Novel Co-processing Methodology To Enable Direct Compression of a Poorly Compressible, Highly Water-Soluble Active Pharmaceutical Ingredient for Controlled Release

Erdemir, Deniz; Rosenbaum, Tamar; Chang, Shih‐Ying; Wong, Benjamin C.Y.; Kientzler, Donald; Wang, Steve; Desai, Divyakant; Kiang, San

doi:10.1021/acs.oprd.8b00204

Cited by 17 publications

(8 citation statements)

References 37 publications

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“…5,38−42 The improvement in the tableting properties of these agglomerates is mainly due to the increased particle size of co-processed particles compared to that of API alone and changes in particle shape from needle-like or platelike to nearly spheroidal. This concept was extended for preparation of API and excipient agglomerates of highly watersoluble drugs to improve flow and compaction properties, 43,44 where the APIs were crystallized in the presence of polymers and agglomeration was achieved by relying on swelling behavior of polymers in water/organic mixtures. Another example of precipitating API in the presence of excipients is the method developed to manufacture amorphous formulations of high-melting and low-solubility compounds, where both hot melt extrusion and spray drying are not options.…”

Section: ■ Routes To Generate Co-processed Apimentioning

confidence: 99%

“…Crystallo- co -agglomeration, a variation of the spherical crystallization technique wherein the drug is crystallized and agglomerated in the presence of a material via the use of an antisolvent and bridging liquid, has been demonstrated on numerous drugs to improve tableting properties and allow for direct compression. ,− The improvement in the tableting properties of these agglomerates is mainly due to the increased particle size of co-processed particles compared to that of API alone and changes in particle shape from needle-like or plate-like to nearly spheroidal. This concept was extended for preparation of API and excipient agglomerates of highly water-soluble drugs to improve flow and compaction properties, , where the APIs were crystallized in the presence of polymers and agglomeration was achieved by relying on swelling behavior of polymers in water/organic mixtures.…”

Section: Routes To Generate Co-processed Apimentioning

confidence: 99%

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

et al. 2020

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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.

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Section: ■ Routes To Generate Co-processed Apimentioning

confidence: 99%

Section: Routes To Generate Co-processed Apimentioning

confidence: 99%

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

et al. 2020

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“…The transformation of small molecule active pharmaceutical ingredients (APIs) into high-quality solid oral dosage forms faces two major challenges. First, a vast majority of APIs exhibit poor powder flow properties that restrict their processability − and maximum loading in the final dosage form. − Second, a significant fraction of commercial APIs and those in discovery pipelines are hydrophobic, which limits their oral bioavailability in vivo. − Both powder flow and bioavailability of solid API are governed by the interplay of their critical quality attributes including particle morphology, − size, , and solid-state. ,,− Co-processing APIs with excipients is a promising particle engineering technique to gain control over these critical attributes and manifest superior API performance. − Excipients, although non-therapeutic, play an indispensable role in oral dosage by serving as matrices to control drug loading, , solid-state outcomes, , and tune drug release. , With the APIs being exposed to varied pH conditionshighly acidic in the stomach (1–3) to physiological values (6–7.5) in the saliva and intestinesacross the gastrointestinal tract, the use of pH-responsive excipients to modulate their release has gained significant traction in the last two decades . Eudragit E100, belonging to a class of polymethacrylate-based copolymers, is one such widely used excipient with solubility in gastric fluid up to pH 5. − E100 is reportedly non-toxic and is utilized for modulating drug release − and taste masking ,,,, in pharmaceutical formulations either on its own or in combination with other Eudragit , and non-Eudragit polymers. ,− …”

Section: Introductionmentioning

confidence: 99%

Microfluidic Particle Engineering of Hydrophobic Drug with Eudragit E100─Bridging the Amorphous and Crystalline Gap

et al. 2022

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Co-processing active pharmaceutical ingredients (APIs) with excipients is a promising particle engineering technique to improve the API physical properties, which can lead to more robust downstream drug product manufacturing and improved drug product attributes. Excipients provide control over critical API attributes like particle size and solid-state outcomes. Eudragit E100 is a widely used polymeric excipient to modulate drug release. Being cationic, it is primarily employed as a precipitation inhibitor to stabilize amorphous solid dispersions. In this work, we demonstrate how co-processing of E100 with naproxen (NPX) (a model hydrophobic API) into monodisperse emulsions via droplet microfluidics followed by solidification via solvent evaporation allows the facile fabrication of compact, monodisperse, and spherical particles with an expanded range of solidstate outcomes spanning from amorphous to crystalline forms. Low E100 concentrations (≤26% w/w) yield crystalline microparticles with a stable NPX polymorph distributed uniformly across the matrix at a high drug loading (∼89% w/w). Structurally, E100 incorporation reduces the size of primary particles comprising the co-processed microparticles in comparison to neat API microparticles made using the same technique and the as-received API powder. This reduction in primary particle size translates into an increased internal porosity of the co-processed microparticles, with specific surface area and pore volume ∼9 times higher than the neat API microparticles. These E100-enabled structural modifications result in faster drug release in acidic media compared to neat API microparticles. Additionally, E100-NPX microparticles have a significantly improved flowability compared to neat API microparticles and as-received API powder. Overall, this study demonstrates a facile microfluidics-based co-processing method that broadly expands the range of solid-state outcomes obtainable with E100 as an excipient, with multiscale control over the key attributes and performance of hydrophobic API-laden microparticles.

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“…The bridging liquid is added, forming bridging liquid droplets under stirring due to the immiscibility between the bridging liquid and the mixture of solvent and anti‐solvent, which can effectively wet the individual crystals into spherical agglomerates 3 . Compared with the traditional granulation technology (Figure 1A), this technology (Figure 1B) significantly simplifies the equipment and process, achieving equipment space and cost savings, energy conservation, less carbon emission, consumption reduction, and reduced production cycle by over 40% 4–8 . Furthermore, the greatly enhanced powder properties of the spherical products achieve advanced functions, for example, direct tableting for drugs, 9–12 anti‐caking ability for food and fertilizers, 13 superior skin feeling for cosmetics, 14 high performance for explosives, 15–17 and so on.…”

Section: Introductionmentioning

confidence: 99%

Design of the spherical agglomerate size in crystallization by developing a two‐step bridging mechanism and the model

Yao

et al. 2021

AIChE Journal

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Spherical agglomeration technology can produce high‐performance spherical particles in a single crystallization unit, although it is still challenging to control the particle size and shape. To solve this issue, a two‐step bridging (TSB) mechanism containing a preconditioning period, size period, and shape period is proposed. The dynamic balance among the forces of adhesion, dispersion, and capillary action in the multi‐liquid phases plays a key role. This is fully considered to establish the TSB‐based thermodynamic size model and particle design framework by weighting the force action regions in multi‐liquid phases with dynamic composition. The spherical agglomerates of benzoic acid, celecoxib, and salicylic acid with narrow particle size distributions and tunable particle size ranges of 2000–5000, 800–3500, and 1500–4500 μm, respectively, were designed and prepared successfully, showing good correlation with the calculation, which is superior to the reported methods and indicates that the mechanism has certain universality and guiding significance.

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Novel Co-processing Methodology To Enable Direct Compression of a Poorly Compressible, Highly Water-Soluble Active Pharmaceutical Ingredient for Controlled Release

Cited by 17 publications

References 37 publications

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

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

Microfluidic Particle Engineering of Hydrophobic Drug with Eudragit E100─Bridging the Amorphous and Crystalline Gap

Design of the spherical agglomerate size in crystallization by developing a two‐step bridging mechanism and the model

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