Solid dispersion technology is an advanced technology to improve the solubility and bioavailability of poorly soluble drugs. Inhibition of the recrystallization and amorphous phase separation of amorphous solid dispersion (ASD) active pharmaceutical ingredients are important to ensure product stability, so the characterization of ASD phase separation is essential. Based on the principle of phase separation, this paper analyzed and summarized the advantages, disadvantages and applicability of the various characterization techniques, in order to provide an efficient reference for the characterization and stability study of ASD.

1.Li N, Cape JL, Mankani BR, et al. Water-induced phase separation of spray-dried amorphous solid dispersions[J]. Mol Pharm, 2020, 17(10): 4004-4017. DOI: 10.1021/acs.molpharmaceut.0c00798.

2.施秦, 蔡挺. 无定型态药物结晶行为的研究进展 [J].中国药科大学学报, 2017, 48(6): 654-662. [Shi Q, Cai T. Recent progress on crystallizations of amorphous pharmaceutical solids[J]. Journal of China Pharmaceutical University, 2017, 48(6): 654-662.] DOI: 10.11665/j.issn.1000-5048.20170604.

3.Dedroog S, Pas T, Vergauwen B, et al. Solid-state analysis of amorphous solid dispersions: why DSC and XRPD may not be regarded as stand-alone techniques[J]. J Pharm Biomed Anal, 2020, 178: 112937. DOI: 10.1016/j.jpba.2019.112937.

4.Moseson DE, Taylor LS. Crystallinity: a complex critical quality attribute of amorphous solid dispersions[J]. Mol Pharm, 2023, 20(10): 4802-4825. DOI: 10.1021/acs.molpharmaceut.3c00526.

5.Baird JA, Taylor LS. Evaluation of amorphous solid dispersion properties using thermal analysis techniques[J]. Adv Drug Deliv Rev, 2012, 64(5): 396-421. DOI: 10.1016/j.addr.2011.07.009.

6.Qian F, Huang J, Zhu Q, et al. Is a distinctive single Tg a reliable indicator for the homogeneity of amorphous solid dispersion[J]. Int J Pharm, 2010, 395(1-2): 232-235. DOI: 10.1016/j.ijpharm.2010.05.033.

7.Newman A, Engers D, Bates S, et al. Characterization of amorphous API: polymer mixtures using X-ray powder diffraction[J]. J Pharm Sci, 2008, 97(11): 4840-4856. DOI: 10.1002/jps.21352.

8.Péter-Haraszti A, Záhonyi P, Farkas A, et al. Thermal investigation of relaxations of interacting and non-interacting amorphous solid dispersions[J]. J Ther Anal Calorim, 2024: 1-17. DOI: 10.1007/s10973-024-13281-7.

9.Tian Y, Jones DS, Donnelly C, et al. A new method of constructing a drug-polymer temperature-composition phase diagram using hot-melt extrusion[J]. Mol Pharm, 2017, 15(4): 1379-1391. DOI: 10.1021/acs.molpharmaceut.7b00445.

10.Liu X, Feng X, Williams RO, et al. Characterization of amorphous solid dispersions[J]. J Pharm Investig, 2018, 48: 19-41. DOI: 10.1007/s40005-017-0361-5.

11.田芳, ZIMMERMANN Anne, MCGOVERIN Cushla, 等. 拉曼技术在药物逆向工程中的应用[J].药学进展, 2016, 40(12):897-905. [Tian F, Anne Z, Cushla M, et al. Application of raman technique in pharmaceutical reverse engineering[J]. Progress in Pharmaceutical Sciences, 2016, 40(12): 897-905.] DOI: CNKI:SUN:YXJZ.0.2016-12-005.

12.Kilpeläinen T, Pajula K, Ervasti T, et al. Raman imaging of amorphous-amorphous phase separation in small molecule co-amorphous systems[J]. Eur J Pharm Biopharm, 2020, 155: 49-54. DOI: 10.1016/j.ejpb.2020.08.007.

13.Luebbert C, Klanke C, Sadowski G. Investigating phase separation in amorphous solid dispersions via Raman mapping[J]. Int J Pharm, 2018, 535(1-2): 245-252. DOI: 10.1016/j.ijpharm.2017.11.014.

14.Hurley D, Davis M, Walker GM, et al. The effect of cooling on the degree of crystallinity, solid-state properties, and dissolution rate of multi-component hot-melt extruded solid dispersions[J]. Pharmaceutics, 2020, 12(3): 212. DOI: 10.3390/pharmaceutics12030212.

15.Padilla AM, Ivanisevic I, Yang Y, et al. The study of phase separation in amorphous freeze-dried systems. Part I: Raman mapping and computational analysis of XRPD data in model polymer systems[J]. J Pharm Sci, 2011, 100(1): 206-222. DOI: 10.1002/jps.22269.

16.Widjaja E, Kanaujia P, Lau G, et al. Detection of trace crystallinity in an amorphous system using Raman microscopy and chemometric analysis[J]. Eur J Pharm Sci, 2011, 42(1-2): 45-54. DOI: 10.1016/j.ejps.2010.10.004.

17.Thakore SD, Das K, Dalvi SV, et al. Microscopic cracks modulate nucleation and solid-state crystallization tendency of amorphous celecoxib[J]. Mol Pharm, 2023, 21(1): 76-86. DOI: 10.1021/acs.molpharmaceut.3c00457.

18.Yao X, Yu L, Zhang GGZ. Impact of crystal nuclei on dissolution of amorphous drugs[J]. Mol Pharm, 2023, 20(3): 1796-1805. DOI: 10.1021/acs.molpharmaceut.2c00989.

19.Okada H, Ueda K, Yasuda Y, et al. Correlation between drug dissolution and resistance to water-induced phase separation in solid dispersion formulations revealed by solid-state NMR spectroscopy[J]. Int J Pharm, 2020, 577: 119086. DOI: 10.1016/j.ijpharm.2020.119086.

20.Lubach JW, Hau J. Solid-state NMR investigation of drug-excipient interactions and phase behavior in indomethacin-Eudragit E amorphous solid dispersions[J]. Pharm Res, 2018, 35(3): 65. DOI: 10.1007/s11095-018-2364-y.

21.Purohit HS, Ormes JD, Saboo S, et al. Insights into nano-and micron-scale phase separation in amorphous solid dispersions using fluorescence-based techniques in combination with solid state nuclear magnetic resonance spectroscopy[J]. Pharm Res, 2017, 34(7): 1364-1377. DOI: 10.1007/s11095-017-2145-z.

22.Sarpal K, Tower CW, Munson EJ. Investigation into intermolecular interactions and phase behavior of binary and ternary amorphous solid dispersions of ketoconazole[J]. Mol Pharm, 2019, 17(3): 787-801. DOI: 10.1021/acs.molpharmaceut.9b00970.

23.Wang Y, Wang Y, Cheng J, et al. Recent advances in the application of characterization techniques for studying physical stability of amorphous pharmaceutical solids[J]. Crystals, 2021, 11(12): 1440. DOI: 10.3390/cryst11121440.

24.Okada K, Ono T, Hayashi Y, et al. Use of time-domain NMR for 1H T1 relaxation measurement and fitting analysis in homogeneity evaluation of amorphous solid dispersion[J]. J Pharm Sci, 2024, 113(3): 680-687. DOI: 10.1016/j.xphs.2023.08.021.

25.Van Eerdenbrugh B, Lo M, Kjoller K, et al. Nanoscale mid-infrared imaging of phase separation in a drug-polymer blend[J]. J Pharm Sci, 2012, 101(6): 2066-2073. DOI: 10.1002/jps.23099.

26.Mansuri A, Munzner P, Heermant A, et al. Molecular dynamics and diffusion in amorphous solid dispersions containing imidacloprid[J]. Mol Pharm, 2023, 20(4): 2067-2079. DOI: 10.1021/acs.molpharmaceut.2c01042.

27.Lim H, Yu D, Hoag SW. Application of near-infrared spectroscopy in detecting residual crystallinity in carbamazepine-Soluplus® solid dispersions prepared with solvent casting and hot-melt extrusion[J]. J Drug Delivery Sci Technol, 2021, 65: 102713. DOI: 10.1016/j.jddst.2021.102713.

28.Tian B, Tang X, Taylor LS. Investigating the correlation between miscibility and physical stability of amorphous solid dispersions using fluorescence-based techniques[J]. Mol Pharm, 2016, 13(11): 3988-4000. DOI: 10.1021/acs.molpharmaceut.6b00803.

29.Xu Y, Shen C, Yuan H, et al. Mapping multiple phases in curcumin binary solid dispersions by fluorescence contrasting[J]. Chinese Chem Lett, 2024, 35(9): 109324. DOI: 10.1016/j.cclet.2023.109324.

30.Li Z, Luo J, Chen X, et al. Optimization of precipitation conditions for producing physically stable amorphous solids using pair distribution function and reduced crystallization temperature[J]. J Drug Deliv Sci Technol, 2024, 91: 105268.DOI:10.1016/j.jddst.2023.105268.

31.de Araujo GLB, Benmore CJ, Byrn SR. Local structure of ion pair interaction in lapatinib amorphous dispersions characterized by synchrotron X-ray diffraction and pair distribution function analysis[J]. Sci Rep, 2017, 7(1): 46367. DOI: 10.1038/srep46367.

32.Wang X, Zhang L, Ma D, et al. Characterizing and exploring the differences in dissolution and stability between crystalline solid dispersion and amorphous solid dispersion[J]. AAPS PharmSciTech, 2020, 21(7): 262. DOI: 10.1208/s12249-020-01802-0.

33.Rusdin A, Gazzali AM, Thomas NA, et al. Advancing drug delivery paradigms: polyvinyl pyrolidone (PVP)-based amorphous solid dispersion for enhanced physicochemical properties and therapeutic efficacy[J]. Polymers, 2024, 16(2): 286. DOI: 10.3390/polym16020286.

34.Nurzyńska K, Booth J, Roberts CJ, et al. Long-term amorphous drug stability predictions using easily calculated, predicted, and measured parameters[J]. Mol Pharm, 2015, 12(9): 3389-3398. DOI: 10.1021/acs.molpharmaceut.5b00409.

35.严梦梦, 吴秀娟, 朱恒清, 等. 基于溶解度参数法和差式扫描量热法优化筛选奥拉帕利固体分散体聚合物[J]. 药学学报, 2022, 57(5): 1486-1494. [Yan MM, Wu XJ, Zhu  HQ, et al. Optimization and screening of carrier for solid dispersion of olaparib based on the solubility parameter and differential scanning calorimetry[J]. Acta Pharmaceutica Sinica, 2022, 57(5): 1486-1494.] DOI: 10.16438/j.0513-4870.2021-1261.

36.Vasanthavada M , Tong WQ , Joshi Y ,et al. Phase behavior of amorphous molecular dispersions II: role of hydrogen bonding in solid solubility and phase separation kinetics[J].Pharm Res, 2005, 22(3): 440-448. DOI: 10.1007/s11095-004-1882-y.

37.Thakore SD, Akhtar J, Jain R, et al. Analytical and computational methods for the determination of drug-polymer solubility and miscibility[J]. Mol Pharm, 2021, 18(8): 2835-2866. DOI: 10.1021/acs.molpharmaceut. 1c00141.

38.Marsac PJ, Shamblin SL, Taylor LS. Theoretical and practical approaches for prediction of drug–polymer miscibility and solubility[J]. Pharm Res, 2006, 23(10): 2417-2426. DOI: 10.1007/s11095-006-9063-9.

39.Marsac PJ, Li T, Taylor LS. Estimation of drug-polymer miscibility and solubility in amorphous solid dispersions using experimentally determined interaction parameters[J]. Pharm Res, 2009, 26(1): 139-151. DOI: 10.1007/s11095-008-9721-1.