Abstract：
Our previous work (Mol Pharm, 20 (2023) 3427) showed that crystalline excipients, specifically anhydrous dibasic calcium phosphate (DCPA), facilitated the dehydration of carbamazepine dihydrate (CBZDH) and the formation of an amorphous product phase during the mixing stage of continuous tablet manufacturing. Understanding the mechanism of this excipient-induced effect was the object of this study. Blending with DCPA for 15 min caused pronounced lattice disorder in CBZDH. This was evident from the 190% increase in the apparent lattice strain determined by the Williamson-Hall plot. The rapid dehydration was attributed to the increased reactivity of CBZDH caused by this lattice disorder. Lattice disorder in CBZDH was induced by a second method, cryomilling it with DCPA. The dehydration was accelerated in the milled sample. Annealing the cryomilled sample reversed the effect, thus confirming the effect of lattice disorder on the dehydration kinetics. The hardness of DCPA appeared to be responsible for the disordering effect. DCPA exhibited a similar effect in other hydrates, thereby revealing that the effect was not unique to CBZDH. However, its magnitude varied on a case-by-case basis. The high shear powder mixing was necessary for rapid and efficient powder mixing during continuous drug product manufacturing. The mechanical stress imposed on the CBZDH, and exacerbated by DCPA, caused this unexpected destabilization.
摘要：
我们以前的工作(MolPharm，20(2023)3427)表明，结晶赋形剂，特别是无水磷酸氢钙（DCPA），在连续片剂制造的混合阶段，促进了卡马西平二水合物（CBZDH）的脱水和无定形产品相的形成。了解这种赋形剂诱导作用的机制是本研究的目的。与DCPA共混15分钟会导致CBZDH中明显的晶格紊乱。从Williamson-Hall图确定的表观晶格应变增加190%可以明显看出这一点。快速脱水归因于由这种晶格无序引起的CBZDH的增加的反应性。CBZDH的晶格紊乱是通过第二种方法诱发的，用DCPA冷冻。在研磨的样品中加速脱水。退火的冷冻样品逆转了效果，从而证实了晶格无序对脱水动力学的影响。DCPA的硬度似乎是造成无序效应的原因。DCPA在其他水合物中表现出类似的效果，从而揭示该效应不是CBZDH独有的。然而,它的大小根据具体情况而有所不同。在连续药物产品制造过程中，高剪切粉末混合对于快速有效的粉末混合是必需的。施加在CBZDH上的机械应力，DCPA加剧了，造成了这种意想不到的不稳定。
