Tipduangta Pratchaya, Takieddin Khaled, Fábián László, Belton Peter, Qi Sheng
School of Pharmacy, University of East Anglia Norwich Norfolk NR4 7TJ UK
Department of Pharmaceutical Sciences, Faculty of Pharmacy, Chiang Mai University Chiang Mai Thailand 50200.
RSC Adv. 2018 Apr 10;8(24):13513-13525. doi: 10.1039/c8ra01182f. eCollection 2018 Apr 9.
Fenofibrate (FEN) is a dyslipidemia treatment agent which is poorly soluble in water. FEN has tendency to form polymorphs and its crystallisation behaviour is difficult to predict. The nucleation process can be initiated by mechanical disruption such as ball milling or surface scratching which may result in different crystallisation behaviour to that observed in the unperturbed system. This study has obtained insights into the controllability of FEN crystallisation by means of regulating the exposed surface and growth temperatures during its crystallisation. The availability of an open top surface (OTS) during the crystallisation of the FEN melt resulted in a mixture containing FEN form I and IIa (I ≫ IIa) at room temperature, and in the range 40 to 70 °C. Covering the surface led to significant increases in the yield of form IIa at room temperature and at 40 and 50 °C. These temperatures also yielded the highest amount of form IIa in the OTS samples whilst crystallisation at 70 °C led to only FEN form I crystals regardless of the availability of the free surface. The metastable FEN form IIa transforms to the stable form I under the influence of a mechanical stress. Additionally, the introduction of OTS before the completion of crystallisation of form IIa led to a 'switch' of from IIa growth to form I. This study demonstrates that the polymorph selection of FEN can be obtained by the manipulation of the crystallisation conditions.
非诺贝特（FEN）是一种治疗血脂异常的药物，其在水中的溶解度很低。FEN有形成多晶型物的倾向，其结晶行为难以预测。成核过程可由机械破坏引发，如球磨或表面刮擦，这可能导致与未受干扰系统中观察到的不同的结晶行为。本研究通过在FEN结晶过程中调节暴露表面和生长温度，深入了解了FEN结晶的可控性。FEN熔体结晶过程中开放顶面（OTS）的存在导致在室温以及40至70°C范围内形成含有FEN I型和IIa型（I≫IIa）的混合物。覆盖表面导致室温以及40和50°C时IIa型的产率显著增加。这些温度在OTS样品中也产生了最高量的IIa型，而在70°C结晶时，无论自由表面是否存在，都只产生FEN I型晶体。亚稳态的FEN IIa型在机械应力的影响下会转变为稳定的I型。此外，在IIa型结晶完成之前引入OTS会导致从IIa型生长向I型的“转变”。本研究表明，通过控制结晶条件可以实现FEN的多晶型选择。
