Effect of Polymer Additives on the Transformation of BMS-566394 Anhydrate to the Dihydrate Form

Betigeri, Seema S; Thakur, Ajit B.; Shukla, R. K.; Raghavan, Krishnaswamy

doi:10.1007/s11095-007-9455-5

Cited by 16 publications

(8 citation statements)

References 30 publications

(32 reference statements)

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“…27 The use of low levels (generally <5 wt %, and often <0.1 wt %) of carefully selected, pharmaceutically acceptable additives to alter conventional crystallization processes has been explored to improve API physical properties during crystallization. Pharmaceutically acceptable additives have demonstrated the ability to alter API crystal form, 25,27,28 morphology, 27,72−77 surface features, 78 nucleation, 79,80 and supersaturation relief/growth rate. 81,82 In one case, the ability to impact API and not impurity supersaturation relief kinetics allowed for greater impurity rejection.…”

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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“…Different grades of cellulosic polymers have been found to protect polymorphic transformation of BMS-566394 [44], carbamazepine [45,46] and L-phenylalanine [43]. Cellulosic polymers have also been responsible for preventing destabilization of acetaminophen suspensions [47].…”

Section: A B C Dmentioning

confidence: 99%

Understanding Pharmaceutical Polymorphic Transformations II: Crystallization Variables and Influence on Dosage Forms

et al. 2015

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Excipients or formulation variables have often been exploited to improve stability, modify release, or improve physicochemical properties of dosage forms. In pharmaceutical field, it is generally expected that excipients work at macromolecular level where they might influence the crystal structure of a solid. These polymers/colloidal particles may modify the rate and direction of crystal growth. It has also been observed, that different polymorphic crystals exhibit different colors on exposure to same colorant, predominantly due to difference in surface pH of different crystal lattices. Apart from physicochemical affect, crystal habit also influences pharmacokinetic parameters of the dosage form. Crystals with smaller size or lower lattice energy have shown to exhibit higher bioavailability with faster rate of release.

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“…The 2008 literature also contained additional reports relating to investigations of the effects of secondary processing on phase composition, and aspects of these182–189 have been summarized in Table 4.…”

Section: Effects Associated With Secondary Processing Of Crystal Formsmentioning

confidence: 99%

Polymorphism Solvatomorphism 2008

Brittain¹

2010

Journal of Pharmaceutical Sciences

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Effect of Polymer Additives on the Transformation of BMS-566394 Anhydrate to the Dihydrate Form

Abstract: The anhydrate form of BMS-566394 is stabilized in the presence of cellulose ether polymers. Spectroscopic evidence is offered to postulate a molecular interaction between drug and polymers.

Cited by 16 publications

References 30 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

Understanding Pharmaceutical Polymorphic Transformations II: Crystallization Variables and Influence on Dosage Forms

Polymorphism Solvatomorphism 2008

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