Synthesis and Solid State Pharmaceutical Centre (SSPC), Bernal Institute, University of Limerick, Limerick V94 T9PX, Ireland; Department of Chemical Sciences, Bernal Institute, University of Limerick, Limerick V94 T9PX, Ireland.
Department of Chemical Sciences, Bernal Institute, University of Limerick, Limerick V94 T9PX, Ireland; Laboratory of Computational Modeling of Drugs, South Ural State University, 76 Lenin Prospekt, 454080 Chelyabinsk, Russia.
Int J Pharm. 2021 May 15;601:120514. doi: 10.1016/j.ijpharm.2021.120514. Epub 2021 Mar 22.
Discovery of novel cocrystal systems and improvement of their physicochemical properties dominates the current literature on cocrystals yet the required end-product formulation is rarely addressed. Drug product manufacturing includes complex API solid state processing steps such as milling, granulation, and tableting. These all require high mechanical stress which can lead to solid-state phase transformations into polymorphs and solvates, or lead to dissociation of cocrystals into their individual components. Here we measured the effect of tablet excipients on solid-state processing of a range of pharmaceutical cocrystal formulations. Our findings were rationalised using Density Functional Theory (DFT) calculations of intermolecular binding energies of cocrystal constituents and co-milling excipients. A 1:1 stoichiometric ratio of API Theophylline (THP) and co-former 4-Aminobenzoic acid (4ABA) was co-milled with five different excipients: hydroxypropylmethylcellulose (HPMC), polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), lactose, and microcrystalline cellulose (MCC). The experiments were carried out in 10 and 25 ml milling jars at 30 Hz for different milling times. Co-milled samples were characterised for formation of cocrystals and phase transformation using powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC). Our data shows that co-milling in the presence of PEG, HMPC or lactose yields purer cocrystals, supported by the calculated stronger excipient interactions for PVP and MCC. We identify a suitably-prepared THP-4ABA pharmaceutical cocrystal formulation that is stable under extended milling conditions.
新型共晶体系的发现及其物理化学性质的改善主导着当前关于共晶的文献，但很少涉及所需的最终产品配方。药物产品制造包括复杂的 API 固态加工步骤，如研磨、造粒和压片。这些都需要高机械应力，这可能导致固态相转化为多晶型物和溶剂化物，或者导致共晶分解为其各个组成部分。在这里，我们测量了片剂赋形剂对一系列药物共晶配方的固态加工的影响。我们的发现使用共晶成分和共研磨赋形剂的分子间结合能的密度泛函理论（DFT）计算进行了合理化。API 茶碱（THP）和共晶形成剂 4-氨基苯甲酸（4ABA）的 1:1 化学计量比与五种不同的赋形剂：羟丙基甲基纤维素（HPMC）、聚乙烯吡咯烷酮（PVP）、聚乙二醇（PEG）、乳糖和微晶纤维素（MCC）一起进行共研磨。在 30 Hz 的 10 和 25 ml 研磨罐中进行不同的研磨时间。使用粉末 X 射线衍射（PXRD）和差示扫描量热法（DSC）对共研磨样品进行共晶形成和相转变的表征。我们的数据表明，在 PEG、HMPC 或乳糖存在下共研磨会产生更纯的共晶，这得到了计算出的 PVP 和 MCC 更强赋形剂相互作用的支持。我们确定了一种经过适当制备的 THP-4ABA 药物共晶配方，在扩展的研磨条件下稳定。
