Releasing fast and slow: Non-destructive prediction of density and drug release from SLS 3D printed tablets using NIR spectroscopy.

Selective laser sintering (SLS) 3D printing is a revolutionary 3D printing technology that has been found capable of creating drug products with varied release profiles by changing the laser scanning speed. Here, SLS 3D printed formulations (printlets) loaded with a narrow therapeutic index drug (theophylline) were produced using SLS 3D printing at varying laser scanning speeds (100-180 mm/s). The use of reflectance Fourier Transform - Near Infrared (FT-NIR) spectroscopy was evaluated as a non-destructive approach to predicting 3D printed tablet density and drug release at 2 h and 4 h. The printed drug products formulated with a higher laser speed exhibited an accelerated drug release and reduced density compared with the slower laser scanning speeds. Univariate calibration models were developed based on a baseline shift in the spectra in the third overtone region upon changing physical properties. For density prediction, the developed univariate model had high linearity (R2 value = 0.9335) and accuracy (error < 0.029 mg/mm3). For drug release prediction at 2 h and 4 h, the developed univariate models demonstrated a linear correlation (R2 values of 0.9383 and 0.9167, respectively) and accuracy (error < 4.4%). The predicted vs. actual dissolution profiles were found to be statistically similar (f2 > 50) for all of the test printlets. Overall, this article demonstrates the feasibility of SLS 3D printing to produce drug products containing a narrow therapeutic index drug across a range of drug release profiles, as well as the potential for FT-NIR spectroscopy to predict the physical characteristics of SLS 3D printed drug products (drug release and density) as a non-destructive quality control method at the point-of-care.

Prediction of Solid-State Form of SLS 3D Printed Medicines Using NIR and Raman Spectroscopy.

Selective laser sintering (SLS) 3D printing is capable of revolutionising pharmaceutical manufacturing, by producing amorphous solid dispersions in a one-step manufacturing process. Here, 3D-printed formulations loaded with a model BCS class II drug (20% w/w itraconazole) and three grades of hydroxypropyl cellulose (HPC) polymer (-SSL, -SL and -L) were produced using SLS 3D printing. Interestingly, the polymers with higher molecular weights (HPC-L and -SL) were found to undergo a uniform sintering process, attributed to the better powder flow characteristics, compared with the lower molecular weight grade (HPC-SSL). XRPD analyses found that the SLS 3D printing process resulted in amorphous conversion of itraconazole for all three polymers, with HPC-SSL retaining a small amount of crystallinity on the drug product surface. The use of process analytical technologies (PAT), including near infrared (NIR) and Raman spectroscopy, was evaluated, to predict the amorphous content, qualitatively and quantitatively, within itraconazole-loaded formulations. Calibration models were developed using partial least squares (PLS) regression, which successfully predicted amorphous content across the range of 0-20% w/w. The models demonstrated excellent linearity (R2 = 0.998 and 0.998) and accuracy (RMSEP = 1.04% and 0.63%) for NIR and Raman spectroscopy models, respectively. Overall, this article demonstrates the feasibility of SLS 3D printing to produce solid dispersions containing a BCS II drug, and the potential for NIR and Raman spectroscopy to quantify amorphous content as a non-destructive quality control measure at the point-of-care.

Continuous mixing technology: Validation of a DEM model.

Continuous powder mixing is an important technology used in the development and manufacturing of solid oral dosage forms. Since critical quality attributes of the final product greatly depend on the performance of the mixing step, an analysis of such a process using the Discrete Element Method (DEM) is of crucial importance. On one hand, the number of expensive experimental runs can be reduced dramatically. On the other hand, numerical simulations can provide information that is very difficult to obtain experimentally. In order to apply such a simulation technology in product development and to replace experimental runs, an intensive model validation step is required. This paper presents a DEM model of the vertical continuous mixing device termed CMT (continuous mixing technology) and an extensive validation workflow. First, a cohesive contact model was calibrated in two small-scale characterization experiments: a compression test with spring-back and a shear cell test. An improved, quicker calibration procedure utilizing the previously calibrated contact models is presented. The calibration procedure is able to differentiate between the blend properties caused by different API particle sizes in the same formulation. Second, DEM simulations of the CMT were carried out to determine the residence time distribution (RTD) of the material inside the mixer. After that, the predicted RTDs were compared with the results of tracer spike experiments conducted with two blend material properties at two mass throughputs of 15 kg/h and 30 kg/h. Additionally, three hold-up masses (500, 730 and 850 g) and three impeller speeds (400, 440 and 650 rpms) were considered. Finally, both RTD datasets from DEM and tracer experiments were used to predict the damping behavior of incoming feeder fluctuations and the funnel of maximum duration and magnitude of incoming deviations that do not require a control action. The results for both tools in terms of enabling a control strategy (the fluctuation damping and the funnel plot) are in excellent agreement, indicating that DEM simulations are well suited to replace process-scale tracer spike experiments to determine the RTD.

Continuous Mixing Technology: Characterization of a Vertical Mixer Using Residence Time Distribution.

Continuous powder mixing technology (CMT) application during continuous direct compression has emerged as a leading technology used in the development and manufacture of solid oral dosage forms. The critical quality attributes of the final product are heavily dependent on the performance of the mixing step as the quality of mixing directly influences the drug product quality attributes. This study investigates the impact of blend material properties (bulk density, API particle size distribution) and process parameters (process throughput, hold up mass and impeller speed) on the mixing performance. Mixing of the blend was characterized using the Residence Time Distribution (RTD) of the process by trending the outlet stream of the mixer using a near-infrared (NIR) probe after the injection of a small mass of tracer at the inlet stream. The outcomes of this study show that the RTDs of the mixer with throughput ranging between 15 and 30 kg/h; impeller speed ranging between 400 and 600 rpm and hold up mass (HUM) ranging between 500 and 850 g can be described by a series of two ideal Continuous Stirred Tank Reactors (CSTRs) with different volumes, and correspondingly, different mean residence times. It is also observed that the mixing is mainly occurring in the lower chamber of the CMT and the normalized RTDs of the mixer are similar across the range of process conditions and material attributes studied. The results also showed that the formulation blend with different API particle sizes and bulk properties, like bulk density and flowability, provide insignificant impact on the mixing performance. The CMT allows independent selection of target set points for HUM, impeller rotational speed and line throughput and it shows great robustness and flexibility for continuous blending in solid oral dose manufacturing.

Non-destructive dose verification of two drugs within 3D printed polyprintlets.

Three-dimensional printing (3DP) is a revolutionary technology in pharmaceuticals, enabling the personalisation of flexible-dose drug products and 3D printed polypills (polyprintlets). A major barrier to entry of this technology is the lack of non-destructive quality control methods capable of verifying the dosage of multiple drugs in polyprintlets at the point of dispensing. In the present study, 3D printed films and cylindrical polyprintlets were loaded with flexible, therapeutic dosages of two distinct drugs (amlodipine and lisinopril) across concentration ranges of 1-5% w/w and 2-10% w/w, respectively. The polyprintlets were non-destructively analysed for dose content using a portable near infrared (NIR) spectrometer and validated calibration models were developed using partial least squares (PLS) regression, which showed excellent linearity (R2 Pred = 0.997, 0.991), accuracy (RMSEP = 0.24%, 0.24%) and specificity (LV1 = 82.77%, 79.55%) for amlodipine and lisinopril, respectively. X-ray powder diffraction (XRPD) and thermogravimetric analysis (TGA) showed that sintering partially transformed the phase of both drugs from the crystalline to amorphous forms. For the first time, we report a non-destructive method for quality control of two separate active ingredients in a single 3D printed drug product using NIR spectroscopy, overcoming a major barrier to the integration of 3D printing into clinical practice.

3D printed drug products: Non-destructive dose verification using a rapid point-and-shoot approach.

Three-dimensional printing (3DP) has the potential to cause a paradigm shift in the manufacture of pharmaceuticals, enabling personalised medicines to be produced on-demand. To facilitate integration into healthcare, non-destructive characterisation techniques are required to ensure final product quality. Here, the use of process analytical technologies (PAT), including near infrared spectroscopy (NIR) and Raman confocal microscopy, were evaluated on paracetamol-loaded 3D printed cylindrical tablets composed of an acrylic polymer (Eudragit L100-55). Using a portable NIR spectrometer, a calibration model was developed, which predicted successfully drug concentration across the range of 4-40% w/w. The model demonstrated excellent linearity (R2 = 0.996) and accuracy (RMSEP = 0.63%) and results were confirmed with conventional HPLC analysis. The model maintained high accuracy for tablets of a different geometry (torus shapes), a different formulation type (oral films) and when the polymer was changed from acrylic to cellulosic (hypromellose, HPMC). Raman confocal microscopy showed a homogenous drug distribution, with paracetamol predominantly present in the amorphous form as a solid dispersion. Overall, this article is the first to report the use of a rapid 'point-and-shoot' approach as a non-destructive quality control method, supporting the integration of 3DP for medicine production into clinical practice.

In-depth experimental analysis of pharmaceutical twin-screw wet granulation in view of detailed process understanding.

Twin-screw wet granulation is gaining increasing interest within the pharmaceutical industry for the continuous manufacturing of solid oral dosage forms. However, limited prior fundamental physical understanding has been generated relating to the granule formation mechanisms and kinetics along the internal compartmental length of a twin-screw granulator barrel, and about how process settings, barrel screw configuration and formulation properties such as particle size, density and surface properties influence these mechanisms. One of the main reasons for this limited understanding is that experimental data is generally only collected at the exit of the twin-screw granulator barrel although the granule formation occurs spatially along the internal length of the barrel. The purpose of this study is to analyze the twin-screw wet granulation process using both hydrophilic and hydrophobic formulations, manufactured under different process settings such as liquid-to-solid ratio, mass throughput and screw speed, in such a way that the mechanisms occurring in the individual granulator barrel compartments (i.e., the wetting and different conveying and kneading compartments) and their impact upon granule formation are understood. To achieve this, a unique experimental setup was developed allowing granule characteristic data-collection such as size, shape, liquid and porosity distribution at the different compartments along the length of the granulator barrel. Moreover, granule characteristic information per granule size class was determined. The experimental results indicated that liquid-to-solid ratio is the most important factor dictating the formation of the granules and their corresponding properties, by regulating the degree of aggregation and breakage in the different compartments along the internal length of the twin-screw granulator barrel. Collecting appropriate and detailed experimental data about granule formation along the internal length of the granulator barrel is thus crucial for gaining fundamental physical understanding of the twin-screw wet granulation process.