From Physical Mixtures to Co-Crystals: How the Coformers Can Modify Solubility and Biological Activity of Carbamazepine
From Physical Mixtures to Co-Crystals: How the Coformers Can Modify Solubility and Biological Activity of Carbamazepine
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DOI：
10.1021/acs.molpharmaceut.7b00899
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发表时间：
2018-01-01
影响因子：
4.9
通讯作者：
Pastore, Mariachiara
中科院分区：
文献类型：
--
作者：
Dalpiaz, Alessandro;Ferretti, Valeria;Pastore, Mariachiara
对卡马西平（CBZ）、三种共晶（COCs）及其母体物理混合物（MIXs）的溶解度和生物活性进行了实验和计算相结合的研究，以揭示可能的药物性质调节。两种被考虑的共晶，CBZ与香草酸（VAN）和CBZ与4-硝基吡啶n -氧化物（NPO）是新合成的，而第三种CBZ与琥珀酸（SUC）是已知的。COC - CBZ- van和MIX - CBZ- npo对CBZ的溶解没有影响，MIX - CBZ- suc和COCs - CBZ- suc和CBZ- npo直接抑制了CBZ的溶解。另一方面，MIX CBZ-VAN诱导药物溶解度显著增加。类似地，其从MIX和COCs中溶解后，CBZ的渗透性值也不同：CBZ和MIXs的CBZ- suc和CBZ- van略微降低了肠细胞单层的完整性，而MIX CBZ- npo和COCs的CBZ- suc、CBZ- van和CBZ- npo维持了单层的完整性。在溶液中形成的分子聚集体是解释这些不同行为的关键，为药物共晶的药物利用和定义开辟了新的可能性。
A combined experimental and computational study on the solubility and biological activity of carbamazepine (CBZ), three co-crystals (COCs), and their parent physical mixtures (MIXs) is carried out to shed light onto the possible modulation of the drug properties. Two of the considered co-crystals, CBZ with vanillic acid (VAN) and CBZ with 4-nitropyridine N-oxide (NPO), are newly synthesized, while the third, CBZ with succinic acid (SUC), is already known. While COC CBZ-VAN and MIX CBZ-NPO did not alter the CBZ dissolution profile, MIX CBZ-SUC and COCs CBZ-SUC and CBZ-NPO inhibit straightaway its solubility. On the other hand, MIX CBZ-VAN induced a remarkable increase of the drug solubility. Analogously, different CBZ permeability values were registered following its dissolution from MIXs and COCs: CBZ and MIXs CBZ-SUC and CBZ-VAN slightly reduce the integrity of intestinal cell monolayers, whereas MIX CBZ-NPO and COCs CBZ-SUC, CBZ-VAN, and CBZ-NPO maintain the monolayer integrity. The molecular aggregates formed in solution were found to be the key to interpret these different behaviors, opening new possibilities in the pharmaceutical utilization and definition of drug co-crystals.