Enantiotropic inconstancy, crystalline solid solutions and co-crystal in the salicylic acid–anthranilic acid system

Nordström, Fredrik; Mohajerani, Seyed Sepehr; Linehan, Brian; Ricci, Francesco

doi:10.1039/d2cp04200b

Cited by 9 publications

(65 citation statements)

References 39 publications

(68 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The thermal events observed in the DSC thermograms at a heating rate of 1 °C min −1 were characterized using four thermal parameters across the same endotherm, 4 when available. These were the inset temperature, T inset (first deviation from baseline), onset temperature, T onset , peak temperature, T peak , and offset temperature, T offset (return to baseline).…”

Section: Resultsmentioning

confidence: 99%

“…Similar experimental procedures, instruments and methods were used as outlined in ref. 4. Provided in this section are summaries of these methods used in this work as well as details in methods that differ from the previous work.…”

Section: Methodsmentioning

confidence: 99%

“…A recent experimental example reported by these authors include T – X phase diagrams where the solvi have been determined at around room temperature and where the solubility increase from CSSs has been measured. 4…”

Section: Introductionmentioning

confidence: 99%

“…The analysis is contrasted with experimental determination of the solvi at 25 °C using the solubility of the solid solutions in solvent, where the tie lines in the ternary phase diagram are exploited, as outlined in ref. 4. Importantly, this latter approach also provides the solubility enhancement resulting from the incorporation of the second component into the crystal lattice of the main component.…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Solubility enhancements through crystalline solid solutions, the non-linear Tammann diagram and the T–X phase diagram of salicylic acid–benzoic acid

2023

Self Cite

View full text Add to dashboard Cite

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Solubility enhancements through crystalline solid solutions, the non-linear Tammann diagram and the T–X phase diagram of salicylic acid–benzoic acid

2023

Self Cite

View full text Add to dashboard Cite

show abstract

“…The incorporation of the impurity molecules within the host lattice carries a free energy penalty, which results in a solubility enhancement of the product. This effect can be considerable 39 and is observable in the SLIP test because of the varying impurity levels in the solid phase, leading to changes in the observed solubility for different process volumes (Figure 5d).…”

Section: Identification Of Solidmentioning

confidence: 99%

Prevalence of Impurity Retention Mechanisms in Pharmaceutical Crystallizations

Nordström

Sirota

Hartmanshenn

et al. 2023

Org. Process Res. Dev.

Self Cite

View full text Add to dashboard Cite

The rejection of process impurities from crystallizing products is an essential step for the purification of pharmaceutical drugs and for the isolation of active pharmaceutical ingredients with the right crystal quality attributes. While several impurity incorporation mechanisms have been reported in the literature, the frequency of those mechanisms in actual industrial processes is largely unknown. This work presents the outcome of a joint investigation by crystallization scientists from two pharmaceutical companies and an academic institution, on the prevalence of impurity retention mechanisms in cooling and antisolvent crystallizations. A total of 52 product-impurity pairs have been explored in detail using the so-called Solubility-Limited Impurity Purge (SLIP) test as the diagnostic tool to identify the underlying impurity retention mechanism of already crystallized materials with challenging impurities. The results show that formation of solid solutions is the most common mechanism, where the impurity and product are partially miscible in the solid state. In 73% of cases, only one solid solution phase was obtained in which the impurity became incorporated into the crystal lattice of the product (α phase). In 6% of the examples, two solid solution phases were obtained, where the second solid phase (β phase) comprised predominantly the impurity and the product was the minor component. The remaining impurity retention mechanisms (21%) are related to solid-state immiscible impurities that precipitated from solution resulting in a physical mixture between the product and the impurity. The reasons for the results are discussed through a comprehensive analysis of theoretical reported retention mechanisms, which includes physical constraints for the scale-up of isolation processes, thermodynamic assessments using ternary phase diagrams, and restrictions in the context of current pharmaceutical syntheses of small organic molecules. Three industrial case studies are presented that exemplify how knowledge of the retention mechanisms can be used to delineate appropriate strategies for process design and to effectively purge these impurities during crystallization or washing.

show abstract

Polymorphic Stability Shifts, Co-Crystals, and Crystalline Solid Solutions: The T-X Phase Diagram of Salicylic Acid–Salicylamide

Paolello,

Mohajerani,

Linehan

et al. 2024

Crystal Growth & Design

Self Cite

View full text Add to dashboard Cite

The thermodynamic phases of salicylic acid (SA) and salicylamide (SM) and their respective domains in a T-X diagram were determined experimentally from 25 °C to melting. Besides a new SA-SM cocrystal, three crystalline solid solutions (CSSs) were found, of which two belonged to polymorphic forms of SM. Form I of SM is thermodynamically stable across all temperatures when chemically pure. However, when SA is added to SM, a complete thermodynamic stability transition takes place to the CSS of SM Form III between ca. 59 and 72 mol % SM in SA at temperatures between 115 and 127 °C. In addition, a relatively large coexistence domain exists wherein the CSS phases of SM Forms I and III are equally stable thermodynamically and persist indefinitely. The polymorphic coexistence domain and stability shift provide a striking example of how CSSs can seemingly alter thermodynamic stabilities in polymorphic systems in the presence of a second component such as impurities. Implications for polymorph screening are discussed, together with a thermodynamic explanation for the phenomenon of disappearing polymorphs. The reasons for the complex T-X phase diagram are explained in concert with a detailed analysis of thermal events observed in differential scanning calorimetry (DSC) analyses. Finally, a solvent-free solid−liquid equilibrium (SLE) diagram (Roozeboom plot) is presented using 40 wt % MeOH in H 2 O. The solvent solubility enhancing effects from the CSS phases of SA and SM Form I were measured experimentally up to the respective solvi at 25 °C. These solvi correspond to the limits of miscibility of 5.8 mol % SM incorporated in the SA lattice and 2.0 mol % SA incorporated in the SM lattice.

show abstract

Enantiotropic inconstancy, crystalline solid solutions and co-crystal in the salicylic acid–anthranilic acid system

Abstract: T–X phase diagram of salicylic acid–anthranilic acid with three crystalline solid solution phases and a co-crystal, resulting in variable enantiotropic transition temperature and a polymorphic co-existence domain.

Cited by 9 publications

References 39 publications

Solubility enhancements through crystalline solid solutions, the non-linear Tammann diagram and the T–X phase diagram of salicylic acid–benzoic acid

Solubility enhancements through crystalline solid solutions, the non-linear Tammann diagram and the T–X phase diagram of salicylic acid–benzoic acid

Prevalence of Impurity Retention Mechanisms in Pharmaceutical Crystallizations

Polymorphic Stability Shifts, Co-Crystals, and Crystalline Solid Solutions: The T-X Phase Diagram of Salicylic Acid–Salicylamide

Contact Info

Product

Resources

About