Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, Groningen, The Netherlands.
Eur J Pharm Sci. 2009 Oct 8;38(3):224-9. doi: 10.1016/j.ejps.2009.07.005. Epub 2009 Jul 22.
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.
在之前的研究中，我们开发了一种生产药物纳米晶体的新方法。该方法“冷冻干燥过程中的控制结晶”已被证明是提高难溶性药物溶解速率的成功方法[de Waard, H., Hinrichs, W.L.J., Frijlink, H.W., 2008. 一种生产药物纳米晶体的新型自下而上方法：冷冻干燥过程中的控制结晶。J. Control. Release 128, 179-183]。该方法由两个步骤组成：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，然后在相对较高的温度（-25°C）下冷冻干燥。由于水-TBA 混合物中基质和药物的溶液处于热力学不稳定状态，因此必须在制备后立即快速冷冻，以防止药物过早结晶，从而形成过大的药物晶体。因此，少量药物手动混合在小瓶中，然后将小瓶浸入液氮中。为了使该方法适用于大规模生产，研究了通过应用三通喷嘴将批处理方法修改为半连续方法。使用该喷嘴，将水相和 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瞬间混合。通过第三个通道提供的雾化空气促进了彻底混合。由于混合物立即被喷射到液氮中，因此防止了过早结晶。进一步的优点是，雾化空气产生的小液滴直接浸入液氮中。因此，混合物的冻结速度比批处理过程更快。这导致药物晶体的尺寸减小，从而提高了溶解速率。因此，使用半连续方法不仅成功地使该方法适用于控制结晶分散体的大规模生产，而且还产生了更好的产品。
