An Investigation of the Causes of Cocrystal Dissociation at High Humidity

Eddleston, Mark D.; Thakuria, Ranjit; Aldous, Barry J.; Jones, William

doi:10.1002/jps.23865

Cited by 69 publications

(72 citation statements)

References 39 publications

(63 reference statements)

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“…In contrast, for the combination of caffeine and adipic acid, where the corresponding cocrystal is known to dissociate at high humidity, only partial conversion of caffeine hydrate and adipic acid to cocrystal occurs on slurrying these compounds in water …”

Section: Resultsmentioning

confidence: 99%

“…It is now well established that cocrystallization, the preparation of crystal forms containing two or more neutral molecules (coformers) in the lattice, is a key methodology for improving solid‐state properties of compounds such as dissolution rate, melting point, and chemical stability . In an accompanying paper, however, it is shown that cocrystals can be susceptible to dissociation at high humidity because of coformer solubility differences, with cocrystals of hydrate‐forming compounds being particularly vulnerable. For cocrystals to reach their full potential in an industrial context, this tendency to dissociation must be better understood and, ultimately, avoided.…”

Section: Introductionmentioning

confidence: 99%

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Cocrystal Dissociation in the Presence of Water: A General Approach for Identifying Stable Cocrystal Forms

Eddleston

Madusanka

Jones

2014

Journal of Pharmaceutical Sciences

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Cocrystal Dissociation in the Presence of Water: A General Approach for Identifying Stable Cocrystal Forms

Eddleston

Madusanka

Jones

2014

Journal of Pharmaceutical Sciences

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“…Certain API and coformer components tend to dissociate during storage, particularly in high-humidity and high-temperature environments (i.e., they tend to undergo disproportionation) 57) (Table 3). Some excipients formulated with a cocrystal can replace the original coformer during storage.…”

Section: )mentioning

confidence: 99%

“…Contact with water during oral administration often removes or alters coformers in cocrystals in the same manner as that under high-humidity storage conditions, leading to low-solubility and practically insoluble solids, such as API crystals, hydrate crystals, and other cocrystals. 57,76) Some cocrystals, such as those comprising CBZ, form metastable intermediates upon exposure to aqueous solutions.…”

Section: Solution-mediated Phase Transformation Andmentioning

confidence: 99%

Characterization and Quality Control of Pharmaceutical Cocrystals

Izutsu¹,

Koide²,

Takata

et al. 2016

Chem. Pharm. Bull.

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Recent active research and new regulatory guidance on pharmaceutical cocrystals have increased the rate of their development as promising approaches to improve handling, storage stability, and bioavailability of poorly soluble active pharmaceutical ingredients (APIs). However, their complex structure and the limited amount of available information related to their performance may require development strategies that differ from those of single-component crystals to ensure their clinical safety and efficacy. This article highlights current methods of characterizing pharmaceutical cocrystals and approaches to controlling their quality. Different cocrystal regulatory approaches between regions are also discussed. The physical characterization of cocrystals should include elucidating the structure of their objective crystal form as well as their possible variations (e.g., polymorphs, hydrates). Some solids may also contain crystals of individual components. Multiple processes to prepare pharmaceutical cocrystals (e.g., crystallization from solutions, grinding) vary in their applicable ingredients, scalability, and characteristics of resulting solids. The choice of the manufacturing method affects the quality control of particular cocrystals and their formulations. In vitro evaluation of the properties that govern clinical performance is attracting increasing attention in the development of pharmaceutical cocrystals. Understanding and mitigating possible factors perturbing the dissolution and/ or dissolved states, including solution-mediated phase transformation (SMPT) and precipitation from supersaturated solutions, are important to ensure the bioavailability of orally administrated lower-solubility APIs. The effect of polymer excipients on the performance of APIs emphasizes the relevance of formulation design for appropriate use.

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“…13, 29 Cocrystal stability is not yet well understood, but studies have shown that cocrystals can dissociate spontaneously on heating or through partial dissolution of one of the coformers. 2,24,25,[30][31][32] Theophylline is a pharmaceutically active compound used as a treatment for asthma and COPD for which seven polymorphic forms have been reported. [33][34][35][36][37][38] Over 40 cocrystals of theophylline are present in the Cambridge Structural Database (version 5.36, see Supporting Information Table S1), three of which comprise coformers having an amide functionality (a 1:1 cocrystal of theophylline and saccharin, a 1:1 cocrystal of theophylline and urea, and a 2:1 cocrystal monohydrate of theophylline and 5-fluorouracil).…”

Section: Introductionmentioning

confidence: 99%

Investigation of an Amide-Pseudo Amide Hydrogen Bonding Motif within a Series of Theophylline:Amide Cocrystals

Eddleston

Arhangelskis

Fábián

et al. 2015

Crystal Growth & Design

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The pharmaceutically active compound theophylline (T) was cocrystallized with the amides formamide (1), acetamide (2), N-methylformamide (3), N,N-dimethylformamide (4), benzamide (5), and pyrazinamide (6), with systems T:1, T:5, and T:6 displaying polymorphic behavior. The cocrystals with formamide (T:1), acetamide (T:2), and benzamide (T:5), and one polymorph of the cocrystal with pyrazinamide (T:6-I), contain an R 2 2 (9) hydrogen bonding motif between the amide cocrystal formers and the HN−C−CO moiety of the theophylline molecule (an amide-pseudo amide synthon). This motif was, however, absent from the other polymorph of the pyrazinamide cocrystal (T:6-II) and also from the N-methylformamide cocrystal (T:3) (and is not possible in the N,N-dimethylformamide cocrystal (T:4)). These observations are rationalized using hydrogen bond propensity calculations, although limitations of using such calculations for predicting cocrystallization are noted. The amide-pseudo amide synthon is favored when theophylline cocrystallizes with both primary amides and with secondary amides which are locked in a cis configuration. On heating, all cocrystals were found to dissociate before melting due to loss of the amide, making stability to dissociation a more meaningful measure of cocrystal stability than melting point for these systems. On dissociation of the cocrystals, theophylline typically crystallizes as the commonly observed polymorph Form II. In the case of the acetamide cocrystal (T:2), however, the rarely observed metastable polymorph, Form V, crystallizes concomitantly with Form II suggesting that cocrystal dissociation on heating could be a strategy for identifying novel polymorphic forms of compounds.

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An Investigation of the Causes of Cocrystal Dissociation at High Humidity

Cited by 69 publications

References 39 publications

Cocrystal Dissociation in the Presence of Water: A General Approach for Identifying Stable Cocrystal Forms

Cocrystal Dissociation in the Presence of Water: A General Approach for Identifying Stable Cocrystal Forms

Characterization and Quality Control of Pharmaceutical Cocrystals

Investigation of an Amide-Pseudo Amide Hydrogen Bonding Motif within a Series of Theophylline:Amide Cocrystals

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