Effect of Material Properties and Variability of Mannitol on Tablet Formulation Development.

PURPOSE: Using a high level of mannitol as a diluent in oral formulations can potentially result in tablet defects (e.g., chipping, cracking) during compression. This work aims to scrutinize the linkage between the mechanical properties and material attributes of mannitol and also uncover how variations between vendors and lots can lead to significant changes in the compaction performance of tablet formulations containing mannitol. METHODS: The mechanical properties (Poisson's ratio, fracture energy) and mechanical performance (ejection force, pressure transmission ratio, residual radial die-wall stress, and tensile strength) of mannitol compacts were assessed on a compaction simulator for four lots of mannitol from two different vendors. The variation of material attributes of each lot, including particle size distribution (PSD), crystal form, primary crystal size and morphology, specific surface area (SSA), powder flow, and moisture absorption were investigated. RESULTS: The variability of material attributes in mannitol lots, especially primary crystal size and SSA, can result in significant changes in mechanical properties and mechanical performance such as ejection force and residual radial die-wall stresses, which potentially led to chipping during compression. CONCLUSION: The study elucidated the linkage between fundamental material attributes and mechanical properties of mannitol, highlighting their impact on tablet defects and compaction performance in compression. A comprehensive understanding of the variability in mannitol properties between vendors and lots is crucial for successful formulation development, particularly when high percentages of mannitol are included as a brittle excipient.

A comparative study of applying backscattering and transmission Raman spectroscopy to quantify solid-state form conversion in pharmaceutical tablets.

Selecting appropriate Raman measurement and data processing method are of importance to enable effective quantification of solid form conversions upon processing or storage. Therefore, a comparative evaluation is presented herein on using backscattering and transmission Raman spectroscopy to quantify salt disproportionation in tablet matrices. The second part focuses on different spectra processing approaches and calibration models for quantifications. Finally, samples under different mechanical stresses were comprehensively analyzed using different Raman measurements. Much as transmission Raman spectrometry may provide accuracy on bulk measurements by having large sampling volume, it has the drawback of signal attenuation and may overlook process-induced phase transitions occurring on local regions of tablet surface. To overcome this limitation, backscattering Raman with deliberate subsampling can be used as an orthogonal method to probe the existence of low-level form conversion distributed over a tablet's surface. In the present case, different levels of the form conversions were found at the edge and the center of tablets due to the uneven shear stress distribution invoked during tablet compression. In such a scenario, it would be beneficial to apply deliberate-focused backscattering and transmission Raman spectrometry together as complementary techniques to capture chemical information both locally and within the bulk of the tablet.

Characterization of Spray Dried Particles Through Microstructural Imaging.

Spray drying is commonly used to produce amorphous solid dispersions (ASD) to improve the bioperformance of poorly water-soluble drugs. In this study, imaging techniques such as focused ion beam-scanning electron microscopy (FIB-SEM) and X-ray microcomputed tomography (XRCT) were used to study the microstructure of spray dried (SD) particles. Spray drying at higher outlet temperature (Tout) was found to produce more spherical hollow particles with smooth surface and thinner walls, while more raisin-like particles with thicker walls were generated at lower Tout. For the first time, an artificial intelligence-facilitated XRCT image analysis tool was developed to make quantitative analysis of thousands of particles individually possible. The particle size distribution through XRCT image analysis is generally in line with what is measured by laser diffraction. The image analysis reveals envelope density as a more sensitive physical attribute for process change than conventional bulk/tap density. Further, the tensile strength of SD particle compacts correlates with the particle wall thickness, and this is likely caused by the larger interparticle contact area generated by more deformation of particles with thinner walls. The knowledge gained here can help enable SD particle engineering and drug product with more robust process and optimized performance.

The Effect of Inorganic Salt on Disintegration of Tablets with High Loading of Amorphous Solid Dispersion Containing Copovidone.

PURPOSE: While including amorphous solid dispersion (ASD) in tablet formulations is increasingly common, tablets containing high ASD loading are associated with slow disintegration, which presents a challenge to control pill burden for less potent compounds. METHODS: We use a model ASD, composed of a hydrophobic drug with copovidone and a non-ionic surfactant, to explore formulation options that can prevent slow disintegration. RESULTS: In addition to the ASD loading, the pH of the disintegration medium and the inclusion of inorganic salts in the tablet also have an impact on the tablet disintegration time. Certain kosmotropic salts, when added in the formulation, can significantly accelerate tablet disintegration, though the rank order in their effectiveness does not exactly follow the Hofmeister series at pH 1.8. The particle size and dissolution rate of the salt can contribute to its overall effectiveness. CONCLUSION: We provided a mechanistic explanation of the disintegration process: fast-dissolving kosmotropic salt results in a concentrated salt solution inside the restrained tablet matrix, thus inhibiting the dissolution of copovidone and preventing polymer gelling which is the main cause leading the slow disintegration. The outcome of this study has enabled the design of a higher ASD loading platform formulation for copovidone based ASD. Graphical Abstract MicroCT aids the mechanistic understanding of the role of inorganic salt in the tablet disintegration of amorphous solid dispersion based formulation.

Modeling the Air Pressure Increase Within a Powder Bed During Compression-A Step Toward Understanding Tablet Defects.

The cause of tablet defects, such as cracking, bubbling, and capping, during compression is currently not fully understood. Prior experimental work suggests that an increase in internal air pressure on powder compression can directly contribute to the formation of cracks within a tablet. The present study examines the air pressure increase on compression in a fully two-dimensional axisymmetric tablet geometry while being coupled to a plasticity model describing the evolution of tablet relative density on consolidation. It is shown numerically that increasing compression speed results in a large air pressure increase on the order of 1-1.5 MPa which approaches the diametrical tensile strength of tablets. In addition, it is shown experimentally through X-ray microcomputed tomography scans of tablets made at various dwell times that increasing dwell times equivalent to that on a tablet press has no effect on the degree of cracking within the tablet. Only when dwell times reach a time scale of 10 to 100 s does the air pressure diminish to a point at which cracking is eliminated. The reduction in air pressure during these extended dwells is captured by the current model. The experimental and numerical work presented here couples for the first time an air pressure model and plasticity model on compression. In addition, it provides a foundation for understanding how realistic tableting aspects such as precompression and tablet size impact the air pressure increase on consolidation.

Understanding Compression-Induced Amorphization of Crystalline Posaconazole.

Process-induced phase transformations (PIPTs) of active pharmaceutical ingredients (APIs) can alter APIs' physicochemical properties and impact performance of pharmaceutical drug products. In this study, we investigated compression-induced amorphization of crystalline posaconazole (POSA), where the impact of mechanical stresses and excipients on amorphization were explored. 19F solid-state NMR (ssNMR) was utilized to detect and quantify amorphous content in the compressed tablets, and finite element analysis (FEA) was conducted to understand stress distributions in the compression process. Both applied macroscopic axial stress and shear stress were found to be important to amorphization of crystalline POSA. Punch velocity, an important compression process parameter, had negligible effect on amorphization up to 100 mm/s. Two diluents, microcrystalline cellulose (MCC) and dibasic calcium phosphate anhydrous (DCPA), and one lubricant, magnesium stearate (MgSt), were evaluated for their impact on amorphization in this study. It was found that both MCC and DCPA significantly enhanced amorphization of POSA at a low drug loading (5% w/w). The 1% (w/w) blended lubricant effectively reduced the amorphous content in MCC-POSA tablets; however, it had minimal effect on either neat POSA or DCPA-POSA tablets. Drug loading, or excipient concentration, was demonstrated to have a significant impact on the extent of amorphization. These observed excipient effects support the important role of interparticulate stresses in amorphization of crystalline POSA.

Pharmaceutical 3D printing: Design and qualification of a single step print and fill capsule.

Fused deposition modeling (FDM) 3D printing (3DP) has a potential to change how we envision manufacturing in the pharmaceutical industry. A more common utilization for FDM 3DP is to build upon existing hot melt extrusion (HME) technology where the drug is dispersed in the polymer matrix. However, reliable manufacturing of drug-containing filaments remains a challenge along with the limitation of active ingredients which can sustain the processing risks involved in the HME process. To circumvent this obstacle, a single step FDM 3DP process was developed to manufacture thin-walled drug-free capsules which can be filled with dry or liquid drug product formulations. Drug release from these systems is governed by the combined dissolution of the FDM capsule 'shell' and the dosage form encapsulated in these shells. To prepare the shells, the 3D printer files (extension '.gcode') were modified by creating discrete zones, so-called 'zoning process', with individual print parameters. Capsules printed without the zoning process resulted in macroscopic print defects and holes. X-ray computed tomography, finite element analysis and mechanical testing were used to guide the zoning process and printing parameters in order to manufacture consistent and robust capsule shell geometries. Additionally, dose consistencies of drug containing liquid formulations were investigated in this work.

A Simplified Model of Moisture Transport in Hydrophilic Porous Media With Applications to Pharmaceutical Tablets.

This work establishes a predictive model that explicitly recognizes microstructural parameters in the description of the overall mass uptake and local gradients of moisture into tablets. Model equations were formulated based on local tablet geometry to describe the transient uptake of moisture. An analytical solution to a simplified set of model equations was solved to predict the overall mass uptake and moisture gradients with the tablets. The analytical solution takes into account individual diffusion mechanisms in different scales of porosity and diffusion into the solid phase. The time constant of mass uptake was found to be a function of several key material properties, such as tablet relative density, pore tortuosity, and equilibrium moisture content of the material. The predictions of the model are in excellent agreement with experimental results for microcrystalline cellulose tablets without the need for parameter fitting. The model presented provides a new method to analyze the transient uptake of moisture into hydrophilic materials with the knowledge of only a few fundamental material and microstructural parameters. In addition, the model allows for quick and insightful predictions of moisture diffusion for a variety of practical applications including pharmaceutical tablets, porous polymer systems, or cementitious materials.

Understanding the effect of environmental history on bilayer tablet interfacial shear strength.

PURPOSE: To understand the effect of post production environmental conditions on the interfacial strength of bilayer tablets. METHODS: Bilayer tablets of microcrystalline cellulose/dicalcium phosphate were exposed to several humidity conditions higher/lower than production conditions and tested in shear to assess interfacial strength. Specific failure mechanisms were observed using x-ray microtomography and scanning electron microscopy. RESULTS: Transients in moisture diffusion of bilayer tablets with significant differential moisture absorption characteristics are responsible for the reduction of strength in both high and low moisture environments. X-ray microtomography and SEM experiments have shown that two different mechanisms of interfacial crack formation are present. For low moisture exposure, interfacial cracks close to the surface were produced, whereas at high moisture conditions, internal interfacial cracks were created. In both cases the fracture modes are consistent with the tensile stresses that develop locally due to the volumetric strains induced by moisture absorption. CONCLUSIONS: The insight gained from this work will be useful for material selection and packaging of bilayer tablet systems. While additional work is needed to develop specific guidelines for the optimization of bilayer strength, the results presented here provide a rational basis upon which such work can be conducted.