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Research and Prospects on the Evaluation of Drug Cocrystal Permeability
  • Shuang Li 1,   
  • Meiru Liu 1,   
  • Dezhi Yang 1, *,   
  • Li Zhang 1, *,   
  • Yang Lu 1, *,   
  • Guanhua Du 2

Received: 29 Aug 2024 | Revised: 14 Oct 2024 | Accepted: 15 Oct 2024 | Published: 24 Feb 2025

Abstract

In developing new drugs, drug permeability assessment is crucial. Lead compounds exhibiting inadequate permeability often produce low bioavailability, rendering them inappropriate as drugs. The cocrystallization technique is a valuable tool for optimizing the physical and chemical properties of active pharmaceutical ingredients (APIs) and enhancing drug properties. This technique involves the introduction and weak interaction with cocrystal formers to produce supramolecular substances without altering the chemical structure of APIs, effectively improving their solubility and permeability and thereby significantly increasing their bioavailability. Consequently, drug cocrystal research has become a focal point for researchers in drug development. This study provides a comprehensive overview of four commonly employed methods for evaluating drug permeability and summarizes the applicability of each method to provide a reference for improving and refining the permeability evaluation method of drug cocrystals.

References 

  • 1.
    Mehta, M.; Polli, J.E.; Seo, P.; et al. Drug permeability-best practices for Biopharmaceutics Classification System (BCS)-based biowaivers: A workshop summary report. J. Pharm. Sci. 2023, 112, 1749–1762. https://doi.org/10.1016/j.xphs.2023.04.016.
  • 2.
    Khan, K.U.; Minhas, M.U.; Badshah, S.F.; et al. Overview of nanoparticulate strategies for solubility enhancement of poorly soluble drugs. Life Sci. 2022, 291, 120301. https://doi.org/10.1016/j.lfs.2022.120301.
  • 3.
    Dahlgren, D.; Lennernäs, H. Intestinal permeability and drug absorption: Predictive experimental, computational and in vivo approaches. Pharmaceutics 2019, 11, 411. https://doi.org/10.3390/pharmaceutics11080411.
  • 4.
    Alqahtani, M.S.; Kazi, M.; Alsenaidy, M.A.; et al. Advances in oral drug delivery. Front. Pharmacol. 2021, 12, 618411. https://doi.org/10.3389/fphar.2021.618411.
  • 5.
    Hidalgo, I.J. Assessing the absorption of new pharmaceuticals. Curr. Top. Med. Chem. 2001, 1, 385–401. https://doi.org/10.2174/1568026013395010.
  • 6.
    Kavanagh, O.N.; Croker, D.M.; Walker, G.M.; et al. Pharmaceutical cocrystals: From serendipity to design to application. Drug Discov. Today 2019, 24, 796–804. https://doi.org/10.1016/j.drudis.2018.11.023.
  • 7.
    Bolla, G.; Sarma, B.; Nangia, A.K. Crystal Engineering of Pharmaceutical Cocrystals in the Discovery and Development of Improved Drugs. Chem. Rev. 2022, 122, 11514–11603. https://doi.org/10.1021/acs.chemrev.1c00987.
  • 8.
    Braham, D.; Choudhary, M.; Budhwar, V. A brief discussion of multi-component organic solids: Key emphasis on co-crystallization. Turk. J. Pharm. Sci. 2022, 19, 220. https://doi.org/10.4274/tjps.galenos.2020.78700.
  • 9.
    Bhattacharyya, S.; Manjunath, A. A comprehensive review on pharmaceutical cocrystal-a subtle technique for solubility enhancement. J. Pharm. Sci. 2022, 46, 622.
  • 10.
    Duggirala, N.K.; Perry, M.L.; Almarsson, Ö.; et al. Pharmaceutical cocrystals: Along the path to improved medicines. Chem. Commun. 2016, 52, 640–655. https://doi.org/10.1039/c5cc08216a.
  • 11.
    Mannava, M.K.C.; Garai, A.; Nangia, A.K. Diffusion and Flux Improvement of Drugs through Complexation. Mol. Pharm. 2023, 20, 2293–2316. https://doi.org/10.1021/acs.molpharmaceut.3c00159.
  • 12.
    Saladi, V.N.; Kammari, B.R.; Mandad, P.R.; et al. Novel Pharmaceutical Cocrystal of Apalutamide, a Nonsteroidal Antiandrogen Drug: Synthesis, Crystal Structure, Dissolution, Stress, and Excipient Compatibility. Cryst. Growth Des. 2022, 22, 1130–1142. https://doi.org/10.1021/acs.cgd.1c01087.
  • 13.
    Ji, X.; Wu, D.; Li, C.; et al. Enhanced solubility, dissolution, and permeability of abacavir by salt and cocrystal formation. Cryst. Growth Des. 2021, 22, 428–440. https://doi.org/10.1021/acs.cgd.1c01051.
  • 14.
    Dai, X.L.; Voronin, A.P.; Gao, W.; et al. Intermolecular interactions and permeability of 5-fluorouracil cocrystals with a series of isomeric hydroxybenzoic acids: A combined theoretical and experimental study. Cryst. Eng. Comm. 2019, 21, 5095–5105. https://doi.org/10.1039/C9CE00661C.
  • 15.
    Zhang, Y.X.; Wang, L.Y.; Dai, J.K.; et al. The comparative study of cocrystal/salt in simultaneously improving solubility and permeability of acetazolamide. J. Mol. Struct. 2019, 1184, 225–232. https://doi.org/10.1016/j.molstruc.2019.01.090.
  • 16.
    U.S. Food and Drug Administration. Guidance for Industry: Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System; FDA: Washington, DC, USA, 2015.
  • 17.
    European Medicines Agency. Note for Guidance on the Investigation of Bioavailability and Bioequivalence; CPMP/EWP/QWP/1401/98 Rev1, Appendix Ⅲ; EMA: Amsterdam, The Netherlands, 2010.
  • 18.
    China Food and Drug Administration. Guidelines for the Exemption of Human Bioequivalence Test; Medical Science Press: Beijing: China, 2016.
  • 19.
    Balimane, P.V.; Chong, S.; Morrison, R.A. Current methodologies used for evaluation of intestinal permeability and absorption. J. Pharmacol. Toxicol. Methods 2000, 44, 301–12. https://doi.org/10.1016/S1056-8719(00)00113-1.
  • 20.
    Application of Parallel Artificial Membrane Permeation Technology (PAMPA) in Drug Screening. Available online: https://m.biomart.cn/news/16/3218140_0.htm (accessed on28August2024).
  • 21.
    Qiang, Y. Application Status and Future Trend of the Single-Layer Model of Differentiated Caco-2 Cells in the Study of Food-Intestinal Interaction. Available online: https://www.163.com/dy/article/FSRSN47L0530N4P3.html (accessed on 28 August 2024).
  • 22.
    Franz Cell—The Original. Available online: https://permegear.com/franz-cells/ (accessed on29August2024).
  • 23.
    Kansy, M.; Senner, F.; Gubernator, K. Physicochemical high throughput screening: Parallel artificial membrane permeation assay in the description of passive absorption processes. J. Med. Chem. 1998, 41, 1007–1010. https://doi.org/10.1021/jm970530e.
  • 24.
    Ottaviani, G.; Martel, S.; Carrupt, P.A. Parallel artificial membrane permeability assay: A new membrane for the fast prediction of passive human skin permeability. J. Med. Chem. 2006, 49, 3948–3954. https://doi.org/10.1021/jm060230+.
  • 25.
    Alex, A. The rise of PAMPA. Expert Opin. Drug Metab. Toxicol. 2005, 1, 325–342. https://doi.org/10.1517/17425255.1.2.325.
  • 26.
    Winiwarter, S.; Bonham, N.M.; Ax, F.; et al. Correlation of human jejunal permeability (in vivo) of drugs with experimentally and theoretically derived parameters. A multivariate data analysis approach. J. Med. Chem. 1998, 41, 4939–4949. https://doi.org/10.1021/jm9810102.
  • 27.
    Avdeef, A.; Tsinman, O. PAMPA—A drug absorption in vitro model: 13. Chemical selectivity due to membrane hydrogen bonding: In combo comparisons of HDM-, DOPC-, and DS-PAMPA models. Eur. J. Pharm. Sci. 2006, 28, 43–50. https://doi.org/10.1016/j.ejps.2005.12.008.
  • 28.
    Di, L.; Kerns, E.H.; Fan, K.; et al. High throughput artificial membrane permeability assay for blood–brain barrier. Eur. J. Med. Chem. 2003, 38, 223–232. https://doi.org/10.1016/s0223-5234(03)00012-6.
  • 29.
    Sinkó B.; Garrigues, T.M.; Balogh, G.T.; et al. Skin–PAMPA: A new method for fast prediction of skin penetration. Eur. J. Pharm. Sci. 2012, 45, 698–707. https://doi.org/10.1016/j.ejps.2012.01.011.
  • 30.
    Sinkó B.; Pálfi, M.; Béni, S.; et al. Synthesis and characterization of long-chain tartaric acid diamides as novel ceramide-like compounds. Molecules 2010, 15, 824–833. https://doi.org/10.3390/molecules15020824.
  • 31.
    Vizserálek G, Berkó S, Tóth G; et al. Permeability test for transdermal and local therapeutic patches using Skin PAMPA method. Eur. J. Pharm. Sci. 2015, 76, 165–172. https://doi.org/10.1016/j.ejps.2015.05.004.
  • 32.
    Seo, P.R.; Teksin, Z.S.; Kao, J.P.Y.; et al. Lipid composition effect on permeability across PAMPA. Eur. J. Pharm. Sci. 2006, 29, 259–268. https://doi.org/10.1016/j.ejps.2006.04.012.
  • 33.
    Carrara, S.; Reali, V.; Misiano, P.; et al. Evaluation of in vitro brain penetration: Optimized PAMPA and MDCKII-MDR1 assay comparison. Int. J. Pharm. 2007, 345, 125–133. https://doi.org/10.1016/j.ijpharm.2007.05.057.
  • 34.
    Palaiokostas, M.; Ding, W.; Shahane, G.; et al. Effects of lipid composition on membrane permeation. Soft Matter 2018, 14, 8496–8508. https://doi.org/10.1039/c8sm01262h.
  • 35.
    Gan, L.S.; Thankker, D.R. Applications of the Caco-2 model in the design and development of biochemical and physical barriers posed by the intestinal epithelium. Adv. Drug Deliv. Rev. 1997, 23, 77–98.
  • 36.
    Lipinski, C.A.; Lombardo, F.; Dominy, B.W.; et al. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Deliv. Rev. 2001, 46, 3–26. https://doi.org/10.1016/s0169-409x(00)00129-0.
  • 37.
    Lee, J.B.; Zgair, A.; Taha, D.A.; et al. Quantitative analysis of lab-to-lab variability in Caco-2 permeability assays. Eur. J. Pharm. Biopharm. 2017, 114, 38–42. https://doi.org/10.1016/j.ejpb.2016.12.027.
  • 38.
    Hidalgo, I.J.; Raub, T.J.; Borchardt, R.T. Characterization of the human colon carcinoma cell line (Caco-2) as a model system for intestinal epithelial permeability. Gastroenterology 1989, 96, 736–749. https://doi.org/10.1016/S0016-5085(89)80072-1.
  • 39.
    Yee, S. In vitro permeability across Caco-2 cells (colonic) can predict in vivo (small intestinal) absorption in man—Fact or myth. Pharm. Res. 1997, 14, 763–766. https://doi.org/10.1023/a:1012102522787.
  • 40.
    Srinivasan, B.; Kolli, A.R.; Esch, M.B.; et al. TEER measurement techniques for in vitro barrier model systems. J. Lab. Autom. 2015, 20, 107–126. https://doi.org/10.1177/2211068214561025.
  • 41.
    Xiao, G.; Li, J.; Yi, W.; et al. Influence of glutamine on barrier function of heat-stressed intestinal epithelial caco-2 cells. Med. J. Chin. People's Lib. Army 2017, 12, 506–510.
  • 42.
    Dong, L.; Ping, G. Limitations and countermeasures of Caco-2 cell model in evaluating oral absorption of drugs. Chin. Pharm. J. 2011, 46, 565–568.
  • 43.
    Madin, S.H.; Darby, N.B., Jr. Established kidney cell lines of normal adult bovine and ovine origin. Proc. Soc. Exp. Biol. Med. 1958, 98, 574–576. https://doi.org/10.3181/00379727-98-24111.
  • 44.
    Gaush, C.R.; Hard, W.L.; Smith, T.F. Characterization of an established line of canine kidney cells (MDCK). Proc. Soc. Exp. Biol. Med. 1966, 122, 931–935. https://doi.org/10.3181/00379727-122-31293.
  • 45.
    Irvine, J.D.; Takahashi, L.; Lockhart, K.; et al. MDCK (Madin–Darby canine kidney) cells: A tool for membrane permeability screening. J. Pharm. Sci. 1999, 88, 28–33. https://doi.org/10.1021/js9803205.
  • 46.
    Chen, R.; Shen, C.; Xu, Q.; et al. The permeability characteristics and interaction of main components from Si-Ni-San in a MDCK epithelial cell monolayer model. Xenobiotica 2021, 51, 239–248. https://doi.org/10.1080/00498254.2017.1359433.
  • 47.
    Bokulić A.; Padovan, J.; Stupin-Polančec, D; et al. Isolation of MDCK cells with low expression of mdr1 gene and their use inmembrane permeability screening. Acta Pharm. 2022, 72, 275–288. https://doi.org/10.2478/acph-2022-0003.
  • 48.
    Bartosova, L.; Bajgar, J. Transdermal drug delivery in vitro using diffusion cells. Curr. Med. Chem. 2012, 19, 4671–4677. https://doi.org/10.2174/092986712803306358.
  • 49.
    Supe, S.; Takudage, P. Methods for evaluating penetration of drug into the skin: A review. Skin. Res. Technol. 2021, 27, 299–308. https://doi.org/10.1111/srt.12968.
  • 50.
    Akram, M.R.; Ahmad, M.; Abrar, A.; et al. Formulation design and development of matrix diffusion controlled transdermal drug delivery of glimepiride. Drug Des. Dev. Ther. 2018, 12, 349–364. https://doi.org/10.2147/dddt.s147082.
  • 51.
    Seo, J.E.; Kim, S.; Kim, B.H. In vitro skin absorption tests of three types of parabens using a Franz diffusion cell. J. Expo. Sci. Environ. Epidemiol. 2017, 27, 320–325. https://doi.org/10.1038/jes.2016.33.
  • 52.
    An, Q.; Xing, C.; Wang, Z.; et al. Metformin-Mediated Improvement in Solubility, Stability, and Permeability of Nonsteroidal Anti-Inflammatory Drugs. Pharmaceutics 2024, 16, 382. https://doi.org/10.3390/pharmaceutics16030382.
  • 53.
    Wang, Z.; Li, S.; Li, Q.; et al. A Novel Cocrystal of Daidzein with Piperazine to Optimize the Solubility, Permeability and Bioavailability of Daidzein. Molecules 2024, 29, 1710. https://doi.org/10.3390/molecules29081710.
  • 54.
    Kumar, M.; Sharma, A.; Mahmood, S.; et al. Franz diffusion cell and its implication in skin permeation studies. J. Dispers. Sci. Technol. 2024, 45, 943–956. https://doi.org/10.1080/01932691.2023.2188923.
  • 55.
    Sun, R.; Han, Y.; Swanson JMJ.; et al. Molecular transport through membranes: Accurate permeability coefficients from multidimensional potentials of mean force and local diffusion constants. J. Chem. Phys. 2018, 149, 072310. https://doi.org/10.1063/1.5027004.
  • 56.
    Diukendjieva, A.; Tsakovska, I.; Alov, P.; et al. Advances in the prediction of gastrointestinal absorption: Quantitative Structure-Activity Relationship (QSAR) modelling of PAMPA permeability. Comput. Toxicol. 2019, 10, 51–59. https://doi.org/10.1016/j.comtox.2018.12.008.
  • 57.
    Tsopelas, F.; Vallianatou, T.; Tsantili-Kakoulidou, A. Recent developments in the application of immobilized artificial membrane (IAM) chromatography to drug discovery. Expert. Opin. Drug Discov, 2024, 19, 1087–1098. https://doi.org/10.1080/17460441.2024.2374409.
  • 58.
    Meng, F.; Xu, W. Drug permeability prediction using PMF method. J. Mol. Model. 2013, 19, 991–997. https://doi.org/10.1007/s00894-012-1655-1.
  • 59.
    Di, J.; Gao, X.; Du, Y.; et al. Size, shape, charge and “stealthy” surface: Carrier properties affect the drug circulation time in vivo. Asian J. Pharm. Sci. 2021, 16, 444–458. https://doi.org/10.1016/j.ajps.2020.07.005.
  • 60.
    Jung, S.J.; Choi, S.O.; Um, S.Y.; et al. Prediction of the permeability of drugs through study on quantitative structure–permeability relationship. J. Pharm. Biomed. Anal. 2006, 41, 469–475. https://doi.org/10.1016/j.jpba.2005.12.020.
  • 61.
    Ong, S.; Liu, H.; Pidgeon, C. Immobilized-artificial-membrane chromatography: Measurements of membrane partition coefficient and predicting drug membrane permeability. J. Chromatogr. A 1996, 728, 113–128. https://doi.org/10.1016/0021-9673(95)00837-3.
  • 62.
    Huang, E.T.; Yang, J.S.; Liao, K.Y.; et al. Predicting blood–brain barrier permeability of molecules with a large language model and machine learning. Sci. Rep. 2024, 14, 15844. https://doi.org/10.1038/s41598-024-66897-y.
  • 63.
    Alsenan, S.; Al-Turaiki, I.; Hafez, A. A deep learning approach to predict blood-brain barrier permeability. PeerJ Comput. Sci. 2021, 7, e515. https://doi.org/10.7717/peerj-cs.515.
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DOI
10.53941/ijddp.2025.100005
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Volume 4, Issue 1
How to Cite
Li, S.; Liu, M.; Yang, D.; Zhang, L.; Lu, Y.; Du, G. Research and Prospects on the Evaluation of Drug Cocrystal Permeability. International Journal of Drug Discovery and Pharmacology 2025, 4 (1), 100005. https://doi.org/10.53941/ijddp.2025.100005.
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