Purpose

To efficiently develop a tablet formulation of carbamazepine using a soluble cocrystal with excess coformer to maintain phase stability during dissolution.

Methods

The carbamazepine – glutaric acid cocrystal (CBZ-GLA, 1:1) and excess glutaric acid (GLA) were mixed with suitable tablet excipients, which were selected to address powder flowability and tabletability deficiencies specifically. Tablet friability and dissolution profiles were evaluated to guide formulation optimization. Dry granules were prepared by milling simulated ribbons.

Results

A binary blend of CBZ-GLA and GLA had poor flowability and marginal tabletability. Therefore, silica coated Avicel PH-102 (sMCC) was applied as a binder to improve the flow property and tabletability. A formulation consisting of sMCC, CBZ-GLA, and GLA exhibited good manufacturability but did not show improved dissolution because of rapid precipitation of CBZ dihydrate when CBZ-GLA came in contact with water. Dry granulation of CBZ-GLA and GLA dramatically improved dissolution profile due to the intimate contact between CBZ-GLA and GLA. Such cocrystal - coformer granules also led to much improved tablet manufacturability and dissolution.

Conclusion

The successful tablet development of CBZ-GLA, using < 3 g of the cocrystal in <3 weeks, demonstrates an efficient workflow for tablet formulation development based on material-sparing and predictive powder characterization techniques. This workflow is useful for early tablet development using enabling solid form, such as cocrystal, when only a small amount of material is available.

中文翻译：

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卡马西平谷氨酸共结晶片制剂的材料节约和加速开发-QbD方法。

目的

为了有效地开发卡马西平的片剂，使用具有过量共形成物的可溶性共晶体在溶解过程中保持相稳定性。

方法

将卡马西平-戊二酸共晶体（CBZ-GLA，1：1）和过量的戊二酸（GLA）与合适的片剂赋形剂混合，选择这些赋形剂是为了解决粉末的流动性和可压片性缺陷。评估片剂的易碎性和溶出度，以指导制剂优化。通过研磨模拟色带来制备干颗粒。

结果

CBZ-GLA和GLA的二元混合物的流动性和边缘压片性差。因此，将二氧化硅涂覆的Avicel PH-102（sMCC）用作粘合剂，以改善流动性和可压片性。由sMCC，CBZ-GLA和GLA组成的配方具有良好的可制造性，但由于CBZ-GLA与水接触时CBZ二水合物的快速沉淀，因此溶解性没有改善。由于CBZ-GLA和GLA紧密接触，CBZ-GLA和GLA的干法制粒大大改善了溶出度。此类共晶-共形成剂颗粒还导致片剂可制造性和溶解度大大改善。

结论

在不到3周的时间内使用不足3 g的共晶体成功开发了CBZ-GLA片剂，证明了基于材料节省和预测性粉末表征技术的片剂配方开发的有效流程。当只有少量材料可用时，此工作流程对于使用启用的固态形式（例如共晶）的早期片剂开发非常有用。