共晶提供了一個良好的機會來提高藥物的物理化學性質，如熔點、溶解度、穩定性、生物利用度和滲透度。我們的目標是探討混合效應對苯甲酸-苯甲酸鈉共晶體的化學計量數的影響。將8 mL 濃度3.36 M的鹽酸水溶液以3.5或20 mL/min的速率在75或600 rpm的攪拌速率下加入到攪拌槽中，並與192 mL 濃度1.74 M的苯甲酸鈉水溶液反應形成苯甲酸，苯甲酸與苯甲酸鈉結晶得到其共晶。微觀混合和巨觀混合是由攪拌葉片的攪拌速率所造成的，而介混合是由鹽酸水溶液的進料速率所造成的。透過熱重分析儀(TGA)， X射線粉末繞射儀(PXRD)和光學顯微鏡(OM)檢測其化學計量、晶體結構和晶貌。攪拌速率和鹽酸水溶液的進料速率可能影響苯甲酸-苯甲酸鈉共晶的組成。隨著混合強度的增加和鹽酸水溶液的進料速率的降低，進料口的苯甲酸局部濃度降低。反之，隨著混合強度的降低和鹽酸水溶液的進料速率的增加，進料口的苯甲酸的局部濃度增加。介混合對苯甲酸-苯甲酸鈉共晶組成的影響在75 rpm下可被觀察。苯甲酸-苯甲酸鈉的Form A 2：1共晶僅在75 rpm以及3.36 M鹽酸水溶液進料速率20 mL/min時間為20分鐘時獲得。Form B 2:1的苯甲酸-苯甲酸鈉共晶並沒有被檢測到。無論在75 rpm或600 rpm以及3.5或20 mL/min的鹽酸水溶液的進料速率下，如果予以充足的時間，固體皆會轉化為1：1和2：1苯甲酸-苯甲酸鈉共晶的混合物。此外，還進行了攪拌速率和鹽酸水溶液進料速率的極端條件的實驗。以600 rpm和0.4 mL/min濃度3.36 M的鹽酸水溶液的進料速率，在10分鐘時獲得苯甲酸-苯甲酸鈉的1：1共晶。攪拌速率也影響了粒徑分佈，由於晶體磨損和破裂，在高攪拌速率下粒徑分佈也隨之減少。;Co-crystallization offers a great opportunity to enhance the physicochemical properties of drug products, such as melting point, solubility, stability, bioavailability and permeability. Our aim was to probe the mixing effect on the stoichiometry diversity of benzoic acid-sodium benzoate (HBz-NaBz) co-crystals. 8 mL of 3.36 M hydrochloric acid were fed with a rate of 3.5 or 20 mL/min into the agitated tank having the agitation rate of 75 or 600 rpm and reacted with 192 mL of the 1.74 M aqueous solution of sodium benzoate to form benzoic acid, and benzoic acid was then co-crystallized with sodium benzoate to give the co-crystals of HBz-NaBz. Micromixing and macromixing were contributed by the agitation rate of a propeller, and mesomixing was originated by the feeding rate of HCl(aq). The stoichiometric ratios, crystal structures, and crystal habit of solids were characterized by thermal gravimetric analysis (TGA), powder X-ray diffraction (PXRD), and optical microscopy (OM). The agitation rate and the feeding rate of HCl(aq) could influence the compositions of HBz-NaBz co-crystals. The local concentration of benzoic acid at the feeding point was decreased with the increase in the mixing intensity and the decrease in the feeding rate of HCl(aq). By contrast, the local concentration of benzoic acid at the feeding point was increased with the decrease in the mixing intensity and the increase in the feeding rate of HCl(aq). The effect of mesomixing on the compositions of HBz-NaBz co-crystals could be observed under 75 rpm. Pure Form A 2:1 co-crystals of HBz-NaBz were only obtained at 75 rpm and with a feeding rate of 3.36 M HCl(aq) of 20 mL/min at 20 min. Form B 2:1 co-crystals of HBz-NaBz were not detected at all. Finally, the solids were transformed to the mixtures of 1:1 and 2:1 co-crystals of HBz-NaBz at 75 rpm or 600 rpm and the feeding rate of 3.36 M HCl(aq) of 3.5 or 20 ml/min if given a long enough time. In addition, the extreme conditions for the agitation rate of propeller and the feeding rate of HCl(aq) were carried out. Pure 1:1 co-crystals of HBz-NaBz were obtained at 600 rpm and 0.4 mL/min with a feeding rate of 3.36 M HCl(aq) of 0.4 mL/min at 10 min. Agitation rate had also influenced the particle size distribution (PSD), and the PSD decreased under a high agitation rate due to crystal attrition and breakage.
