Improved Synthesis and Crystal Structure of Dalcetrapib

Laus, Gerhard; Kahlenberg, Volker; Richter, Frank; Nerdinger, Sven; Schottenberger, Herwig

doi:10.3390/cryst2041455

Cited by 3 publications

(4 citation statements)

References 8 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In numerous solvent-based crystallization trials only one crystal polymorph, form A, was observed at ambient pressure and temperature. Differential scanning calorimetry and X-ray powder diffraction experiments reveal that at about −87 °C form A undergoes a reversible order–disorder phase transition to another polymorph, form B, that has been reported previously 21 (see Supplementary Fig. 1 ).…”

Section: Resultssupporting

confidence: 82%

Combined crystal structure prediction and high-pressure crystallization in rational pharmaceutical polymorph screening

Neumann¹,

et al. 2015

View full text Add to dashboard Cite

Organic molecules, such as pharmaceuticals, agro-chemicals and pigments, frequently form several crystal polymorphs with different physicochemical properties. Finding polymorphs has long been a purely experimental game of trial-and-error. Here we utilize in silico polymorph screening in combination with rationally planned crystallization experiments to study the polymorphism of the pharmaceutical compound Dalcetrapib, with 10 torsional degrees of freedom one of the most flexible molecules ever studied computationally. The experimental crystal polymorphs are found at the bottom of the calculated lattice energy landscape, and two predicted structures are identified as candidates for a missing, thermodynamically more stable polymorph. Pressure-dependent stability calculations suggested high pressure as a means to bring these polymorphs into existence. Subsequently, one of them could indeed be crystallized in the 0.02 to 0.50 GPa pressure range and was found to be metastable at ambient pressure, effectively derisking the appearance of a more stable polymorph during late-stage development of Dalcetrapib.

show abstract

Section: Resultssupporting

confidence: 82%

Combined crystal structure prediction and high-pressure crystallization in rational pharmaceutical polymorph screening

Neumann¹,

et al. 2015

View full text Add to dashboard Cite

show abstract

“…PXRD analysis of FD APIs at 10 min aging time precipitated in the presence or absence of additives at 5 °C (A) for FF with reference to form I (CCDC number 214632) and form IIa (CCDC number 1822341); peaks of form IIa showed by red circle; (B) for DCP with reference to form A (CCDC number 895592).…”

Section: Resultsmentioning

confidence: 99%

“…The FD FF precipitated in the absence of additives showed peaks from both polymorphic form I and form II (CCDC number 1822341 51 ). All FF samples that were FD in the presence of additives showed characteristic peaks of only stable form I. PXRD patterns of "as-received" DCP along with FD DCP in the presence or absence of additives showed characteristic peaks for stable polymorph form A (CCDC number 895592 52 ). Although all peaks including those of "asreceived" DCP were somewhat shifted toward higher angle compared to the peaks in reference-simulated PXRD from Cambridge structural database calculated at 100 K, all FD DCP peaks precipitated in the absence or presence of additives were in same position as the "as-received" DCP peaks, as shown in Figure 5B.…”

Section: Solid-state Analysis Of Fd Apis 321 Polymorphic Formmentioning

confidence: 99%

Impact of Additives on Drug Particles during Liquid Antisolvent Crystallization and Subsequent Freeze-Drying

Ghosh,

Rasmuson,

Hudson

2023

Org. Process Res. Dev.

View full text Add to dashboard Cite

The impact of single or combinations of additives on the generation of nanosuspensions of two poorly water-soluble active pharmaceutical ingredients (APIs), fenofibrate (FF) and dalcetrapib (DCP), and their isolation to the dry state via antisolvent (AS) crystallization followed by freeze-drying was explored in this work. Combinations of polymeric and surfactant additives such as poly(vinyl alcohol) or hydroxypropyl methyl cellulose and sodium docusate were required to stabilize nanoparticles (∼200−300 nm) of both APIs in suspension before isolation to dryness. For both FF and DCP, multiple additives generated the narrowest, moststable particle size distribution, with the smallest particles in suspension, compared with using a single additive. An industrially recognized freeze-drying process was used for the isolation of these nanoparticles to dryness. When processed by the liquid AS crystallization followed by freeze-drying in the presence of multiple additives, a purer monomorphic powder for FF resulted than when processed in the absence of any additive or in the presence of a single additive. It was noted that all nanoparticles freeze-dried in the presence of additives had a flat, flaky habit resulting in large surface areas. Agglomeration occurred during freeze-drying, resulting in micron-size particles. However, after freeze-drying, powders produced with single or multiple additives showed similar dissolution profiles, irrespective of aging time before drying, thus attenuating the advantage of multiple additives in terms of size observed before the freeze-drying process.

show abstract

“…The PXRD profile of dried DCP–MMT nanocomposite microparticles along with that of the as-received DCP and physical mixtures of as-received DCP with MMT is presented in Figure . As-received DCP was in the stable polymorphic form, Form A, , with characteristic peaks at 8.0, 17.1, and 18.6°, whereas MMT has a strong peak at 26.7°. In the physical mixtures, all the diffraction peaks of DCP were clearly visible with unchanged positions beside the peaks of MMT.…”

Section: Resultsmentioning

confidence: 99%

Drug Loading and Dissolution Properties of Dalcetrapib–Montmorillonite Nanocomposite Microparticles

Bodnár

Hudson

Rasmuson

2020

Org. Process Res. Dev.

View full text Add to dashboard Cite

This work aims to transfer the fast dissolution performances of drug nanosuspensions into the solid state via a carrier particle-mediated isolation method and explores the factors affecting the maximum achievable drug loading of the prepared nanocomposite microparticles. The solid composites of fast dissolving dalcetrapib (DCP) nanoparticles on larger montmorillonite (MMT) carrier microparticles have been prepared by an antisolvent precipitation method. The very high dissolution rate of the DCP nanoparticles is combined with the simple solid–liquid separation and drying of the MMT composite microparticles. The fast dissolution rate of DCP from the solid-state nanocomposite microparticles was maintained up to a drug loading of 20.9%, and the formulation was stable for a minimum of 10 weeks in the solid state. Surface functionalization of the MMT particles was not needed for a high and uniform attachment of nanoparticles. Addition of soluble surfactant and polymeric additives, generally used for stabilization of nanosuspensions, was not required and even decreased the DCP nanoparticle attachment and thus limited drug loading.

show abstract

Improved Synthesis and Crystal Structure of Dalcetrapib

Cited by 3 publications

References 8 publications

Combined crystal structure prediction and high-pressure crystallization in rational pharmaceutical polymorph screening

Combined crystal structure prediction and high-pressure crystallization in rational pharmaceutical polymorph screening

Impact of Additives on Drug Particles during Liquid Antisolvent Crystallization and Subsequent Freeze-Drying

Drug Loading and Dissolution Properties of Dalcetrapib–Montmorillonite Nanocomposite Microparticles

Contact Info

Product

Resources

About