Promotion of Mefenamic Acid Nucleation by a Surfactant Additive, Docusate Sodium

Bodnár, Katalin; Hudson, Sarah P.; Rasmuson, Åke C.

doi:10.1021/acs.cgd.8b00995

Cited by 16 publications

(13 citation statements)

References 42 publications

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“…14,42 Similar results were obtained by Heffernan et al, 64 where the presence of structurally similar impurities (demethoxycurcumin (DMC) and bisdemethoxycurcumin (BDMC)) in the curcumin solution did not inuence the interfacial energy of the crystallising solute, but instead changed the pre-exponential factor. 64 Another report by Bodnár et al 65 also presents similar ndings, where the presence of docusate sodium (DOSS) in a mefenamic acid solution in dimethylacetamide (DMA)-water mixtures resulted in an approximately 50% increase in the pre-exponential factor, while the interfacial energy remained uninuenced. Hence, the nucleation of organics in the presence of heterosurfaces in either a dissolved or undissolved state is inuenced by the change in the pre-exponential factor, while the interfacial energy remains uninuential.…”

Section: Papermentioning

confidence: 69%

Studying the impact of the pre-exponential factor on templated nucleation

et al. 2022

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Section: Papermentioning

confidence: 69%

Studying the impact of the pre-exponential factor on templated nucleation

et al. 2022

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“…As discussed in a previous study, the Zeldovich factor z depends on the supersaturation ratio, Boltzmann constant, temperature, molecular volume in the crystal, and the interfacial energy, and these values are unlikely to change due to the presence of impurities . Instead, impurities may interact with nucleation interfaces, effectively lowering the concentration of nucleation sites C 0 for PA.…”

Section: Resultsmentioning

confidence: 81%

“…Consequently, the solubility of the product may decrease due to the presence of common ions or increase as a result of complex formation or the presence of foreign ions . Impurities furthermore may influence the nucleation process by changing the solid–liquid interfacial energy and/or the kinetic factor, or they may act as heterogeneous surfaces. , For instance, amphiphilic, polymeric, and surfactant additives were found to promote nucleation. − In other studies, it was found that additives and impurities did not significantly influence the interfacial energy but instead led to a reduction in the kinetics. , These findings were explained using the additional energy that is required to remove the impurity from the clustering process. Finally, additives can be used to influence the processability of pharmaceutical compounds by changing the intrinsic physical properties.…”

Section: Introductionmentioning

confidence: 99%

Influence of Impurities on the Solubility, Nucleation, Crystallization, and Compressibility of Paracetamol

Keshavarz

Steendam

Blijlevens

et al. 2019

Crystal Growth & Design

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The striking ability of impurities to significantly influence crystallization processes is a topic of paramount interest in the pharmaceutical industry. Despite being present in small quantities, impurities tend to considerably change a crystallization process as well as the final crystalline product. In the present work, the effect of two markedly different impurities 4-nitrophenol and 4′-chloroacetanilide on the solubility, nucleation, and crystallization of paracetamol is described. In the first part of this work, the fundamentals are outlined and show that, although each impurity led to a small increase in solubility of paracetamol, their effect as a nucleation inhibitor was much more pronounced. Induction time experiments were used in conjunction with the classical nucleation theory to show that the impurities did not affect the solid−liquid interfacial energy but instead significantly reduced the kinetic factor, overall resulting in reduced nucleation rates. Intriguingly, both impurities influenced the solubility and nucleation of paracetamol in a similar fashion despite their significant differences in terms of molecular structure, solubility, and ability to incorporate into the crystal structure of paracetamol. In the second part of this work, the incorporation of 4′-chloroacetanilide into the solid phase of paracetamol was investigated. The presence of 4′-chloroacetanilide in the solid phase of paracetamol significantly increased the compressibility of paracetamol, resulting in improved processability properties of paracetamol. The compressibility efficiency of paracetamol could be controlled using the amount of incorporated 4′-chloroacetanilide. Therefore, an experimental design space was developed and utilized to select the most important process parameters for impurity incorporation. Intriguingly, the number of carbon atoms in the aliphatic chain of the alcohol solvent strongly correlated to the impurity incorporation efficiency. As a result, it was feasible to accurately control the compressibility and the amount of 4′-chloroacetanilide in the solid phase of paracetamol by simply choosing the required alcohol as the solvent for crystallization. Thus, the present work comprehensively shows how different impurities impact the key crystallization mechanisms and properties of a pharmaceutical product. Rational process control over the incorporation of impurities and additives allows for advanced manufacturing of products with tailored specifications.

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“…Table 1 presents the influence of solvent on these parameters for tolbutamide, 36 salicylic acid, 37 and risperidone 38 which clearly show a solvent effect in determining the values of the preexponential factors and interfacial energies. Two studies on curcumin 39 and 3-nitrophenol 40 demonstrate the effects of impurities on the pre-exponential factors and interfacial energies and finally there are 4 studies which show how these factors change for polymorph pairs, namely eflucimibe, 11 D-mannitol, 12 mefenamic acid, 41 and famotidine. 13 Perusals of the data in Table 1 indicated that ratio of preexponential factors for the various crystallizations encountered rarely exceed 10 3 .…”

Section: Introductionmentioning

confidence: 99%