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.

Construction of GSH-responsive polyethyleneimine-based delivery vector for effective gene transfection.

The rise of gene therapy has solved many diseases that cannot be effectively treated by conventional methods. Gene vectors is very important to protect and deliver the therapeutic genes to the target site. Polyethyleneimine (PEI) modified with mannitol could enhance the gene transfection efficiency reported by our group previously. In order to further control and improve the effective gene release to action site, disulfide bonds were introduced into mannitol-modified PEI to construct new non-viral gene vectors PeiSM. The degrees of mannitol linking with disulfide bonds were screened. Among them, moderate mannitol-modified PEI with disulfide bonds showed the best transfection efficiency, and significantly enhanced long-term systemic transgene expression for 72 hin vivoeven at a single dose administration, and could promote caveolae-mediated uptake through up-regulating the phosphorylation of caveolin-1 and increase the loaded gene release from the nanocomplexes in high glutathione intracellular environment. This functionalized gene delivery system can be used as an potential and safe non-viral nanovector for further gene therapy.

Cryomilled electrospun nanofiber mats containing d-mannitol exhibit suitable for aerosol delivery of proteins.

Dry powder inhalers (DPIs) are the first choice for inhalation drug development. However, some conventional DPI formulation processes require heating, which may damage high molecular weight drugs such as proteins and nucleic acids. In this study, we propose a novel DPI preparation process that avoids the use of heat. Dry powders were prepared by cryomilling nanofiber mats composed of polyvinyl alcohol, D(-)-mannitol (Man), and α-chymotrypsin (α-Chy) as the model drug using the electrospinning method. The addition of Man conferred high dispersibility and excellent in vitro aerosol performance to the nanofiber mat powder in a very short milling time (less than 0.5 min) as assessed using the Andersen cascade impactor. Powders were classified according to the degree of friability, and among these, nanofiber mats containing 15 % Man and milled for 0.25 min exhibited the highest aerosol performance. Nanofiber mats containing Man milled for less than 0.5 min also exhibited greater α-Chy enzymatic activity than a nebulized α-Chy solution. Furthermore, single inhalation induced no significant lung tissue damage as evidenced by lactate dehydrogenase activity assays of mouse bronchoalveolar lavage fluid. This novel DPI formulation process may facilitate the safe and efficient inhalational delivery of therapeutic proteins.

Riboflavin overproduction from diverse feedstocks with engineeredCorynebacterium glutamicum.

Riboflavin overproduction byCorynebacterium glutamicumwas achieved by screening synthetic operons, enabling fine-tuned expression of the riboflavin biosynthetic genesribGCAH.The synthetic operons were designed by means of predicted translational initiation rates of each open reading frame, with the best-performing selection enabling riboflavin overproduction without negatively affecting cell growth. Overexpression of the fructose-1,6-bisphosphatase (fbp) and 5-phosphoribosyl 1-pyrophosphate aminotransferase (purF) encoding genes was then done to redirect the metabolic flux towards the riboflavin precursors. The resulting strain produced 8.3 g l-1of riboflavin in glucose-based fed-batch fermentations, which is the highest reported riboflavin titer withC. glutamicum. Further genetic engineering enabled both xylose and mannitol utilization byC. glutamicum, and we demonstrated riboflavin overproduction with the xylose-rich feedstocks rice husk hydrolysate and spent sulfite liquor, and the mannitol-rich feedstock brown seaweed hydrolysate. Remarkably, rice husk hydrolysate provided 30% higher riboflavin yields compared to glucose in the bioreactors.

Mannitol-coated hydroxypropyl methylcellulose as an alternative directly compressible controlled release excipient.

One of the most common forms of controlled release technology for oral drug delivery comprises an active ingredient dispersed in a hydrophilic matrix forming polymer such as hydroxypropyl methylcellulose (HPMC), which is tableted via direct compression. However, HPMC may pose problems in direct compression due to its poor flowability. Hence, mannitol syrup was spray-coated over fluidized HPMC particles to produce co-processed HPMC-mannitol at ratios of 20:80, 50:50, and 70:30. Particles of pure HPMC, co-processed HPMC-mannitol, and their respective physical mixtures were evaluated for powder flowability, compression profiles, and controlled release performance. It was found that co-processed HPMC-mannitol consisted of particles with improved flow compared to pure HPMC particles. Sufficiently strong tablets of >2 MPa could be produced at moderate to high compression forces of 150-200 MPa. The dissolution profile could be tuned to obtain desired release profiles by altering HPMC-mannitol ratios. Co-processed HPMC-mannitol offers an interesting addition to the formulator's toolbox in the design of controlled release formulations for direct compression.

Development of Robust Freeze-Drying Process for Long-Term Stability of rVSV-SARS-CoV-2 Vaccine.

The thermostability of vaccines, particularly enveloped viral vectored vaccines, remains a challenge to their delivery wherever needed. The freeze-drying of viral vectored vaccines is a promising approach but remains challenging due to the water removal process from the outer and inner parts of the virus. In the case of enveloped viruses, freeze-drying induces increased stress on the envelope, which often leads to the inactivation of the virus. In this study, we designed a method to freeze-dry a recombinant vesicular stomatitis virus (VSV) expressing the SARS-CoV-2 spike glycoprotein. Since the envelope of VSV is composed of 50% lipids and 50% protein, the formulation study focused on both the protein and lipid portions of the vector. Formulations were prepared primarily using sucrose, trehalose, and sorbitol as cryoprotectants; mannitol as a lyoprotectant; and histidine as a buffer. Initially, the infectivity of rVSV-SARS-CoV-2 and the cake stability were investigated at different final moisture content levels. High recovery of the infectious viral titer (~0.5 to 1 log loss) was found at 3-6% moisture content, with no deterioration in the freeze-dried cakes. To further minimize infectious viral titer loss, the composition and concentration of the excipients were studied. An increase from 5 to 10% in both the cryoprotectants and lyoprotectant, together with the addition of 0.5% gelatin, resulted in the improved recovery of the infectious virus titer and stable cake formation. Moreover, the secondary drying temperature of the freeze-drying process showed a significant impact on the infectivity of rVSV-SARS-CoV-2. The infectivity of the vector declined drastically when the temperature was raised above 20 °C. Throughout a long-term stability study, formulations containing 10% sugar (sucrose/trehalose), 10% mannitol, 0.5% gelatin, and 10 mM histidine showed satisfactory stability for six months at 2-8 °C. The development of this freeze-drying process and the optimized formulation minimize the need for a costly cold chain distribution system.

Synergistic Therapeutic Effects of D-Mannitol-Cerium-Quercetin (Rutin) Coordination Polymer Nanoparticles on Acute Lung Injury.

Acute lung injury (ALI) remains a significant global health issue, necessitating novel therapeutic interventions. In our latest study, we pioneered the use of D-mannitol-cerium-quercetin/rutin coordination polymer nanoparticles (MCQ/R NPs) as a potential treatment for ALI. The MCQ/R NPs, which integrate rutin and quercetin for their therapeutic potential and D-mannitol for its pulmonary targeting, displayed exceptional efficacy. By utilizing cerium ions for optimal nanoparticle assembly, the MCQ/R NPs demonstrated an average size of less than 160 nm. Impressively, these nanoparticles outperformed conventional treatments in both antioxidative capabilities and biocompatibility. Moreover, our in vivo studies on LPS-induced ALI mice showed a significant reduction in lung tissue inflammation. This groundbreaking research presents MCQ/R NPs as a promising new approach in ALI therapeutics.

Design of easily swallowable xerogel pill with enough physical strength through hardening-process under heating and humidification.

The xerogel pill has been developed as a novel dosage form with dose-adjusting and swallow-assisting functions by using drop freeze-drying (DFD) technique. It was double-structured small sphere composed of an inner drug core and an outer dried-gel layer, however, had problem of insufficient physical strength. In this study, it was attempted to use dextrin (DEX), one of oligosaccharides, to strengthen the xerogel pill. DEX was co-dissolved in the dropping fluid in the DFD process and co-loaded in the conventional pill, which was mainly composed of mannitol (MNT) as a filler, to prepare the rigid body. DEX-loaded pill could be successfully prepared with high recovery (>90 %) by optimizing the ratio of DEX and MNT. Further, the representative pills with and without DEX (P-DEX and P-MNT, respectively) were hardening-processed under humidification. The physical strength of P-DEX pill was significantly increased when humidified under severe condition, resulting in enough hardness (>5N) and friability (<1.0 %). Processed P-DEX was found to have dense structure covered with a thick outer shell, which would be formed by interparticle bridge of DEX. It was also found that processed P-DEX pill suppressed initial drug dissolution significantly and exhibited sustained dissolution behavior, suggesting the potential function of bitter taste masking. Processed P-DEX pill had excellent sliding behavior with low friction forces as a result of lubricant effect of xanthan gum (XG) surrounding the pills. Furthermore, the sliding test also suggested that processed P-DEX pill had hard candy-like texture, in contrast unprocessed P-DEX pill had orally disintegrating (OD) tablet-like texture. Various xerogel pills with such different swallowing texture would have a potential to accommodate the children's preferences when taking medication.

Specific surface area of mannitol rather than particle size dominant the dissolution rate of poorly water-soluble drug tablets: A study of binary mixture.

The dissolution behavior of tablets, particularly those containing poorly water-soluble drugs, is a critical factor in determining their absorption and therapeutic efficacy. Traditionally, the particle size of excipients has been considered a key property affecting tablet dissolution. However, lurasidone hydrochloride (LH) tablets prepared by similar particle size mannitol, namely M200 (D90 = 209.68 ± 1.42 µm) and 160C (D90 = 195.38 ± 6.87 µm), exhibiting significant differences in their dissolution behavior. In order to find the fundamental influential factors of mannitol influencing the dissolution of LH tablets, the properties (particle size, water content, true density, bulk density, tapped density, specific surface area, circularity, surface free energy, mechanical properties and flowability) of five grades mannitol including M200 and 160C were investigated. Principal component analysis (PCA) was used to establish a relationship between mannitol properties and the dissolution behavior of LH. The results demonstrated that specific surface area (SSA) emerged as the key property influencing the dissolution of LH tablets. Moreover, our investigation based on the percolation theory provided further insights that the SSA of mannitol influences the probability of LH-LH bonding and LH infinite cluster formation, resulting in the different percolation threshold states, then led to different dissolution behaviors. Importantly, it is worth noting that these findings do not invalidate previous conclusions, as reducing particle size generally increases SSA, thereby affecting the percolation threshold and dissolution behavior of LH. Instead, this study provides a deeper understanding of the underlying role played by excipient SSA in the dissolution of drug tablets. This study provides valuable guidance for the development of novel excipients aimed at improving drug dissolution functionality.

Spray freeze dried cannabidiol with dipalmitoylphosphatidylcholine (DPPC) for inhalation and solubility enhancement.

Pulmonary delivery is an efficient route of administration to deliver cannabidiol (CBD) due to the high bioavailability and fast onset of action. The major formulation challenge is the poor aqueous solubility of CBD. This study aimed to produce inhalable CBD powders with enhanced solubility and characterise their solid-state properties. CBD was spray freeze dried with mannitol or trehalose dihydrate with and without dipalmitoylphosphatidylcholine (DPPC). All four powders had acceptable yields at > 70 % with porous and spherical particles. The two crystalline mannitol powders contained less residual solvent than both amorphous trehalose ones. The addition of DPPC did not affect the crystallinity and residual solvent level of the powders. Instead, DPPC made the particles more porous, decreased the particle size from 19-23 µm to 11-13 µm, and increased CBD solubility from 0.36 µg/mL to over 2 µg/mL. The two DPPC powders were dispersed from a low resistance RS01 inhaler, showing acceptable aerosol performance with emitted fractions at 91-93 % and fine particle fractions < 5 µm at 34-43 %. These formulations can be used as a platform to deliver CBD and other cannabinoids by inhalation.

Development of novel 3D printable inks for protein delivery.

The application of 3D printing technology in the delivery of macromolecules, such as proteins and enzymes, is limited by the lack of suitable inks. In this study, we report the development of novel inks for 3D printing of constructs containing proteins while maintaining the activity of the proteins during and after printing. Different ink formulations containing Pluronic F-127 (20-35 %, w/v), trehalose (2-10 %, w/v) or mannitol, poly (ethylene glycol) diacrylate (PEGDA) (0 or 10 %, w/w), and diphenyl(2,4,6-trimethylbenzoyl) phosphine oxide (TPO, 0 or 0.2 mg/mL) were prepared for 3D-microextrusion printing. The F2 formulation that contained ß-galactosidase (ß-gal) as a model enzyme, Pluronic F-127 (30 %), and trehalose (10 %) demonstrated the desired viscosity, printability, and dose flexibility. The shear-thinning property of the F2 formulation enabled the printing of ß-gal containing constructs with a good peak force during extrusion. After 3D printing, the enzymatic activity of the ß-gal in the constructs was maintained for an extended period, depending on the construct design and storage conditions. For instance, there was a 50 % reduction in ß-gal activity in the two-layer constructs, but only a 20 % reduction in the four-layer construct (i.e., 54.5 ± 1.2 % and 82.7 ± 9.9 %, respectively), after 4 days of storage. The ß-gal activity in constructs printed from the F2 formulation was maintained for up to 20 days when stored in sealed bags at room temperatures (21 ± 2 °C), but not when stored unsealed in the same conditions (e.g., ∼60 % activity loss within 7 days). The ß-gal from constructs printed from F2 started to release within 5 min and reached 100 % after 20 min. With the design flexibility offered by the 3D printing, the ß-gal release from the constructs was delayed to 3 h by printing a backing layer of ß-gal-free F5 ink on the constructs printed from the F2 ink. Finally, ovalbumin as an alternative protein was also incorporated in similar ink compositions. Ovalbumin exhibited a release profile like that of the ß-gal, and the release can also be modified with different shape design and/or ink composition. In conclusion, ink formulations that possess desirable properties for 3D printing of protein-containing constructs while maintaining the protein activity during and after printing were developed.

Coupling protein scaffold and biosilicification: A sustainable and recyclable approach for d-mannitol production via one-step purification and immobilization of multienzymes.

Enzymatic synthesis of biochemicals in vitro is vital in synthetic biology for its efficiency, minimal by-products, and easy product separation. However, challenges like enzyme preparation, stability, and reusability persist. Here, we introduced a protein scaffold and biosilicification coupled system, providing a singular process for the purification and immobilization of multiple enzymes. Using d-mannitol as a model, we initially constructed a self-assembling EE/KK protein scaffold for the co-immobilization of glucose dehydrogenase and mannitol dehydrogenase. Under an enzyme-to-scaffold ratio of 1:8, a d-mannitol yield of 0.692 mol/mol was achieved within 4 h, 2.16-fold higher than the free enzymes. The immobilized enzymes retained 70.9 % of the initial joint activity while the free ones diminished nearly to inactivity after 8 h. Furthermore, we incorporated the biosilicification peptide CotB into the EE/KK scaffold, inducing silica deposition, which enabled the one-step purification and immobilization process assisted by Spy/Snoop protein-peptide pairs. The coupled system demonstrated a comparable d-mannitol yield to that of EE/KK scaffold and 1.34-fold higher remaining activities after 36 h. Following 6 cycles of reaction, the immobilized system retained the capability to synthesize 56.4 % of the initial d-mannitol titer. The self-assembly co-immobilization platform offers an effective approach for enzymatic synthesis of d-mannitol and other biochemicals.

Lyophilised protein formulations as a patient-centric dosage form: A contribution toward sustainability paradigm.

At present, society has embraced the fact apropos population aging and climate changes, that demand, amongst others, innovative pharmaceutical technologies, emphasising the development of patient-specific delivery systems and thus the provision of efficient and sustainable drugs. Protein drugs for subcutaneous administration, by allowing less frequent application, represent one of the most important parts of the pharmaceutical field, but their development is inevitably faced with obstacles in providing protein stability and suitable formulation viscosity. To gain further knowledge and fill the gaps in the already constructed data platform for the development of monoclonal antibody formulations, we designed a study that examines small model proteins, i.e., bovine serum albumin. The main aim of the presented work is to evaluate the effect of protein concentrations on critical quality attributes of both, pre-lyophilised liquid formulations, and lyophilised products. Through the study, the hypothesis that increasing protein concentration leads to higher viscosity and higher reconstitution time without affecting the stability of the protein was confirmed. The most important finding is that sucrose plays a key role in the lyophilisation of investigated protein, nevertheless, it can be predicted that, to ensure the beneficial effect of mannitol, its amount has to prevail over the amount of sucrose.

The effect of unloading and ejection conditions on the properties of pharmaceutical tablets.

This study investigates decompression and ejection conditions on tablet characteristics by comparing compact densities and tensile strengths made using regular rigid dies and custom-built die systems that enable triaxial decompression. Die-wall pressure evolution during decompression and ejection stresses did not meaningfully impact the density and tensile strength of the materials tested: microcrystalline cellulose, crystalline lactose monohydrate, and mannitol. Furthermore, the apparent differences in tensile strength between rectangular cuboids and cylindrical compacts are unrelated to decompression and ejection conditions, but rather a consequence of their shapes and of the test configurations. This suggests that elastic and plastic deformations that may occur during decompression and ejection are not significantly influenced by die-wall pressure evolution. We thus conclude that while triaxial decompression and constraint-free ejection may allow the production of defect-free compacts for materials that otherwise are defect prone using a rigid die, they seem to pose no benefits when the materials already produce defect-free compacts using a rigid die.

Tableting behavior of freeze and spray-dried excipients in pharmaceutical formulations.

Most of biopharmaceuticals, in their liquid form, are prone to instabilities during storage. In order to improve their stability, lyophilization is the most commonly used drying technique in the pharmaceutical industry. In addition, certain applications of biopharmaceutical products can be considered by oral administration and tablets are the most frequent solid pharmaceutical dosage form used for oral route. Thus, the tableting properties of freeze-dried products used as cryo and lyoprotectant could be a key element for future pharmaceutical developments and applications. In this study, we investigated the properties that might play a particular role in the specific compaction behavior of freeze-dried excipients. The tableting properties of freeze-dried trehalose, lactose and mannitol were investigated and compared to other forms of these excipients (spray-dried, commercial crystalline and commercial crystalline milled powders). The obtained results showed a specific behavior in terms of compressibility, tabletability and brittleness for the amorphous powders obtained after freeze-drying. The comparison with the other powders showed that this specific tableting behavior is linked to both the specific texture and the physical state (amorphization) of these freeze-dried powders.

The Fabrication, Drug Loading, and Release Behavior of Porous Mannitol.

Porous materials are widely used as an effective strategy for the solubilization of insoluble drugs. In order to improve the solubility and bioavailability of low water-solubility drugs, it is necessary to prepare porous materials. Mannitol is one of the most popular excipients in food and drug formulations. In this study, porous mannitol was investigated as a drug carrier for low water solubility drugs. Its fabrication, drug loading, and drug release mechanisms were investigated. Porous mannitol was fabricated using the co-spray-antisolvent process and utilizing polyvinylpyrrolidone K30 (PVP K30) as the template agent. Porous mannitol particles were prepared by changing the proportion of the template agent, spraying the particles with mannitol, and eluting with ethanol in order to regulate their pore structure. In subsequent studies, porous mannitol morphology and characteristics were determined systematically. Furthermore, curcumin and ibuprofen, two poorly water-soluble drugs, were loaded into porous mannitol, and their release profiles were analyzed. The results of the study indicated that porous mannitol can be prepared using PVP K30 as a template and that the amount of template agent can be adjusted in order to control the structure of the porous mannitol. When the template agent was added in amounts of 1%, 3%, and 5%, the mannitol pore size increased by 167.80%, 95.16%, and 163.98%, respectively, compared to raw mannitol. Molecular docking revealed that mannitol and drugs are adsorbents and adhere to each other by force interaction. The cumulative dissolution of curcumin and ibuprofen-loaded porous mannitol reached 69% and 70%, respectively. The release mechanism of curcumin and ibuprofen from drug-loaded mannitol was suitable for the Korsmeyer-Peppas kinetic model. In summary, the co-spray-antisolvent method proved effective in fabricating porous materials rapidly, and porous mannitol had a remarkable effect on drug solubilization. The results obtained are conducive to the development of porous materials.

Effects of freezing and drying programs on IgY aggregation and activity during microwave freeze-drying: Protective effects and interactions of trehalose and mannitol.

The acquisition of high quality lyophilized IgY products, characterized by an aesthetically pleasing visage, heightened stability, and a marked preservation of activity, constitutes an indispensable pursuit in augmenting the safety and pragmatic utility of IgY. Within this context, an exploration was undertaken to investigate an innovative modality encompassing microwave freeze-drying (MFD) as a preparatory methodology of IgY. Morphological assessments revealed that both cryogenic freezing and subsequent MFD procedures resulted in aggregation of IgY, with the deleterious influence posed by the MFD phase transcending that of the freezing phase. The composite protective agent comprised of trehalose and mannitol engendered a safeguarding effect on the structural integrity of IgY, thereby attenuating reducing aggregation between IgY during the freeze-drying process. Enzyme-linked immunosorbent assay (ELISA) outcomes demonstrated a discernible correlation between IgY aggregation and a notable reduction in its binding affinity towards the pertinent antigen. Comparative analysis vis-à-vis the control sample delineated that when the trehalose-to-mannitol ratio was upheld at 1:3, a two-fold outcome was achieved: a mitigation of the collapse susceptibility within the final product as well as a deterrence of IgY agglomeration, concomitant with an elevated preservation rate of active antibodies (78.57 %).

Crystal defects creation in Mannitol@CaCl2 metal-organic framework by induced dehydration strategy for enhanced excipient mechanical properties.

The mechanical properties of solid pharmaceutical excipients are important for assisting drug tables production, and they determine the quality of the drug tablets. The purpose of this study was to explore the potential and mechanism of crystal defect engineering to improve the mechanical properties of Mannitol@CaCl2 MOF, a pharmaceutical excipient with metal-organic framework (MOF) structure designed and prepared in our previous study. In this study, a simple and efficient "induced dehydration strategy" was proposed to prepare Mannitol@CaCl2 MOF with crystal defects (DEMOF). SEM, TEM, HRTEM, PXRD, FTIR, DSC-TGA, and N2 adsorption-desorption isotherm revealed the successful introduction of lattice vacancy and macrostructural defects while preserving MOF's skeleton structure. Tabletability profiles indicated that DEMOF presented much better mechanical properties than the original MOF at the powder level. On single crystal and atomic scales, nanoindentation and DFT calculations revealed that the defect structure increased plasticity, decreased brittleness, and improved compressibility, resulting in DEMOF tablets with much higher tensile strength that met the criteria for direct compression excipients. The achieved performance modification illustrated the capability of defect engineering to tune mechanical properties of MOFs, and the Mannitol@CaCl2 DEMOF exhibited great potential to serve as a new direct compression pharmaceutical excipient.

Understanding the impact of mannitol on physical stability and aerosolization of spray-dried protein powders for inhalation.

Pulmonary delivery of protein-based therapeutics, including antibodies, is a promising option for treating respiratory diseases. Spray drying is a widely used method for producing dry powder formulations with mannitol being a commonly used excipient for these inhalation formulations. There is limited research available concerning the utilization of mannitol as an excipient in the spray drying of proteins and its impact on aerosol performance. This study highlights the importance to understand mannitol's potential role and impact in this context. To investigate the impact of mannitol on physical stability and aerosolization of spray-dried protein formulations, bovine serum albumin (BSA) was employed as a model protein and formulated with different concentrations of mannitol via spray drying. The spray-dried solids were characterized for their particle size using Malvern mastersizer and aerodynamic particle size using next generation impactor (NGI). Additionally, the solids were characterized with solid-state Fourier-transform infrared spectroscopy (ssFTIR), powder X-ray diffraction (PXRD), scanning electron microscopy (SEM) and solid-state nuclear magnetic resonance spectroscopy (ssNMR) to analyze the change in their secondary structure, crystallinity, particle morphology, and protein-excipient interaction, respectively. Size exclusion chromatography (SEC) was used to investigate changes in monomer content resulting from storage under stressed condition of 40 °C. Protein formulations containing more than 33 % mannitol by weight showed crystallization tendencies, causing an increase in monomer loss over time. ssNMR data also showed mixing heterogeneity of BSA and mannitol in the formulations with high mannitol contents. Futhermore, fine particle fraction (FPF) was found to decrease over time for the formulations containing BSA: Mannitol in the ratios of 2:1, 1:2, and 1:5, due to particle agglomeration induced by crystallization of mannitol. This study underscores the significant influence of excipients such as mannitol on the aerosol performance and storage stability of spray-dried protein formulations.

Development of a novel direct compressible co-processed excipient and its application for formulation of Mirtazapine orally disintegrating tablets.

INTRODUCTION: Orally disintegrating tablets (ODTs) are designed to dissolve in the oral cavity within 3 min, providing a convenient option for patients as they can be taken without water. Direct compression is the most common method used for ODTs formulations. However, the availability of single composite excipients with desirable characteristics such as good compressibility, fast disintegration, and a good mouthfeel suitable for direct compression is limited. OBJECTIVE: This research was proposed to develop a co-processed excipient composed of xylitol, mannitol, and microcrystalline cellulose for the formulation of ODTs. METHODS: A total of 11 formulations of co-processed excipients with different ratios of ingredients were prepared, which were then compressed into ODTs, and their characteristics were thoroughly examined. The primary focus was on evaluating the disintegration time and hardness of the tablets, as these factors are important in ensuring the ODTs meet the desired criteria. The model drug, Mirtazapine was then incorporated into the chosen optimized formulation. RESULTS: The results showed that the formulation comprised of 10% xylitol, 10% mannitol and 80% microcrystalline cellulose demonstrated the fastest disintegration time (1.77 ± 0.119 min) and sufficient hardness (3.521 ± 0.143 kg) compared to the other formulations. Furthermore, the drug was uniformly distributed within the tablets and fully released within 15 min. CONCLUSION: Therefore, the developed co-processed excipients show great potential in enhancing the functionalities of ODTs, offering a promising solution to improve the overall performance and usability of ODTs in various therapeutic applications.