Polymer-Directed Crystallization of Atorvastatin

Choi, H. K.; Lee, Hyeseung; Lee, Min Kyung; Lee, Jonghwi

doi:10.1002/jps.23206

Cited by 17 publications

(11 citation statements)

References 32 publications

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“…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. 75 While many of the studies do not quantify residual levels of the additive, some do highlight that polymer may be present in isolated materials.…”

Section: ■ Routes To Generate Co-processed Apimentioning

confidence: 99%

“…The proposed definition of co-processed API is in line with the ICH Q7 definition of an API or drug substance, which includes “Any substance or mixture of substances to be used in the manufacture of a drug (medicinal) product and that, when used in the production of a drug, becomes an active ingredient of the drug product,” and the clarification in the ICH Q7 Q&A that mixtures with “the addition of substance(s) to an API (e.g., to stabilize the API)” can be classified in the regulatory filing as an API . A co-processed API may improve the drug substance stability, for example, if a polymorphic form is stabilized by the presence of the nonactive component(s). − Furthermore, we suggest that an additional appropriate justification to include nonactive components in a drug substance is for the purpose of optimization of API physical properties. There are already some limited examples of regulatory acceptance of inclusion of nonactive components in a commercial drug substance with justification based on stabilization of an amorphous form or improvement of physical properties .…”

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: Introductionmentioning

confidence: 99%

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

et al. 2020

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“…Atorvastatin calcium [82] Eudragit RL100 Griseofulvin [85] Poly(aspartic acid-citric acid) copolymer, polymaleic acid Ca 3 (PO4) 2 [91] Poly(citric acid) CaSO 4 [92] Polyaspartic acid/furfurylamine graft copolymer CaCO 3 , Ca 3 (PO4) 2 [93] Acrylic acid-allyloxy polyethoxy glutamate copolymer CaCO 3 [94] Starch-graft-poly(acrylic acid) CaCO 3 [95] Epoxysuccinic acid derivative CaCO 3 [97] Epoxysuccinic acid derivative CaCO 3 , CaSO 4 , Ca 3 (PO 4 ) 2 [98] Table 3. Cont.…”

Section: Crystal Surface Screening/nucleation Inhibitionmentioning

confidence: 99%

“…Choi et al reported studies on biomimetic polymer-directed crystallization techniques applied to the crystallization of atorvastatin (a popular drug belonging to statins) [ 82 ]. In the presence of poly(ethylene glycol) (PEG), polyethylene imine (PEI), hydroxypropyl cellulose (HPC), polyethylene oxide-polypropylene oxide triblock copolymer (PEO– b -PPO– b -PEO) and PAA, nucleation and growth of atorvastatin at improved conditions led to obtaining composite crystals with significant polymer contents and unusual characteristics, such as a decreased melting point, improved stability, and sustained-release patterns.…”

Section: Present and Future Perspectives Of Applications Of Crystallization Phenomena In The Presence Of Polymersmentioning

confidence: 99%

Application of Polymers as a Tool in Crystallization—A Review

et al. 2021

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The application of polymers as a tool in the crystallization process is gaining more and more interest among the scientific community. According to Web of Science statistics the number of papers dealing with “Polymer induced crystallization” increased from 2 in 1990 to 436 in 2020, and for “Polymer controlled crystallization”—from 4 in 1990 to 344 in 2020. This is clear evidence that both topics are vivid, attractive and intensively investigated nowadays. Efficient control of crystallization and crystal properties still represents a bottleneck in the manufacturing of crystalline materials ranging from pigments, antiscalants, nanoporous materials and pharmaceuticals to semiconductor particles. However, a rapid development in precise and reliable measuring methods and techniques would enable one to better describe phenomena involved, to formulate theoretical models, and probably most importantly, to develop practical indications for how to appropriately lead many important processes in the industry. It is clearly visible at the first glance through a number of representative papers in the area, that many of them are preoccupied with the testing and production of pharmaceuticals, while the rest are addressed to new crystalline materials, renewable energy, water and wastewater technology and other branches of industry where the crystallization process takes place. In this work, authors gathered and briefly discuss over 100 papers, published in leading scientific periodicals, devoted to the influence of polymers on crystallizing solutions.

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“…On the basis of this approach, immediately processable crystalline drugs can be produced by application of convenient additives and well-controlled process conditions in the course of the crystallization process. Such additives can be divided into several groups: organic compounds similar in structure to the product to be crystallized [3][4][5], different polymers (polyvinylpyrrolidone (PVP) [6], hydroxypropylmethylcellulose [7], methylcellulose, polyethylene glycol [8], polypropylene glycol), surface-active ingredients [9][10][11], peptides, proteins [12], and low-molecular-weight organic and inorganic compounds. PVP was already used successfully in drug crystallization to improve formulation properties or dissolution rates [13][14][15][16].…”

Section: Introductionmentioning

confidence: 99%

Controlled Formation of Free‐Flowing Carvedilol Particles in the Presence of Polyvinylpyrrolidone

et al. 2014

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Carvedilol precipitation by combined antisolvent-cooling crystallization was performed in the presence of polyvinylpyrrolidone (PVP) of different molecular weight. Drug emulsion was formed as a result of water addition and crystal growth occurred after cooling. In the absence of the additive, the kinetically preferred Form II polymorph crystallized while PVP facilitated the formation of the thermodynamically stable Form III (hemihydrate) polymorph. Crystallization was monitored by real-time Raman spectrometry to indicate the polymorphic form and the endpoint of the process. The thermodynamic relationship between these polymorphs was established also by real-time Raman spectrometry using ethanol and water as solvent mixture. In all cases, just a small amount of PVP, adsorbed on the crystal surface, was sufficient to affect the crystal form advantageously and induce excellent flowability of the products. The modification of crystal morphology assisted by the applied additives is ascribed to the altered way of crystal growth.

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Polymer-Directed Crystallization of Atorvastatin

Cited by 17 publications

References 32 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

Application of Polymers as a Tool in Crystallization—A Review

Controlled Formation of Free‐Flowing Carvedilol Particles in the Presence of Polyvinylpyrrolidone

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