokinetic parameters: Cmax and AUC) and the elastic property of PEO films determined with the nanoindentation method, demonstrating that film level can also be used for the in vivo prediction of drug dissolution. The study confirmed that polymer molecular weight and its viscosity are the most important critical material attributes affecting drug dissolution (in vitro) and in vivo bioavailability (e.g. Cmax and AUC). Our research revealed that the nanoindentation technique can distinguish well between various types of polymers, classifying PEO as the most ductile and polyvinyl alcohol as the most brittle. Finally, our study provides an approach for the determination of exact physical attributes of PEO as a critical material attribute from clinically relevant data, and it therefore fulfills the basic principles of product development by Quality by Design.

Polymorphism in Sulfanilamide: 14N Nuclear Quadrupole Resonance Study.

To demonstrate the selectivity of 14N nuclear quadrupole resonance (14N NQR) spectroscopy in chemistry and pharmacy, a study of sulfanilamide polymorphism was undertaken. We studied 3 known polymorphs of sulfanilamide by 14N NQR. We found at room temperature 2 sets of 3 14N NQR transition frequencies, corresponding to 2 different nitrogen sites in the crystal structure for each of 3 polymorphs. We measured the temperature dependence of all quadrupole frequencies ν+, ν-. In each set, only 1 of the 3 14N NQR frequencies is enough to characterize the polymorph. Spin-lattice relaxation time (T1) measurement is supplemental information. We also measured the transition temperature between polymorphs and estimated the ratio of polymorphs after thermal treatment of sample.

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.

Application of miscibility analysis and determination of Soluplus solubility map for development of carvedilol-loaded nanofibers.

Electrospinning was used to produce carvedilol-loaded Soluplus polymer nanofibers using a systematic approach. Miscibility between drug and polymer was determined through calculation of the interaction parameter, χ, and the difference between the total solubility parameters, Δdt. A solubility map for Soluplus was obtained by examining different solvent systems, carrying out electrospinning, and characterizing the nanofibers formed. Miscibility studies showed that carvedilol and Soluplus can form a miscible system (χ=-2.3054; Δδt<7.0MPa1/2). Based on the Soluplus solubility map, acetone: chloroform (90:10; w/w) represents a suitable solvent system for electrospinning of carvedilol-loaded Soluplus nanofibers. Scanning electron microscopy of these nanofiber samples showed smooth surface morphology. The nanofibers had a regular cylindrical morphology. Beads appeared along the nanofibers more frequently in formulations with lower percentages of carvedilol. Differential scanning calorimetry showed no melting endothermic peak for carvedilol, which suggests its complete conversion from the crystalline to the amorphous form (at polymer: carvedilol 1:1). The infrared spectrum of the carvedilol-loaded Soluplus nanofibers showed no characteristic carvedilol peak at 3344.5cm-1, which suggests interactions between carvedilol and Soluplus. Dissolution studies of these nanofibers showed improved pure carvedilol dissolution properties, with >85% of the carvedilol released in the first 15min, versus 20% for pure carvedilol. The use of miscibility analysis and polymer solubility studies demonstrate great technological potential to tackle the challenge for inadequate dissolution of poorly water-soluble drugs.

Spherical agglomerates of lactose with enhanced mechanical properties.

The aim of this study was to prepare spherical agglomerates of lactose and to evaluate their physicochemical properties, flow properties, particle friability and compaction properties, and to compare them to commercially available types of lactose for direct compression (spray-dried, granulated and anhydrous ß-lactose). Porous spherical agglomerates of α-lactose monohydrate with radially arranged prism-like primary particles were prepared exhibiting a high specific surface area. All types of lactose analysed had passable or better flow properties, except for anhydrous ß-lactose, which had poor flowability. Particle friability was more pronounced in larger granulated lactose particles; however, particle structure was retained in all samples analysed. The mechanical properties of spherical agglomerates of lactose, in terms of compressibility, established with Walker analysis, and compactibility, established with a compactibility profile, were found to be superior to any commercially available types of lactose. Higher compactibility of spherical agglomerates of lactose is ascribed to significantly higher particle surface area due to a unique internal structure with higher susceptibility to fragmentation.

Novel Spray Dried Glycerol 2-Phosphate Cross-Linked Chitosan Microparticulate Vaginal Delivery System-Development, Characterization and Cytotoxicity Studies.

Chitosan microparticulate delivery systems containing clotrimazole were prepared by a spray drying technique using glycerol 2-phosphate as an ion cross-linker. The impact of a cross-linking ratio on microparticle characteristics was evaluated. Drug-free and drug-loaded unmodified or ion cross-linked chitosan microparticles were examined for the in vitro cytotoxicity in VK2/E6E7 human vaginal epithelial cells. The presence of glycerol 2-phosphate influenced drug loading and encapsulation efficacy in chitosan microparticles. By increasing the cross-linking ratio, the microparticles with lower diameter, moisture content and smoother surface were observed. Mucoadhesive studies displayed that all formulations possessed mucoadhesive properties. The in vitro release profile of clotrimazole was found to alter considerably by changing the glycerol 2-phosphate/chitosan ratio. Results from cytotoxicity studies showed occurrence of apoptotic cells in the presence of chitosan and ion cross-linked chitosan microparticles, followed by a loss of membrane potential suggesting that cell death might go through the mitochondrial apoptotic pathway.

Stability and solubility of trans-resveratrol are strongly influenced by pH and temperature.

Recently trans-resveratrol (trans-RSV) has received great attention due to its prophylactic and therapeutic properties. Its limited bioavailability provides compelling evidence of the need for more suitable formulations in order to attain better clinical effectiveness. Some physicochemical properties of trans-RSV are still unknown or research findings are contradictory. Therefore, this paper presents newly determined trans-RSV solubility and stability at various pH and temperatures, and the importance of such data for the studies of novel trans-RSV-loaded nanofibers. In acidic pH trans-RSV was stable, whereas its degradation started to increase exponentially above pH 6.8. Consequently, it is worthwhile to note that special consideration has to be dedicated to long dissolution testing or biological assays on cell lines in order to obtain relevant data. Measurements were done by validated UV/VIS spectroscopy, HPLC, and newly developed UPLC methods. Specificity was confirmed for HPLC and UPLC method, whereas UV/VIS spectroscopy resulted in false higher trans-RSV concentrations in conditions under which it was not stable (alkaline pH, light, increased temperature). The study is of interest because it draws attention to the importance of careful selected experimental conditions, their influence on the trans-RSV stability and the implications this has for formulation development, storage, and maintenance of therapeutic doses.

Electrospun polycaprolactone nanofibers as a potential oromucosal delivery system for poorly water-soluble drugs.

The number of poorly water-soluble drug candidates is rapidly increasing; this represents a major challenge for the pharmaceutical industry. As a consequence, novel formulation approaches are required. Furthermore, if such a drug candidate is intended for the therapy of a specific group of the population, such as geriatric or pediatric, the formulation challenge is even greater, with the need to produce a dosage form that is acceptable for specific patients. Therefore, the goal of our study was to explore electrospun polycaprolactone (PCL) nanofibers as a novel nanodelivery system adopted for the oromucosal administration of poorly water-soluble drugs. The nanofibers were evaluated in comparison with polymer films loaded with ibuprofen or carvedilol as the model drugs. Scanning electron microscopy revealed that the amount of incorporated drug affects the diameter and the morphology of the nanofibers. The average fiber diameter increased with a higher drug loading, whereas the morphology of the nanofibers was noticeably changed in the case of nanofibers with 50% and 60% ibuprofen. The incorporation of drugs into the electrospun PCL nanofibers was observed to reduce their crystallinity. Based on the morphology of the nanofibers and the films, and the differential scanning calorimetry results obtained in this study, it can be assumed that the drugs incorporated into the nanofibers were partially molecularly dispersed in the PCL matrix and partially in the form of dispersed nanocrystals. The incorporation of both model drugs into the PCL nanofibers significantly improved their dissolution rates. The PCL nanofibers released almost 100% of the incorporated ibuprofen in 4h, whereas only up to 77% of the incorporated carvedilol was released during the same time period, indicating the influence of the drug's properties, such as molecular weight and solubility, on its release from the PCL matrix. The obtained results clearly demonstrated the advantages of the new nanodelivery system compared to the drug-loaded polymer films that were used as the reference formulation. As a result, electrospinning was shown to be a very promising nanotechnology-based approach to the formulation of poorly water-soluble drugs in order to enhance their dissolution. In addition, the great potential of the produced drug-loaded PCL nanofiber mats for subsequent formulation as oromucosal drug delivery systems for children and the elderly was confirmed.

(14) N nuclear quadrupole resonance study of piroxicam: confirmation of new polymorphic form V.

A new polymorphic crystal form of piroxicam was discovered while preparing crystalline samples of piroxicam for (14) N nuclear quadrupole resonance (NQR) analysis. The new crystal form, designated as V, was prepared by evaporative recrystallization from dichloromethane. Three known polymorphic forms (I, II, and III) were also prepared. Our aim was to apply (14) N NQR to characterize the new polymorphic form of piroxicam and compare the results with those of the other known polymorphic forms. Additional analytical methods used for characterization were X-ray powder diffraction (XRPD), thermal analysis, and vibrational spectroscopy. For the first time, a complete set of nine characteristic (14) N NQR frequencies was found for each prepared polymorph of piroxicam. The consistent set of measured frequencies and calculated characteristic quadrupole parameters found for the new polymorphic form V is a convincing evidence that we are dealing with a new form. The already known piroxicam polymorphic forms were characterized similarly. The XRPD results were in accordance with the conclusions of (14) N NQR analysis. The performed study clearly demonstrates a strong potential of (14) N NQR method to be applied as a highly discriminative spectroscopic analytical tool to characterize polymorphic forms.

¹4N nuclear quadrupole resonance study of polymorphism in famotidine.

(14)N nuclear quadrupole resonance (NQR) in two known polymorphs of famotidine was measured. At room temperature, seven quadrupolar sets of transition frequencies (ν(+), ν(-), and ν(0)) corresponding to seven different nitrogen sites in the crystal structure of each of the two polymorphs were found. This confirms the expected ability of NQR to distinguish polymorph B from its analog A. NQR can also measure their ratio in a solid mixture and in the final dosage form, that is, a tablet. The NQR frequencies, line shapes, and tentative assignation to all seven molecular (14)N atoms were obtained. Unravelment of these two entangled NQR spectra presents a valuable contribution to the NQR database and enables studies of some possible correlations therein. Moreover, nondestructive (14)N NQR studies of commercial famotidine tablets can reveal some details of the drug fabrication process connected with compression.

Application of 14N NQR to the study of piroxicam polymorphism.

A study was conducted to test the capability of the (14)N nuclear quadrupole resonance (NQR) method to discriminate qualitatively and quantitatively among different forms of piroxicam. Samples of commercial piroxicam form I and its monohydrate were obtained on the local market. Additionally, samples of form I and II were prepared by recrystallization in 1,2-dichloroethane and ethanol, respectively. DSC and FT-IR were employed as reference methods. A (14)N NQR spectrometer was used to measure samples of different forms and mixtures of piroxicam at 2587 and 3439 kHz. DSC and FT-IR clearly confirmed differences between the different piroxicam forms. Measurements of (14)N NQR signals of different forms of piroxicam at 2587 kHz detected only spectral peaks of form I. The dependence of (14)N NQR signal intensity on the concentration of form I in mixtures with the monohydrate showed a clear linear relationship at both measured frequencies, though the scattering of data was greater at 3439 kHz due to the lower S/N ratio. The (14)N NQR method has the potential to become an additional and important spectroscopic tool in the study of solid-state forms, not only of pure active pharmaceutical ingredients or excipients, but also of their mixtures. This ability lends the method to a possible successful utilization at different levels of pharmaceutical manufacturing and product quality control.