Recent Advances in Co-processed APIs and Proposals for Enabling Commercialization of These Transformative Technologies.

Optimized physical properties (e.g., bulk, surface/interfacial, and mechanical properties) of active pharmaceutical ingredients (APIs) are key to the successful integration of drug substance and drug product manufacturing, robust drug product manufacturing operations, and ultimately to attaining consistent drug product critical quality attributes. However, an appreciable number of APIs have physical properties that cannot be managed via routes such as form selection, adjustments to the crystallization process parameters, or milling. Approaches to control physical properties in innovative ways offer the possibility of providing additional and unique opportunities to control API physical properties for both batch and continuous drug product manufacturing, ultimately resulting in simplified and more robust pharmaceutical manufacturing processes. Specifically, diverse opportunities to significantly enhance API physical properties are created if allowances are made for generating co-processed APIs by introducing nonactive components (e.g., excipients, additives, carriers) during drug substance manufacturing. The addition of a nonactive coformer during drug substance manufacturing is currently an accepted approach for cocrystals, and it would be beneficial if a similar allowance could be made for other nonactive components with the ability to modify the physical properties of the API. In many cases, co-processed APIs could enable continuous direct compression for small molecules, and longer term, this approach could be leveraged to simplify continuous end-to-end drug substance to drug product manufacturing processes for both small and large molecules. As with any novel technology, the regulatory expectations for co-processed APIs are not yet clearly defined, and this creates challenges for commercial implementation of these technologies by the pharmaceutical industry. The intent of this paper is to highlight the opportunities and growing interest in realizing the benefits of co-processed APIs, exemplified by a body of academic research and industrial examples. This work will highlight reasons why co-processed APIs would best be considered as drug substances from a regulatory perspective and emphasize the areas where regulatory strategies need to be established to allow for commercialization of innovative approaches in this area.

A scaled down method for identifying the optimum range of L/S ratio in twin screw wet granulation using a regime map approach.

Twin screw wet granulation (TSWG) has gained momentum in the pharmaceutical industry for effective continuous granulation of solid dosage products. Liquid-to-solid (L/S) ratio is a key process parameter affecting granule properties. Identifying an optimum range of L/S ratio while reducing the number of full scale experiments can minimize material requirements and streamline formulation and process development. In this work, microcrystalline cellulose-based (MCC) formulations of varying drug loads were granulated using a kneading element screw configuration at a wide range of L/S ratios until pasting was visually determined. Quantitative criteria based on process relevant granule size and mass % of fines were established to identify undesirable granulation conditions. Key mechanical properties of wet compacts measured using a small scale approach are discussed. The stress-strain behavior is used to predict pasting, and natural strain at peak yield stress and total work of deformation are used to identify undergranulation and overgranulation respectively. The small scale method is used to establish viable ranges of L/S ratios in advance of at-scale experiments. A quantitative predictive growth regime map is proposed based fully on small scale experiments and input process parameters. Strategies for establishing a generalized growth regime map for various systems of interest are discussed.

The role of electrochemical reactions during electrophoretic particle deposition.

Platinum microelectrodes were fabricated on a sapphire substrate by lithographic patterning and used to manipulate 1.58 microm silica particles in the plane of the substrate. A digital video system captured the motion of particles far from the electrodes and their deposition onto the working electrode during application of a DC potential. The role of electrode reversibility was investigated by comparing as-deposited electrodes with electrodes modified by electrolytic plating of platinum. Particles were also observed adhering to the substrate before reaching the electrode. The zeta potential of the particles and substrate was measured. The differing surface chemistry of the two systems and a local reduction in pH due to the production of hydrogen ion at the anode can explain the adhesion phenomena. Force distance curves were recorded using a colloid probe atomic force microscopy technique to directly measure the interaction of the silica particles with the sapphire substrate. These data validated the observed adhesion at the electrode and provided further support for the temporal and spatial reduction in pH. The role of Faradaic processes and the diffusion of potential determining ions in electrophoretic deposition were also considered.

Orientation dependence of the isoelectric point of TiO2 (rutile) surfaces.

The electroosmotic behavior of the rutile polymorph of titanium dioxide was explored as a function of the crystallographic orientation. Atomic force microscopy (AFM) was employed to make high-resolution force spectroscopy measurements between a silica sphere attached to a traditional, contact-mode AFM cantilever and TiO2(110), TiO2(100), and TiO2(001) surfaces in aqueous solutions. Measurements were taken in multiple solution conditions across a broad range of pH values, and the resultant force-distance curves were used to deduce relative behaviors of each orientation of rutile, with particular interest in changes of the isoelectric point (iep). Differences in the iep as a function of orientation are explained in terms of differences in both the coordination number and density of acidic and basic sites on the surface. The results were supported by angle-resolved X-ray photoelectron spectroscopy (XPS) measurements of a nominal monolayer of palladium metal deposited on each of the three orientations studied. The palladium monolayer served as a means of probing the relative electron affinities of the three surfaces studied, which were exhibited in shifts of the palladium XPS peak that corresponded to differences in the binding energy as a function of the substrate orientation. The correlation between the rutile orientation and the shift in the palladium binding energy corresponded directly to the relationship between the isoelectric point and the orientation, with the surface of lowest isoelectric point exhibiting the highest Pd binding energy.

Zeta potential orientation dependence of sapphire substrates.

The zeta potential of planar sapphire substrates for three different crystallographic orientations was measured by a streaming potential technique in the presence of KCl and (CH3)4NCl electrolytes. The streaming potential was measured for large single crystalline C-plane (0001), A-plane (1120), and R-plane (1102) wafers over a full pH range at three or more ionic strengths ranging from 1 to 100 mM. The roughness of the epi-polished wafers was verified using atomic force microscopy to be on the order of atomic scale, and X-ray photoelectron spectroscopy (XPS) was used to ensure that the samples were free of silica and other contaminants. The results reveal a shift in the isoelectric point (iep) of the three samples by as much as two pH units, with the R-plane surface exhibiting the most acidic behavior and the C-plane samples having the highest iep. The iep at all ionic strengths was tightly centered around a single pH for each wafer. These values of iep are substantially different from the range of pH 8-10 consistently reported in the literature for alpha-Al2O3 particles. Particle zeta potential measurements were performed on a model powder using phase analysis light scattering, and the iep was confirmed to occur at pH 8. Modified Auger parameters (MAP) were calculated from XPS spectra of a monolayer of iridium metal deposited on the sapphire by electron beam deposition. A shift in MAP consistent with the observed differences in iep of the surfaces confirms the effect of surface structure on the transfer of charge between the Ir and sapphire, hence accounting for the changes in acidity as a function of crystallographic orientation.