激光衍射法测定地拉罗司的粒径分布及其与体外溶出度的相关性研究

doi:10.5246/jcps.2021.11.079

中国药学(英文版) ›› 2021, Vol. 30 ›› Issue (11): 912-923.DOI: 10.5246/jcps.2021.11.079

激光衍射法测定地拉罗司的粒径分布及其与体外溶出度的相关性研究

陈谕园, 吴松, 陈丽青, 张媛媛, 高钟镐, 李天磊, 黄伟, 杨庆云^*()

中国医学科学院北京协和医学院药物研究所天然药物活性物质与功能国家重点实验室, 北京 100050

收稿日期:2021-05-10 修回日期:2021-06-25 接受日期:2021-07-26 出版日期:2021-11-28 发布日期:2021-11-28
通讯作者: 杨庆云
作者简介:
+ Tel.: +86-13683270346, E-mail: yqy@imm.ac.cn
基金资助:
CAMS Innovation Fund for Medical Sciences (CIFMS No. 2016-I2M-3-010 and CIFMS No. 2017-I2M-1-011).

Determination of deferasirox particle size distribution via laser diffraction and its application in establishing a correlation between particle size and drug dissolution in vitro

Yuyuan Chen, Song Wu, Liqing Chen, Yuanyuan Zhang, Zhonggao Gao, Tianlei Li, Wei Huang, Qingyun Yang^*()

State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of MateriaMedica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China

Received:2021-05-10 Revised:2021-06-25 Accepted:2021-07-26 Online:2021-11-28 Published:2021-11-28
Contact: Qingyun Yang

摘要/Abstract

摘要：

地拉罗司是用于治疗成人和儿童地中海贫血患者铁超载的一线药物, 属于BSC分类第II类, 在生产过程中应严格控制其原料药(API)的粒度及分布。本研究通过关键操作参数的摸索和优化, 建立了一种准确、便捷的激光衍射法方法, 应用于地拉罗司原料药粒径分布的测定。方法学验证和实际样品测定的d (0.1)、d (0.5)、d (0.9)、d (4,3)值的相对标准偏均小于3%, 表明该方法具有良好的精密度和准确度。采用不同粒径的地拉罗司原料药制备相应的分散片, 并测定不同批次分散片在四种溶解介质中的溶出度曲线, 考察粒径对药物体外溶出度的影响。结果表明, 地拉罗司原料药的粒径分布对其分散片的释放有显著影响。

关键词: 地拉罗司, 粒度分布, 激光衍射法, 溶出曲线

Abstract:

Deferasirox is the first-line drug for iron overload due to thalassemia in adults and pediatric patients. It is classified as a type II compound in the Biopharmaceutics Classification System, and thus the particle size of its active pharmaceutical ingredient (API) should be strictly controlled during the manufacturing process. In the present study, laser diffraction was adopted to measure the particle size distribution of deferasirox API. We also developed and validated an accurate and convenient method by investigating important optical parameters and sample dispersing conditions. The relative standard deviation values, namely, d (0.1), d (0.5), d (0.9), and d (4,3), measured via methodology validation and actual sample measurement were < 3%. The dissolution curves of several batches of dispersible tablets prepared using deferasirox with different particle sizes were compared in the four dissolved media to investigate the influence of particle size on drug dissolution in vitro. Results indicated that the particle size distribution of deferasirox API significantly affected the release of its dispersible tablet.

Key words: Deferasirox, Particle size distribution, Laser diffraction, Dissolution curve

Supporting: http://www.jcps.ac.cn/attached/file/20211129/20211129190139_832.pdf

陈谕园, 吴松, 陈丽青, 张媛媛, 高钟镐, 李天磊, 黄伟, 杨庆云. 激光衍射法测定地拉罗司的粒径分布及其与体外溶出度的相关性研究[J]. 中国药学(英文版), 2021, 30(11): 912-923.

Yuyuan Chen, Song Wu, Liqing Chen, Yuanyuan Zhang, Zhonggao Gao, Tianlei Li, Wei Huang, Qingyun Yang. Determination of deferasirox particle size distribution via laser diffraction and its application in establishing a correlation between particle size and drug dissolution in vitro[J]. Journal of Chinese Pharmaceutical Sciences, 2021, 30(11): 912-923.

图/表 6

Figure 1. Deferasirox structure and particle size distribution. (A) Deferasirox structure; (B) Deferasirox particle size distribution under different obscurations; (C) Deferasirox particle size distribution under different stirrer speeds; (D) Deferasirox particle size distribution under different sonication intensities.

Table 1. Investigation results of the NP-40 solutions (n = 3).

Table 2. Investigation results of optical parameters and sample dispersing conditions (n = 3).

Table 3. Summary of the validation report.

Table 4. Measurement results of the deferasirox API particle size distribution (n = 3).

Figure 2. Dissolution curve comparison of the deferasirox dispersible tablets. (A) In the hydrochloric acid solution of 0.5% Tween-20 pH 1.0; (B) In the acetate-buffered solution of 0.5% Tween-20 pH 4.5; (C) In the phosphate-buffered solution of 0.5% Tween-20 pH 6.8; (D) In the aqueous solution of 0.5% Tween-20. The d (4,3) values of the deferasirox API used in preparing three batches of dispersion tablets (Batch No. 20180622, 20180629 and 20191209) were 4, 7 and 2 μm, respectively.

参考文献 26

[1]	Muncie, H.L.; Campbell, J. Alpha and beta thalassemia. Am. Fam. Physician. 2009, 80, 339–344.
[2]	Weatherall, D.J. The definition and epidemiology of non-transfusion-dependent thalassemia. Blood Rev. 2012, 26, S3–S6.
[3]	Shirley, M.; Plosker, G.L. Deferasirox: a review of its use for chronic iron overload in patients with non-transfusion-dependent thalassaemia. Drugs. 2014, 74, 1017–1027.
[4]	Bollig, C.; Schell, L.K.; Rücker, G.; Allert, R.; Motschall, E.; Niemeyer, C.M.; Bassler, D.; Meerpohl, J.J. Deferasirox for managing iron overload in people with thalassaemia. Cochrane Database Syst. Rev. 2017, 8, CD007476.
[5]	Díaz-García, J.D.; Gallegos-Villalobos, A.; Gonzalez-Espinoza, L.; Sanchez-Niño, M.D.; Villarrubia, J.; Ortiz, A. Deferasirox nephrotoxicity-the knowns and unknowns. Nat. Rev. Nephrol. 2014, 10, 574–586.
[6]	Martin-Sanchez, D.; Gallegos-Villalobos, A.; Fontecha-Barriuso, M.; Carrasco, S.; Sanchez-Niño, M.D.; Lopez-Hernandez, F.J.; Ruiz-Ortega, M.; Egido, J.; Ortiz, A.; Sanz, A.B. Deferasirox-induced iron depletion promotes BclxL downregulation and death of proximal tubular cells. Sci. Rep. 2017, 7, 41510.
[7]	Bird, S.T.; Swain, R.S.; Tian, F.; Okusanya, O.O.; Waldron, P.; Khurana, M.; Durmowicz, E.L.; Ma, Y.; Major, J.M.; Gelperin, K. Effects of deferasirox dose and decreasing serum ferritin concentrations on kidney function in paediatric patients: an analysis of clinical laboratory data from pooled clinical studies. Lancet Child Adolesc. Heal. 2019, 3, 15–22.
[8]	Vichinsky, E. Clinical application of deferasirox: Practical patient management. Am. J. Hematol. 2008, 83, 398–402.
[9]	US FDA.Exjade_ (deferasirox): prescribing information. accessed 14 Mar 20 2013. http://www.accessdata.fda.gov/drugsatfda _docs/label/2013/021882s019lbl.pdf.
[10]	The European Medicines Agency. Exjade: summary of product characteristics. accessed 14 Mar 2014. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000670/WC500033925.pdf.
[11]	The European Medicines Agency. EMEA/COMP/50/02 Rev.2 [online], 2007. http://www.ema.europa.eu/docs/en_GB/document_library/Orphan_designation/2009/10/WC500005470.pdf.
[12]	Pinto, E.C.; Carmo, F.A.; Honório Tda, S.; Barros Rde, C.; Castro, H.C.; Rodrigues, C.R.; Esteves, V.S.; Rocha, H.V.; Sousa, V.P.; Cabral, L.M. Influence of the efavirenz micronization on tableting and dissolution. Pharmaceutics. 2012, 4, 430–441.
[13]	Berkland, C.; Kim, K.K.; Pack, D.W. PLG microsphere size controls drug release rate through several competing factors. Pharm. Res. 2003, 20, 1055–1062.
[14]	Tan, L.X.; Cai, Y.X.; Yu, Z.M.; Liang, T.R. Research of the technology on different characterization of particle size. Mater. Res. Appl. 2011, 5, 57–61.
[15]	Ouyang, Z.Q.; Zhu, J.G.; Lv, Q.G.; Wang, J.; Hou, H.M. Particle Characteristics of Anthracite Powder Preheated Quickly in Circulating Fluidized Bed. 2013 International Conference on Materials for Renewable Energy and Environment. Chengdu. 2013, 796–801.
[16]	van Beers, M.M.C.; Slooten, C.; Meulenaar, J.; Sediq, A.S.; Verrijk, R.; Jiskoot, W. Micro-Flow Imaging as a quantitative tool to assess size and agglomeration of PLGA microparticles. Eur. J. Pharm. Biopharm. 2017, 117, 91–104.
[17]	Rawle, A. Basic principles of particle size analysis. Technical Paper Malvern Instruments, UK. 1993.
[18]	Heywood, H. Evaluation of powders. J. Pharm. Pharmacol. 1963, 15, 56–74.
[19]	Silva, A.F.T.; Burggraeve, A.; Denon, Q.; van der Meeren, P.; Sandler, N.; van den Kerkhof, T.; Hellings, M.; Vervaet, C.; Remon, J.P.; Lopes, J.A.; De Beer, T. Particle sizing measurements in pharmaceutical applications: Comparison of in-process methods versus off-line methods. Eur. J. Pharm. Biopharm. 2013, 85, 1006–1018.
[20]	Frank, K.J.; Boeck, G. Development of a nanosuspension for iv administration: From miniscale screening to a freeze dried formulation. Eur. J. Pharm. Sci. 2016, 87, 112–117.
[21]	Pilcer, G.; Vanderbist, F.; Amighi, K. Correlations between cascade impactor analysis and laser diffraction techniques for the determination of the particle size of aerosolised powder formulations. Int. J. Pharm. 2008, 358, 75–81.
[22]	Desroches, M.J.; Castillo, I.A.; Munz, R.J. Determination of particle size distribution by laser diffraction of doped-CeO₂ powder suspensions: effect of suspension stability and sonication. Part. Part. Syst. Charact. 2005, 22, 310–319.
[23]	Tsabet, È.; Fradette, L. Effect of processing parameters on the production of Pickering emulsions. Ind. Eng. Chem. Res. 2015, 54, 2227–2236.
[24]	Chinese Pharmacopeia Commission. Pharmacopoeia of the People’s Republic of China, China Medical Science Press, Beijing, China. 2015, 121–124.
[25]	Chakravarthy, V.K.; Sankar, D.G. LC determination of deferasirox in pharmaceutical formulation. J. Global Trends Pharm. Sciences. 2010, 1, 42–52.
[26]	Yu, C.M.; Han,L.H.; Liang, D.L.; Feng, G.S. Comparison and analysis on samples dispersing methods for application by laser diffraction particle size analyzer. Res. Exp. Laboratory. 2015, 34, 43–46.

激光衍射法测定地拉罗司的粒径分布及其与体外溶出度的相关性研究

Determination of deferasirox particle size distribution via laser diffraction and its application in establishing a correlation between particle size and drug dissolution in vitro

RichHTML

PDF (PC)

可视化

摘要/Abstract

引用本文

使用本文

图/表 6

参考文献 26

相关文章 1

编辑推荐

Metrics

本文评价