Formation mechanism of amorphous drug nanoparticles using the antisolvent precipitation method elucidated by varying the preparation temperature

Morikawa, Chikako; Ueda, Keisuke; Omori, Masaki; Higashi, Kenjirou; Moribe, Kunikazu

doi:10.1016/j.ijpharm.2021.121210

Cited by 7 publications

(4 citation statements)

References 44 publications

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“…During the suspension of the frozen pellets, the free stabilizer molecules provide a thermodynamically stable environment for the suspension of the microcrystals through spatial potential stabilization or electrostatic stabilization. 56,57 The case of NFD confirms that the addition of additives to solutions containing NFD results in better-quality NFD inhalation microcrystals than the addition of stabilizers to its antisolvent (Figure S12). Furthermore, it has been reported that surfactants usually increase the solubility of insoluble drugs in organic solvents or in water.…”

Section: Fdt Mechanism For Inhalable Microcrystalsmentioning

confidence: 75%

“…Second, the additives can selectively adsorb on specific crystal facets of the microcrystals, which will not only change the growth rates of different crystal facets and ultimately change the morphology and particle size of the microcrystals but also avoid the adhesion of the drug microcrystals in the limiting space of the iced pellet. During the suspension of the frozen pellets, the free stabilizer molecules provide a thermodynamically stable environment for the suspension of the microcrystals through spatial potential stabilization or electrostatic stabilization. , The case of NFD confirms that the addition of additives to solutions containing NFD results in better-quality NFD inhalation microcrystals than the addition of stabilizers to its antisolvent (Figure S12).…”

Section: Resultsmentioning

confidence: 99%

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A Scalable Freeze-Dissolving Approach to Prepare Ultrafine Crystals for Inhalation: Mechanism and Validation

Guo,

Cao,

Zhang

et al. 2024

Crystal Growth & Design

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Inhaled drug delivery has garnered increasing attention due to its inherent advantages including rapid onset of action, targeted delivery, high bioavailability, and reduced side effects, which holds promise for the treatment of localized lung diseases and systemic diseases. The currently dominant technologies for the preparation of inhalants are air flow pulverization, media milling, and spray drying, which encounter challenges such as inaccurate particle size control, inefficiency, instability, and difficulties in scaling up. The present study proposes a freezedissolving technique (FDT) for the preparation of inhalable microcrystals, comprising two essential steps: rapid freezing of microdroplets into iced pellets within seconds and subsequent dissolution of a solvent in the iced pellets to release the microcrystals in a suspension. By employing the FDT technique, griseofulvin, a representative inhalant, was successfully engineered into a bipyramidal morphology with a targeted particle size (<5 μm), minimal agglomeration (<3%), and an aspect ratio below 2, in which the solvent and stabilizer systems played pivotal roles in facilitating or impeding nucleation and crystal growth processes. To verify the universality of the FDT, six other typical inhalant preparation processes were successfully developed based on the FDT with a controllable crystal size between 1 and 10 μm. Furthermore, three out of the aforementioned seven model substances were randomly selected, and their preparation was scaled up by a factor of 100, yielding consistent results with those obtained at a smaller test scale. This study outlines the freeze-dissolving mechanism in ultrafine crystal formation and demonstrates that the FDT is a robust and scalable approach for the production of inhalants.

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Section: Fdt Mechanism For Inhalable Microcrystalsmentioning

confidence: 75%

Section: Resultsmentioning

confidence: 99%

A Scalable Freeze-Dissolving Approach to Prepare Ultrafine Crystals for Inhalation: Mechanism and Validation

Guo,

Cao,

Zhang

et al. 2024

Crystal Growth & Design

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“…Spray-drying (chitosan-graphene oxide) [14] Freeze-drying (Sulfasalazine-chitosan) [15] Vacuum-drying (Itraconazole) [16] Aerosol flow reactor (glucocorticosteroid) [17] Electrospraying (Medroxyprogesterone acetate -PLA) [18] Fluid-bed coating/granulation/drying (Indomethacin) [19] Wet-casing drying (Sunitinib-PHBV) [20] Nanoextrusion (Griseofulvin) [21] Precipitation methods Solvent-antisolvent (Glibenclamide-HPMC) [22] High-gravity precipitation (Sorafenib) [23] Flash precipitation (soybean protein) [24] Sonocrystallization (Nobiletin) [25] Confined impinging liquid jet precipitation (loratadine) [26] Multi-inlet vortex mixing (lysozyme and erythromycin) [27] Sono precipitation (Clotrimazole, Isradipine) [28,29] Supercritical fluid precipitation (Rosuvastatin calcium) [30] Top-down High-pressure homogenization Microfluidification (Gadolinium diethylenetriamine penta-acetic acid) [31] Piston gap homogenization Bead milling (Griseofulvin -hydroxypropyl cellulose and sodium dodecyl sulfate) [32] Cryomilling (Phenytoin-PVP) [33] magnitude proportional to the concentration gradient and characterizing solute behavior, and Fick's second law, which predicts the effect of diffusion on varying concentrations. One can classify solute diffusion as either Fickian or non-Fickian, into one of which drug delivery systems frequently fall.…”

Section: Bottom-up Evaporation Methodsmentioning

confidence: 99%

Kinetic Modeling to Explain the Release of Medicine from Drug Delivery Systems

Askarizadeh,

Esfandiari,

Honarvar

et al. 2023

ChemBioEng Reviews

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Proper medication dissolution must be ensured when developing or manufacturing a new solid dosage form. Quantitative analyses performed in dissolution or release tests become simpler when applying mathematical formulae which represent dissolution outcomes as a function of several dosage form properties. Methodologies utilized to examine the kinetics of drug release from controlled‐release formulations are reviewed. The analysis of variance was conducted using statistical, model‐independent, and ‐dependent techniques for the dissolution profile comparison and fitting, respectively. Model equations, including zero‐ and first‐order, Hixson‐Crowell, Weibull, Higuchi, Korsmeyer‐Peppas, Baker‐Lonsdale, Hopfenberg, etc., were employed to match the experimental data. Additional release parameters were taken to illustrate the drug release patterns. Using correlation factors and the Akaike information criterion (AIC), the best‐fitting model was discovered, as were the transport phenomena affecting the behavior of the recognized formulations.

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“…The assessment process, however, is characterized by its time-consuming and labor-intensive nature. Moreover, the X-ray powder diffraction (PXRD) patterns of amorphous drugs displayed a solitary halo peak, posing challenges in distinguishing different amorphous samples solely based on their PXRD patterns [8,9]. Therefore, PXRD is not deemed sufficiently accurate for evaluating the physical stability in amorphous drugs.…”

Section: Introductionmentioning

confidence: 99%

The Optimization of Pair Distribution Functions for the Evaluation of the Degree of Disorder and Physical Stability in Amorphous Solids

Yuan,

Li,

Luo

et al. 2024

Molecules

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The amorphous form of poorly soluble drugs is physically unstable and prone to crystallization, resulting in decreased solubility and bioavailability. However, the conventional accelerated stability test for amorphous drugs is time-consuming and inaccurate. Therefore, there is an urgent need to develop rapid and accurate stability assessment technology. This study used the antitumor drug nilotinib free base as a model drug. The degree of disorder and physical stability in the amorphous form was assessed by applying the pair distribution function (PDF) and principal component analysis (PCA) methods based on powder X-ray diffraction (PXRD) data. Specifically, the assessment conditions, such as the PDF interatomic distance range, PXRD detector type, and PXRD diffraction angle range were also optimized. The results showed that more reliable PCA data could be obtained when the PDF interatomic distance range was 0–15 Å. When the PXRD detector was a semiconductor-type detector, the PDF data obtained were more accurate than other detectors. When the PXRD diffraction angle range was 5–40°, the intermolecular arrangement of the amorphous drugs could be accurately predicted. Finally, the accelerated stability test also showed that under the above-optimized conditions, this method could accurately and rapidly assess the degree of disorder and physical stability in the amorphous form of drugs, which has obvious advantages compared with the accelerated stability test.

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Formation mechanism of amorphous drug nanoparticles using the antisolvent precipitation method elucidated by varying the preparation temperature

Cited by 7 publications

References 44 publications

A Scalable Freeze-Dissolving Approach to Prepare Ultrafine Crystals for Inhalation: Mechanism and Validation

A Scalable Freeze-Dissolving Approach to Prepare Ultrafine Crystals for Inhalation: Mechanism and Validation

Kinetic Modeling to Explain the Release of Medicine from Drug Delivery Systems

The Optimization of Pair Distribution Functions for the Evaluation of the Degree of Disorder and Physical Stability in Amorphous Solids

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