scholarly journals The Crystallization of Active Pharmaceutical Ingredients with Low Melting Points in the Presence of Liquid–Liquid Phase Separation

Crystals ◽  
2021 ◽  
Vol 11 (11) ◽  
pp. 1326
Author(s):  
Wei Han Lin ◽  
Zai-Qun Yu ◽  
Pui Shan Chow ◽  
Reginald Beng Hee Tan
Keyword(s):  
Phase Separation ◽  
Liquid Phase ◽  
Hydroxypropyl Methylcellulose ◽  
Tween 80 ◽  
Liquid Phase Separation ◽  
Water Mixture ◽  
Active Pharmaceutical Ingredients ◽  
Melting Points ◽  
Pharmaceutical Ingredients ◽  
Liquid Liquid Phase Separation

Liquid–liquid phase separation (LLPS) during the crystallization of active pharmaceutical ingredients (APIs) often causes agglomeration and other quality issues in crystal products; thus, it should be avoided if possible. However, LLPS in the crystallization of APIs with low melting points cannot be circumvented in some cases due to yield considerations. The crystallization of ibuprofen in an ethanol/water mixture was studied to explore methods to reduce agglomeration in the presence of LLPS. It was found that unseeded crystallization produced agglomerates when LLPS took place. The two liquid phases resulting from LLPS underwent LLPS again when they were cooled separately, indicating the dynamic nature of LLPS. Seeding and seed ageing at a low supersaturation were very effective in mitigating agglomeration. The effects of two widely used surfactants, i.e., Tween 80 and hydroxypropyl methylcellulose (HPMC), on LLPS and crystallization were confirmed preliminarily. More work needs to be conducted to explore their usefulness in LLPS handling. The findings and techniques presented in this study may be applicable to the crystallization of other APIs with low melting points.

scholarly journals Relevance of Liquid-Liquid Phase Separation of Supersaturated Solution in Oral Absorption of Albendazole from Amorphous Solid Dispersions

Pharmaceutics ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 220
Author(s):  
Kyosuke Suzuki ◽  
Kohsaku Kawakami ◽  
Masafumi Fukiage ◽  
Michinori Oikawa ◽  
Yohei Nishida ◽  
...  
Keyword(s):  
Phase Separation ◽  
Liquid Phase ◽  
Oral Absorption ◽  
Hydroxypropyl Methylcellulose ◽  
Amorphous Solid ◽  
Liquid Phase Separation ◽  
Quantitative Prediction ◽  
Amorphous Solid Dispersion ◽  
Supersaturated Solution ◽  
Liquid Liquid Phase Separation

Amorphous solid dispersion (ASD) is one of the most promising formulation technologies for improving the oral absorption of poorly soluble drugs, where the maintenance of supersaturation plays a key role in enhancing the absorption process. However, quantitative prediction of oral absorption from ASDs is still difficult. Supersaturated solutions can cause liquid-liquid phase separation through the spinodal decomposition mechanism, which must be adequately comprehended to understand the oral absorption of drugs quantitatively. In this study, albendazole (ALZ) was formulated into ASDs using three types of polymers, poly(methacrylic acid-co-methyl methacrylate) (Eudragit) L100, Vinylpyrrolidone-vinyl acetate copolymer (PVPVA), and hydroxypropyl methylcellulose acetate succinate (HPMCAS). The oral absorption of ALZ in rats administered as ASD suspensions was not explained by dissolution study but was predicted using liquid-liquid phase separation concentration, which suggested that the absorption of ALZ was solubility-limited. The oral administration study in dogs performed using solid capsules demonstrated the low efficacy of ASDs because the absorption was likely to be limited by dissolution rate, which indicated the importance of designing the final dosage form of the ASDs.

Quasi-Isothermal Liquid/Liquid Phase Separation in a n-Butoxyethanol/Water Mixture under Reduced Gravity

Langmuir ◽  
1994 ◽  
Vol 10 (3) ◽  
pp. 629-631 ◽  
Author(s):  
Barbara Braun ◽  
Christian Ikier ◽  
Hermann Klein ◽  
Gerd Schmitz ◽  
Kurt Wanders ◽  
...  
Keyword(s):  
Phase Separation ◽  
Liquid Phase ◽  
Liquid Phase Separation ◽  
Water Mixture ◽  
Reduced Gravity ◽  
Liquid Liquid Phase Separation

scholarly journals Role of protein conformation and weak interactions on γ-gliadin liquid-liquid phase separation

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Line Sahli ◽  
Denis Renard ◽  
Véronique Solé-Jamault ◽  
Alexandre Giuliani ◽  
Adeline Boire
Keyword(s):  
Phase Separation ◽  
Liquid Phase ◽  
Electrostatic Interactions ◽  
Storage Proteins ◽  
Liquid Phase Separation ◽  
Water Mixture ◽  
Terminal Domain ◽  
Liquid Liquid Phase Separation

Abstract Wheat storage proteins, gliadins, were found to form in vitro condensates in 55% ethanol/water mixture by decreasing temperature. The possible role of this liquid-liquid phase separation (LLPS) process on the in vivo gliadins storage is elusive and remains to be explored. Here we use γ-gliadin as a model of wheat proteins to probe gliadins behavior in conditions near physiological conditions. Bioinformatic analyses suggest that γ-gliadin is a hybrid protein with N-terminal domain predicted to be disordered and C-terminal domain predicted to be ordered. Spectroscopic data highlight the disordered nature of γ-gliadin. We developed an in vitro approach consisting to first solubilize γ-gliadin in 55% ethanol (v/v) and to progressively decrease ethanol ratio in favor of increased aqueous solution. Our results show the ability of γ-gliadin to self-assemble into dynamic droplets through LLPS, with saturation concentrations ranging from 25.9 µM ± 0.85 µM (35% ethanol (v/v)) to 3.8 µM ± 0.1 µM (0% ethanol (v/v)). We demonstrate the importance of the predicted ordered C-terminal domain of γ-gliadin in the LLPS by highlighting the protein condensates transition from a liquid to a solid state under reducing conditions. We demonstrate by increasing ionic strength the role displayed by electrostatic interactions in the phase separation. We also show the importance of hydrogen bonds in this process. Finally, we discuss the importance of gliadins condensates in their accumulation and storage in the wheat seed.

scholarly journals Liquid-Liquid Phase Separation of Tau Driven by Hydrophobic Interaction Facilitates Fibrillization of Tau

2021 ◽  
Vol 433 (2) ◽  
pp. 166731
Author(s):  
Yanxian Lin ◽  
Yann Fichou ◽  
Andrew P. Longhini ◽  
Luana C. Llanes ◽  
Pengyi Yin ◽  
...  
Keyword(s):  
Phase Separation ◽  
Liquid Phase ◽  
Hydrophobic Interaction ◽  
Liquid Phase Separation ◽  
Liquid Liquid Phase Separation

scholarly journals Amyloid Aggregation under the Lens of Liquid–Liquid Phase Separation

2020 ◽  
pp. 368-378
Author(s):  
Yanting Xing ◽  
Aparna Nandakumar ◽  
Aleksandr Kakinen ◽  
Yunxiang Sun ◽  
Thomas P. Davis ◽  
...  
Keyword(s):  
Phase Separation ◽  
Liquid Phase ◽  
Liquid Phase Separation ◽  
Amyloid Aggregation ◽  
Liquid Liquid Phase Separation

scholarly journals Observation of liquid-liquid phase separation of ataxin-3 and quantitative evaluation of its concentration in a single droplet using Raman microscopy

2021 ◽  
Author(s):  
Kazuki Murakami ◽  
Shinji Kajimoto ◽  
Daiki Shibata ◽  
Kunisato Kuroi ◽  
Fumihiko Fujii ◽  
...  
Keyword(s):  
Phase Separation ◽  
Liquid Phase ◽  
Neurodegenerative Diseases ◽  
Protein Aggregation ◽  
Quantitative Evaluation ◽  
Raman Microscopy ◽  
Liquid Phase Separation ◽  
Biological Processes ◽  
Single Droplet ◽  
Liquid Liquid Phase Separation

Liquid–liquid phase separation (LLPS) plays an important role in a variety of biological processes and is also associated with protein aggregation in neurodegenerative diseases. Quantification of LLPS is necessary to...

scholarly journals Targeting NSD2-mediated SRC-3 liquid–liquid phase separation sensitizes bortezomib treatment in multiple myeloma

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jing Liu ◽  
Ying Xie ◽  
Jing Guo ◽  
Xin Li ◽  
Jingjing Wang ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Drug Resistance ◽  
Phase Separation ◽  
Liquid Phase ◽  
Liquid Phase Separation ◽  
Acquired Drug Resistance ◽  
Bortezomib Treatment ◽  
Liquid Liquid Phase Separation

AbstractDevelopment of chemoresistance is the main reason for failure of clinical management of multiple myeloma (MM), but the genetic and epigenetic aberrations that interact to confer such chemoresistance remains unknown. In the present study, we find that high steroid receptor coactivator-3 (SRC-3) expression is correlated with relapse/refractory and poor outcomes in MM patients treated with bortezomib (BTZ)-based regimens. Furthermore, in immortalized cell lines, high SRC-3 enhances resistance to proteasome inhibitor (PI)-induced apoptosis. Overexpressed histone methyltransferase NSD2 in patients bearing a t(4;14) translocation or in BTZ-resistant MM cells coordinates elevated SRC-3 by enhancing its liquid–liquid phase separation to supranormally modify histone H3 lysine 36 dimethylation (H3K36me2) modifications on promoters of anti-apoptotic genes. Targeting SRC-3 or interference of its interactions with NSD2 using a newly developed inhibitor, SI-2, sensitizes BTZ treatment and overcomes drug resistance both in vitro and in vivo. Taken together, our findings elucidate a previously unrecognized orchestration of SRC-3 and NSD2 in acquired drug resistance of MM and suggest that SI-2 may be efficacious for overcoming drug resistance in MM patients.

scholarly journals Deciphering the Role of π-Interactions in Polyelectrolyte Complexes Using Rationally Designed Peptides

Polymers ◽  
2021 ◽  
Vol 13 (13) ◽  
pp. 2074
Author(s):  
Sara Tabandeh ◽  
Cristina Elisabeth Lemus ◽  
Lorraine Leon
Keyword(s):  
Hydrogen Bonding ◽  
Phase Separation ◽  
Liquid Phase ◽  
Charge Density ◽  
Secondary Structures ◽  
Liquid Phase Separation ◽  
Polyelectrolyte Complexes ◽  
Π Interactions ◽  
Liquid Liquid Phase Separation

Electrostatic interactions, and specifically π-interactions play a significant role in the liquid-liquid phase separation of proteins and formation of membraneless organelles/or biological condensates. Sequence patterning of peptides allows creating protein-like structures and controlling the chemistry and interactions of the mimetic molecules. A library of oppositely charged polypeptides was designed and synthesized to investigate the role of π-interactions on phase separation and secondary structures of polyelectrolyte complexes. Phenylalanine was chosen as the π-containing residue and was used together with lysine or glutamic acid in the design of positively or negatively charged sequences. The effect of charge density and also the substitution of fluorine on the phenylalanine ring, known to disrupt π-interactions, were investigated. Characterization analysis using MALDI-TOF mass spectroscopy, H NMR, and circular dichroism (CD) confirmed the molecular structure and chiral pattern of peptide sequences. Despite an alternating sequence of chirality previously shown to promote liquid-liquid phase separation, complexes appeared as solid precipitates, suggesting strong interactions between the sequence pairs. The secondary structures of sequence pairs showed the formation of hydrogen-bonded structures with a β-sheet signal in FTIR spectroscopy. The presence of fluorine decreased hydrogen bonding due to its inhibitory effect on π-interactions. π-interactions resulted in enhanced stability of complexes against salt, and higher critical salt concentrations for complexes with more π-containing amino acids. Furthermore, UV-vis spectroscopy showed that sequences containing π-interactions and increased charge density encapsulated a small charged molecule with π-bonds with high efficiency. These findings highlight the interplay between ionic, hydrophobic, hydrogen bonding, and π-interactions in polyelectrolyte complex formation and enhance our understanding of phase separation phenomena in protein-like structures.

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