Spherical Cocrystallization—An Enabling Technology for the Development of High Dose Direct Compression Tablets of Poorly Soluble Drugs

Chen, Hongbo; Guo, Yiwang; Wang, Chenguang; Dun, Jiangnan; Sun, Changquan Calvin

doi:10.1021/acs.cgd.9b00219

Cited by 27 publications

(17 citation statements)

References 49 publications

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“…83 In another clear example of the impact of changes in physical properties, morphology modification brought about by crystallization in the presence of hydroxypropyl cellulose polymer yielded improved compactability of the API. 8,84 Another study showed levels of polymer of 0. resulted in composite particles with improved API physical properties, while higher levels of polymer (∼9−12 wt %) stabilized a kinetic crystalline phase. 26 Work has also shown changes in morphology between rods and rectangular plates along with beneficial effects on compactability.…”

Section: ■ Routes To Generate Co-processed Apimentioning

confidence: 99%

“…Pharmaceutically acceptable additives have demonstrated the ability to alter API crystal form, ,, morphology, ,− surface features, nucleation, , and supersaturation relief/growth rate. , In one case, the ability to impact API and not impurity supersaturation relief kinetics allowed for greater impurity rejection . In another clear example of the impact of changes in physical properties, morphology modification brought about by crystallization in the presence of hydroxypropyl cellulose polymer yielded improved compactability of the API. , Another study showed levels of polymer of 0.4–5 wt % altered morphology and resulted in composite particles with improved API physical properties, while higher levels of polymer (∼9–12 wt %) stabilized a kinetic crystalline phase . Work has also shown changes in morphology between rods and rectangular plates along with beneficial effects on compactability .…”

Section: Routes To Generate Co-processed Apimentioning

confidence: 99%

“…However, this is by no means a universal solution and at times may only offer marginal improvement. Yet another approach of spherical crystallization, which involves intentional controlled agglomeration during isolation/drying, can greatly improve physical properties. − Emulsion based crystallization processes to generate spherical agglomerates of API − offer another alternative. A recent study outlines spherical crystallization via quasi-emulsion solvent diffusion, antisolvent and pH shift .…”

Section: Introductionmentioning

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%

Section: Introductionmentioning

confidence: 99%

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

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“…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. In addition, spherical agglomeration technology improves the efficiency of downstream product handling in most cases, for example, washing, filtration, drying, and others 18–20 …”

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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“…Cocrystallization is a crystal engineering technique widely used in pharmaceutical research and the development of drugs [3,4]. It exploits non-covalent interactions between neutral or ionic components with a defined stoichiometry in a solid-state structure [5], which could improve the physicochemical properties of active pharmaceutical ingredients (API), including solid-state stability, such as sublimation tendency and hydration tendency [6,7], solubility [8] and dissolution [9], mechanical properties [10], permeability [11], and punch sticking propensity [12,13].…”

Section: Introductionmentioning

confidence: 99%

Discovery, Characterization, and Pharmaceutical Applications of Two Loratadine–Oxalic Acid Cocrystals

et al. 2020

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Loratadine (Lor) is an antihistamine drug commonly used to relieve the symptoms of allergy. It has high permeability but low solubility under physiological conditions. To overcome the problem of low solubility, we synthesized and characterized two Loratadine multi-component crystalline phases with oxalic acid (Oxa), i.e., a 1:1 Lor-Oxa conjugate acid-base (CAB) cocrystal (Lor-Oxa CAB) and a 2:1 Lor-Oxa cocrystal monohydrate (Lor-Oxa hydrate). Both cocrystals exhibited an enhanced solubility and intrinsic dissolution rate (IDR) compared to Lor and adequate physical stability. The intrinsic dissolution rate of Lor-Oxa CAB is 95 times that of Lor, which makes it a promising candidate for tablet formulation development.

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Spherical Cocrystallization—An Enabling Technology for the Development of High Dose Direct Compression Tablets of Poorly Soluble Drugs

Cited by 27 publications

References 49 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

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

Discovery, Characterization, and Pharmaceutical Applications of Two Loratadine–Oxalic Acid Cocrystals

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