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.
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.
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.
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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.
Determination of residence time distribution is considered essential for continuous pharmaceutical unit operations, in order to enable process understanding and control. A common way for determining ...residence times are tracer based methods, yet at the moment most realizations are found in liquid systems whereas use of those methods on granular samples is rarely encountered.
Here, we compare two different methods for applying and detecting tracers in granular material processed in a pharmaceutical capsule-filling unit. As first method, a simple colorimetric procedure, i.e. using a dye and a camera as photometer is used. As second method, light induced fluorescence, i.e. using a fluorescent tracer material, a stimulating source and the camera as photometer again, is used.
Both methods are tested and compared for their performance and appeared to be sufficient for the use in residence time distribution determination, yet none of the two proved to be superior. Consequently, side issues rather than analytic performance determined the final preference for the colorimetric method.
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•Powder flow behavior in a capsule filling process is characterized.•Dye and fluorescent materials were used as tracer.•The effects of the tracer materials on the particles was evaluated.•The two tracer methods are compared regarding their performance.
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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.
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 DissolvIt apparatus for measurement of dissolution. Different media were used in the DissolvIt 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 DissolvIt 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 DissolvIt 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 (C max, T max, 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.
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 TiO
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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.
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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.
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 ( C
, T
, and AUC
) 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.
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