Both pretty low solubility and high membrane permeability of diflunisal (DIF) would affect significantly its oral bioavailability as a typical non-steroidal anti-inflammatory substance. Meanwhile, pyrazinamide (PZA), known as one kind of important anti-tuberculosis drugs, has also several certain side effects. These deficiencies affect the large-scale clinical use of such drugs. Solid-state pharmaceutical co-crystallization is of contemporary interest since it offers an easy and efficient way to produce prospective materials with tunable improved properties. In the current work, a novel solid phase drug-drug co-crystal involving DIF and PZA with molar ratio 1:1 was prepared through the mechanical grinding approach, and vibrational spectroscopic techniques including terahertz time-domain spectroscopy (THz-TDS) and Raman spectroscopy were performed to identify DIF, PZA and their pharmaceutical drug-drug co-crystal. The absorption peaks observed in the THz spectra of the co-crystal were at 0.35, 0.65, 1.17, 1.31 and 1.42 THz respectively, which are obviously different from parent materials. Similarly, Raman spectra could also be used to characterize the difference shown between the co-crystal and parent compounds. Structures and vibrational patterns of three kinds of possible co-crystal theoretical forms (form I, II and III) between DIF and PZA have been simulated by performing density functional theory (DFT) calculations. Theoretical results and THz/Raman vibrational spectra of DIF-PZA co-crystal show that the DIF links to PZA via the carboxylic acid-pyridine hetero-synthon association establishing the theoretical form I, which is a much-higher degree of agreement with experimental results than those of other two co-crystal forms. These results provide us a unique method for characterizing the composition of co-crystal structures, and also provide a wealth of drug-drug co-crystal structural information for improving physicochemical properties and pharmacological activities of specific drugs at the molecular-level.

二氟菊酯（DIF）的低溶解度和高膜通透性都将显着影响其作为典型的非甾体类抗炎物质的口服生物利用度。同时，吡嗪酰胺（PZA）被认为是一种重要的抗结核药物，也有一些副作用。这些缺陷影响了这类药物的大规模临床使用。固态药物共结晶是当代关注的问题，因为它提供了一种简单有效的方法来生产具有可调改进性能的预期材料。在目前的工作中，通过机械研磨的方法制备了一种新型的固相药物-药物共晶体，其包含摩尔比为1：1的DIF和PZA，并采用振动光谱技术，包括太赫兹时域光谱（THz-TDS）和拉曼光谱，以鉴定DIF，PZA及其药用药物-药物共晶体。共晶体的THz光谱中观察到的吸收峰分别为0.35、0.65、1.17、1.31和1.42 THz，与母体材料明显不同。同样，拉曼光谱也可用于表征共晶体和母体化合物之间的差异。通过执行密度泛函理论（DFT）计算，模拟了DIF和PZA之间三种可能的共晶理论形式（形式I，II和III）的结构和振动模式。DIF-PZA共晶体的理论结果和THz / Raman振动光谱表明，DIF通过羧酸-吡啶杂合子缔合连接到PZA，建立了理论形式I，与实验结果的吻合度更高。比其他两种共晶形式的 这些结果为我们提供了表征共晶体结构组成的独特方法，并且还提供了丰富的药物-药物共晶体结构信息，可在分子水平上改善特定药物的理化性质和药理活性。