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Twin-screw wet granulation (TWSG) is a promising continuous alternative of pharmaceutical wet granulation. One of its benefits is that the components dissolved in the granulation liquid are distributed homogeneously in the granules. This provides an elegant way to manufacture products with ultralow drug doses. Near-infrared (NIR) and Raman spectroscopy are well-established process analytical technology (PAT) tools that can be used for the in-line monitoring of TSWG. However, their detection limit does not enable the measurement of components in the ultralow (i.e., ppm) range. In this paper, an indirect approach is presented that enables the real-time determination of the concentration of a drug in concentrations between 40 and 100 ppm by using the signal of an excipient, in this case, the polyvinylpyrrolidone (PVP). This component is also dissolved in the granulation liquid; therefore, it is distributed in the same way as the active ingredient. Results of HPLC measurements have proved that the models trained to quantify the concentration of PVP in real-time gave an accurate determination for the active ingredient as well (root mean squared error was 7.07 ppm for Raman and 5.31 ppm for NIR spectroscopy, respectively). These findings imply that it is possible to indirectly predict the concentration of ultralow dose drugs with in-line analytical techniques based on the concentration of an excipient.

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Twin-screw wet granulation (TSG) is a continuous manufacturing technique either for granules as final dosage form or as an intermediate before tableting or capsule filling. A comprehensive process understanding is required to implement TSG, considering various parameters influencing granule and tablet quality. This study investigates the impact of screw configuration on granule properties followed by tableting, using a systematic approach for lactose-microcrystalline cellulose (lactose-MCC) and ibuprofen-mannitol (IBU) formulations. The most affecting factor, as observed by other researchers, was the L/S ratio impacting the granule size, strength and tabletability. Introducing tooth-mixing-elements at the end of the screw, as for the IBU formulation, resulted in a high proportion of oversized granules, with values between 36% and 78%. Increasing the thickness of kneading elements (KEs) produced denser, less friable granules with reduced tablet tensile strength. Granulation with more KEs, larger thickness or stagger angle increased torque values and residence time from 30 to 65 s. Generally, IBU granules exhibited high tabletability, requiring low compression pressure for sufficient tensile strength. At a compression pressure of 50 MPa, IBU tablets where at least one kneading zone was included resulted in approximately 2.5 MPa compared to lactose-MCC with 0.5 MPa. In conclusion, the TSG process demonstrated robustness by varying the screw design with minimal impact on subsequent tableting processes.

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The barrel fill level is defined as the fraction of the free available volume for a given screw configuration that is occupied by the wet material and is an interplay of the material throughput, screw speed, screw setup, barrel length of the twin-screw granulator used and the properties of the starting material. The fill level has a major impact on mixing and densification of the wetted mass and thus on the granules produced. It influences the twin-screw granulation process accordingly. In the current study, a model has been developed which is predictive in terms of material hold-ups in the barrel at various process settings by considering the geometries of the different screw elements in a configuration and the conveying velocity of the wet mass through the barrel. The model was checked on two granulators of different dimensions with various screw configurations, different materials and at different process settings. The model represents a step forward in predicting the barrel fill level but further research with a broader spectrum of materials, screw configurations and process settings is still needed and additional twin-screw granulators of other dimensions must be investigated.

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PURPOSE: Twin-screw wet granulation (TSWG) is a manufacturing process that offers several advantages for the processing of water-insoluble active pharmaceutical ingredients (APIs) and has been used for increasing the solubility and dissolution rates. Here we introduce a novel TSWG approach with reduced downstream processing steps by using non-volatile solvents as granulating binders. METHODS: Herein, TSWG was carried out using Transcutol a non-volatile protic solvent as a granulating binder and dissolution enhancer of ibuprofen (IBU) blends with cellulose polymer grades (Pharmacoat® 603, Affinisol™, and AQOAT®). RESULTS: The physicochemical characterisation of the produced granules showed excellent powder flow and the complete transformation of IBU into the amorphous state. Dissolution studies presented immediate release rates for all IBU formulations due to the high drug-polymer miscibility and the Transcutol solubilising capacity. CONCLUSIONS: Overall, the study demonstrated an innovative approach for the development of extruded granules by processing water-insoluble APIs with non-volatile solvents for enhanced dissolution rates at high drug loadings.

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Tablet disintegration is crucial for drug release and subsequent systemic absorption. Although factors affecting the disintegrant's functionality have been extensively studied, the impact of wet granulation on the performance of disintegrants in a poorly water-soluble matrix has received much less attention. In this study, the disintegrants, crospovidone (XPVP), croscarmellose sodium (CCS) and sodium starch glycolate (SSG), were wet-granulated with dibasic calcium phosphate dihydrate as the poorly water-soluble matrix and polyvinylpyrrolidone as the binder. The effect of wet granulation was studied by evaluating tablet tensile strength and disintegratability. Comparison between tablets with granulated or ungranulated disintegrants as well those without disintegrants were also made. Different formulations showed different degrees of sensitivity to changes in tablet tensile strength and disintegratability post-wet granulation. Tablet tensile strength decreased for tablets with granulated disintegrant XPVP or CCS, but to a smaller extent for SSG. While tablets with granulated XPVP or CCS had increased disintegration time, the increment was lesser than for SSG, suggesting that wet granulation impacted a swelling disintegrant more. The findings showed that tablets with wet-granulated disintegrant had altered the disintegrant's functionality. These findings could provide better insights into changes in the disintegrant's functionality after wet granulation.

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Binder selection is a crucial step in continuous twin-screw wet granulation (TSWG), as the material experiences a much shorter residence time (2-40 s) in the granulator barrel compared to batch-wise granulation processes. Polyvinyl alcohol (PVA) 4-88 was identified as an effective binder during TSWG, but the potential of other PVA grades-differing in polymerization and hydrolysis degree-has not yet been studied. Therefore, the aim of the current study was to evaluate the potential of different PVA grades as a binder during TSWG. The breakage and drying behavior during the fluidized bed drying of drug-loaded granules containing the PVA grades was also studied. Three PVA grades (4-88, 18-88, and 40-88) were characterized and their attributes were compared to previously investigated binders by Vandevivere et al. through principal component analysis. Three binder clusters could be distinguished according to their attributes, whereby each cluster contained a PVA grade and a previously investigated binder. PVA 4-88 was the most effective binder of the PVA grades for both a good water-soluble and water-insoluble formulation. This could be attributed to its high total surface energy, low viscosity, good wettability of hydrophilic and hydrophobic surfaces, and good wettability by water of the binder. Compared to the previously investigated binders, all PVA grades were more effective in the water-insoluble formulation, as they yielded strong granules (friability below 30%) at lower L/S-ratios. This was linked to the high dispersive surface energy of the high-energy sites on the surface of PVA grades and their low surface tension. During fluidized bed drying, PVA grades proved suitable binders, as the acetaminophen (APAP) granules were dried within a short time due to the low L/S-ratio, at which high-quality granules could be produced. In addition, no attrition occurred, and strong tablets were obtained. Based on this study, PVA could be the preferred binder during twin screw granulation due to its high binder effectiveness at a low L/S-ratio, allowing efficient downstream processing. However, process robustness must be controlled by the included excipients, as PVA grades are operating in a narrow L/S-ratio range.

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The study aimed to fingerprint the physical manufacturing properties of five commonly used acid sources in effervescent systems for designing the formulation and process of such systems. The hygroscopicity, texture properties, rheological torque, compressibility, tabletability, etc., were investigated to inspect 'powder direct compression (DC)' and 'wet granulation and compression' properties of citric (CA), tartaric (TA), malic (MA), fumaric (FA), and adipic acid (AA). The DC ability was evaluated by the SeDeM expert system. The results indicated that all acid powders failed to meet flowability requirements for DC, and plastic deformation dominated during compression. Furthermore, CA exhibited strong hygroscopicity and punch sticking, while MA demonstrated the best tabletability. TA had a large wet granulation space and was relatively the most suitable for DC. AA was extremely hygroscopic, and its flowability improved significantly as particle size increased. Finally, FA displayed the lowest hygroscopicity and ejection force as well as great compressibility and wet granulation space, and did not exhibit punch sticking, while the granule fragments dissolved slowly during disintegration. Generally speaking, the formulation or granulation affected the tabletability, indicating that pairing with other acids or suitable fillers could potentially improve its disadvantages. These multidimensional assessments effectively reduce the pre-exploration and enhance the efficiency of the development of effervescent systems.

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The influence of hydroxypropyl cellulose type (HPC-SSL SFP, HPC-SSL), concentration (2 %, 3.5 %, 5 %) and filler (lactose, calcium hydrogen phosphate (DCP)/microcrystalline cellulose (MCC)) on twin-screw wet granulation and subsequent tableting was studied. The aim was to identify the formulation of the highest tabletability which still fulfills the requirements of the disintegration. Lactose combined with 5 % binder enabled a higher tabletability and a faster disintegration than DCP/MCC. It was found that tabletability of lactose formulations can be increased by higher binder concentration and higher compression pressure while tabletability of DCP/MCC formulations can be only increased by higher compression pressure. It was observed that batches containing DCP/MCC failed the disintegration test, if the highest binder concentration and the highest compression pressure were used. To ensure a fast disintegration, the compression pressure or at least the binder concentration had to be low. Changing the disintegrant and its localization improved the DCP/MCC formulation, resulting in faster disintegration than lactose tablets. However, it also resulted in a lower tabletability. In this study best tablets were achieved with 3.5 % or 5 % binder and lactose as filler. These tablets presented the highest tabletability but still disintegrated in less than 500 s.

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Traditional operation modes, such as running the production processes at constant process settings or within a narrow design space, do not fully exploit the advantages of continuous pharmaceutical manufacturing. Integrating Quality by Control (QbC) algorithms as a standard component of production processes can mitigate the effect of diverse process disturbances and enhance process efficiency, particularly in terms of production costs and environmental footprint. This paper explores the potential of QbC algorithms for optimizing twin-screw wet granulation in the ConsiGmaTM-25 manufacturing line, specifically addressing granule size. It represents the second part of a study (Celikovic et al. (2024)) focused on granule composition. The concepts proposed in this work rely on process analytical technology (PAT) equipment for real-time monitoring of the granulation CQAs and a dynamic process model linking the granulation process parameters and the monitored CQAs. The granule size model identified via the local-linear-model-tree (LoLiMoT) algorithm is used to develop both a model predictive controller (MPC) and a granule size soft sensor. The MPC employs this model as a core component for selecting optimal granulation parameters to ensure the production of granules with target size. A digital operator assistant is developed to address disturbances that cannot be mitigated via MPC but can be eliminated by the plant operators. This study systematically outlines a workflow, starting from conceptualization, moving through simulation development, and finally ending with real-world application on a production line. In this final step, all proposed concepts are transferred to the ConsiGmaTM-25 manufacturing line, where their performance is validated through selected disturbance scenarios.

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Continuous manufacturing of pharmaceuticals offers several benefits, such as increased production efficiency, enhanced product quality control, and lower environmental footprint. To fully exploit these benefits, standard operation mode (production processes with no or minimal disturbance mitigation measures) should be supported by adopting novel quality-by-control (QbC) methodologies. The paper at hand is the first part of a study focused on developing QbC algorithms for optimizing twin-screw wet granulation in the industrial manufacturing line ConsiGmaTM-25, specifically addressing granule composition. This work relies on previously established process-analytical-technology (PAT) equipment for real-time monitoring of the granule composition, i.e., the active pharmaceutical ingredient (API) and liquid content in wet granules. The developed control platform integrates model-based process control algorithms that aim to keep the API- and liquid content at target values through real-time adjustments of the process parameters. Furthermore, the platform integrates a digital operator assistant, which aims to detect and classify granulation disturbances and provides messages and instructions for the plant operator. The present manuscript systematically outlines all design steps from the development phase in the simulation environment to the final real system application and validation. The control platform's performance is demonstrated through selected test scenarios on the ConsiGmaTM-25 manufacturing line. The obtained results indicate improved disturbance robustness and an increase in intermediate/final product quality (compared to conventional operating modes): The process control algorithms successfully maintained the API- and liquid content at target values despite process disturbances. Furthermore, realistic disturbances (feeder, pump, and material) were accurately detected and classified by the digital assistant algorithm. The information was provided through a user interface, offering real-time support for plant personnel.

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Pharmaceutical twin-screw wet granulation is a multifaceted and intricate process pivotal to drug product development. Accurate modeling of this process is indispensable for optimizing manufacturing parameters and ensuring product quality. The fluid bed dryer, an integral component of this granulation process, significantly influences the granular critical quality attributes. This study builds upon prior research by integrating experimental findings on granule segregation during fluid bed drying into an existing compartmental model, enhancing its predictive capabilities. An additional model layer on granule segregation behavior is composed and integrated into the existing model structure in this study. The added model compartment describes probability distributions on the vertical position of granules within each granule size class considered. To beware of overfitting, predictions of both the moisture content after drying and the granule bed temperature throughout drying are discussed in this study relative to experimental data from earlier published studies. These independent analyses demonstrated a marked improvement in prediction accuracy compared to earlier published model structures. The refined model accurately predicts the residual moisture content after drying for an untrained formulation. Moreover, it simultaneously makes accurate predictions of the granular bed temperature, which emboldens its structural correctness. This advancement makes it a powerful tool for predicting the behavior of the pharmaceutical fluid bed drying, which holds significant promise to facilitate pharmaceutical product development.

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Hydroxypropyl methylcellulose (HPMC) is a preferred hydrophilic matrix former for controlled release formulations produced through continuous twin-screw wet granulation. However, a non-homogeneous API distribution over sieve fractions with underdosing in the fines fraction (<150 µm) was previously reported. This could result in content uniformity issues during downstream processing. Therefore, the current study investigated the root cause of the non-homogeneous theophylline distribution. The effect of process parameters (L/S-ratio and screw configuration) and formulation parameters (matrix former and filler type) on content uniformity was studied. Next, the influence of the formulation parameters on tableting and dissolution behavior was investigated. Altering the L/S-ratio or using a more aggressive screw configuration did not result in a homogeneous API distribution over the granule sieve fractions. Using microcrystalline cellulose (MCC) as filler improved the API distribution due to its similar behavior as HPMC. As excluding HPMC or including a hydrophobic matrix former (Kollidon SR) yielded granules with a homogeneous API distribution, HPMC was identified as the root cause of the non-homogeneous API distribution. This was linked to its fast hydration and swelling (irrespective of the HPMC grade) upon addition of the granulation liquid.

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PURPOSE: Wet granulation (WG) is one of the most versatile processes to improve blend properties for processing. However, due to its need for moisture and heat, it is often considered not amenable to active pharmaceutical ingredients (APIs) prone to forming hydrates. Despite this claim, little literature exists evaluating the extent to which polymorphic form conversions occur for such API when processed with WG. This work sets out to explore two common WG methods, high-shear (HSG) and fluid-bed (FBG), and two drying processes, tray-drying (TD) and fluid-bed drying (FBD), and evaluate the risk they pose to hydrate form conversion. METHODS: The progression of anhydrous to hydrate form conversion of two model compounds with vastly different solubilities, fexofenadine hydrochloride and carbamazepine, was monitored throughout the various processes using powder X-ray diffraction. The resultant granules were characterized using thermogravimetric analysis, differential scanning calorimetry, BET adsorption, and sieve analysis. RESULTS: FBG and FBD processing resulted in the preservation of the original form of both APIs, while HSG+TD resulted in the complete conversion of the API. The FBD of fexofenadine and carbamazepine granules prepared with HSG resulted in partial and complete re-conversion back to the original anhydrous forms, respectively. CONCLUSION: The drying process is a critical factor in anhydrous form conservation. FBG and FBD yielded better preservation of the initial anhydrous forms. HSG could be an acceptable granulation method for API susceptible to hydrate formation if the API solubility is low. Selecting an FBG+FBD process minimizes API hydrate formation and preserves the original anhydrous form.

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Bacterial cellulose (BC) is an interesting material for drug delivery applications due to its high purity. This study aimed to compare the properties of tablets prepared by the wet granulation method using bacterial cellulose prepared by different methods as a diluent, using acetaminophen as a model drug. BC used as diluents were prepared using two different methods: freeze-drying (BC-FD) and phase-inversion (BC-PI), and their characteristics were analyzed and compared with that of commercial microcrystalline cellulose PH 101 (Comprecel® M101). Acetaminophen tablets were prepared by wet granulation using BC-FD, BC-PI, or Comprecel® M101 as diluents, and their tablet properties were examined. The result showed that the morphology, polymorph, and crystallinity of BC-PI and Comprecel® M101 were similar but they were different compared with that of BC-FD. Tablets could be successfully formed using BC-PI and Comprecel® M101 as diluents without any physical defects but the tablet prepared using BC-FD as diluent appeared chipped edge. The characteristics (thickness, weight variation, hardness, friability, disintegration, drug content, and dissolution) of the tablets prepared using BC-PI diluent were also similar to those prepared using Comprecel® M101 diluent, but those of BC-FD diluent were inferior. This indicates that BC prepared in BC-PI can potentially be used as a diluent for tablets prepared by wet granulation.

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Twin-screw wet granulation is an emerging continuous manufacturing technology for solid oral dosage forms. This technology has been successfully employed for the commercial manufacture of immediate-released tablets. However, the higher polymer content in extended-release (ER) formulations may present challenges in developing and operating within a desired design space. The work described here used a systematic approach for defining the optimum design space by understanding the effects of the screw design, operating parameters, and their interactions on the critical characteristics of granules and ER tablets. The impacts of screw speed, powder feeding rate, and the number of kneading (KEs) and sizing elements on granules and tablets characteristics were investigated by employing a definitive screening design. A semi-mechanistic model was used to calculate the residence time distribution parameters and validated using the tracers. The results showed that an increase in screw speed decreased the mean residence time of the material within the barrel, while an increase in the powder feeding rate or number of KEs did the opposite and increased the barrel residence time. Screw design and operating parameters affected the flow and bulk characteristics of granules. The screw speed was the most significant factor impacting the tablet's breaking strength. The dissolution profiles revealed that granule characteristics mainly influenced the early phase of drug release. This study demonstrated that a simultaneous optimization of both operating and screw design parameters was beneficial in producing ER granules and tablets of desired performance characteristics while mitigating any failure risks, such as swelling during processing.

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Resin-based friction materials (RBFMs) strengthened by polyether ether ketone (PEEK) fiber were designed and prepared in this study. Specimens incorporating PEEK fiber of 2-8 wt.% were fabricated based on wet granulation, and then the effects of the PEEK fiber content on the mechanical and tribological properties of RBFMs were systematically investigated. The results showed that PEEK fiber can sense the braking temperature and then effectively regulate the comprehensive properties of RBFMs. The specimen incorporating 6 wt.% PEEK fiber obtained the optimal comprehensive performance with a stable friction coefficient (COF), excellent fade resistance and recovery properties, and better wear resistance. The worn surface was inspected using a scanning electron microscope. After the friction-wear test, the specimen with 6 wt.% PEEK fiber presented a number of primary and secondary plateaus and a reduced number of pits with wear debris on the worn surface. The study indicated that PEEK fiber could not only enhance the mechanical and tribological properties of RBFMs at low temperatures because of their high strength and self-lubrication but also adhere to wear debris to reduce abrasive wear at high temperatures; furthermore, the adhered wear debris could form a secondary plateau under normal pressure, which could alleviate abrasion.

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Prospectively planned designs of experiments (DoEs) offer a valuable approach to preventing collinearity issues that can result in statistical confusion, leading to misinterpretation and reducing the predictability of statistical models. However, it is also possible to develop models using historical data, provided that certain guidelines are followed to enhance and ensure proper statistical modeling. This article presents a methodology for constructing a design space using process data, while avoiding the common pitfalls associated with retrospective data analysis. For this study, data from a real wet granulation process were collected to pragmatically illustrate all the concepts and methods developed in this article.

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The focus of this study was to investigate the sensitivity of different drug formulations to differences in process parameters based on previously developed scale-up strategies. Three different formulations were used for scale-up experiments from a QbCon® 1 with a screw diameter of 16 mm and a throughput of 2 kg/h to a QbCon® 25 line with a screw diameter of 25 mm and a throughput of 25 kg/h. Two of those formulations were similar in their composition of excipients but had a different API added to the blend to investigate the effect of solubility of the API during twin-screw wet granulation, while the third formulation was based on a controlled release formulation with different excipients and a high fraction of HPMC. The L/S-ratio had to be set specifically for each formulation as depending on the binder and the overall composition the blends varied significantly in their response to water addition and their overall granulation behavior. Before milling there were large differences in granule size distributions based on scale (Earth Mover's Distance 140-1100 µm, higher values indicating low similarity) for all formulations. However, no major differences in granule properties (e.g. Earth Mover's Distance for GSDs: 23-88 µm) or tablet tensile strength (> 1.8 MPa at a compaction pressure of 200 MPa for all formulations with a coefficient of variation < 0.1, indicating high robustness for all formulations) were observed after milling, which allowed for a successful scale-up independent of the selected formulations.

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This paper presents an application case of model-based design of experiments for the continuous twin-screw wet granulation and fluid-bed drying sequence. The proposed framework consists of three previously developed models. Here, we are testing the applicability of previously published unit operation models in this specific part of the production line to a new active pharmaceutical ingredient. Firstly, a T-shaped partial least squares regression model predicts d-values of granules after wet granulation with different process settings. Then, a high-resolution full granule size distribution is computed by a hybrid population balance and partial least squares regression model. Lastly, a mechanistic model of fluid-bed drying simulates drying time and energy efficiency, using the outputs of the first two models as a part of the inputs. In the application case, good operating conditions were calculated based on material and formulation properties as well as the developed process models. The framework was validated by comparing the simulation results with three experimental results. Overall, the proposed framework enables a process designer to find appropriate process settings with a less experimental workload. The framework combined with process knowledge reduced 73.2% of material consumption and 72.3% of time, especially in the early process development phase.

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This work presents a granule size prediction approach applicable to diverse formulations containing new active pharmaceutical ingredients (APIs) in continuous twin-screw wet granulation. The approach consists of a surrogate selection method to identify similar materials with new APIs and a T-shaped partial least squares (T-PLS) model for granule size prediction across varying formulations and process conditions. We devised a surrogate material selection method, employing a combination of linear pre-processing and nonlinear classification algorithms, which effectively identified suitable surrogates for new materials. Using only material properties obtained through four characterization methods, our approach demonstrated its predictive prowess. The selected surrogate methods were seamlessly integrated with our developed T-PLS model, which was meticulously validated for high-dose formulations involving three new APIs. When surrogating new APIs based on Gaussian process classification, we achieved the lowest prediction errors, signifying the method's robustness. The predicted d-values were within the range of uncertainty bounds for all cases, except for d90 of API C. Notably, the approach offers a direct and efficient solution for early-phase formulation and process development, considerably reducing the need for extensive experimental work. By relying on just four material characterization methods, it streamlines the research process while maintaining a high degree of accuracy.

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