Impact of Post Manufacturing Handling of Protein-Based Biologic Drugs on Product Quality and User Centricity.

This article evaluates the current gaps around the impact of post-manufacturing processes on the product qualities of protein-based biologics, with a focus on user centricity. It includes the evaluation of the regulatory guidance available, describes a collection of scientific literature and case studies to showcase the impact of post-manufacturing stresses on product and dosing solution quality. It also outlines the complexity of clinical handling and the need for communication, and alignment between drug providers, healthcare professionals, users, and patients. Regulatory agencies provide clear expectations for drug manufacturing processes, however, guidance supporting post-product manufacturing handling is less defined and often misaligned. This is problematic as the pharmaceutical products experience numerous stresses and processes which can potentially impact drug quality, safety and efficacy. This article aims to stimulate discussion amongst pharmaceutical developers, health care providers, device manufacturers, and public researchers to improve these processes. Patients and caregivers' awareness can be achieved by providing relevant educational material on pharmaceutical product handling.

How are we handling protein drugs in hospitals? A human factors and systems engineering approach to compare two hospitals and suggest a best practice.

Biopharmaceuticals are complex biological molecules that require careful storage and handling to ensure medication integrity. In this study, a work system analysis of real-world protein drug (PD) handling was performed with the following goals: identify main barriers and facilitators for successful adherence to accepted recommendations in PD handling, analyse differences in two organizations, and define a Best Current Practice in the real-life handling of PDs based on the results of the work system analysis. Observational study was held in two university hospitals in Spain and Sweden. Based on the Systems Engineering Initiative for Patient Safety (SEIPS) model, the tools chosen were: the PETT scan, in order to indicate the presence of barriers or facilitators for the PETT components (People, Environment, Tools, Tasks); the Tasks and tools matrices to construct a checklist to record direct observations during the real-life handling of biopharmaceuticals, and the Journey map to depict the work process. Observations were performed between March and November 2022. Each episode of direct observation included a single protein drug in some point of the supply chain and considered all the elements in the work system. Based on the results of the work system analysis and the literature review, the authors propose a list of items which could be assumed as Best Current Practice for PDs handling in hospitals. There were a total of 34 observations involving 19 PDs. Regarding People involved in the work process, there was a diversity of professionals with different previous training and knowledge, leading to an information gap. With respect to Environment, some structural and organizational differences between hospitals lead to risks related to the time exposure of PDs to room temperature and mechanical stress. Some differences also existed in the Tools and Tasks involved in the process, being especially relevant to the lack of compatibility information of PDs with new technologies, such as pneumatic tube system, robotic reconstitution, or closed-system transfer devices. Finally, 15 suggestions for best current practice are proposed. Main barriers found for compliance with accepted recommendations were related to the information gap detected in professionals involved in the handling of protein drugs, unmonitored temperature, and the lack of compatibility information of protein drugs with some new technologies. By applying a Human Factors and Systems Engineering Approach, the comparison of two European hospitals has led to a suggested list of Best Current Practices in the handling of protein drugs in a hospital.

Formulation factors affecting foam properties during vacuum foam-drying.

This paper explores how vacuum foam-drying of a protein is influenced by formulation parameters by investigating the foam structure, physical properties of the foam, and the stability of the protein. Recombinant human bile salt-stimulated lipase was used as a model of a protein drug. The stability of the lipase was evaluated through activity measurements. Two disaccharides (sucrose and trehalose), strongly tending to an amorphous form, were used as matrix formers, and the physical properties were assessed through residual water content, glass transition temperature, and crystalline state. Moreover, some formulations included surfactants with different sizes and structures of the head group. The alkyl chain length was kept constant to only investigate the impact of the surfactant head group, in the presence of the lipase, on the foamability and surface coverage of the lipase. The study demonstrated that the lipase allowed for a dry, solid foam with a foam overrun of up to 2600 %. The wall thickness of the dry, solid foam was estimated to be 20-50 µm. Clear differences between sucrose and trehalose as matrix former were identified. The lipase showed no tendency to lose activity because of the drying and rehydration, despite a proportion of the lipase covering the surfaces of the dry material.

Lysozyme-Sucrose Interactions in the Solid State: Glass Transition, Denaturation, and the Effect of Residual Water.

The freeze-drying of proteins, along with excipients, offers a solution for increasing the shelf-life of protein pharmaceuticals. Using differential scanning calorimetry, thermogravimetric analysis, sorption calorimetry, and synchrotron small-angle X-ray scattering (SAXS), we have characterized the properties at low (re)hydration levels of the protein lysozyme, which was freeze-dried together with the excipient sucrose. We observe that the residual moisture content in these samples increases with the addition of lysozyme. This results from an increase in equilibrium water content with lysozyme concentration at constant water activity. Furthermore, we also observed an increase in the glass transition temperature (Tg) of the mixtures with increasing lysozyme concentration. Analysis of the heat capacity step of the mixtures indicates that lysozyme does not participate in the glass transition of the sucrose matrix; as a result, the observed increase in the Tg of the mixtures is the consequence of the confinement of the amorphous sucrose domains in the interstitial space between the lysozyme molecules. Sorption calorimetry experiments demonstrate that the hydration behavior of this formulation is similar to that of the pure amorphous sucrose, while the presence of lysozyme only shifts the sucrose transitions. SAXS analysis of amorphous lysozyme-sucrose mixtures and unfolding of lysozyme in this environment show that prior to unfolding, the size and shape of lysozyme in a solid sucrose matrix are consistent with its native state in an aqueous solution. The results obtained from our study will provide a better understanding of the low hydration behavior of protein-excipient mixtures and support the improved formulation of biologics.

Development of an All-Marine 3D Printed Bioactive Hydrogel Dressing for Treatment of Hard-to-Heal Wounds.

Current standard wound care involves dressings that provide moisture and protection; however, dressings providing active healing are still scarce and expensive. We aimed to develop an ecologically sustainable 3D printed bioactive hydrogel-based topical wound dressing targeting healing of hard-to-heal wounds, such as chronic or burn wounds, which are low on exudate. To this end, we developed a formulation composed of renewable marine components; purified extract from unfertilized salmon roe (heat-treated X, HTX), alginate from brown seaweed, and nanocellulose from tunicates. HTX is believed to facilitate the wound healing process. The components were successfully formulated into a 3D printable ink that was used to create a hydrogel lattice structure. The 3D printed hydrogel showed a HTX release profile enhancing pro-collagen I alpha 1 production in cell culture with potential of promoting wound closure rates. The dressing has recently been tested on burn wounds in Göttingen minipigs and shows accelerated wound closure and reduced inflammation. This paper describes the dressings development, mechanical properties, bioactivity, and safety.

Examination of the Protein Drug Supply Chain in a Swedish University Hospital: Focus on Handling Risks and Mitigation Measures.

Protein drugs, such as monoclonal antibodies, have proved successful in treating cancer and immune system diseases. The structural complexity of these molecules requires careful handling to ensure integrity and stability of the drug. In this study, a failure mode and effects analysis was performed based on a Gemba Walk method in a Swedish University Hospital. The Gemba Walk is focused on pharmacists observing the actual supply process steps from distributor, pharmacy cleanroom to patient administration. Relevant protein drugs are chosen based on sales statistics within the hospital and the corresponding wards were observed. Further is the Double Diamond design method used to identify major risks and deliver mitigation strategies. The study identified potential stress factors such as temperature, shock by impact, shaking, vibration and light exposure. There were also risks associated with porters' and healthcare professionals' lack of awareness and access to information. These risk factors may cause loss of efficacy and quality of the protein drug, potentially leading to patient safety concerns. In this study, a simulation is also performed to list measures that theoretically should be in place to ensure the quality of the protein drug, for example validated and protocol-based compounding in cleanroom, training and validated transports.

Temperature and Heat Transfer Control During Freeze Drying. Effect of Vial Holders and Influence of Pressure.

OBJECTIVE: A common issue of freeze drying is the inhomogeneity between samples, both in regards to water content and structure. The purpose of this study is to address this issue, and try to understand the cause of inhomogeneity in the heat transfer and sample temperature. METHODS: The temperature and the heat transfer was measured using different setups, both with and without vial holders at various positions at different shelf temperature and chamber pressures. By comparing sublimation rate measurements (water sample) with temperature equilibrium measurements with a non-evaporating liquid (oil sample), the heat transfer contribution from radiation and conduction could be separated and investigated individually. RESULTS: The oil sample temperature increases each time the pressure is decreased; the increase is highest at lower shelf temperatures. Using vial holder reduces the deviation between the samples but have limited effect on the temperature increase. The sublimation rate for water sample is pressure dependent and samples close to the walls have a higher sublimation rate than vials in the center. The sublimation rate increases slightly when using a vial holder but the deviation between vials becomes more random. CONCLUSIONS: The heat transfer consists of conduction through rectified vapor and radiation from surrounding walls, about 65-75% of the heat is transferred by conduction and 25-35% by radiation under normal operational conditions. As the vial holder is also influenced by the radiation, the vial inside the holder is indirectly affected by the surrounding radiation.

Influence of Cooling Rate on Ice Crystallization and Melting in Sucrose-Water System.

The ice crystallization and melting in systems where the equilibrium state is difficult to reach is one of the growing areas in pharmaceutical freeze-drying research. The quality of the final freeze-dried product depends on the parameters of the cooling step, which affect the ice nucleation and growth. In this paper, we present a DSC study of ice crystallization and melting in a sucrose-water system. Using two different types of thermal cycles, we examine the influence of cooling and heating rates on the thermal behavior of sucrose-water solutions with water contents between 50 and 100 wt%. The DSC results show that low cooling rates provide crystallization at higher temperatures and lead to lower amount of non-freezing water. Consequently, the glass transition and ice melting properties observed upon heating depend on the cooling conditions in the preceding step. Based on the experimental results, we investigate the reasons for the existence of the two steps on DSC heating curves in sucrose-water systems: the glass transition step and the onset of ice melting. We show that diffusion of water can be the limiting factor for ice growth and melting in the sucrose-water system when the amorphous phase is in a liquid state. In particular, when the diffusion coefficient drops below 10-14 m2/sec, the ice crystals growth or melting becomes strongly suppressed even above the glass transition temperature. Understanding the diffusion limitations in the sucrose-water system can be used for the optimization of the freeze-drying protocols for proteins and probiotics.

The role of water in the reversibility of thermal denaturation of lysozyme in solid and liquid states.

Although unfolding of protein in the liquid state is relatively well studied, its mechanisms in the solid state, are much less understood. We evaluated the reversibility of thermal unfolding of lysozyme with respect to the water content using a combination of thermodynamic and structural techniques such as differential scanning calorimetry, synchrotron small and wide-angle X-ray scattering (SWAXS) and Raman spectroscopy. Analysis of the endothermic thermal transition obtained by DSC scans showed three distinct unfolding behaviors at different water contents. Using SWAXS and Raman spectroscopy, we investigated reversibility of the unfolding for each hydration regime for various structural levels including overall molecular shape, secondary structure, hydrophobic and hydrogen bonding interactions. In the substantially dehydrated state below 37 wt% of water the unfolding is an irreversible process and can be described by a kinetic approach; above 60 wt% the process is reversible, and the thermodynamic equilibrium approach is applied. In the intermediate range of water contents between 37 wt% and 60 wt%, the system is phase separated and the thermal denaturation involves two processes: melting of protein crystals and unfolding of protein molecules. A phase diagram of thermal unfolding/denaturation in lysozyme - water system was constructed based on the experimental data.

Hydration enthalpies of amorphous sucrose, trehalose and maltodextrins and their relationship with heat capacities.

The mechanisms of glass transitions and the behavior of small solute molecules in a glassy matrix are some of the most important topics of modern thermodynamics. Water plays an important role in the physical and chemical stability of lyophilized biologics formulations, in which glassy carbohydrates act as cryoprotectants and stabilizers. In this study, sorption calorimetry was used for simultaneous measurements of water activity and the enthalpy of water sorption by amorphous sucrose, trehalose and maltodextrins. Moreover, the heat capacity of these carbohydrates in mixtures with water was measured by DSC in a broad range of water contents. The hydration enthalpies of glassy sucrose, trehalose and maltodextrins are exothermic, and the enthalpy change of water-induced isothermal glass transitions is higher for small molecules. The partial molar enthalpy of mixing of water in slow experiments is about -18 kJ mol-1, but less exothermic in the case of small molecules at fast hydration scan rates. By measuring the heat capacities of disaccharides and maltodextrins as a function of water content, we separated the contributions of carbohydrates and water to the total heat capacities of the mixtures. The combination of these data allowed testing of thermodynamic models describing the hydration-induced glass transitions. The heat capacity changes calculated by the fitting of the hydration enthalpy data for disaccharides are in good agreement with the heat capacity data obtained by DSC, while for maltodextrins, the effect of sub-Tg transitions should be taken into account. Combining the data obtained by different techniques, we found a distinct difference in the behavior of water in glassy polymers compared to that in glassy disaccharides. By understanding the behavior of water in glassy carbohydrates, these results can be used to improve the design of freeze-dried formulations of proteins and probiotics.

A broad spectrum anti-bacterial peptide with an adjunct potential for tuberculosis chemotherapy.

Alternative ways to prevent and treat infectious diseases are needed. Previously, we identified a fungal peptide, NZX, that was comparable to rifampicin in lowering M. tuberculosis load in a murine tuberculosis (TB) infection model. Here we assessed the potential synergy between this cationic host defence peptide (CHDP) and the current TB drugs and analysed its pharmacokinetics. We found additive effect of this peptide with isoniazid and ethambutol and confirmed these results with ethambutol in a murine TB-model. In vivo, the peptide remained stable in circulation and preserved lung structure better than ethambutol alone. Antibiotic resistance studies did not induce mutants with reduced susceptibility to the peptide. We further observed that this peptide was effective against nontuberculous mycobacteria (NTM), such as M. avium and M. abscessus, and several Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus. In conclusion, the presented data supports a role for this CHDP in the treatment of drug resistant organisms.

Freeze-dried cake structural and physical heterogeneity in relation to freeze-drying cycle parameters.

Freeze-drying is the preferred method to manufacture proteins in their solid state thus the understanding of the relationship between cycle parameters and cake properties remains of great interest. The present study aims to investigate the influence of the freezing conditions in the material properties at different layers throughout the dried structure, in the presence and absence of a protein. Placebo and protein formulations were dried applying different cooling rates: slow, fast and fast cooling with annealing. Non-uniform visual cake appearance, different pore sizes and endothermic events for release of structural water were observed throughout the cake at different freezing rates indicating heterogeneous properties of the dried material likely due to heating gradients during freezing. However, annealing increased the crystallinity and eliminated material inhomogeneities across the cake. The crystalline phase was mainly comprised of δ and hemihydrate mannitol (MHH) distributed at different ratios and influenced by the presence of the protein. The undesired formation of MHH is associated to currently used freezing temperatures or amorphous to crystalline material ratios. Thus, the correlation between the freezing step parameters and resulting material structure is a step forward to provide a better understanding of the freeze-dried cake formation and product quality improvement.

Hydration-Induced Structural Changes in the Solid State of Protein: A SAXS/WAXS Study on Lysozyme.

The stability of biologically produced pharmaceuticals is the limiting factor to various applications, which can be improved by formulation in solid-state forms, mostly via lyophilization. Knowledge about the protein structure at the molecular level in the solid state and its transition upon rehydration is however scarce, and yet it most likely affects the physical and chemical stability of the biological drug. In this work, synchrotron small- and wide-angle X-ray scattering (SWAXS) are used to characterize the structure of a model protein, lysozyme, in the solid state and its structural transition upon rehydration to the liquid state. The results show that the protein undergoes distortion upon drying to adopt structures that can continuously fill the space to remove the protein-air interface that may be formed upon dehydration. Above a hydration threshold of 35 wt %, the native structure of the protein is recovered. The evolution of SWAXS peaks as a function of water content in a broad range of concentrations is discussed in relation to the structural changes in the protein. The findings presented here can be used for the design and optimization of solid-state formulations of proteins with improved stability.

Freeze-dried and re-hydrated liquid crystalline nanoparticles stabilized with disaccharides for drug-delivery of the plectasin derivative AP114 antimicrobial peptide.

Liquid crystalline nanoparticles (LCNPs), e.g. cubosomes and hexosomes, are receiving more and more attraction as drug delivery vehicles. Dry powder formulation that forms LCNPs upon hydration can be advantageous to make new routes of administration accessible. In this work, we investigate use of three disaccharides (lactose, trehalose and sucrose) as protective matrices for glycerol monooleate based LCNP forming powders produced by freeze-drying. Phase behavior, particle size and size distributions at the different preparation steps were monitored by small angle x-ray scattering (SAXS) and dynamic light scattering (DLS). Particle appearance was imaged by cryogenic transmission electron microscopy (cryo-TEM). Moreover, the therapeutic relevant antimicrobial peptide AP114 (plectasin derivative) was incorporated in the formulations. Peptide encapsulation and release as well as in vitro antibacterial effect were investigated. Results showed that all freeze-dried powders did form particles with liquid crystalline structure upon hydration. However, a phase transition from the bicontinuous cubic Pn3m to the reversed hexagonal was observed, as a consequence of sugar addition and the freeze-drying procedure. Data indicates that trehalose is the preferred choice of lyo-protectant in order to maintain a mono-modal particle size distribution. In addition, antimicrobial activity of AP114-containing formulations was found to be highest for the formulation containing trehalose. The release kinetics of AP114 from the nanoparticles was strongly affected by the dimensions of the hexagonal phase. Larger dimension of the hexagonal phase, significantly improved the release of AP114 and antimicrobial activity of the formulation.

Milling induced amorphisation and recrystallization of α-lactose monohydrate.

Preprocessing of pharmaceutical powders is a common procedure to condition the materials for a better manufacturing performance. However, such operations may induce undesired material properties modifications when conditioning particle size through milling, for example. Modification of both surface and bulk material structure will change the material properties, thus affecting the processability of the powder. Hence it is essential to control the material transformations that occur during milling. Topographical and mechanical changes in surface properties can be a preliminary indication of further material transformations. Therefore a surface evaluation of the α-lactose monohydrate after short and prolonged milling times has been performed. Unprocessed α-lactose monohydrate and spray dried lactose were evaluated in parallel to the milled samples as reference examples of the crystalline and amorphous lactose structure. Morphological differences between unprocessed α-lactose, 1 h and 20 h milled lactose and spray dried lactose were detected from SEM and AFM images. Additionally, AFM was used to simultaneously characterize particle surface amorphicity by measuring energy dissipation. Extensive surface amorphicity was detected after 1 h of milling while prolonged milling times showed only a moderate particle surface amorphisation. Bulk material characterization performed with DSC indicated a partial amorphicity for the 1 h milled lactose and a fully amorphous thermal profile for the 20 h milled lactose. The temperature profiles however, were shifted somewhat in the comparison to the amorphous reference, particularly after extended milling, suggesting a different amorphous state compared to the spray-dried material. Water loss during milling was measured with TGA, showing lower water content for the lactose amorphized through milling compared to spray dried amorphous lactose. The combined results suggest a surface-bulk propagation of the amorphicity during milling in combination with a different amorphous structural conformation to that of the amorphous spray dried lactose. The hardened surface may be due to either surface crystallization of lactose or to formation of a low-water glass transition.

AFM Colloidal Probe Measurements Implicate Capillary Condensation in Punch-Particle Surface Interactions during Tableting.

Adhesion of the powders to the punches is a common issue during tableting. This phenomenon is known as sticking and affects the quality of the manufactured tablets. Defective tablets increase the cost of the manufacturing process. Thus, the ability to predict the tableting performance of the formulation blend before the process is scaled-up is important. The adhesive propensity of the powder to the tableting tools is mostly governed by the surface-surface adhesive interactions. Atomic force microscopy (AFM) colloidal probe is a surface characterization technique that allows the measurement of the adhesive interactions between two materials of interest. In this study, AFM steel colloidal probe measurements were performed on ibuprofen, MCC (microcrystalline cellulose), α-lactose monohydrate, and spray-dried lactose particles as an approach to modeling the punch-particle surface interactions during tableting. The excipients (lactose and MCC) showed constant, small, attractive, and adhesive forces toward the steel surface after a repeated number of contacts. In comparison, ibuprofen displayed a much larger attractive and adhesive interaction increasing over time both in magnitude and in jump-in/jump-out separation distance. The type of interaction acting on the excipient-steel interface can be related to a van der Waals force, which is relatively weak and short-ranged. By contrast, the ibuprofen-steel interaction is described by a capillary force profile. Even though ibuprofen is not highly hydrophilic, the relatively smooth surfaces of the crystals allow "contact flooding" upon contact with the steel probe. Capillary forces increase because of the "harvesting" of moisture-due to the fast condensation kinetics-leaving a residual condensate that contributes to increase the interaction force after each consecutive contact. Local asperity contacts on the more hydrophilic surface of the excipients prevent the flooding of the contact zone, and there is no such adhesive effect under the same ambient conditions. The markedly different behavior detected by force measurements clearly shows the sticky and nonsticky propensity of the materials and allows a mechanistic description.

Porous calcium carbonate as a carrier material to increase the dissolution rate of poorly soluble flavouring compounds.

Two different food grade functionalised porous calcium carbonates (FCC), with different pore size and pore size distributions, were characterised and used as carrier materials to increase the dissolution rate of poorly soluble flavouring compounds in aqueous solution. The loading level was varied between 1.3% by weight (wt%) and 35 wt%, where the upper limit of 35 wt% was the total maximum loading capacity of flavouring compound in FCC based on the fraction of the total weight of FCC plus flavouring compound. Flavouring compounds (l-carvone, vanillin, and curcumin) were selected based on their difference in hydrophilicity and capacity to crystallise. Release kinetic studies revealed that all flavouring compounds showed an accelerated release when loaded in FCC compared to dissolution of the flavouring compound itself in aqueous medium. The amorphous state and/or surface enlargement of the flavouring compound inside or on FCC explains the faster release. The flavouring compounds capable of crystallising (vanillin and curcumin) were almost exclusively amorphous within the porous FCC material as determined by X-ray powder diffraction one week after loading and after storing the loaded FCC material for up to 9 months at room temperature. A small amount of crystalline vanillin and curcumin was detected in the FCC material with large pores and high flavouring compound loading (≥30 wt%). Additionally, two different loading strategies were evaluated, loading by dissolving the flavouring compound in acetone or loading by a hot melt method. Porosimetry data showed that the melt method was more efficient in filling the smallest pores (<100 nm). The main factor influencing the release rate appears to be the amorphous state of the flavouring compound and the increase in exposed surface area. The confinement in small pores prevents crystallisation of the flavouring compounds during storage, providing a stable amorphous form retaining high release rate also after storage.

Determination of Interfacial Amorphicity in Functional Powders.

The nature of the surfaces of particles of pharmaceutical ingredients, food powders, and polymers is a determining factor for their performance in for example tableting, powder handling, or mixing. Changes on the surface structure of the material will impact the flow properties, dissolution rate, and tabletability of the powder blend. For crystalline materials, surface amorphization is a phenomenon which is known to impact performance. Since it is important to measure and control the level of amorphicity, several characterization techniques are available to determine the bulk amorphous content of a processed material. The possibility of characterizing the degree of amorphicity at the surface, for example by studying the mechanical properties of the particles' surface at the nanoscale, is currently only offered by atomic force microscopy (AFM). The AFM PeakForce QNM technique has been used to measure the variation in energy dissipation (eV) at the surface of the particles which sheds light on the mechanical changes occurring as a result of amorphization or recrystallization events. Two novel approaches for the characterization of amorphicity are presented here. First, since particles are heterogeneous, we present a methodology to present the results of extensive QNM analysis of multiple particles in a coherent and easily interpreted manner, by studying cumulative distributions of dissipation data with respect to a threshold value which can be used to distinguish the crystalline and amorphous states. To exemplify the approach, which is generally applicable to any material, reference materials of purely crystalline α-lactose monohydrate and completely amorphous spray dried lactose particles were compared to a partially amorphized α-lactose monohydrate sample. Dissipation data are compared to evaluations of the lactose samples with conventional AFM and SEM showing significant topographical differences. Finally, the recrystallization of the surface amorphous regions in response to humidity was followed by studying the dissipation response of a well-defined surface region over time, which confirms both that dissipation measurement is a useful measure of surface amorphicity and that significant recrystallization occurs at the surface in response to humidity.

Phase Segregation in Individually Dried Particles Composed of Biopolymers.

Mixing of two biopolymers can results in phase separation due to their thermodynamically incompatibility under certain conditions. This phenomenon was first reported when the solution was allowed to equilibrate, but it has later been observed also as a consequence of drying. The challenges of this study were to observe phase segregation by confocal Raman microscopy and LV-SEM on dried film, individually dried particles, and spray dried particles. The influence of the solid content and the phase ratio (composition) of a HPMC/maltodextrin mixture on the localization of the ingredients in the individually dried particles was investigated. We observed that phase segregation of HPMC and maltodextrin is induced by solvent evaporation in film drying, single particle drying, as well as spray drying. The phase ratio is an important parameter that influences the localization of the HPMC-enriched phase and maltodextrin-enriched phase, i.e., to the particle surface, to the core, or in a more or less bicontinuous pattern. The drying time, affected by the solids content, was found to control the level of advancement of the phase segregation.

Tablet mechanics depend on nano and micro scale adhesion, lubrication and structure.

Tablets are the most convenient form for drug administration. However, despite the ease of manufacturing problems such as powder adhesion occur during the production process. This study presents surface and structural characterization of tablets formulated with commonly used excipients (microcrystalline cellulose (MCC), lactose, mannitol, magnesium (Mg) stearate) pressed under different compaction conditions. Tablet surface analyses were performed with scanning electron microscopy (SEM), profilometry and atomic force microscopy (AFM). The mechanical properties of the tablets were evaluated with a tablet hardness test. Local adhesion detected by AFM decreased when Mg stearate was present in the formulation. Moreover, the tablet strength of plastically deformable excipients such as MCC was significantly decreased after addition of Mg stearate. Combined these facts indicate that Mg stearate affects the particle-particle bonding and thus elastic recovery. The MCC excipient also displayed the highest hardness which is characteristic for a highly cohesive material. This is discussed in the view of the relatively high adhesion found between MCC and a hydrophilic probe at the nanoscale using AFM. In contrast, the tablet strength of brittle materials like lactose and mannitol is unaffected by Mg stearate. Thus fracture occurs within the excipient particles and not at particle boundaries, creating new surfaces not previously exposed to Mg stearate. Such uncoated surfaces may well promote adhesive interactions with tools during manufacture.