恩诺沙星新盐的制备、表征及溶解性研究

doi:10.16431/j.cnki.1671-7236.2022.10.036

Abstract

Abstract: 【Objective】 A new enrofloxacin (ENR) salt was prepared and its solubility was investigated,aiming to improve the solubility of ENR and enrich its crystal form.【Method】 The new ENR salt was prepared by slurry method,and the single crystal was cultivated by slow evaporation method.The new salt was characterized and analyzed by powder X-ray diffraction (PXRD),single crystal X-ray diffraction (SXRD),Fourier transform infrared spectroscopy (FTIR),differential scanning calorimetry (DSC),thermogravimetric analysis (TGA) and scanning electron microscopy (SEM).The dissolution rates of ENR and new salt in pH 6.8 phosphate buffer at 37 ℃ were investigated by powder dissolution rate test.【Result】 The prepared new ENR salt was ENR-2,6-dihydroxybenzoic acid hemihydrate (ENR-2,6-DHBA·1/2H₂O).According to the analysis of single crystal structure,ENR-2,6-DHBA·1/2H₂O belonged to triclinic crystal system,P-1 space group,and the unit cell parameters were a=13.2495(7)Å,b=13.8266(11)Å,c=16.0672(8)Å,α=114.301°(6),β=90.322°(4),and γ=114.438°(7).The asymmetric unit of new salt contained two ENR cations,two 2,6-DHBA anions and one H₂O molecule in which a proton was transferred from the carboxyl group of 2,6-DHBA to the nitrogen atom of the piperazine in ENR and formed N⁺-H…O^-,confirming that the new form was salt.ENR and H₂O were connected by O-H…O hydrogen bonds.FTIR results indicated that the C=O absorption peak on 2,6-DHBA shifted from 1 680 to 1 725 cm^-1 due to proton transfer.The melting point of the new salt was 253 ℃,different from those of ENR and 2,6-DHBA.The morphology of the new salt was smooth rod-like shape.The powder dissolution rate curve showed that the apparent solubility of ENR-2,6-DHBA·1/2H₂O at equilibrium was 0.65 mg/mL,which was 1.86 times that of ENR.【Conclusion】 The results showed that ENR-2,6-dihydroxybenzoic acid hemihydrate salt was successfully prepared.The new salt improved the solubility of ENR,which provided reference basis for improving the bioavailability of ENR and enhancing the antibacterial effect.

Key words: enrofloxacin(ENR); salt; characterization; dissolution rate

CLC Number:

S859.79⁺6

WANG Kairu, MAO Yanan, XU Ruitao, ZHAO Xinghua, HE Xin. Preparation,Characterization and Solubility of New Enrofloxacin Salt[J]. China Animal Husbandry and Veterinary Medicine, 2022, 49(10): 4032-4041.

References

[1] MENG K Y,CHEN D M,YANG F,et al.Intracellular delivery,accumulation,and discrepancy in antibacterial activity of four enrofloxacin-loaded fatty acid solid lipid nanoparticles[J].Colloids and Surfaces B:Biointerfaces,2020,194(6):111196.
[2] 许颖,邱阳阳,沈悦,等.恩诺沙星纳米乳的制备及喷雾给药的药效学评价[J].华南农业大学学报,2021,42(1):42-48. XU Y,QIU Y Y,SHEN Y,et al.Preparation of enrofloxacin nanoemulsion and evaluation of pharmacodynamics of spray administration[J].Journal of South China Agricultural University,2021,42(1):42-48.(in Chinese)
[3] BLOKHINA S V,SHARAPOVA A V,OKHOVICH M V,et al.Solubility,lipophilicity and membrane permeability of some fluoroquinolone antimicrobials[J].European Journal of Pharmaceutical Sciences,2016,93:29-37.
[4] UNEY K,TERZI E,CORUM D D,et al.Pharmacokinetics and pharmacokinetic/pharmacodynamic integration of enrofloxacin following single oral administration of different doses in brown trout (Salmo trutta)[J].Animals,2021,11(11):3086.
[5] PANG H,SUN Y B,ZHOU J W,et al.Pharmaceutical salts of enrofloxacin with organic acids[J].Crystals,2020,10(8):646.
[6] 黄铢玉,方龙香,宋超,等.抗生素恩诺沙星在渔业中的研究进展[J].农学学报,2019,9(11):57-62. HUANG Z Y,FANG L X,SONG C,et al.Antibiotic enrofloxacin in fishery:A review[J].Journal of Agriculture,2019,9(11):57-62.(in Chinese)
[7] ZHOU K,HUO M,MA W,et al.Application of a physiologically based pharmacokinetic model to develop a veterinary amorphous enrofloxacin solid dispersion[J].Pharmaceutics,2021,13(5):602.
[8] 何赛飞.沃替西汀新盐:设计、制备、表征及性质研究[D].广州:华南理工大学,2016. HE S F.New vortioxetine salts:Design,prepartion,characterization and properties[D].Guangzhou:South China University of Technology,2016.(in Chinese)
[9] 翁兴业,庞遵霆,钱帅,等.晶体工程学技术改善药物理化性质以提高成药性[J].药学学报,2020,55(12):2883-2891. WENG X Y,PANG Z T,QIAN S,et al.Druggability enhancement by modification of physicochemical properties of drugs via crystal engineering[J].Acta Pharmaceutica Sinica,2020,55(12):2883-2891.(in Chinese)
[10] SETYAWAN D,PARAMITA D P,ADYAKSA F R,et al.Cocrystal formation of loratadine-succinic acid and its improved solubility[J].Journal of Basic and Clinical Physiology and Pharmacology,2021,32(4):623-630.
[11] BOFILL L,BARBAS R,SANDE D,et al.A novel,extremely bioavailable cocrystal of pterostilbene[J].Crystal Growth & Design,2021,21(4):2315-2323.
[12] LIU L,ZOU D,ZHANG Y,et al.Pharmaceutical salts/cocrystals of enoxacin with dicarboxylic acids:Enhancing in vitro antibacterial activity of enoxacin by improving the solubility and permeability[J].European Journal of Pharmaceutics and Biopharmaceutics,2020,154(3):62-73.
[13] DAI X L,YAO J,WU C,et al.Solubility and permeability improvement of allopurinol by cocrystallization[J].Crystal Growth & Design,2020,20(8):5160-5168.
[14] GOLOVNEV N N,VASILIEV A D,KIRIK S D.Enrofloxacinium citrate monohydrate:Preparation,crystal structure,thermal stability and IR-characterization[J].Journal of Molecular Structure,2012,1021:112-117.
[15] KARANAM M,CHOUDHURY A R.Structural landscape of pure enrofloxacin and its novel salts:Enhanced solubility for better pharmaceutical applicability[J].Crystal Growth & Design,2013,13(4):1626-1637.
[16] BROTHERS A M,GIBBS P S,WOOLEY R E.Development of resistant bacteria isolated from dogs with otitis externa or urinary tract infections after exposure to enrofloxacin in vitro[J].Veterinary Therapeutics:Research in Applied Veterinary,2002,3(4):493-500.
[17] TERHUNE T N,SKOGERBOE T L,SHOSTROM V K,et al.Comparison of pharmacokinetics of danofloxacin and enrofloxacin in calves challenged with Mannheimia haemolytica[J].American Journal of Veterinary Research,2005,66(2):342-349.
[18] MESALLATI H,UMERSKA A,TAJBER L.Fluoroquinolone amorphous polymeric salts and dispersions for veterinary uses[J].Pharmaceutics,2019,11(6):268.
[19] 秦雪,王成港,兰静,等.新药研发中药物盐型的筛选策略[J].现代药物与临床,2012,27(4):414-417. QIN X,WANG C G,LAN J,et al.Salt type selection strategy in research and development of new drugs[J].Drugs & Clinic,2012,27(4):414-417.(in Chinese)
[20] CHEN J M,WANG Z Z,WU C B,et al.Crystal engineering approach to improve the solubility of mebendazole[J].Crystengcomm,2012,14(19):6221-6229.
[21] 翟立海,夏祥来,张洪美,等.奥希替尼-苹果酸-丙酮合物共晶的合成、晶体结构及性质研究[J].山东化工,2022,51(8):5-8. ZHAI L H,XIA X L,ZHANG H M,et al.Synthesis,crystal structure and properties of osimertinib-malic acid-acetone co-crystal[J].Shandong Chemical Industry,2022,51(8):5-8.(in Chinese)
[22] 张亚晴,吕宝兴,牛景梅,等.药物共晶的制备表征及体外释放的研究进展[J].中国药剂学杂志,2019,17(3):77-82. ZHANG Y Q,LYU B X,NIU J M,et al.Progress in preparation,characterization and in vitro release of drug eutectics[J].Chinese Journal of Pharmaceutics,2019,17(3):77-82.(in Chinese)
[23] KUMAR S,NANDA A.Pharmaceutical cocrystals:An overview[J].Indian Journal of Pharmaceutical Sciences,2017,79(6):858-871.
[24] WANG K R,HAO Y S,WANG C G,et al.Simultaneous improvement of physical stability,dissolution,bioavailability,and antithrombus efficacy of aspirin and ligustrazine through cocrystallization[J].International Journal of Pharmaceutics,2022,616:121541.
[25] LIU W,DANG L,WEI H.Thermal,phase transition,and thermal kinetics studies of carbamazepine[J].Journal of Thermal Analysis and Calorimetry,2013,111(3):1999-2004.
[26] 周凯,翁莹,侯青青,等.黄连素-染料木素有机盐水合物的制备、晶体结构及溶解性[J].应用化学,2019,36(2):230-235. ZHOU K,WENG Y,HOU Q Q,et al.Preparation,crystal structure and solubility of organic salt hydrate of berberine-genistein[J].Chinese Journal of Applied Chemistry,2019,36(2):230-235.(in Chinese)
[27] DENG J H,LU T B,SUN C C,et al.Dapagliflozin-citric acid cocrystal showing better solid state properties than dapagliflozin[J]. European Journal of Pharmaceutical Sciences,2017,104:255-261.
[28] GOOD D J,RODRIGUEZ-HORNEDO N.Solubility advantage of pharmaceutical cocrystals[J].Crystal Growth & Design,2009,9(5):2252-2264.
[29] THAKURIA R,DELORI A,JONES W,et al.Pharmaceutical cocrystals and poorly soluble drugs[J].International Journal of Pharmaceutics,2013,453(1):101-125.
[30] THOMAS U.Pharmacological aspects of candesartan,an effective AT1-receptor blocker[J].European Heart Journal Supplements,2004,6:11-16.
[31] SRIVASTAVA D,FATIMA Z,KAUR C D,et al.Pharmaceutical cocrystal:A novel approach to tailor the biopharmaceutical properties of a poorly water soluble drug[J].Recent Patents on Drug Delivery & Formulation,2019,13(1):62-69.

Preparation,Characterization and Solubility of New Enrofloxacin Salt

PDF (PC)

Knowledge

Abstract

Cite this article

share this article

References

Related Articles 15

Recommended Articles

Metrics

Comments

[1]	HE Zhanxing, HUANG Meifen, CHENG Yumei, ZHANG Quanpeng, ZHANG Jicai, YANG Kai, WANG Ankui, ZHOU Yaping, HUANG Bizhi. Comparison of Colostrum Physicochemical Characterization Between Dulong Cattle and Yunling Cattle [J]. China Animal Husbandry and Veterinary Medicine, 2022, 49(6): 2156-2164.
[2]	SUN Haifeng, TAN Aijuan, LYU Shiming, LUO Yujia, JI Qiqi, AI Renli, LU Xingxing, FENG Dan. Effect of Hypertonicity on Gene Expression of Efflux Pump and Outer Membrane Protein in Multidrug Resistant Escherichia coli and Its Growth [J]. China Animal Husbandry and Veterinary Medicine, 2021, 48(9): 3473-3482.
[3]	YANG Yushuai, LI Ze, JIN Tianming, YANG Sheng. Preparation and Characterization of Altrenogest-β-cyclodextrin Water-soluble Derivative Inclusion Complex [J]. China Animal Husbandry and Veterinary Medicine, 2021, 48(11): 4094-4104.
[4]	GUO Yingcheng, FU Shoupeng, GAO Xueyong, LI Xudong. Molecular Epidemiological Investigation and Genetic Evolution Analysis of Porcine Circovirus Type 3 in Jilin Province [J]. , 2019, 46(5): 1483-1490.
[5]	LUO Dandan, LIAO Dangjin, YE Yonggang. Cloning and Molecular Characterization Analysis of E2 Gene of Classical Swine Fever Virus [J]. , 2018, 45(8): 2095-2103.
[6]	YANG Kunming, REN Hang, SU Yating, GUO Xiaohua. Comparative Evaluation of Probiotic Characterization of Commercial Bacillus Products [J]. , 2018, 45(5): 1241-1250.
[7]	LONG Lishu, HUA Min, WAN Run, OU Deyuan, GOU Wanli, WEN Ming. Cloning and Sequence Analysis of SOCS1 Gene in Sansui Duck [J]. , 2018, 45(3): 590-597.
[8]	LIANG Zijing, ZHANG Jingyan, ZHANG Kai, WANG Lei, WANG Xurong, ZHANG Kang, LI Jianxi. Analysis on Outputs of Polysaccharide Characterization Research Papers Based on Web of Science^TM [J]. , 2018, 45(3): 830-840.
[9]	TIAN Lang, WEN Guilan, ZHANG Shengbo, YANG Baiqi, LI Changhong, XU Li, LIN Hanqing, GUAN Guodan. Isolation and Biological Characterization of the Pathogenic Aeromonas veronii from Ictalurus punctatus [J]. , 2018, 45(11): 3203-3210.
[10]	CHEN Zhi-hui, YAN Lin, MO Hai-fei, CHEN Lian-hong, REN Jing-qi, WU Hong. Isolation and Identification of Endophyte Strain Producing β-mannanase and the Studies of Its Characterization [J]. , 2017, 44(8): 2496-2502.
[11]	ZHANG Ji-pei, TAN Hua-long, CHEN Gang, ZENG Qiang, ZHANG Fu-ying, CHEN Jian-hong. Evaluation of Virulence and Immune Effect of a Duck Paramyxovirus Type Ⅰ Strain [J]. , 2017, 44(4): 1168-1174.
[12]	WANG Jie-qiong, ZHAO Yu-jie, ZHOU Yun-fei, HUANG Zong-mei, CHEN Pan-pan, ZHOU Wei-fan, LIU Lin, LI Xin-sheng. Prokaryotic Expression and Bioinformatics Analysis of VP2 Gene of Infectious Bursal Disease Virus C4 Strain [J]. , 2017, 44(12): 3585-3591.
[13]	CHANG Yu, JIAO Yang, HUANG Wen-ming, YANG Yi, YE Jun-an. Effect of Anionic Salts on Health and Production Performance of Holstein Cows in Peripartum [J]. , 2017, 44(1): 80-86.
[14]	KONG Ping, CHEN Hong-li, WANG Shu-jie, XU Na, WU Yan-yan, GAO Wei. Effects of Pasting Anionic Salt and RPC on Production Performance and Blood Biochemical Indexes of Perinatal Dairy Cows [J]. , 2015, 42(8): 2011-2019.
[15]	WANG Li-wei，SHI Yan-jin，QU Yong-gang，LIANG Yan，LI Fei，ANG Ya-dong，YANG Yi-ming，WANG Xiao-lan. Characterization and Antibiotic Resistance of E.coli Isolated from Bovine Mastitis in Shihezi Area in Xinjiang [J]. , 2014, 41(1): 203-206.