Development and comprehensive evaluation of a guanfacine hydrochloride extended-release drug delivery system: in vitro and in vivo insights

doi:10.5246/jcps.2025.12.080

Abstract

Abstract:

In the present study, an extended-release (ER) suspension of guanfacine hydrochloride (GFN) was successfully formulated using a self-synthesized cation-exchange resin characterized by a narrow particle size distribution. The drug-resin complex was prepared through a static adsorption method, employing the resin as a pharmaceutical carrier. Subsequently, guanfacine hydrochloride-coated microcapsules (GFN-CM) were fabricated via an emulsion solvent evaporation technique to achieve sustained-release functionality. Characterization revealed that the in-house resin exhibited a smoother surface and a narrower size distribution (Span value: 0.74) compared to the commercial counterpart, Amberlite^® IRP69. In vitro release studies demonstrated that the GFN-CM followed a zero-order kinetic model over 10 h, with a cumulative drug release of 81.88% observed at 12 h. Furthermore, pharmacokinetic evaluation in New Zealand rabbits showed that the mean residence time (MRT_0–24) of the GFN suspension extended from 7.619 to 8.336 h, displaying a more stable plasma concentration-time profile and an average relative bioavailability (F_r) of 111.36% compared to marketed ER GFN tablets. These findings highlighted the successful development of a novel cation exchange resin-based delivery system, offering a promising strategy for enhancing the performance of ER pharmaceutical formulations.

Key words: Guanfacine hydrochloride, Cation-exchange resin, Centrifugal boundary film emulsification, Emulsification-solvent evaporation method

Supporting:

Ze He, Yingshu Feng, Caleb Kesse Firempong, Jingru Lu, Hongfei Liu, Xiaofeng Yu. Development and comprehensive evaluation of a guanfacine hydrochloride extended-release drug delivery system: in vitro and in vivo insights[J]. Journal of Chinese Pharmaceutical Sciences, 2025, 34(12): 1063-1080.

Figures/Tables 19

Table 1. GFN-CM prescriptions.

Table 2. Particle size distribution data for Amberlite® IRP69 and self-made resin.

Table 3. Fitting results of the GFN-CM release mechanism.

Table 4. Pharmacokinetic parameters of GFN self-made suspension and commercially available GFN ER tablets.

References 34

[1]	Qu, Y.; Lai, W.L.; Xin, Y.R.; Zhu, F.Q.; Zhu, Y.; Wang, L.; Ding, Y.P.; Xu, Y.; Liu, H.F. Development, optimization, and evaluation in vitro/in vivo of oral liquid system for synchronized sustained release of levodopa/benserazide. AAPS PharmSciTech. 2019, 20, 312.
[2]	Chaudhary, V.; Sharma, S. Effect of various synthesis parameters on styrene–divinylbenzene copolymer properties. J. Porous Mater. 2019, 26, 1559–1571.
[3]	Gokmen, M.T.; Du Prez, F.E. Porous polymer particles: a comprehensive guide to synthesis, characterization, functionalization and applications. Prog. Polym. Sci. 2012, 37, 365–405.
[4]	Seo, S.D.; Kang, K.C.; Jeong, J.W.; Lee, S.M.; Lee, J.D.; Kim, D.H. Preparation and characterization of poly methyl methacrylate/clay nanocomposite powders by microwave-assisted in-situ suspension polymerization. J. Nanosci. Nanotechnol. 2020, 20, 4193–4197.
[5]	Santos, J.C.; Lopes, C.N.; Reis, M.M.; Giudici, R.; Sayer, C.; Machado, R.A.F.; Araújo, P.H.H. Comparison of techniques for the determination of conversion during suspension polymerization reactions. Braz. J. Chem. Eng. 2008, 25, 399–407.
[6]	Yao, C.R.; Wang, L.; Yang, W.T. Cycloketyl radical mediated suspension polymerization of styrene. RSC Adv. 2016, 6, 69743–69747.
[7]	Chaudhary, V.; Sharma, S. Suspension polymerization technique: parameters affecting polymer properties and application in oxidation reactions. J. Polym. Res. 2019, 26, 102.
[8]	Board, A.W.; Perry, V.P.; Shepperson, B.E.; Nyman, C.E.; Carchman, S.H. A postmarketing evaluation of guanfacine hydrochloride in mild to moderate hypertension. Clin. Ther. 1988, 10, 761–775.
[9]	Cornish, L.A. Guanfacine hydrochloride: a centrally acting antihypertensive agent. Clin. Pharm. 1988, 7, 187–197.
[10]	Gande, S.; Rao, Y. Sustained-release effervescent floating matrix tablets of baclofen: development, optimization and in vitro-in vivo evaluation in healthy human volunteers. Daru. 2011, 19, 202–209.
[11]	Iayadene, F.; Guettaf, H.; Bencheikh, Z.; Saggou, A.; Rabia, I. Structure and properties of styrene–divinylbenzene–methylmethacrylate terpolymers: I. effect of methylmethacrylate as third comonomer. Eur. Polym. J. 1998, 34, 219–223.
[12]	Lei, Y.L.; Luo, Y.J.; Chen, F.; Mei, L.H. Sulfonation process and desalination effect of polystyrene/PVDF semi-interpenetrating polymer network cation exchange membrane. Polymers. 2014, 6, 1914–1928.
[13]	Liu, H.F.; Liu, D.; Chen, C.; He, Y.; Zhu, F.Q.; Zhang, P.; Liang, C.F. Preparation and evaluation of carbinoxamine maleate sustained-release suspensions with ion exchange resin as the carriers. Lat. Am. J. Pharm. 2017, 36, 797–809.
[14]	Li, C.H.; Han, X.L.; Hong, X.X.; Li, X.F.; Zhang, H.; Wang, Z.M.; Zheng, A.P. Study on the complexation and release mechanism of methylphenidate hydrochloride ion exchange resin complex. Polymers. 2021, 13, 4394.
[15]	Liu, H.F.; Chen, C.; Ruan, X.; He, Y.; Zhao, S.; Yang, R.; He, Y.; Ding, Y.P.; Xu, Y. Investigation of the kinetics thermodynamics of the ion exchange process for the phenytoin natricum resinates. Lat. Am. J. Pharm. 2019, 38, 2088–2097
[16]	Liu, H.F.; Bao, Y.; Lai, X.P.; Feng, Y.S.; Yang, D.; Sun, R.; Firempong, C.K.; He, H.B. Construction and in vitro/in vivo evaluation of menantine hydrochloride oral liquid sustained-release drug delivery system. Drug Dev. Ind. Pharm. 2024, 50, 363–375.
[17]	Zhang, T.Y.; Du, R.F.; Wang, Y.J.; Hu, J.L.; Wu, F.; Feng, Y. Research progress of preparation technology of ion-exchange resin complexes. AAPS PharmSciTech. 2022, 23, 105.
[18]	Walia, N.; Dasgupta, N.; Ranjan, S.; Ramalingam, C.; Gandhi, M. Methods for nanoemulsion and nanoencapsulation of food bioactives. Environ. Chem. Lett. 2019, 17, 1471–1483.
[19]	Xin, Y.R.; Dou, Y.T.; Chen, X.L.; Feng, Y.S.; Liu, X.S.; Firempong, C.K.; Yang, D.; Liu, H.F.; He, H.B. Preparation and in vitro/in vivo evaluation of oral oseltamivir phosphate sustained-release suspension. J. Chin. Pharm. Sci. 2025, 1–32.
[20]	Shah, V.P.; Tsong, Y.; Sathe, P.; Liu, J.P. In vitro dissolution profile comparison: statistics and analysis of the similarity factor, f2. Pharm. Res. 1998, 15, 889–896.
[21]	Jebaliya, H.; Patel, M.; Dabhi, B.; Jadeja, Y.; Shah, A. An isocratic assay method validation for the determination of five most potent antihypertensive drugs by a new generation liquid chromatographic technique. Chem. Biol. Interface. 2016, 6, 38–46.
[22]	Yamamoto, Y.; Kumagai, H.; Haneda, M.; Vertzoni, M.; Ouwerkerk, N.; Murayama, D.; Katakawa, Y.; Motonaga, K.; Reppas, C.; Tajiri, T. The mechanism of solifenacin release from a pH-responsive ion-complex oral suspension in the fasted upper gastrointestinal lumen. Eur. J. Pharm. Sci. 2020, 142, 105107.
[23]	Kouchak, M.; Ramezani, Z.; Bagheri, F. Preparation and evaluation of taste masking iron suspension: taking advantage of weak cationic exchange resin. AAPS PharmSciTech. 2018, 19, 719–729.
[24]	Wang, J.; Yu, J.; Li, M.X.; Zhang, Y.D. Synthesis of sodium polystyrene sulfonate resins for the removal of methylene blue from wastewater. J. Taiwan Inst. Chem. Eng. 2024, 159, 105501.
[25]	Tran, A.T.K.; Pham, T.T.; Nguyen, Q.H.; Hoang, N.T.T.; Bui, D.T.; Nguyen, M.T.; Nguyen, M.K.; Van der Bruggen, B. From waste disposal to valuable material: Sulfonating polystyrene waste for heavy metal removal. J. Environ. Chem. Eng. 2020, 8, 104302.
[26]	Negm, S.H.; Abd El-Hamid, A.A.M.; Gado, M.A.; El-Gendy, H.S. Selective uranium adsorption using modified acrylamide resins. J. Radioanal. Nucl. Chem. 2019, 319, 327–337.
[27]	Yang, Y.J.; Du, Y.; He, H.B.; Yu, Y.; Li, D.L.; Liu, H.F. Fabrication and evaluation for the novel ranitidine hydrochloride resinates and calculation of the kinetics and thermodynamics parameter for the ion exchange process. Pak. J. Pharm. Sci. 2021, 34, 1715–1722.
[28]	Deng, Y.X.; Wang, T.T.; Li, J.L.; Sun, W.X.; He, H.B.; Gou, J.X.; Wang, Y.J.; Yin, T.; Zhang, Y.; Tang, X. Studies on the in vitro ion exchange kinetics and thermodynamics and in vivo pharmacokinetics of the carbinoxamine-resin complex. Int. J. Pharm. 2020, 588, 119779.
[29]	Jeong, S.H.; Park, K. Drug loading and release properties of ion-exchange resin complexes as a drug delivery matrix. Int. J. Pharm. 2008, 361, 26–32.
[30]	Li, C.H.; Han, X.L.; Hong, X.X.; Li, X.F.; Zhang, H.; Wang, Z.M.; Zheng, A.P. Study on the complexation and release mechanism of methylphenidate hydrochloride ion exchange resin complex. Polymers. 2021, 13, 4394.
[31]	Han, M.P.; Du, Y.; Wu, X.W.; Zhang, X.; Yang, Q.Z.; Firempong, C.K.; Liu, H.F.; Li, D.L. Development, optimization, and in vitro/in vivo evaluation of ranitidine hydrochloride resinate sustained release suspension. Trop. J. Pharm. Res. 2023, 22, 457–467.
[32]	Liu, H.F.; Ding, H.; Liu, D.; Pan, W.S.; Feng, Y.S.; He, Y.; Sun, C.S. Preparation, characterization of ambroxol hydrochloride resinates and investigation of the kinetics and thermodynamics of the ion exchange process. Lat. Am. J. Pharm. 2015, 34, 21–29.
[33]	Liu, H.F.; Lai, X.P.; Chen, C.; Feng, Y.S.; Yu, Y.; Yin, X.Z.; He, H.B. Preparation, characterization of clonidine hydrochloride resinates and investigation of the kinetics and thermodynamics of the ion exchange process. Pak. J. Pharm. Sci. 2022, 35, 721–729.
[34]	Jeong, S.H.; Berhane, N.H.; Haghighi, K.; Park, K. Drug release properties of polymer coated ion-exchange resin complexes: experimental and theoretical evaluation. J. Pharm. Sci. 2007, 96, 618–632.