Department of Pharmaceutical Chemistry, Rayat Institute of Pharmacy, Punjab, India.
Drug Dev Ind Pharm. 2012 Nov;38(11):1319-27. doi: 10.3109/03639045.2011.650644. Epub 2012 Jan 28.
The aim of the present study was to prepare the amino acid prodrugs of bromhexine hydrochloride to improve its solubility.
All the prodrugs were synthesized by first reacting bromhexine with tert-butoxycarbonyl (Boc) protected amino acid and then deprotection was carried out by using trifluoroacetic acid. These prodrugs were characterized by their melting points, NMR, mass and FTIR spectroscopy. Solubility and partition coefficient of bromhexine and various prodrugs were determined. The solution stability of various prodrugs was also determined in various buffers of pH ranging from 2 to 10. Degradation rate constants and half-life were also determined at various pH.
The structures of all the synthesized prodrugs were confirmed by NMR, mass and FTIR spectra. The prodrug 2-N-L-alanyl-bromhexine hydrochloride showed maximum solubility and minimum partition coefficient value. These prodrugs may hydrolyze by one or more mechanisms. The order of decreasing rates of hydrolysis was 2-N-L-prolyl-bromhexine hydrochloride > 2-N-glycyl-bromhexine hydrochloride > 2-N-L-alanyl-bromhexine hydrochloride. All the prodrugs exhibited maximum stability in the acidic pH range and undergo base catalyzed hydrolysis.
Solubility studies and partition coefficient values indicated that the synthesized prodrug, 2-N-L-alanyl-bromhexine hydrochloride, was least lipophilic as compared to other synthesized prodrugs. Solution stability studies showed that this prodrug undergo minimum hydrolysis at 37°C. So, it is concluded that 2-N-L-alanyl-bromhexine hydrochloride exhibits better solubility and stability as compared to other synthesized prodrugs.
本研究旨在制备盐酸溴己新的氨基酸前药，以提高其溶解度。
所有前药均通过首先使溴己新与叔丁氧羰基（Boc）保护的氨基酸反应，然后使用三氟乙酸进行脱保护来合成。通过熔点、NMR、质谱和傅里叶变换红外光谱对这些前药进行了表征。测定了溴己新和各种前药的溶解度和分配系数。还在 pH 值从 2 到 10 的各种缓冲液中测定了各种前药的溶液稳定性。还在各种 pH 值下测定了降解速率常数和半衰期。
通过 NMR、质谱和傅里叶变换红外光谱证实了所有合成前药的结构。前药 2-N-L-丙氨酸-盐酸溴己新的溶解度最高，分配系数值最小。这些前药可能通过一种或多种机制水解。水解速率降低的顺序为 2-N-L-脯氨酸-盐酸溴己新>2-N-甘氨酸-盐酸溴己新>2-N-L-丙氨酸-盐酸溴己新。所有前药在酸性 pH 范围内表现出最大的稳定性，并发生碱催化水解。
溶解度研究和分配系数值表明，与其他合成前药相比，合成的前药 2-N-L-丙氨酸-盐酸溴己新的亲脂性最低。溶液稳定性研究表明，该前药在 37°C 下水解最少。因此，可以得出结论，与其他合成前药相比，2-N-L-丙氨酸-盐酸溴己新表现出更好的溶解度和稳定性。
