Investigation of the Influence of Copovidone Properties and Hot-Melt Extrusion Process on Level of Impurities, In Vitro Release, and Stability of an Amorphous Solid Dispersion Product.

Hot-melt extrusion (HME) is a widely used method for creating amorphous solid dispersions (ASDs) of poorly soluble drug substances, where the drug is molecularly dispersed in a solid polymer matrix. This study examines the impact of three different copovidone excipients, their reactive impurity levels, HME barrel temperature, and the distribution of colloidal silicon dioxide (SiO2) on impurity levels, stability, and drug release of ASDs and their tablets. Initial peroxide levels were higher in Kollidon VA 64 (KVA64) and Plasdone S630 (PS630) compared to Plasdone S630 Ultra (PS630U), leading to greater oxidative degradation of the drug in fresh ASD tablets. However, stability testing (50 °C, closed container, 50 °C/30% RH, open conditions) showed lower oxidative degradation impurities in ASD tablets prepared at higher barrel temperatures, likely due to greater peroxide degradation. Plasdone S630 is suitable for ASDs with drugs prone to oxidative degradation, while standard purity grades may benefit drugs susceptible to free radical degradation, as they generate fewer free radicals post-HME. ASD tablets exhibited greater physical stability than milled extrudate samples, likely due to reduced exposure to stability conditions within the tablet matrix. Including SiO2 in the extrudate composition resulted in greater physical stability of the ASD system in the tablet; however, it negatively affected chemical stability, promoting greater oxidative degradation and hydroxylation of the drug substance. No impact of the distribution of SiO2 on drug release was observed. The study also confirmed the congruent release of copovidone, the drug substance, and Tween 80 using flow NMR coupled with in-line UV/vis. This research highlights the critical roles of peroxide levels and SiO2 in influencing the dissolution and physical and chemical stability of ASDs. The findings provide valuable insights for developing stable and effective pharmaceutical formulations, emphasizing the importance of controlling reactive impurities and excipient characteristics in ASD products prepared by using HME.

Effect of processing and formulation factors on Catalase activity in tablets.

The manufacturing of tablets containing biologics exposes the biologics to thermal and shear stresses, which are likely to induce structural changes (e.g., aggregation and denaturation), leading to the loss of their activity. Saccharides often act as stabilizers of proteins in formulations, yet their stabilizing ability throughout solid oral dosage processing, such as tableting, has been barely studied. This work aimed to investigate the effects of formulation and process (tableting and spray-drying) variables on catalase tablets containing dextran, mannitol, and trehalose as potential stabilizers. Non-spray-dried and spray-dried formulations were prepared and tableted (100, 200, and 400 MPa). The enzymatic activity, number of aggregates, reflecting protein aggregation and structure modifications were studied. A principal component analysis was performed to reveal underlying correlations. It was found that tableting and spray-drying had a notable negative effect on the activity and number of aggregates formed in catalase formulations. Overall, dextran and mannitol failed to preserve the catalase activity in any unit operation studied. On the other hand, trehalose was found to preserve the activity during spray-drying but not necessarily during tableting. The study demonstrated that formulation and process variables must be considered and optimized together to preserve the characteristics of catalase throughout processing.

Amorphous Solid Dispersions: Implication of Method of Preparation and Physicochemical Properties of API and Excipients.

The present study investigated the effect of different polymers and manufacturing methods (hot melt extrusion, HME, and spray drying, SD) on the solid state, stability and pharmaceutical performance of amorphous solid dispersions. In the present manuscript, a combination of different binary amorphous solid dispersions containing 20% and 30% of drug loadings were prepared using SD and HME. The developed solid-state properties of the dispersions were evaluated using small- and wide-angle X-ray scattering (WAXS) and modulated differential scanning calorimetry (mDSC). The molecular interaction between the active pharmaceutical ingredients (APIs) and polymers were investigated via infrared (IR) and Raman spectroscopy. The in vitro release profile of the solid dispersions was also evaluated to compare the rate and extend of drug dissolution as a function of method of preparation. Thereafter, the effect of accelerated stability conditions on the physicochemical properties of the solid dispersions were also evaluated. The results demonstrated higher stability of Soluplus® (SOL) polymer-based solid dispersions as compared to hydroxypropyl methylcellulose (HPMC)-based solid dispersions. Moreover, the stability of the solid dispersions was found to be higher in the case of API having high glass transition temperature (Tg) and demonstrated higher interaction with the polymeric groups. Interestingly, the stability of the melt-extruded dispersions was found to be slightly higher as compared to the SD formulations. However, the down-processing of melt-extruded strands plays critical role in inducing the API crystal nuclei formation. In summary, the findings strongly indicate that the particulate properties significantly influence the performance of the product.

The comparison of melt technologies based on mesoporous carriers for improved carvedilol dissolution.

High-shear (HS) melt granulation and hot melt extrusion (HME) were compared as perspective melt-based technologies for preparation of amorphous solid dispersions (ASDs). ASDs were prepared using mesoporous carriers (SyloidⓇ 244FP or NeusilinⓇ US2), which were loaded with carvedilol dispersed in polymeric matrix (polyethylene glycol 6000 or SoluplusⓇ). Formulations with high carvedilol content were obtained either by HME (11 extrudates with polymer:carrier ratio 1:1) or HS granulation (6 granulates with polymer:carrier ratio 3:1). DSC and XRD analysis confirmed the absence of crystalline carvedilol for the majority of prepared ADSs, thus confirming the stabilizing effect of selected polymers and carriers over amorphous carvedilol. HME produced larger particles compared to HS melt granulation, which was in line with better flow time and Carr index of extrudates. Moreover, SEM images revealed smoother surface of ASDs obtained by HME, contributing to less obstructed flow. The rougher and more porous surface of HS granules was correlated to larger granule specific surface area, manifesting in faster carvedilol release from SyloidⓇ 244FP-based granules, as compared to their HME counterparts. Regarding dissolution, the two HS-formulations performed superior to pure crystalline carvedilol, thereby confirming the suitability of HS melt granulation for developing dosage forms with improved carvedilol dissolution.

Integration of mucus and its impact within in vitro setups for inhaled drugs and formulations: Identifying the limits of simple vs. complex methodologies when studying drug dissolution and permeability.

Traditionally, developing inhaled drug formulations relied on trial and error, yet recent technological advancements have deepened the understanding of 'inhalation biopharmaceutics' i.e. the processes that occur to influence the rate and extent of drug exposure in the lungs. This knowledge has led to the development of new in vitro models that predict the in vivo behavior of drugs, facilitating the enhancement of existing formulation and the development of novel ones. Our prior research examined how simulated lung fluid (SLF) affects the solubility of inhaled drugs. Building on this, we aimed to explore drug dissolution and permeability in lung mucosa models containing mucus. Thus, the permeation of four active pharmaceutical ingredients (APIs), salbutamol sulphate (SS), tiotropium bromide (TioBr), formoterol fumarate (FF) and budesonide (BUD), was assayed in porcine mucus covered Calu-3 cell layers, cultivated at an air liquid interface (ALI) or submerged in a liquid covered (LC) culture system. Further analysis on BUD and FF involved their transport in a mucus-covered PAMPA system. Finally, their dissolution post-aerosolization from Symbicort® was compared using 'simple' Transwell and complex DissolvIt® apparatuses, alone or in presence of porcine mucus or polymer-lipid mucus simulant. The presence of porcine mucus impacted both permeability and dissolution of inhaled drugs. For instance, permeability of SS was reduced by a factor of ten in the Calu-3 ALI model while the permeability of BUD was reduced by factor of two in LC and ALI setups. The comparison of dissolution methodologies indicated that drug dissolution performance was highly dependent on the setup, observing decreased release efficiency and higher variability in Transwell system compared to DissolvIt®. Overall, results demonstrate that relatively simple methodologies can be used to discriminate between formulations in early phase drug product development. However, for more advanced stages complex methods are required. Crucially, it was clear that the impact of mucus and selection of its composition in in vitro testing of dissolution and permeability should not be neglected when developing drugs and formulations intended for inhalation.

In-situ monitoring of in vitro drug release processes in tablets using optical coherence tomography.

Film-coated modified-release tablets are an important dosage form amenable to targeted, controlled, or delayed drug release in the specific region of the gastrointestinal (GI) tract. Depending on the film composition and interaction with the GI fluid, such coated products can modulate the local bioavailability, systemic absorption, protection as an enteric barrier, etc. Although the interaction of a dosage form with the surrounding dissolution medium is vital for the resulting release behavior, the underlying physicochemical phenomena at the film and core levels occurring during the drug release process have not yet been well described. In this work, we attempted to tackle this limitation by introducing a novel in vitro test based on optical coherence tomography (OCT) that allows an in-situ investigation of the sub-surface processes occurring during the drug release. Using a commercially available tablet based on osmotic-controlled release oral delivery systems (OROS), we demonstrated the performance of the presented prototype in terms of monitoring the membrane thickness and thickness variability, the surface roughness, the core swelling behavior, and the porosity of the core matrix throughout the in vitro drug release process from OROS. The superior spatial (micron scale) and temporal (less than 10 ms between the subsequent tomograms) resolution achieved in the proposed setup provides an improved understanding of the dynamics inside the microstructure at any given time during the dissolution procedure with the previously unattainable resolution, offering new opportunities for the design and testing of patient-centric dosage forms.

Accelerative Solid-State Oxidation Behaviour of Amorphous and Partially Crystalline Venetoclax.

There is a growing focus on solid-state degradation, especially for its relevance in understanding interactions with excipients. Performing a solid-state degradation of Venetoclax (VEN), we delve into VEN's stability in different solid-state oxidative stress conditions, utilizing Peroxydone™ complex and urea peroxide (UHP). The investigation extends beyond traditional forced degradation scenarios, providing insights into VEN's behavior over 32 h, considering temperature and crystallinity conditions. Distinct behaviors emerge in the cases of Peroxydone™ complex and UHP. The partially crystalline (PC-VEN) form proves more stable with Peroxydone™, while the amorphous form (A-VEN) shows enhanced stability with UHP. N-oxide VEN, a significant degradation product, varies between these cases, reflecting the impact of different oxidative stress conditions. Peroxydone™ complex demonstrates higher reproducibility and stability, making it a promising option for screening impurities in solid-state oxidative stress scenarios. This research not only contributes to the understanding of VEN's stability in solid-state but also aids formulators in anticipating excipient incompatibilities owing to presence of reactive impurities (peroxides) and oxidation in the final dosage form.

Machine Learning-Enabled NIR Spectroscopy. Part 3: Hyperparameter by Design (HyD) Based ANN-MLP Optimization, Model Generalizability, and Model Transferability.

Data variations, library changes, and poorly tuned hyperparameters can cause failures in data-driven modelling. In such scenarios, model drift, a gradual shift in model performance, can lead to inaccurate predictions. Monitoring and mitigating drift are vital to maintain model effectiveness. USFDA and ICH regulate pharmaceutical variation with scientific risk-based approaches. In this study, the hyperparameter optimization for the Artificial Neural Network Multilayer Perceptron (ANN-MLP) was investigated using open-source data. The design of experiments (DoE) approach in combination with target drift prediction and statistical process control (SPC) was employed to achieve this objective. First, pre-screening and optimization DoEs were conducted on lab-scale data, serving as internal validation data, to identify the design space and control space. The regression performance metrics were carefully monitored to ensure the right set of hyperparameters was selected, optimizing the modelling time and storage requirements. Before extending the analysis to external validation data, a drift analysis on the target variable was performed. This aimed to determine if the external data fell within the studied range or required retraining of the model. Although a drift was observed, the external data remained well within the range of the internal validation data. Subsequently, trend analysis and process monitoring for the mean absolute error of the active content were conducted. The combined use of DoE, drift analysis, and SPC enabled trend analysis, ensuring that both current and external validation data met acceptance criteria. Out-of-specification and process control limits were determined, providing valuable insights into the model's performance and overall reliability. This comprehensive approach allowed for robust hyperparameter optimization and effective management of model lifecycle, crucial in achieving accurate and dependable predictions in various real-world applications.

Influence of Crystal Disorder on the Forced Oxidative Degradation of Vortioxetine HBr.

The present study investigates the impact of the solid-state disorder of vortioxetine hydrobromide (HBr) on oxidative degradation under accelerated conditions. A range of solid-state disorders was generated via cryogenic ball milling. The solid-state properties were evaluated by calorimetry, infrared-, and Raman spectroscopies. While salt disproportionation occurred upon milling, no chemical degradation occurred by milling. The amorphous fraction remained physically intact under ambient storage conditions. Subsequently, samples with representative disordered fractions were mixed with a solid oxidative stressor (PVP-H2O2 complex) and were compressed to compacts. The compacts were exposed to 40°C/75% RH for up to 6 h. The sample was periodically withdrawn and analyzed for the physical transformations and degradation. Two oxidative degradation products (DPs) were found to be formed, for which dissimilar relations to the degree of disorder and kinetics of formation were observed. The degradation rate of the major DP formation obtained by fitting the exponential model to the experimental data was found to increase up to a certain degree of disorder and decrease with a further increase in the disordered fraction. In contrast, the minor DP formation kinetics was found to increase monotonically with the increase in the disorder content. For the similar crystallinity level, the degradation trend (rate and extent) differed between the single-phase disorder generated by milling and physically mixed two-phase systems. Overall, the study demonstrates the importance of evaluating the physical and chemical (in)stabilities of the disordered solid state of a salt form of a drug substance, generated through mechano-activation.

pH stimuli-responsive hydrogels from non-cellulosic biopolymers for drug delivery.

Over the past several decades, there has been significant growth in the design and development of more efficient and advanced biomaterials based on non-cellulosic biological macromolecules. In this context, hydrogels based on stimuli-responsive non-cellulosic biological macromolecules have garnered significant attention because of their intrinsic physicochemical properties, biological characteristics, and sustainability. Due to their capacity to adapt to physiological pHs with rapid and reversible changes, several researchers have investigated pH-responsive-based non-cellulosic polymers from various materials. pH-responsive hydrogels release therapeutic substances in response to pH changes, providing tailored administration, fewer side effects, and improved treatment efficacy while reducing tissue damage. Because of these qualities, they have been shown to be useful in a wide variety of applications, including the administration of chemotherapeutic drugs, biological material, and natural components. The pH-sensitive biopolymers that are utilized most frequently include chitosan, alginate, hyaluronic acid, guar gum, and dextran. In this review article, the emphasis is placed on pH stimuli-responsive materials that are based on biological macromolecules for the purposes of drug administration.

Investigation of the Impact of Saccharides on the Relative Activity of Trypsin and Catalase after Droplet and Spray Drying.

While using saccharides as stabilizers for therapeutic protein drying is common, the mechanisms underlying the stabilization during drying remain largely unexplored. Herein, we investigated the effect of different saccharides, trehalose dihydrate (TD), dextran (DEX), and hydroxypropyl ß-cyclodextrins (low substitution-HP and high substitution-HPB), on the relative activities of the enzymes trypsin and catalase during miniaturized drying (MD) or spray drying (SD). For trypsin, the presence of saccharides, especially HP, was beneficial, as it significantly improved the enzyme activity following MD. The HPB preserved trypsin's activity during MD and SD. Adding saccharides during MD did not show a notable improvement in catalase activities. Increasing TD was beneficial during the SD of catalase, as indicated by significantly increased activity. Molecular docking and molecular dynamics simulations oftrypsin with HP or HPB revealed the influence of their substitution on the binding affinity for the enzyme. A higher affinity of HP to bind trypsin and itself was observed during simulations. Experimentally, activity reduction was mainly observed during MD, attributable to the higher droplet temperature during MD than during SD. The activities from the experiments and aggregation propensity from molecular modeling helped elucidate the impact of the size of protein and saccharides on preserving the activity during drying.

Pancreatic lipase digestion: The forgotten barrier in oral administration of lipid-based delivery systems?

This review highlights the importance of controlling the digestion process of orally administered lipid-based delivery systems (LBDS) and their performance. Oral LBDS are prone to digestion via pancreatic lipase in the small intestine. Rapid or uncontrolled digestion may cause the loss of delivery system integrity, its structural changes, reduced solubilization capacity and physical stability issues. All these events can lead to uncontrolled drug release from the digested LBDS into the gastrointestinal environment, exposing the incorporated drug to precipitation or degradation by luminal proteases. To prevent this, the digestion rate of orally administered LBDS can be estimated by appropriate choice of the formulation type, excipient combinations and their ratios. In addition, in vitro digestion models like pH-stat are useful tools to evaluate the formulation digestion rate. Controlling digestion can be achieved by conventional lipase inhibitors like orlistat, sterically hindering of lipase adsorption on the delivery system surface with polyethylene glycol (PEG) chains, lipase desorption or saturation of the interface with surfactants as well as formulating LBDS with ester-free excipients. Recent in vivo studies demonstrated that digestion inhibition lead to altered pharmacokinetic profiles, where Cmax and Tmax were reduced in spite of same AUC compared to control or even improved oral bioavailability.

Neutralizing Antibody Validation Testing and Reporting Harmonization.

Evolving immunogenicity assay performance expectations and a lack of harmonized neutralizing antibody validation testing and reporting tools have resulted in significant time spent by health authorities and sponsors on resolving filing queries. A team of experts within the American Association of Pharmaceutical Scientists' Therapeutic Product Immunogenicity Community across industry and the Food and Drug Administration addressed challenges unique to cell-based and non-cell-based neutralizing antibody assays. Harmonization of validation expectations and data reporting will facilitate filings to health authorities and are described in this manuscript. This team provides validation testing and reporting strategies and tools for the following assessments: (1) format selection; (2) cut point; (3) assay acceptance criteria; (4) control precision; (5) sensitivity including positive control selection and performance tracking; (6) negative control selection; (7) selectivity/specificity including matrix interference, hemolysis, lipemia, bilirubin, concomitant medications, and structurally similar analytes; (8) drug tolerance; (9) target tolerance; (10) sample stability; and (11) assay robustness.

On the influence of raw material attributes on process behaviour and product quality in a continuous WET granulation tableting line.

Continuous manufacturing of oral solids is a complex process in which critical material attributes (CMAs), formulation and critical process parameters (CPPs) play a fundamental role. However, assessing their effect on the intermediate and final product's critical quality attributes (CQAs) remains challenging. The aim of this study was to tackle this shortcoming by evaluating the influence of raw material properties and formulation composition on the processability and quality of granules and tablets on a continuous manufacturing line. Powder-to-tablet manufacturing was performed using four formulations in various process settings. Pre-blends of different drug loadings (2.5 % w/w and 25% w/w) and two BCS classes (Class I and II) were continuously processed on an integrated process line ConsiGmaTM 25, including twin screw wet granulation, fluid bed drying, milling, sieving, in-line lubrication and tableting. The liquid-to-solid ratio and the granule drying time were varied to process granules under nominal, dry and wet conditions. It was shown that the BCS class and the drug dosage influenced the processability. Intermediate quality attributes, such as the loss on drying and the particle size distribution, directly correlated with the raw material's properties and process parameters. Process settings had a profound impact on the tablet's hardness, disintegration time, wettability and porosity.

Development of a Digital Interface for Personalized Dosing in Renal Impaired Patients: A Case-Study Using the ACE-Inhibitor Benazepril.

BACKGROUND: Personalized dosing regimens have great potential to improve the standard level of care from "one-fits-all" to the "right dose, to the right patient at the right time". OBJECTIVES: Development of a digital interface that can inform healthcare professionals on the dosing of an ACE inhibitor on an individual basis. METHODS: A physiologically based pharmacokinetic (PBPK) model and a one-compartment model were implemented for the prodrug benazepril and its metabolite benazeprilat, respectively. In sequence, to capture inter-individual differences the models were extended to a population based one (PopPBPK). RESULTS: Both models predicted the pharmacokinetic data in the observed ranges. Application of the models help identify the factors influencing drug concentrations in the body and to find subgroups of patients, in which a dose adjustment is recommended, or a higher degree of caution is required. CONCLUSION: The use of the models via a practical user interface can help inform clinical decisions and design optimal dosing based on the individual anthropometric characteristics and stage of renal impairment.

Impact of Different Saccharides on the In-Process Stability of a Protein Drug During Evaporative Drying: From Sessile Droplet Drying to Lab-Scale Spray Drying.

OBJECTIVES: Solid biopharmaceutical products can circumvent lower temperature storage and transport and increase remote access with lower carbon emissions and energy consumption. Saccharides are known stabilizers in a solid protein produced via lyophilization and spray drying (SD). Thus, it is essential to understand the interactions between saccharides and proteins and the stabilization mechanism. METHODS: A miniaturized single droplet drying (MD) method was developed to understand how different saccharides stabilize proteins during drying. We applied our MD to different aqueous saccharide-protein systems and transferred our findings to SD. RESULTS: The poly- and oligosaccharides tend to destabilize the protein during drying. The oligosaccharide, Hydroxypropyl ß-cyclodextrin (HPßCD) shows high aggregation at a high saccharide-to-protein molar ratio (S/P ratio) during MD, and the finding is supported by nanoDSF results. The polysaccharide, Dextran (DEX) leads to larger particles, whereas HPBCD leads to smaller particles. Furthermore, DEX is not able to stabilize the protein at higher S/P ratios either. In contrast, the disaccharide Trehalose Dihydrate (TD) does not increase or induce protein aggregation during the drying of the formulation. It can preserve the protein's secondary structure during drying, already at low concentrations. CONCLUSION: During the drying of S/P formulations containing the saccharides TD and DEX, the MD approach could anticipate the in-process (in) stability of protein X at laboratory-scale SD. In contrast, for the systems with HPßCD, the results obtained by SD were contradictory to MD. This underlines that depending on the drying operation, careful consideration needs to be applied to the selection of saccharides and their ratios.

Applying Material Science Principles to Chemical Stability: Modelling Solid State Autoxidation in Mifepristone Containing Different Degrees of Crystal Disorder.

Ball-milling and harsh manufacturing processes often generate crystal disorder which have practical implications on the physical and chemical stabilities of solid drugs during subsequent storage, transport, and handling. The impact of the physical state of solid drugs, containing different degrees/levels of crystal disorder, on their autoxidative stability under storage has not been widely investigated. This study investigates the impact of differing degrees of crystal disorder on the autoxidation of Mifepristone (MFP) to develop a predictive (semi-empirical) stability model. Crystalline MFP was subjected to different durations of ambient ball milling, and the resulting disorder/ amorphous content was quantified using a partial least square (PLS) regression model based on Raman spectroscopy data. Samples of MFP milled to generate varying levels of disorder were subjected to a range of (accelerated) stability conditions, and periodically sampled to examine their recrystallization and degradation extents. Crystallinity was monitored by Raman spectroscopy, and the degradation was evaluated by liquid chromatography. The analyses of milled samples demonstrated a competition between recrystallization and degradation via autoxidation of MFP, to different extents depending on stability conditions/exposure time. The degradation kinetics were analyzed by accounting for the preceding amorphous content, and fitted with a diffusion model. An extended Arrhenius equation was used to predict the degradation of stored samples under long-term (25°C/60% RH) and accelerated (40°C/75% RH, 50°C/75% RH) stability conditions. This study highlights the utility of such a predictive stability model for identifying the autoxidative instability in non-crystalline/partially crystalline MFP, owing to the degradation of the amorphous phases. This study is particularly useful for identifying drug-product instability by leveraging the concept of material sciences.

Screening Autoxidation Propensities of Drugs in the Solid-State Using PVP and in the Solution State Using N-Methyl Pyrrolidone.

Oxidative degradation of drugs is one of the major routes of drug substance and drug product instability. Among the diverse routes of oxidation, autoxidation is considered to be challenging to predict and control, potentially due to the multi-step mechanism involving free radicals. C-H bond dissociation energy (C-H BDE) is evidenced to be a calculated descriptor shown to predict drug autoxidation. While computational predictions for the autoxidation propensity of drugs are both swift and possible, no literature to date has highlighted the relationship between the computed C-H BDE and the experimentally-derived autoxidation propensities of solid drugs. The objective of this study is to investigate this missing relationship. The present work is an extension to the previously reported novel autoxidation approach that involves subjecting a physical mixture of pre-milled polyvinyl pyrrolidone (PVP) K-60 and a crystalline drug under high temperature and pressurized oxygen setup. The drug degradation was measured using chromatographic methods. An improved trend between the extent of solid autoxidation and C-H BDE could be observed after normalizing the effective surface area of drugs in the crystalline state, pointing to a positive relationship. Additional studies were conducted by dissolving the drug in N-methyl pyrrolidone (NMP) and exposing the solution under a pressurized oxygen setup at diverse elevated temperatures. Chromatographic results of these samples indicated a similarity in the formed degradation products to the solid-state experiments pointing to the utility of NMP, a PVP monomer surrogate, as a stressing agent for faster and relevant autoxidation screening of drugs in formulations.

Assessment of Tribo-charging and Continuous Feeding Performance of Direct Compression Grades of Isomalt and Mannitol Powders.

Tribo-charging is often a root cause of mass flow deviations and powder adhesion during continuous feeding. Thus, it may critically impact product quality. In this study, we characterized the volumetric (split- and pre-blend) feeding behavior and process-induced charge of two direct compression grades of polyols, galenIQ™ 721 (G721) for isomalt and PEARLITOL® 200SD (P200SD) for mannitol, under different processing conditions. The feeding mass flow range and variability, hopper end fill level, and powder adhesion were profiled. The feeding-induced tribo-charging was measured using a Faraday cup. Both materials were comprehensively characterized for relevant powder properties, and their tribo-charging was investigated for its dependence on particle size and relative humidity. During split-feeding experiments, G721 showed a comparable feeding performance to P200SD with lower tribo-charging and adhesion to the screw outlet of the feeder. Depending on the processing condition, the charge density of G721 ranged from -0.01 up to -0.39 nC/g, and for P200SD from -3.19 up to -5.99 nC/g. Rather than differences in the particle size distribution of the two materials, their distinct surface and structural characteristics were found as the main factors affecting their tribo-charging. The good feeding performance of both polyol grades was also maintained during pre-blend feeding, where reduced tribo-charging and adhesion propensity was observed for P200SD (decreasing from -5.27 to -0.17 nC/g under the same feeding settings). Here, it is proposed that the mitigation of tribo-charging occurs due to a particle size-driven mechanism.

Theoretical and Experimental Investigation of Autoxidation Propensity of Selected Drugs in Solution State.

The C-H bond dissociation energy (BDE) of drug molecules is often used to estimate their relative propensities to undergo autoxidation. BDE calculations based on electronic structures provide a convenient means to estimate the risk for a given compound to degrade via autoxidation. This study aimed to verify the utility of calculated C-H BDEs of a range of drug molecules in predicting their autoxidation propensities, in the solution state. For the autoxidation study, 2,2'-azobis (2-methylpropionitrile) was employed as the solution state stressor, and the experimental reaction rate constants were determined employing ultraperformance liquid chromatographic (UPLC) methods. Reaction rates in the solution state were compared to the calculated C-H BDE values of the respective compounds. The results indicated a poor correlation for compounds in the solution state, and their relative stabilities could not be explained with C-H BDE. On the other hand, a favorable relationship was observed between the relative extent of ionization and the autoxidation rates of the selected compounds. In the solution state, factors such as the type and extent of drug ionization, degree and type of solvation have been shown to contribute to differences in reactivity. By applying the computational method involving the effect of H-atom abstraction and potential ionization sites in the molecule, the calculated C-H BDE should relate better to the experimental autoxidation rates.