Near-Infrared Hyperspectral Imaging as a Monitoring Tool for On-Demand Manufacturing of Inkjet-Printed Formulations.

This study evaluates the potential use of near-infrared hyperspectral imaging (NIR-HSI) for quantitative determination of the drug amount in inkjet-printed dosage forms. We chose metformin hydrochloride as a model active pharmaceutical ingredient (API) and printed it onto gelatin films using a piezoelectric inkjet printing system. An industry-ready NIR-HSI sensor combined with a motorized movable linear stage was applied for spectral acquisition. Initial API-substrate screening revealed best printing results for gelatin films with TiO2 filling. For calibration of the NIR-HSI system, escalating drug doses were printed on the substrate. After spectral pre-treatments, including standard normal variate (SNV) and Savitzky-Golay filtering for noise reduction and enhancement of spectral features, principal component analysis (PCA) and partial least squares (PLS) regression were applied to create predictive models for the quantification of independent printed metformin hydrochloride samples. It could be shown that the concentration distribution maps provided by the developed HSI models were capable of clustering and predicting the drug dose in the formulations. HSI model prediction showed significant better correlation to the reference (HPLC) compared to on-board monitoring of dispensed volume of the printer. Overall, the results emphasize the capability of NIR-HSI as a fast and non-destructive method for the quantification and quality control of the deposited API in drug-printing applications.

Filling of lactose-based formulations in a tamping-pin capsule filler.

We studied three lactose-based formulations in terms of bulk powder properties and capsule-filling behavior in a tamping-pin capsule filling system, to which several mechanical adaptions were made for process optimization in light of future continuous production. The model formulations were thoroughly characterized and filled into size 1 capsules according a well-defined design of experiments (DoE). Overall, the three entirely different formulations were successfully filled within the selected design space. The fill weight and fill weight variability can be adjusted by fine-tuning the process settings, like the pin immersion depth and the maximum compaction pressure (pneumatic or spring-controlled), and by using the appropriate powder bed height and mechanical adaptions. This study demonstrated that selection of process parameters and mechanical adaptions could enhance the filling performance, especially in continuous production, since they reduce the powder volume in the process. Moreover, we showed that a tamping-pin system is capable of successfully filling a broad range of powders with various material characteristics and can potentially be used in a continuous production mode.

Use of PBPK Modeling To Evaluate the Performance of Dissolv It, a Biorelevant Dissolution Assay for Orally Inhaled Drug Products.

The dissolution of inhaled drug particles in the lungs is a challenge to model using biorelevant methods in terms of (i) collecting a respirable emitted aerosol fraction and dose, (ii) presenting this to a small volume of medium that is representative of lung lining fluid, and (iii) measuring the low concentrations of drug released. We report developments in methodology for each of these steps and utilize mechanistic in silico modeling to evaluate the in vitro dissolution profiles in the context of plasma concentration-time profiles. The PreciseInhale aerosol delivery system was used to deliver Flixotide aerosol particles to Dissolv It apparatus for measurement of dissolution. Different media were used in the Dissolv It chamber to investigate their effect on dissolution profiles, these were (i) 1.5% poly(ethylene oxide) with 0.4% l-alphaphosphatidyl choline, (ii) Survanta, and (iii) a synthetic simulated lung lining fluid (SLF) based on human lung fluid composition. For fluticasone proprionate (FP) quantification, solid phase extraction was used for sample preparation with LC-MS/MS analysis to provide an assay that was fit for purpose with a limit of quantification for FP of 312 pg/mL. FP concentration-time profiles in the flow-past perfusate were similar irrespective of the medium used in the Dissolv It chamber (∼0.04-0.07%/min), but these were significantly lower than transfer of drug from air-to-perfusate in isolated perfused lungs (0.12%/min). This difference was attributed to the Dissolv It system representing slower dissolution in the central region of the lungs (which feature nonsink conditions) compared to the peripheral regions that are represented in the isolated lung preparation. Pharmacokinetic parameters ( Cmax, Tmax, and AUC0-∞) were estimated from the profiles for dissolution in the different lung fluid simulants and were predicted by the simulation within 2-fold of the values reported for inhaled FP (1000 µg dose) administered via Flixotide Evohaler 250 µg strength inhaler in man. In conclusion, we report methods for performing biorelevant dissolution studies for orally inhaled products and illustrate how they can provide inputs parameters for physiologically based pharmacokinetic (PBPK) modeling of inhaled medicines.

Monitoring of a Hot Melt Coating Process via a Novel Multipoint Near-Infrared Spectrometer.

The aim of the present work was to develop a PAT strategy for the supervision of hot melt coating processes. Optical fibers were placed at various positions in the process chamber of a fluid bed device. Experiments were performed to determine the most suitable position for in-line process monitoring, taking into account such requirements as a good signal to noise ratio, the mitigation of dead zones, the ability to monitor the product over the entire process, and reproducibility. The experimental evidence suggested that the position at medium fluid bed height, looking towards the center, i.e., normal to particle movement, proved to be the most reliable position. In this study, the advantages of multipoint monitoring are shown, and an in-line-implementation was created. This enabled the real-time supervision of the process, including the fast detection of inhomogeneities and disturbances in the process chamber, and the compensation of sensor malfunction. In addition, a model for estimating the particle size distribution via NIR was successfully created. This ensures that the quality of the product and the endpoint of the coating process can be determined correctly.

Condensation reaction between carbohydrazide and salicylaldehyde: in-line vibrational spectroscopy monitoring and characterization of the reaction products in solution and solid state.

The condensation reaction between carbohydrazide and salicylaldehyde was monitored in-line by using vibrational NIR and Raman spectroscopies and statistical methods. Prior to in-line data analysis the reaction products were fully characterized in solution and solid state in order to check the potential of the in-line approach as a tool for in-process Schiff bases reaction control. It was demonstrated that a combination of vibrational spectroscopy and principal component analysis made it possible to detect and identify the reaction products, e.g. mono(salicylidene)carbohydrazide (1) and bis(salicylidene)carbohydrazide (2) in different solvents, and to determine the reaction end points in real time. Owing to complexity of the reaction mixtures and band overlapping, it was not possible to determine the relative ratio of the reaction products in-line. The off-line analysis showed that 1 was predominant in methanol while the highest portion of 2 was obtained in ethanol.

Monitoring blending of pharmaceutical powders with multipoint NIR spectroscopy.

Blending of powders is a crucial step in the production of pharmaceutical solid dosage forms. The active pharmaceutical ingredient (API) is often a powder that is blended with other powders (excipients) in order to produce tablets. The blending efficiency is influenced by several external factors, such as the desired degree of homogeneity and the required blending time, which mainly depend on the properties of the blended materials and on the geometry of the blender. This experimental study investigates the mixing behavior of acetyl salicylic acid as an API and α-lactose monohydrate as an excipient for different filling orders and filling levels in a blender. A multiple near-infrared probe setup on a laboratory-scale blender is used to observe the powder composition quasi-simultaneously and in-line in up to six different positions of the blender. Partial least squares regression modeling was used for a quantitative analysis of the powder compositions in the different measurement positions. The end point for the investigated mixtures and measurement positions was determined via moving block standard deviation. Observing blending in different positions helped to detect good and poor mixing positions inside the blender that are affected by convective and diffusive mixing.

Residence time distribution of a continuously-operated capsule filling machine: Development of a measurement technique and comparison of three volume-reducing inserts.

This paper presents the measurement and analysis of the residence time distribution (RTD) of a tamping-pin capsule filling machine. The tamping speed and the amount of material inside the powder bowl proved to have a significant effect on the RTD. Various inserts into the powder bowl that reduce the volume and alter mixing and transport in the bowl were experimentally investigated. To obtain the RTD, a tracer-based measurement method was applied and a sophisticated data processing strategy was developed. The tracer-based method also allowed investigations of stagnant zones in the powder bowl, another important aspect in continuous manufacturing (CM). The suitability of tracer material was assessed based on a detailed characterization of bulk and tracer material. Characteristic parameters of the RTD were extracted and compared, proposing a systematic strategy for selection of a suitable insert.

Spatially Resolved Spectral Powder Analysis: Experiments and Modeling.

Understanding the behavior of light in granular media is necessary for determining the sample size, shape, and weight when probing using fiber optic setups. This is required for a correct estimate of the active pharmaceutical ingredient content in a pharmaceutical blend via near-infrared spectroscopy. Several strategies to describe the behavior of light in granular and turbid media exist. A common approach is the Monte-Carlo simulation of individual photons and their description using mean free path lengths for scattering and absorption. In this work, we chose a complementary method by approximating these parameters via real physical counterparts, i.e., the particle size, shape, and density and the resulting chord lengths. Additionally, the wavelength dependence of refractive indices is incorporated. The obtained results were compared with those obtained in an experimental setup that included the SAM-Spec Felin probe head by Indatech for detecting spatially resolved spectra of samples. Our method facilitates the interpretation of the acquired experimental results by contrasting the optical response, the physical particle attributes, and the simulation results.

A Review of PAT Strategies in Secondary Solid Oral Dosage Manufacturing of Small Molecules.

Pharmaceutical solid oral dosage product manufacturing is a well-established, yet revolutionizing area. To this end, process analytical technology (PAT) involves interdisciplinary and multivariate (chemical, physical, microbiological, and mathematical) methods for material (e.g., materials, intermediates, products) and process (e.g., temperature, pressure, throughput, etc.) analysis. This supports rational process modeling and enhanced control strategies for improved product quality and process efficiency. Therefore, it is often difficult to orient and find the relevant, integrated aspects of the current state-of-the-art. Especially, the link between fundamental research, in terms of sensor and control system development, to the application both in laboratory and manufacturing scale, is difficult to comprehend. This review compiles a nonexhaustive overview on current approaches from the recognized academia and industrial practices of PAT, including screening, selection, and final implementations in solid oral dosage manufacturing, through a wide diversity of use cases. Finally, the authors attempt to extract a common consensus toward developing PAT application guidance for different unit operations of drug product manufacturing.

Crystal Engineering in Continuous Plug-Flow Crystallizers.

Size, shape, and polymorphic form are the critical attributes of crystalline particles and represent the major focus of today's crystallization process design. This work demonstrates how crystal properties can be tuned efficiently in solution via a tubular crystallizer that facilitates rapid temperature cycling. Controlled crystal growth, dissolution, and secondary nucleation allow a precise control of the crystal size and shape distribution, as well as polymorphic composition. Tubular crystallizers utilizing segmented flow such as the one presented in our work can provide plug flow characteristics, fast heating and cooling, allowing for rapid changes of the supersaturation. This makes them superior for crystal engineering over common crystallizers. Characterization of particle transport, however, revealed that careful selection of process parameters, such as tubing diameter, flow rates, solvents, etc., is crucial to achieve the full benefits of such reactors.

Microphase separation in solid lipid dosage forms as the cause of drug release instability.

Although lipid excipients are of increasing interest for development of taste-masked and modified release formulations, the drug release instability and the lack of mechanistic understanding in that regard still prevent their larger-scale application. In this work, we investigated the physical stability of a binary (tripalmitin/polysorbate 65) lipid coating formulation with a known stable polymorphism. The coating composition was characterized using DSC to construct the phase diagram of binary system and polarized light microscopy to display the microstructure organization. The water uptake and the erosion of slabs cast from the coating formulations were investigated post-production and after storage. Subsequently, N-acetylcysteine particles were coated with the selected formulations and the drug release stability was investigated. Additionally, microstructure characterization was performed via SEM and X-ray diffraction. The drug release instability was explained by polysorbate 65 and tripalmitin phase growth during storage, especially at 40°C, suggesting that polysorbate 65 can leak out of tripalmitin spherulitic structures, creating lipophilic and impermeable tripalmitin regions. The growth of polysorbate 65 phase leads to larger hydrophilic channels with reduced tortuosity. This work indicates that for obtaining stable drug release profiles from advanced lipid formulations, microphase separation should be prevented during storage.

Designed blending for near infrared calibration.

Spectroscopic methods are increasingly used for monitoring pharmaceutical manufacturing unit operations that involve powder handling and processing. With that regard, chemometric models are required to interpret the obtained spectra. There are many ways to prepare artificial powder blend samples used in a chemometric model for predicting the chemical content. Basically, an infinite number of possible concentration levels exist in terms of the individual components. In our study, design of experiments for ternary mixtures was used to establish a suitable number of blend compositions that represents the entire mixture region of interest for a three component blend. Various experimental designs and their effect on the predictive power of a chemometric model for near infrared spectra were investigated. It was determined that a particular choice of experimental design could change the predictive power of a model, even with the same number of calibration experiments.

The influence of residual water on the secondary structure and crystallinity of freeze-dried fibrinogen.

The purpose of this work was to investigate the influence of water content on the secondary structure of a freeze-dried protein (fibrinogen) after a storage period of two weeks. To that end, attenuated reflectance Fourier transformed infrared (ATR-FTIR) and Raman spectra were generated and evaluated and the crystalline state of the fibrinogen bulks was determined via X-ray diffraction. First, a PCA (principal component analysis) of the spectral data was performed. While the α-helix and ß-turn contents were increasing with the increasing water content, the ß-sheet content was decreasing. A partial least squares (PLS) model was developed to correlate the mid-infrared and Raman spectral changes with the degree of crystallinity. The obtained R(2) value of 0.953 confirmed a correlation between changes in the secondary structure and crystallinity of the samples. The results demonstrated that the combined ATR-FTIR and Raman approach could be used to predict the crystalline state in freeze-dried fibrinogen products.

Fast real-time monitoring of entacapone crystallization and characterization of polymorphs via Raman spectroscopy, statistics and SWAXS.

Crystallization of the drug entacapone from binary solvent mixtures was monitored in situ using a Raman optical probe. The recorded Raman spectra and statistical analysis, which included the principal components method and indirect hard modeling made it possible to estimate the starting point of crystallization, to assess crystallization temperatures and to provide information on the polymorphic content of the mixture. It was established that crystallization temperatures were proportional to the volume content of the solvent in mixtures. The samples were also evaluated off-line via Raman spectroscopy and SWAXS. The collected data showed the presence of forms b and g in all solvent mixtures. In a toluene/methanol 30:70 mixture, in addition to forms b and g, at least one of the forms A, D or a was also indicated by SWAXS. The results have shown that the presence of a particular polymorph is strongly dependent on the nature and portion of the solvent in the binary solvent mixture.

The effects of material attributes on capsule fill weight and weight variability in dosator nozzle machines.

The goal of this work is to identify and understand the complex relationship between the material attributes, capsule fill weight and weight variability of capsules filled with a dosator nozzle machine. Six powders were characterized and filled into size-3 capsules in three volumes of dosing chambers and at two filling speeds. Subsequent multivariate data analysis was used to identify the influence of the material attributes on the capsule fill weight and weight variability. We observed a clear correlation between the capsule fill weight and the particle size, the air permeability and the compressibility. As the fill weight decreases, more factors affect capsule fill weight. For example, the wall friction angle, the tapped density, and the particle shape proved to be important factors. Larger fill weights were more affected by density while lower fill weights by flow and friction characteristics. No correlation was found between the material attributes and the weight variability. Rather, we could also see the major effect of process parameters on capsule fill weight and weight variability.