Towards controlling the crystallisation behaviour of fenofibrate melt: triggers of crystallisation and polymorphic transformation

Tipduangta, Pratchaya; Takieddin, Khaled; Fábián, László; Belton, Peter; Qi, Sheng

doi:10.1039/c8ra01182f

Cited by 10 publications

(9 citation statements)

References 37 publications

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“…PXRD patterns of unprocessed ("as-received") FF showed the characteristic high-intense diffraction peaks of the stable polymorphic form I confirmed with data from the Cambridge Structural Database (CCDC number 214632 50 ), as shown in Figure 5A. 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 ).…”

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

confidence: 68%

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

Ghosh,

Rasmuson,

Hudson

2023

Org. Process Res. Dev.

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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.

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

confidence: 68%

“…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%

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

Ghosh,

Rasmuson,

Hudson

2023

Org. Process Res. Dev.

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“…Its infrared spectrum is between 1800 cm −1 and 630 cm −1 , shown in Figure 11 —purple spectra [ 6 , 39 ]. The available assignments of peaks were collected from the literature, and a summary of them is given in Supplementary Table S1 [ 34 , 35 , 39 , 40 , 41 ]. Similar articles on cyclodextrins (CDs) were scarcely found [ 42 , 43 , 44 , 45 ].…”

Section: Resultsmentioning

confidence: 99%

“…Based on the Spectra of FEN, DIMEB, and "PRODUCT" Macrocrystalline Form-I of fenofibrate was used for the co-grinding experiment. Its infrared spectrum is between 1800 cm −1 and 630 cm −1 , shown in Figure 11-purple spectra [6,39]. The available assignments of peaks were collected from the literature, and a summary of them is given in Supplementary Table S1 [34,35,[39][40][41].…”

Section: Molecular Considerationsmentioning

confidence: 99%

Cyclodextrin Complexation of Fenofibrate by Co-Grinding Method and Monitoring the Process Using Complementary Analytical Tools

et al. 2022

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Solvent-free preparation types for cyclodextrin complexation, such as co-grinding, are technologies desired by the industry. However, in-depth analytical evaluation of the process and detailed characterization of intermediate states of the complexes are still lacking in areas. In our work, we aimed to apply the co-grinding technology and characterize the process. Fenofibrate was used as a model drug and dimethyl-β-cyclodextrin as a complexation excipient. The physical mixture of the two substances was ground for 60 min; meanwhile, samples were taken. A solvent product of the same composition was also prepared. The intermediate samples and the final products were characterized with instrumental analytical tools. The XRPD measurements showed a decrease in the crystallinity of the drug and the DSC results showed the appearance of a new crystal form. Correlation analysis of FTIR spectra suggests a three-step complexation process. In vitro dissolution studies were performed to compare the dissolution properties of the pure drug to the products. Using a solvent-free production method, we succeeded in producing a two-component system with superior solubility properties compared to both the active ingredient and the product prepared by the solvent method. The intermolecular description of complexation was achieved with a detailed analysis of FTIR spectra.

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“…Furthermore, the signal at 1600 cm −1 from the carbonyl stretching region, present in the FEN ( Figure 5 a) and both physical mixtures ( Figure 5 d,e), was missing from the drug-loaded microfibers’ spectrum. This might indicate that FEN was present in an amorphous form in the drug-loaded electrospun microfibrous samples [ 43 , 44 , 45 ].…”

Section: Resultsmentioning

confidence: 99%

Preparation and Characterization of Fenofibrate-Loaded PVP Electrospun Microfibrous Sheets

et al. 2020

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Fenofibrate-loaded electrospun microfibrous sheets were prepared in an attempt to enhance the dissolution of the poorly soluble antihyperlipidemic agent and to improve its bioavailability. Physicochemical changes that appeared during the electrospinning process were monitored using a wide array of solid-state characterization techniques, including attenuated total reflectance Fourier-transformed infrared spectroscopy and positron annihilation lifetime spectroscopy, while fiber morphology was monitored via scanning electron microscopy. Dissolution studies carried out both in 0.025 M sodium dodecyl sulfate and in water revealed an immediate release of the active agent, with an approximately 40-fold release rate enhancement in water when compared to the micronized active agent. The dramatic increase in dissolution was attributed partially to the amorphous form of the originally crystalline active agent and the rapid disintegration of the electrospun microfibrous sheet due to its high surface area and porosity. The obtained results could pave the way for a formulation of the frequently used antihyperlipidemic agent with increased bioavailability.

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Towards controlling the crystallisation behaviour of fenofibrate melt: triggers of crystallisation and polymorphic transformation

Abstract: Fenofibrate is a dyslipidemia treatment agent. Its crystallisation behaviour is difficult to predict. This study investigated the controllability of its crystallisation by means of regulating the exposed surface and growth temperatures.

Cited by 10 publications

References 37 publications

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

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

Cyclodextrin Complexation of Fenofibrate by Co-Grinding Method and Monitoring the Process Using Complementary Analytical Tools

Preparation and Characterization of Fenofibrate-Loaded PVP Electrospun Microfibrous Sheets

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