Dissolution, Nucleation, Crystal Growth, Crystal Aggregation, and Particle Breakage of Amlodipine Salts: Modeling Crystallization Kinetics and Thermodynamic Equilibrium, Scale-up, and Optimization

Calcium orthophosphates (CaP) synthesis involves several chemical equilibria that define the phases present in the final product. From the biomaterials standpoint, it is important to gain knowledge on how synthesis parameters affect phase formation and particle size. This study evaluates the interaction between temperature (24 or 45 °C) and pH conditions (4.5, 6.5, or drifting) on CaP precipitation in terms of yield, phase formation, density, morphology, and size distribution. Calcium and phosphate solutions (Ca/P = 1.0) are mixed and kept under stirring for 3 h. The precipitate is freeze-dried and characterized. Under drifting pH and pH 4.5, dicalcium phosphate dihydrate (DCPD, CaHPO 4 × 2H 2 O) is the predominant phase at both temperatures; however, some samples also present peaks ascribed to dicalcium phosphate anhydrous (DCPA, CaHPO 4 ). At pH 6.5, diffractograms reveal a mixture of low-crystallinity DCPD and DCPA (24 °C) or low crystallinity hydroxyapatite [HAP, Ca 10 (OH) 2 (PO 4 ) 6 ] (45 °C). In spite of the different morphologies (plates or aggregates), particle size remains within a relatively narrow range (D 50 = 12-28 µm). DCPD precipitation is favored under more acidic or drifting pH, while HAP is formed under nearly neutral pH 6.5.

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“…As an alternative, mechanistic modeling simulations could be used in order to obtain a more comprehensive view of crystalline systems. [58,59]…”

Section: Particle Sizementioning

confidence: 99%

Effect of Temperature and pH on Calcium Phosphate Precipitation

Vilela

Rodrigues

Fronza

et al. 2021

Crystal Research and Technology

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“…The presented CFD modeling papers include simulations made in collaboration with or supported by Roche [3], Sanofi [2], Sandoz [4], Krka d.d. [5], Pfizer Inc. [1,6], LEO Pharma A/S [7,8], Astra Zeneca Pharmaceutical Development R&D [9], GlaxoSmithKline [10,11] and one performed with the support of an industrial consortium including BASF, ICI, Malvern Instruments, AstraZeneca, GlaxoSmithKline and Pfizer [12].…”

Section: Introductionmentioning

confidence: 99%

A Review of Computational Fluid Dynamics (CFD) Simulations of Mixing in the Pharmaceutical Industry

Pohar

Babnik²,

Erklavec-Zajec³

et al. 2020

BJSTR

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Due to the increasing computational power and availability of advanced commercial, as well as open-source computational fluid dynamics (CFD) software, performing CFD simulations is becoming more accessible and its use has expanded into many industrial sectors. For the pharmaceutical industry, the topic of mixing is especially of interest, since it is a common unit operation in pharmaceutical processes and empirical and semi-empirical correlations for predicting the hydrodynamic characteristics inside a batch mixing vessel do not consider the complete three-dimensional geometry of the vessel and impeller. This is important in processes such as crystallization, dissolution, compounding, and cellular production in bioreactors, and the obtained information can aid in the selection of the mixer geometry, the choice of mixing speed and for achieving comparable scale-up/down operation of laboratory and industrial mixing vessels. The pharmaceutical industry is not keen on publishing their research and the details of their technology, so the available literature is limited. In this mini review, publications, in which CFD simulations of the mixing process were performed for real pharmaceutical cases are presented, the obtained results are discussed and the software, modeling techniques and methods and their comparisons to measurements are highlighted.

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“…Heteroaromatic compounds, such as pyridine and imidazole, have been grafted onto each kind of polysaccharides. The synthetic strategy was optimized by researchers to meet efficient, simple, and economic purposes [38,39,40,41]. Previously, our team succeeded in the synthesis of N -(aminoethyl) inulin, 6-amino-6-deoxy inulin, and 6-azido-inulin for “click” reactions [42,43,44].…”

Section: Introductionmentioning

confidence: 99%

Radical Scavenging Activities of Novel Cationic Inulin Derivatives

Chen

Zhang

et al. 2018

Polymers

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Many saccharides are attractive targets for biomaterial applications, due to their abundance, biocompatibility, and biodegradability. In this article, a synthesis process of 6-N-substituted cationic inulin derivatives, including 6-pyridyl-6-deoxyinulin bromide (PIL), 6-(2-amino-pyridyl)-6-deoxyinulin bromide (2APIL), 6-(3-amino-pyridyl)-6-deoxyinulin bromide (3APIL), 6-(4-amino-pyridyl)-6-deoxyinulin bromide (4APIL), 6-(2,3-diamino-pyridyl)-6-deoxyinulin bromide (2,3DAPIL), 6-(3,4-diamino-pyridyl)-6-deoxyinulin bromide (3,4DAPIL), and 6-(2,6-diamino-pyridyl)-6-deoxyinulin bromide (2,6DAPIL) was described. The C6-OH of inulin was first activated by PPh3/N-bromosuccinimide (NBS) bromination. Then, pyridine and different kinds of amino-pyridine groups (different position and different numbers of amino) were grafted onto inulin, respectively, via nucleophilic substitution. Then, we confirmed their structure by Fourier transform infrared spectroscopy (FT-IR) and nuclear magnetic resonance (NMR) spectroscopy. After this, their radical scavenging activities against hydroxyl radical and diphenylpicryl phenylhydrazine (DPPH) radical were tested in vitro. Each derivative showed a distinct improvement in radical scavenging activity when compared to inulin. The hydroxyl-radical scavenging effect decreased in the following order: 3APIL > PIL > 3,4DAPIL > 4APIL > 2,3DAPIL > 2,6DAPIL > 2APIL. Amongst them, 3APIL revealed the most powerful scavenging effect on hydroxyl radicals, as well as DPPH radicals. At 1.6 mg/mL, it could completely eliminate hydroxyl radicals and could clear 65% of DPPH radicals. The results also showed that the steric hindrance effect and the substitute position of the amino group had an effect on the radical scavenging activity. Moreover, the application prospects of inulin derivatives as natural antioxidant biomaterials are scientifically proven in this paper.

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Dissolution, Nucleation, Crystal Growth, Crystal Aggregation, and Particle Breakage of Amlodipine Salts: Modeling Crystallization Kinetics and Thermodynamic Equilibrium, Scale-up, and Optimization

Cited by 41 publications

References 32 publications

Effect of Temperature and pH on Calcium Phosphate Precipitation

Effect of Temperature and pH on Calcium Phosphate Precipitation

A Review of Computational Fluid Dynamics (CFD) Simulations of Mixing in the Pharmaceutical Industry

Radical Scavenging Activities of Novel Cationic Inulin Derivatives

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