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. 2024 Mar 13;29(6):1275.
doi: 10.3390/molecules29061275.

Investigation of the Influence of Anti-Solvent Precipitation Parameters on the Physical Stability of Amorphous Solids

Zunhua Li  1 , Zicheng Gong  1 , Bowen Zhang  2 , Asad Nawaz  1
Affiliations

Investigation of the Influence of Anti-Solvent Precipitation Parameters on the Physical Stability of Amorphous Solids

Zunhua Li et al. Molecules. .

Abstract

Amorphous solids exhibit enhanced solubility and dissolution rates relative to their crystalline counterparts. However, attaining optimal bioavailability presents a challenge, primarily due to the need to maintain the physical stability of amorphous solids. Moreover, the precise manner in which precipitation parameters, including the feeding rate of the anti-solvent, agitation speed, and aging time, influence the physical stability of amorphous solids remains incompletely understood. Consequently, this study aimed to investigate these three parameters during the precipitation process of the anticancer drug, nilotinib free base. The physical stability of the resultant samples was evaluated by employing characterization techniques including powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), focused beam reflectance measurement (FBRM), and data analysis methods such as pair distribution function (PDF), reduced crystallization temperature (Rc), and principal component analysis (PCA). This study's findings indicated that amorphous solids exhibited the greatest physical stability under particular conditions, namely a feeding rate of 5 mL/min, an agitation speed of 500 rpm, and an aging time of 10 min. Furthermore, the physical stability of the amorphous solids was primarily influenced by particle size and distribution, molecular interactions, microstructure, surface area, and interfacial energy. Notably, the parameters involved in the anti-solvent precipitation process, including the feeding rate of the anti-solvent, agitation speed, and aging time, exerted a significant impact on these factors. Consequently, they directly affected the physical stability of amorphous solids. Hence, this study comprehensively elucidated the mechanistic influence of these operational parameters on the physical stability of amorphous solids during the anti-solvent precipitation process.

Keywords: amorphous solid; pair distribution function; physical stability; principal component analysis; reduced crystallization temperature.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
The influence of the feeding rate of the anti-solvent on the formation of nilotinib free base solid samples: (a) PXRD patterns; (b) PDF trace (the NNN represents the next nearest neighbor atoms in the nilotinib free base solid samples); (c) GNNN value; (d) PCA scores plot (The R2 represents the goodness of fit, while the Q2 represents the goodness of prediction). The crystalline Form A was used as a reference sample; the agitation speed was fixed at 500 rpm, and the aging time was fixed at 10 min.
Figure 2
Figure 2
The influence of the feeding rate of the anti-solvent on the formation of nilotinib free base solid samples: (a) DSC curves (the TC represents the crystallization temperature of the amorphous solid samples, while the TmA represents the melting temperature of nilotinib free base crystalline Form A); (b) Reduced crystallization temperature, Rc value. (the crystalline Form A was used as a reference sample; the agitation speed was fixed at 500 rpm, and the aging time was fixed at 10 min).
Figure 3
Figure 3
The influence of the feeding rate of the anti-solvent on the formation of nilotinib free base amorphous solids: (a) Filtering rate; (b) Particle size distribution; (c) Volume mean diameter, D4,3. (the agitation speed was fixed at 500 rpm, and the aging time was fixed at 10 min).
Figure 4
Figure 4
The influence of agitation speed on the formation of nilotinib free base amorphous solids: (a) PXRD patterns; (b) PDF trace (the NNN represents the next nearest neighbor atoms in the nilotinib free base solid samples); (c) GNNN value; (d) PCA scores plot (the R2 represents the goodness of fit, while the Q2 represents the goodness of prediction). The crystalline Form A was used as a reference sample; the feeding rate was fixed at 5 mL/min, and the aging time was fixed at 10 min.
Figure 4
Figure 4
The influence of agitation speed on the formation of nilotinib free base amorphous solids: (a) PXRD patterns; (b) PDF trace (the NNN represents the next nearest neighbor atoms in the nilotinib free base solid samples); (c) GNNN value; (d) PCA scores plot (the R2 represents the goodness of fit, while the Q2 represents the goodness of prediction). The crystalline Form A was used as a reference sample; the feeding rate was fixed at 5 mL/min, and the aging time was fixed at 10 min.
Figure 5
Figure 5
The influence of agitation speed on the formation of nilotinib free base amorphous solids: (a) DSC curves (the TC represents the crystallization temperature of the amorphous solid samples, while the TmA represents the melting temperature of nilotinib free base crystalline Form A); (b) Reduced crystallization temperature, Rc value. The crystalline Form A was used as a reference sample; the feeding rate was fixed at 5 mL/min, and the aging time was fixed at 10 min).
Figure 6
Figure 6
The influence of agitation speed on the formation of nilotinib free base amorphous solids: (a) Filtering rate; (b) Particle size distribution; (c) Volume mean diameter, D4,3. The feeding rate was fixed at 5 mL/min, and the aging time was fixed at 10 min.
Figure 7
Figure 7
The influence of aging time on the formation of nilotinib free base amorphous solids: (a) PXRD patterns; (b) PDF trace (the NNN represents the next nearest neighbor atoms in the nilotinib free base solid samples); (c) GNNN value; (d) PCA scores plot (the R2 represents the goodness of fit, while the Q2 represents the goodness of prediction). The crystalline Form A was used as a reference sample; the feeding rate was fixed at 5 mL/min, and the agitation speed was fixed at 500 rpm.
Figure 7
Figure 7
The influence of aging time on the formation of nilotinib free base amorphous solids: (a) PXRD patterns; (b) PDF trace (the NNN represents the next nearest neighbor atoms in the nilotinib free base solid samples); (c) GNNN value; (d) PCA scores plot (the R2 represents the goodness of fit, while the Q2 represents the goodness of prediction). The crystalline Form A was used as a reference sample; the feeding rate was fixed at 5 mL/min, and the agitation speed was fixed at 500 rpm.
Figure 8
Figure 8
The influence of aging time on the formation of nilotinib free base amorphous solids: (a) DSC curves (the TC represents the crystallization temperature of the amorphous solid samples, while the TmA and TmB represent the melting temperature of nilotinib free base crystalline Form A and Form B, respectively); (b) Reduced crystallization temperature, Rc value. The crystalline Form A was used as a reference sample; the feeding rate was fixed at 5 mL/min, and the agitation speed was fixed at 500 rpm.
Figure 9
Figure 9
The influence of aging time on the formation of nilotinib free base amorphous solids: (a) Filtering rate; (b) Particle size distribution; (c) Volume mean diameter, D4,3. The feeding rate was fixed at 5 mL/min, and the agitation speed was fixed at 500 rpm.
Figure 10
Figure 10
Experimental setup for the preparation of nilotinib free base amorphous solids.
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