Microscale freeze-drying with Raman spectroscopy as a tool for process development.

Until recently, the freeze-drying process and formulation development have suffered from a lack of microscale analytical tools. Using such an analytical tool should decrease the required sample volume and also shorten the duration of the experiment compared to a laboratory scale setup. This study evaluated the applicability of Raman spectroscopy for in-line monitoring of a microscale freeze-drying process. The effect of cooling rate and annealing step on the solid-state formation of mannitol was studied. Raman spectra were subjected to principal component analysis to gain a qualitative understanding of the process behavior. In addition, mannitol solid-state form ratios were semiquantitatively analyzed during the process with a classical least-squares regression. A standard cooling rate of 1 °C/min with or without an annealing step at -10 °C resulted in a mixture of α, ß, δ, and amorphous forms of mannitol. However, a standard cooling rate induced the formation of mannitol hemihydrate, and a secondary drying temperature of +60 °C was required to transform the hemihydrate form to the more stable anhydrous polymorphs. A fast cooling rate of 10 °C/min mainly produced δ and amorphous forms of mannitol, regardless of annealing. These results are consistent with those from larger scale equipment. In-line monitoring the solid-state form of a sample is feasible with a Raman spectrometer coupled microscale freeze-drying stage. These results demonstrate the utility of a rapid, in-line, low sample volume method for the semiquantitative analysis of the process and formulation development of freeze-dried products on the microscale.

In-line multipoint near-infrared spectroscopy for moisture content quantification during freeze-drying.

During the past decade, near-infrared (NIR) spectroscopy has been applied for in-line moisture content quantification during a freeze-drying process. However, NIR has been used as a single-vial technique and thus is not representative of the entire batch. This has been considered as one of the main barriers for NIR spectroscopy becoming widely used in process analytical technology (PAT) for freeze-drying. Clearly it would be essential to monitor samples that reliably represent the whole batch. The present study evaluated multipoint NIR spectroscopy for in-line moisture content quantification during a freeze-drying process. Aqueous sucrose solutions were used as model formulations. NIR data was calibrated to predict the moisture content using partial least-squares (PLS) regression with Karl Fischer titration being used as a reference method. PLS calibrations resulted in root-mean-square error of prediction (RMSEP) values lower than 0.13%. Three noncontact, diffuse reflectance NIR probe heads were positioned on the freeze-dryer shelf to measure the moisture content in a noninvasive manner, through the side of the glass vials. The results showed that the detection of unequal sublimation rates within a freeze-dryer shelf was possible with the multipoint NIR system in use. Furthermore, in-line moisture content quantification was reliable especially toward the end of the process. These findings indicate that the use of multipoint NIR spectroscopy can achieve representative quantification of moisture content and hence a drying end point determination to a desired residual moisture level.

Continuous manufacturing of tablets with PROMIS-line - Introduction and case studies from continuous feeding, blending and tableting.

Drug manufacturing technology is in the midst of modernization and continuous manufacturing of drug products is especially the focus of great interest. The adoption of new manufacturing approaches requires extensive cooperation between industry, regulatory bodies, academics and equipment manufacturers. In this paper we introduce PROMIS-line which is a continuous tableting line built at the University of Eastern Finland, School of Pharmacy, PROMIS-centre. PROMIS-line is modular and tablets can be produced via dry granulation or direct compression. In three case studies, continuous feeding, blending and tablet performance is studied to illustrate some basic features of PROMIS-line. In conclusion, the PROMIS-line is an excellent tool for studying the fundamentals of continuous manufacturing of tablets.

Linking granulation performance with residence time and granulation liquid distributions in twin-screw granulation: An experimental investigation.

Twin-screw granulation is a promising wet granulation technique for the continuous manufacturing of pharmaceutical solid dosage forms. A twin screw granulator displays a short residence time. Thus, the solid-liquid mixing must be achieved quickly by appropriate arrangement of transport and kneading elements in the granulator screw allowing the production of granules with a size distribution appropriate for tableting. The distribution of residence time and granulation liquid is governed by the field conditions (such as location and length of mixing zones) in the twin-screw granulator, thus contain interesting information on granulation time, mixing and resulting sub-processes such as wetting, aggregation and breakage. In this study, the impact of process (feed rate, screw speed and liquid-to-solid ratio) and equipment parameters (number of kneading discs and stagger angle) on the residence time (distribution), the granulation liquid-powder mixing and the resulting granule size distributions during twin-screw granulation were investigated. Residence time and axial mixing data was extracted from tracer maps and the solid-liquid mixing was quantified from moisture maps, obtained by monitoring the granules at the granulator outlet using near infra-red chemical imaging (NIR-CI). The granule size distribution was measured using the sieving method. An increasing screw speed dominantly reduced the mean residence time. Interaction of material throughput with the screw speed and with the number of kneading discs led to most variation in the studied responses including residence time and mixing capacity. At a high screw speed, granulation yield improved due to high axial mixing. However, increasing material throughput quickly lowers the yield due to insufficient mixing of liquid and powder. Moreover, increasing liquid-to-solid ratio resulted in more oversized granules, and the fraction of oversized granules further increased at higher throughput. Although an increasing number of kneading discs was found to be critical for achieving a uniform distribution of the granulation liquid, the granulation performance was hampered due to insufficient solid-liquid mixing capacity of the current kneading discs which is essential for wet granulation. Thus, a balance between material throughput and screw speed should be strived for in order to achieve a specific granulation time and solid-liquid mixing for high granulation yield. Additionally, more efforts are needed both in modification of the screw configuration as well as the geometry of the mixing elements to improve the mixing capacity of the twin-screw granulator. The results from the current experimental study improved the understanding regarding the interplay between granulation time and the axial and solid-liquid mixing responsible for the granulation performance in twin-screw wet granulation.

Conceptual framework for model-based analysis of residence time distribution in twin-screw granulation.

Twin-screw granulation is a promising continuous alternative for traditional batchwise wet granulation processes. The twin-screw granulator (TSG) screws consist of transport and kneading element modules. Therefore, the granulation to a large extent is governed by the residence time distribution within each module where different granulation rate processes dominate over others. Currently, experimental data is used to determine the residence time distributions. In this study, a conceptual model based on classical chemical engineering methods is proposed to better understand and simulate the residence time distribution in a TSG. The experimental data were compared with the proposed most suitable conceptual model to estimate the parameters of the model and to analyse and predict the effects of changes in number of kneading discs and their stagger angle, screw speed and powder feed rate on residence time. The study established that the kneading block in the screw configuration acts as a plug-flow zone inside the granulator. Furthermore, it was found that a balance between the throughput force and conveying rate is required to obtain a good axial mixing inside the twin-screw granulator. Although the granulation behaviour is different for other excipients, the experimental data collection and modelling methods applied in this study are generic and can be adapted to other excipients.

Validation of a multipoint near-infrared spectroscopy method for in-line moisture content analysis during freeze-drying.

This study assessed the validity of a multipoint near-infrared (NIR) spectroscopy method for in-line moisture content analysis during a freeze-drying process. It is known that the moisture content affects the stability of a freeze-dried product and hence it is a major critical quality attribute. Therefore assessment of the validity of an analytical method for moisture content determination is vital to ensure the quality of the final product. An aqueous sucrose solution was used as the model formulation of the study. The NIR spectra were calibrated to the moisture content using partial least squares (PLS) regression with coulometric Karl Fischer (KF) titration as the reference method. Different spectral preprocessing methods were compared for the PLS models. A calibration model transfer protocol was established to enable the use of the method in the multipoint mode. The accuracy profile was used as a decision tool to determine the validity of the method. The final PLS model, in which NIR spectra were preprocessed with standard normal variate transformation (SNV), resulted in low root mean square error of prediction value of 0.04%-m/v, i.e. evidence of sufficient overall accuracy of the model. The validation results revealed that the accuracy of the model was acceptable within the moisture content range 0.16-0.70%-m/v that is specific for the latter stages of the freeze-drying process. In addition, the results demonstrated the method's reliable in-process performance and robustness. Thus, the multipoint NIR spectroscopy method was proved capable of providing in-line evaluation of moisture content and it is readily available for use in laboratory scale freeze-drying research and development.

Visualization and understanding of the granulation liquid mixing and distribution during continuous twin screw granulation using NIR chemical imaging.

Over the last decade, there has been increased interest in the application of twin screw granulation as a continuous wet granulation technique for pharmaceutical drug formulations. However, the mixing of granulation liquid and powder material during the short residence time inside the screw chamber and the atypical particle size distribution (PSD) of granules produced by twin screw granulation is not yet fully understood. Therefore, this study aims at visualizing the granulation liquid mixing and distribution during continuous twin screw granulation using NIR chemical imaging. In first instance, the residence time of material inside the barrel was investigated as function of screw speed and moisture content followed by the visualization of the granulation liquid distribution as function of different formulation and process parameters (liquid feed rate, liquid addition method, screw configuration, moisture content and barrel filling degree). The link between moisture uniformity and granule size distributions was also studied. For residence time analysis, increased screw speed and lower moisture content resulted to a shorter mean residence time and narrower residence time distribution. Besides, the distribution of granulation liquid was more homogenous at higher moisture content and with more kneading zones on the granulator screws. After optimization of the screw configuration, a two-level full factorial experimental design was performed to evaluate the influence of moisture content, screw speed and powder feed rate on the mixing efficiency of the powder and liquid phase. From these results, it was concluded that only increasing the moisture content significantly improved the granulation liquid distribution. This study demonstrates that NIR chemical imaging is a fast and adequate measurement tool for allowing process visualization and hence for providing better process understanding of a continuous twin screw granulation system.

Near-infrared imaging for high-throughput screening of moisture induced changes in freeze-dried formulations.

Evaluation of freeze-dried biopharmaceutical formulations requires careful analysis of multiple quality attributes. The aim of this study was to evaluate the use of near-infrared (NIR) imaging for fast analysis of water content and related physical properties in freeze-dried formulations. Model formulations were freeze-dried in well plates. Samples were imaged with a NIR hyperspectral camera after freeze-drying and upon storage. On the basis of Karl Fischer titration reference values, a univariate quantification model was constructed and used to visualize the distribution of water within freeze-dried samples. Differences observed between samples stored at 11% and 43% relative humidity (RH) were found to be related to the amount of amorphous component in the sample. When stored at 43% RH, the moisture content in samples with high sucrose content increased within 2 days and some degree of localized drying was observed within the samples after 3 days of storage. Further investigations with X-ray powder diffraction confirmed this local drying to be related to crystallization of sucrose. The combination of fast analysis of water content and spatial solid-state information makes NIR imaging a powerful tool for formulation development of freeze-dried samples.

Mixing and transport during pharmaceutical twin-screw wet granulation: experimental analysis via chemical imaging.

Twin-screw granulation is a promising continuous alternative for traditional batch high shear wet granulation (HSWG). The extent of HSWG in a twin screw granulator (TSG) is greatly governed by the residence time of the granulation materials in the TSG and degree of mixing. In order to determine the residence time distribution (RTD) and mixing in TSG, mostly visual observation and particle tracking methods are used, which are either inaccurate and difficult for short RTD, or provide an RTD only for a finite number of preferential tracer paths. In this study, near infrared chemical imaging, which is more accurate and provides a complete RTD, was used. The impact of changes in material throughput (10-17 kg/h), screw speed (500-900 rpm), number of kneading discs (2-12) and stagger angle (30-90°) on the RTD and axial mixing of the material was characterised. The experimental RTD curves were used to calculate the mean residence time, mean centred variance and the Péclet number to determine the axial mixing and predominance of convective over dispersive transport. The results showed that screw speed is the most influential parameter in terms of RTD and axial mixing in the TSG and established a significant interaction between screw design parameters (number and stagger angle of kneading discs) and the process parameters (material throughput and number of kneading discs). The results of the study will allow the development and validation of a transport model capable of predicting the RTD and macro-mixing in the TSG. These can later be coupled with a population balance model in order to predict granulation yields in a TSG more accurately.