Novartis-MIT Center for Continuous Manufacturing, Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
J Pharm Sci. 2012 Mar;101(3):1178-88. doi: 10.1002/jps.23024. Epub 2011 Dec 20.
In this paper, an electrospray technique followed by annealing at high temperatures was developed to produce nanocrystals of carbamazepine (CBZ), a poorly water-soluble drug, for continuous pharmaceutical manufacturing process. Electrospraying solutions of CBZ in methanol obeys the expected scaling law of current, which is I ∼ Q(1/2) (I, electrical current; Q, flow rate), for liquids with sufficiently high conductivity and viscosity. Lower flow rates during electrospraying were preferred to produce smaller diameters of monodisperse, dense CBZ nanoparticles. CBZ nanoparticles were predominantly amorphous immediately after electrospraying. Crystallization of CBZ nanoparticles was accelerated by annealing at high temperatures. CBZ nanocrystals with the most stable polymorph, form III, were obtained by annealing at 90°C, which is above the transition temperature, 78°C, for the enantiotropic CBZ form III and form I. The solubility and dissolution rates of CBZ nanocrystals increased significantly as compared with those of CBZ bulk particles. Therefore, electrospray technology has the potential to produce pharmaceutical dosage forms with enhanced bioavailability and can readily be integrated in a continuous pharmaceutical manufacturing process.
本文采用电喷雾技术，随后在高温下退火，制备了难溶性药物卡马西平（CBZ）的纳米晶体，用于连续制药工艺。甲醇中 CBZ 的电喷雾溶液遵循电流的预期缩放定律，即 I∼Q(1/2)（I，电流；Q，流速），对于具有足够高电导率和粘度的液体。在电喷雾过程中，较低的流速有利于产生更小直径的单分散、致密的 CBZ 纳米颗粒。CBZ 纳米颗粒在电喷雾后立即主要呈无定形状态。通过在高温下退火可以加速 CBZ 纳米颗粒的结晶。通过在 90°C 退火获得了最稳定多晶型物 III 型的 CBZ 纳米晶体，该温度高于 CBZ 对映体 III 型和 I 型的转变温度 78°C。与 CBZ 块状颗粒相比，CBZ 纳米晶体的溶解度和溶解速率显著提高。因此，电喷雾技术有可能生产出生物利用度更高的药物剂型，并可轻松集成到连续制药工艺中。
