In this work, the solid-liquid equilibrium (SLE) of four binary systems combining two active pharmaceutical ingredients (APIs) capable of forming co-amorphous systems (CAMs) was investigated. The binary systems studied were naproxen-indomethacin, naproxen-ibuprofen, naproxen-probucol, and indomethacin-paracetamol. The SLE was experimentally determined by differential scanning calorimetry. The thermograms obtained revealed that all binary mixtures investigated form eutectic systems. Melting of the initial binary crystalline mixtures and subsequent quenching lead to the formation of CAM for all binary systems and most of the compositions studied. The experimentally obtained liquidus and eutectic temperatures were compared to theoretical predictions using the perturbed-chain statistical associating fluid theory (PC-SAFT) equation of state and conductor-like screening model for real solvents (COSMO-RS), as implemented in the Amsterdam Modeling Suite (COSMO-RS-AMS). On the basis of the obtained results, the ability of these models to predict the phase diagrams for the investigated API-API binary systems was evaluated. Furthermore, the glass transition temperature (Tg) of naproxen (NAP), a compound with a high tendency to recrystallize, whose literature values are considerably scattered, was newly determined by measuring and modeling the Tg values of binary mixtures in which amorphous NAP was stabilized. Based on this analysis, erroneous literature values were identified.

Department of Physical Chemistry University of Chemistry and Technology Prague Technická 5 166 28 Prague Czech Republic

Faculty of Chemical Engineering University of Chemistry and Technology Prague Technická 5 166 28 Prague Czech Republic

See more in PubMed

Hancock B.C., Parks M. What is the True Solubility Advantage for Amorphous Pharmaceuticals? Pharm. Res. 2000;17:397–404. doi: 10.1023/A:1007516718048. PubMed DOI

Löbmann K., Laitinen R., Grohganz H., Gordon K.C., Strachan C., Rades T. Coamorphous Drug Systems: Enhanced Physical Stability and Dissolution Rate of Indomethacin and Naproxen. Mol. Pharm. 2011;8:1919–1928. doi: 10.1021/mp2002973. PubMed DOI

Iemtsev A., Zemánková A., Hassouna F., Mathers A., Klajmon M., Slámová M., Malinová L., Fulem M. Ball milling and hot-melt extrusion of indomethacin-L-arginine-vinylpyrrolidone-vinyl acetate copolymer: Solid-state properties and dissolution performance. Int. J. Pharm. 2022;613:121424. doi: 10.1016/j.ijpharm.2021.121424. PubMed DOI

Bhujbal S.V., Mitra B., Jain U., Gong Y., Agrawal A., Karki S., Taylor L.S., Kumar S., Zhou Q. Pharmaceutical amorphous solid dispersion: A review of manufacturing strategies. Acta Pharm. Sin. B. 2021;11:2505–2536. doi: 10.1016/j.apsb.2021.05.014. PubMed DOI PMC

Dengale S., Grohganz H., Rades T., Löbmann K. Recent advances in co-amorphous drug formulations. Adv. Drug Deliv. Rev. 2016;100:116–125. doi: 10.1016/j.addr.2015.12.009. PubMed DOI

Chavan R.B., Thipparaboina R., Kumar D., Shastri N.R. Co amorphous systems: A product development perspective. Int. J. Pharm. 2016;515:403–415. doi: 10.1016/j.ijpharm.2016.10.043. PubMed DOI

Yamashita H., Hirakura Y., Yuda M., Teramura T., Terada K. Detection of Cocrystal Formation Based on Binary Phase Diagrams Using Thermal Analysis. Pharm. Res. 2012;30:70–80. doi: 10.1007/s11095-012-0850-1. PubMed DOI

Yamashita H., Hirakura Y., Yuda M., Terada K. Coformer screening using thermal analysis based on binary phase diagrams. Pharm. Res. 2014;31:1946–1957. doi: 10.1007/s11095-014-1296-4. PubMed DOI

Höhne G.W.H., Hemminger W.F., Flammersheim H.-J. Differential Scanning Calorimetry. Springer Verlag; Berlin/Heidelberg, Germany: 2003.

Kissi E.O., Khorami K., Rades T. Determination of Stable Co-Amorphous Drug–Drug Ratios from the Eutectic Behavior of Crystalline Physical Mixtures. Pharmaceutics. 2019;11:628. doi: 10.3390/pharmaceutics11120628. PubMed DOI PMC

Beyer A., Grohganz H., Löbmann K., Rades T., Leopold C.S. Influence of the cooling rate and the blend ratio on the physical stability of co-amorphous naproxen/indomethacin. Eur. J. Pharm. Biopharm. 2016;109:140–148. doi: 10.1016/j.ejpb.2016.10.002. PubMed DOI

Jensen K.T., Larsen F.H., Löbmann K., Rades T., Grohganz H. Influence of variation in molar ratio on co-amorphous drug-amino acid systems. Eur. J. Pharm. Biopharm. 2016;107:32–39. doi: 10.1016/j.ejpb.2016.06.020. PubMed DOI

Baird J.A., Van Eerdenbrugh B., Taylor L.S. A Classification System to Assess the Crystallization Tendency of Organic Molecules from Undercooled Melts. J. Pharm. Sci. 2010;99:3787–3806. doi: 10.1002/jps.22197. PubMed DOI

Paudel A., Van Humbeeck J., Van den Mooter G. Theoretical and Experimental Investigation on the Solid Solubility and Miscibility of Naproxen in Poly(vinylpyrrolidone) Mol. Pharm. 2010;7:1133–1148. doi: 10.1021/mp100013p. PubMed DOI

Blaabjerg L.I., Lindenberg E., Löbmann K., Grohganz H., Rades T. Glass Forming Ability of Amorphous Drugs Investigated by Continuous Cooling and Isothermal Transformation. Mol. Pharm. 2016;13:3318–3325. doi: 10.1021/acs.molpharmaceut.6b00650. PubMed DOI

Kawakami K. Crystallization Tendency of Pharmaceutical Glasses: Relevance to Compound Properties, Impact of Formulation Process, and Implications for Design of Amorphous Solid Dispersions. Pharmaceutics. 2019;11:202. doi: 10.3390/pharmaceutics11050202. PubMed DOI PMC

Seideman P., Melander A. Equianalgesic effects of paracetamol and indomethacin in rheumatoid arthritis. Br. J. Rheumatol. 1988;27:117–122. doi: 10.1093/rheumatology/27.2.117. PubMed DOI

Fael H., Demirel A.L. Indomethacin co-amorphous drug-drug systems with improved solubility, supersaturation, dissolution rate and physical stability. Int. J. Pharm. 2021;600:120448. doi: 10.1016/j.ijpharm.2021.120448. PubMed DOI

Gross J., Sadowski G. Perturbed-Chain SAFT:  An Equation of State Based on a Perturbation Theory for Chain Molecules. Ind. Eng. Chem. Res. 2001;40:1244–1260. doi: 10.1021/ie0003887. DOI

Gross J., Sadowski G. Application of the Perturbed-Chain SAFT Equation of State to Associating Systems. Ind. Eng. Chem. Res. 2002;41:5510–5515. doi: 10.1021/ie010954d. DOI

Klamt A. Conductor-like Screening Model for Real Solvents: A New Approach to the Quantitative Calculation of Solvation Phenomena. J. Phys. Chem. 1995;99:2224–2235. doi: 10.1021/j100007a062. DOI

Pye C.C., Ziegler T., van Lenthe E., Louwen J.N. An implementation of the conductor-like screening model of solvation within the Amsterdam density functional package—Part II. COSMO for real solvents. Can. J. Chem. 2009;87:790–797. doi: 10.1139/V09-008. DOI

Chapman W.G., Gubbins K.E., Jackson G., Radosz M. SAFT: Equation-of-state solution model for associating fluids. Fluid Phase Equilib. 1989;52:31–38. doi: 10.1016/0378-3812(89)80308-5. DOI

Iemtsev A., Hassouna F., Mathers A., Klajmon M., Dendisová M., Malinová L., Školáková T., Fulem M. Physical stability of hydroxypropyl methylcellulose-based amorphous solid dispersions: Experimental and computational study. Int. J. Pharm. 2020;589:119845. doi: 10.1016/j.ijpharm.2020.119845. PubMed DOI

Iemtsev A., Hassouna F., Klajmon M., Mathers A., Fulem M. Compatibility of selected active pharmaceutical ingredients with poly(D, L-lactide-co-glycolide): Computational and experimental study. Eur. J. Pharm. Biopharm. 2022;179:232–245. doi: 10.1016/j.ejpb.2022.09.013. DOI

Groom C., Bruno I., Lightfoot M., Ward S. The Cambridge Structural Database. Acta Crystallogr. Sect. B Struct. Sci. Cryst. Eng. Mater. 2016;72:171–179. doi: 10.1107/S2052520616003954. PubMed DOI PMC

Štejfa V., Pokorný V., Mathers A., Růžička K., Fulem M. Heat capacities of selected active pharmaceutical ingredients. J. Chem. Thermodyn. 2021;163:106585. doi: 10.1016/j.jct.2021.106585. DOI

Acree W., Chickos J. Phase Transition Enthalpy Measurements of Organic and Organometallic Compounds. Sublimation, Vaporization and Fusion Enthalpies From 1880 to 2015. Part 1. C1–C10. J. Phys. Chem. Ref. Data. 2016;45:033101. doi: 10.1063/1.4948363. DOI

Acree W., Chickos J. Phase Transition Enthalpy Measurements of Organic and Organometallic Compounds and Ionic Liquids. Sublimation, Vaporization, and Fusion Enthalpies from 1880 to 2015. Part 2. C 11–C 192. J. Phys. Chem. Ref. Data. 2017;46:013104. doi: 10.1063/1.4970519. DOI

Fukuoka E., Makita M., Nakamura Y. Glassy State of Pharmaceuticals. V. Relaxation during Cooling and Heating of Glass by Differential Scanning Calorimetry. Chem. Pharm. Bull. 1991;39:2087–2090. doi: 10.1248/cpb.39.2087. DOI

Sahra M., Thayyil M.S., Bansal A.K., Ngai K.L., Sulaiman M.K., Shete G., Safna Hussan K.P. Dielectric spectroscopic studies of three important active pharmaceutical ingredients—Clofoctol, droperidol and probucol. J. Non-Cryst. Solids. 2019;505:28–36. doi: 10.1016/j.jnoncrysol.2018.10.046. DOI

Neau S.H., Bhandarkar Sv Fau—Hellmuth E.W., Hellmuth E.W. Differential molar heat capacities to test ideal solubility estimations. Pharm. Res. 1997;14:601–605. doi: 10.1023/A:1012148910975. PubMed DOI

Tammann G. Über die Ermittelung der Zusammensetzung chemischer Verbindungen ohne Hilfe der Analyse. Z. Anorg. Chem. 1903;37:303–313. doi: 10.1002/zaac.19030370121. DOI

Klajmon M. Investigating Various Parametrization Strategies for Pharmaceuticals within the PC-SAFT Equation of State. J. Chem. Eng. Data. 2020;65:5753–5767. doi: 10.1021/acs.jced.0c00707. DOI

Kontogeorgis G.M., Folas G.K. Thermodynamic Models for Industrial Applications: From Classical and Advanced Mixing Rules to Association Theories. Wiley; Chichester, UK: 2010.

Haslam A.J., González-Pérez A., Di Lecce S., Khalit S.H., Perdomo F.A., Kournopoulos S., Kohns M., Lindeboom T., Wehbe M., Febra S., et al. Expanding the Applications of the SAFT-γ Mie Group-Contribution Equation of State: Prediction of Thermodynamic Properties and Phase Behavior of Mixtures. J. Chem. Eng. Data. 2020;65:5862–5890. doi: 10.1021/acs.jced.0c00746. DOI

Peters F.T., Laube F.S., Sadowski G. Development of a group contribution method for polymers within the PC-SAFT model. Fluid Phase Equilib. 2012;324:70–79. doi: 10.1016/j.fluid.2012.03.009. DOI

Peters F.T., Herhut M., Sadowski G. Extension of the PC-SAFT based group contribution method for polymers to aromatic, oxygen- and silicon-based polymers. Fluid Phase Equilib. 2013;339:89–104. doi: 10.1016/j.fluid.2012.11.031. DOI

Yagi N., Terashima Y., Kenmotsu H., Sekikawa H., Takada M. Dissolution Behavior of Probucol from Solid Dispersion Systems of Probucol-Polyvinylpyrrolidone. Chem. Pharm. Bull. 1996;44:241–244. doi: 10.1248/cpb.44.241. DOI

Klamt A., Eckert F., Hornig M., Beck M.E., Bürger T. Prediction of aqueous solubility of drugs and pesticides with COSMO-RS. J. Comput. Chem. 2002;23:275–281. doi: 10.1002/jcc.1168. PubMed DOI

Klajmon M. Purely Predicting the Pharmaceutical Solubility: What to Expect from PC-SAFT and COSMO-RS? Mol. Pharm. 2022;19:4212–4232. doi: 10.1021/acs.molpharmaceut.2c00573. PubMed DOI

Klamt A. The COSMO and COSMO-RS solvation models. Wiley Interdiscip. Rev. Comput. Mol. Sci. 2011;1:699–709. doi: 10.1002/wcms.56. DOI

Bell I.H., Mickoleit E., Hsieh C.-M., Lin S.-T., Vrabec J., Breitkopf C., Jäger A. A Benchmark Open-Source Implementation of COSMO-SAC. J. Chem. Theory Comput. 2020;16:2635–2646. doi: 10.1021/acs.jctc.9b01016. PubMed DOI PMC

Amsterdam Modeling Suite (AMS) 2022.101, Software for Chemistry and Materials (SCM), Theoretical Chemistry. Vrije Universiteit; Amsterdam, The Netherlands: 2022.

Gerber J.J., Caira M.R., Lötter A.P. Structures of two conformational polymorphs of the cholesterol-lowering drug probucol. J. Crystallogr. Spectrosc. Res. 1993;23:863–869. doi: 10.1007/BF01195733. DOI

Baghel S., Fox H., O’Reilly N. Polymeric Amorphous Solid Dispersions: A Review of Amorphization, Crystallization, Stabilization, Solid-State Characterization, and Aqueous Solubilization of Biopharmaceutical Classification System Class II Drugs. J. Pharm. Sci. 2016;105:2527–2544. doi: 10.1016/j.xphs.2015.10.008. PubMed DOI

Kwei T.K. The effect of hydrogen bonding on the glass transition temperatures of polymer mixtures. J. Polym. Sci. Polym. Lett. Ed. 1984;22:307–313. doi: 10.1002/pol.1984.130220603. DOI