首页> 外文期刊>European journal of pharmaceutical sciences >Preparation of drug nanocrystals by controlled crystallization: application of a 3-way nozzle to prevent premature crystallization for large scale production.
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Preparation of drug nanocrystals by controlled crystallization: application of a 3-way nozzle to prevent premature crystallization for large scale production.

机译:通过控制结晶来制备药物纳米晶体:应用三向喷嘴以防止过早结晶以进行大规模生产。

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摘要

In a previous study we have developed a novel process to produce drug nanocrystals. This process, "controlled crystallization during freeze-drying" has shown to be a successful method to increase the dissolution rate of poorly water-soluble drugs [de Waard, H., Hinrichs, W.L.J., Frijlink, H.W., 2008. A novel bottom-up process to produce drug nanocrystals: controlled crystallization during freeze drying. J. Control. Release 128, 179-183]. This process consisted of two steps: a solution of a matrix material (mannitol) in water was mixed with a solution of a drug (fenofibrate) in tertiary butyl alcohol (TBA). This mixture was frozen and subsequently freeze-dried at relatively high temperature (-25 degrees C). Since the solution of matrix and drug in the water-TBA mixture is thermodynamically unstable, it had to be frozen immediately and fast after preparation to prevent premature crystallization of the drug resulting in the formation too large drug crystals. Therefore, small quantities were manually mixed in a vial and this vial was immersed in liquid nitrogen. To make this process ready for large scale production, the modification of this batch process to a semi-continuous process by the application of a 3-way nozzle was studied. With this nozzle, the aqueous and TBA-solutions were pumped into the nozzle via two separate channels and mixed just at the moment they left the nozzle. Thorough mixing was facilitated by the atomizing air, supplied via the third channel. Since the mixture was sprayed immediately into liquid nitrogen, premature crystallization was prevented. A further advantage was that the atomizing air generated small droplets which were directly immersed into liquid nitrogen. Consequently, the mixture was frozen even faster than in the batch process. This resulted in a reduced size of the drug crystals and hence a higher dissolution rate. Therefore, using the semi-continuous process does not only result in successfully making this process suitable for large scale production of the controlled crystallized dispersions, but it also results in a better product.
机译:在先前的研究中,我们开发了一种生产药物纳米晶体的新方法。这个过程“在冷冻干燥过程中控制结晶”已被证明是提高水溶性差的药物溶解速率的成功方法[de Waard,H.,Hinrichs,WLJ,Frijlink,HW,2008。药物纳米晶体的制备过程:在冷冻干燥过程中控制结晶。 J.控制。发行版128,179-183]。该过程包括两个步骤:将基质材料(甘露醇)在水中的溶液与药物(非诺贝特)在叔丁醇(TBA)中的溶液混合。将该混合物冷冻,然后在较高温度(-25℃)下冷冻干燥。由于基质和药物在水-TBA混合物中的溶液在热力学上不稳定,因此必须在制备后立即快速冷冻,以防止药物过早结晶,从而导致形成太大的药物晶体。因此,将少量手工混合在小瓶中,并将该小瓶浸入液氮中。为了使该过程可用于大规模生产,研究了通过使用三向喷嘴将该批过程修改为半连续过程的方法。使用该喷嘴,将水溶液和TBA溶液通过两个单独的通道泵入喷嘴,并在它们离开喷嘴的那一刻混合。经由第三通道供应的雾化空气有助于彻底混合。由于将混合物立即喷雾到液氮中,因此可以防止过早结晶。另一个优点是雾化空气产生的小液滴直接浸入液氮中。因此,混合物的冷冻速度甚至比分批过程更快。这导致药物晶体的尺寸减小,因此溶出速率更高。因此,使用半连续方法不仅导致成功地使该方法适合于受控结晶分散体的大规模生产,而且还导致了更好的产品。

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