The Influence of Impurities and Additives on Crystallization

Nicoud, Lucrèce; Myerson, Allan S.

doi:10.1017/9781139026949.004

Cited by 9 publications

(9 citation statements)

References 120 publications

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“…Several studies have reported that additives can help controlling crystal properties, such as size and shape but also polymorphism and enantiopurity. − Although a comprehensive understanding of the underlying physical mechanisms has not been achieved yet, the action of additives is generally attributed to the disruption of crystal growth due to their adsorption on the crystal surface. Different polymorphs may expose crystal faces that are characterized by different physicochemical properties.…”

Section: Resultsmentioning

confidence: 99%

“…Several models have been proposed in the literature to describe the growth rate reduction in the presence of impurities or additives. ,,, Here, we consider the Kubota model with a Langmuir adsorption isotherm. This leads to where k g,0 I denotes the growth rate of form I in the absence of metacetamol, x m is the metacetamol mole fraction, and H m is the Henry coefficient, which quantifies the adsorption of metacetamol on the surface of crystals of form II.…”

Section: Resultsmentioning

confidence: 99%

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Polymorph Control in MSMPR Crystallizers. A Case Study with Paracetamol

Nicoud

Licordari

Myerson

2019

Org. Process Res. Dev.

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Mixed-suspension mixed-product removal (MSMPR) crystallizers can potentially allow the production of metastable polymorphs. A necessary (but not sufficient) condition is to select operating conditions such that the steady-state concentration remains above the solubility of the metastable form. In this paper, we provide a framework that helps controlling polymorphism in MSMPR. We consider paracetamol as a model system and target the production of form II, which is metastable and rapidly converts to form I in batch. We combine experimental characterization (inline infrared spectroscopy, Raman spectroscopy, and imaging) with population balance modeling to investigate the possibility to produce the metastable form in a continuous manner. We identify a design space allowing the visualization of the regions where each form is obtained at steady state as a function of the kinetic parameters of both forms. We show that form II cannot be obtained at steady state in pure ethanol. However, the addition of a small amount of metacetamol (1% in mass with respect to paracetamol) in the feed is sufficient to obtain form II at steady state. We interpret the effect of metacetamol in light of a kinetic model and quantify its incorporation in the crystals with high-performance liquid chromatography.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Polymorph Control in MSMPR Crystallizers. A Case Study with Paracetamol

Nicoud

Licordari

Myerson

2019

Org. Process Res. Dev.

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“…To compliment these studies, using a mechanistic understanding of impurity rejection to rationally design a crystallization process will provide for consistent and optimized purity profiles. Crystallization textbook chapters , outline the following mechanisms of impurity incorporation during crystallization and product isolation: (1) supersaturation and phase separation of an impurity, (2) incomplete removal of a mother liquor, resulting in nonvolatile impurities remaining on the cake after drying, (3) kinetic inclusion of impurities in a growing crystal, (4) incorporation of an impurity as a thermodynamic solid solution (through lattice substitution of the impurity for the desired compound in the crystal or in interstitial voids).…”

Section: Purification Aspects Of Crystallization Process Designmentioning

confidence: 99%

Perspectives on the Current State, Challenges, and Opportunities in Pharmaceutical Crystallization Process Development

Cote

Erdemir

Girard

et al. 2020

Crystal Growth & Design

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Crystallization is the primary process used to purify synthetic drug substances and intermediates as well as to control bulk properties, including particle size, surface area, and flowability. Accordingly, new or improved tools to aid crystallization design are of central importance to drug development. In this Perspective, we provide a brief review of the state of the art, identify current challenges, and highlight key opportunities within different aspects of crystallization process development for synthetic pharmaceutical compounds.

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“…Understanding the molecular structure of recrystallized solid solutions is thus essential to enhance the purification processes in pharmaceutical manufacturing and may support development of predictive ab initio models. 5 Solid-state NMR (SSNMR) spectroscopy is a promising approach to probe impurities within recrystallized materials. SSNMR spectroscopy is an atomic-level method used to determine the chemical structure, 3D structure, and dynamics of solids and semisolids.…”

Section: ■ Introductionmentioning

confidence: 99%

Probing the Molecular and Macroscopic Structure of Solid Solutions by Dynamic Nuclear Polarization (DNP) Enhanced ¹³C and ¹⁵N Solid-State NMR Spectroscopy

Mi,

Chen,

Atterberry

et al. 2024

Mol. Pharmaceutics

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Crystallization is a widely used purification technique in the manufacture of active pharmaceutical ingredients (APIs) and precursor molecules. However, when impurities and desired compounds have similar molecular structures, separation by crystallization may become challenging. In such cases, some impurities may form crystalline solid solutions with the desired product during recrystallization. Understanding the molecular structure of these recrystallized solid solutions is crucial to devise methods for effective purification. Unfortunately, there are limited analytical techniques that provide insights into the molecular structure or spatial distribution of impurities that are incorporated within recrystallized products. In this study, we investigated model solid solutions formed by recrystallizing salicylic acid (SA) in the presence of anthranilic acid (AA). These two molecules are known to form crystalline solid solutions due to their similar molecular structures. To overcome challenges associated with the long 1 H longitudinal relaxation times (T 1 ( 1 H)) of SA and AA, we employed dynamic nuclear polarization (DNP) and 15 N isotope enrichment to enable solid-state NMR experiments. Results of solid-state NMR experiments and DFT calculations revealed that SA and AA are homogeneously alloyed as a solid solution. Heteronuclear correlation (HETCOR) experiments and plane-wave DFT structural models provide further evidence of the molecular-level interactions between SA and AA. This research provides valuable insights into the molecular structure of recrystallized solid solutions, contributing to the development of effective purification strategies and an understanding of the physicochemical properties of solid solutions.

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The Influence of Impurities and Additives on Crystallization

Cited by 9 publications

References 120 publications

Polymorph Control in MSMPR Crystallizers. A Case Study with Paracetamol

Polymorph Control in MSMPR Crystallizers. A Case Study with Paracetamol

Perspectives on the Current State, Challenges, and Opportunities in Pharmaceutical Crystallization Process Development

Probing the Molecular and Macroscopic Structure of Solid Solutions by Dynamic Nuclear Polarization (DNP) Enhanced ¹³C and ¹⁵N Solid-State NMR Spectroscopy

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The Influence of Impurities and Additives on Crystallization

Cited by 9 publications

References 120 publications

Polymorph Control in MSMPR Crystallizers. A Case Study with Paracetamol

Polymorph Control in MSMPR Crystallizers. A Case Study with Paracetamol

Perspectives on the Current State, Challenges, and Opportunities in Pharmaceutical Crystallization Process Development

Probing the Molecular and Macroscopic Structure of Solid Solutions by Dynamic Nuclear Polarization (DNP) Enhanced 13C and 15N Solid-State NMR Spectroscopy

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Probing the Molecular and Macroscopic Structure of Solid Solutions by Dynamic Nuclear Polarization (DNP) Enhanced ¹³C and ¹⁵N Solid-State NMR Spectroscopy