Thermodynamic Correlation between Liquid–Liquid Phase Separation and Crystalline Solubility of Drug-Like Molecules
The purpose of the present study was to experimentally confirm the thermodynamic correlation between the intrinsic liquid–liquid phase separation (LLPS) concentration (<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics>&...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-11-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/14/12/2560 |
| _version_ | 1797455767352115200 |
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| author | Taiga Uekusa Tomohiro Watanabe Daiju Watanabe Kiyohiko Sugano |
| author_facet | Taiga Uekusa Tomohiro Watanabe Daiju Watanabe Kiyohiko Sugano |
| author_sort | Taiga Uekusa |
| collection | DOAJ |
| description | The purpose of the present study was to experimentally confirm the thermodynamic correlation between the intrinsic liquid–liquid phase separation (LLPS) concentration (<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mrow><msubsup><mi>S</mi><mn>0</mn><mrow><mi>L</mi><mi>L</mi><mi>P</mi><mi>S</mi></mrow></msubsup></mrow></semantics></math></inline-formula>) and crystalline solubility (<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mrow><msubsup><mi>S</mi><mn>0</mn><mi>c</mi></msubsup></mrow></semantics></math></inline-formula>) of drug-like molecules. Based on the thermodynamic principles, the crystalline solubility LLPS concentration melting point (<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mrow><msub><mi>T</mi><mi>m</mi></msub></mrow></semantics></math></inline-formula>) equation (CLME) was derived (<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mrow><mi>l</mi><mi>o</mi><msub><mi>g</mi><mrow><mn>10</mn></mrow></msub><msubsup><mi>S</mi><mn>0</mn><mi>C</mi></msubsup><mo>=</mo><mi>l</mi><mi>o</mi><msub><mi>g</mi><mrow><mn>10</mn></mrow></msub><msubsup><mi>S</mi><mn>0</mn><mrow><mi>L</mi><mi>L</mi><mi>P</mi><mi>S</mi></mrow></msubsup><mo>−</mo><mn>0.0095</mn><mfenced><mrow><msub><mi>T</mi><mi>m</mi></msub><mo>−</mo><mn>310</mn></mrow></mfenced></mrow></semantics></math></inline-formula> for 310 K). The <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mrow><msubsup><mi>S</mi><mn>0</mn><mrow><mi>L</mi><mi>L</mi><mi>P</mi><mi>S</mi></mrow></msubsup></mrow></semantics></math></inline-formula> values of 31 drugs were newly measured by simple bulk phase pH-shift or solvent-shift precipitation tests coupled with laser-assisted visual turbidity detection. To ensure the precipitant was not made crystalline at <10 s, the precipitation tests were also performed under the polarized light microscope. The calculated and observed <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mrow><msub><mrow><mi>log</mi></mrow><mrow><mn>10</mn></mrow></msub><msubsup><mi>S</mi><mn>0</mn><mi>C</mi></msubsup></mrow></semantics></math></inline-formula> values showed a good correlation (root mean squared error: 0.40 log unit, absolute average error: 0.32 log unit). |
| first_indexed | 2024-03-09T15:58:14Z |
| format | Article |
| id | doaj.art-434264bca2f04ce1b34bdab0cc7f2131 |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-09T15:58:14Z |
| publishDate | 2022-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-434264bca2f04ce1b34bdab0cc7f21312023-11-24T17:18:03ZengMDPI AGPharmaceutics1999-49232022-11-011412256010.3390/pharmaceutics14122560Thermodynamic Correlation between Liquid–Liquid Phase Separation and Crystalline Solubility of Drug-Like MoleculesTaiga Uekusa0Tomohiro Watanabe1Daiju Watanabe2Kiyohiko Sugano3Molecular Pharmaceutics Lab., College of Pharmaceutical Sciences, Ritsumeikan University, 1-1-1, Noji-higasi, Kusatsu 525-8577, Shiga, JapanMolecular Pharmaceutics Lab., College of Pharmaceutical Sciences, Ritsumeikan University, 1-1-1, Noji-higasi, Kusatsu 525-8577, Shiga, JapanMolecular Pharmaceutics Lab., College of Pharmaceutical Sciences, Ritsumeikan University, 1-1-1, Noji-higasi, Kusatsu 525-8577, Shiga, JapanMolecular Pharmaceutics Lab., College of Pharmaceutical Sciences, Ritsumeikan University, 1-1-1, Noji-higasi, Kusatsu 525-8577, Shiga, JapanThe purpose of the present study was to experimentally confirm the thermodynamic correlation between the intrinsic liquid–liquid phase separation (LLPS) concentration (<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mrow><msubsup><mi>S</mi><mn>0</mn><mrow><mi>L</mi><mi>L</mi><mi>P</mi><mi>S</mi></mrow></msubsup></mrow></semantics></math></inline-formula>) and crystalline solubility (<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mrow><msubsup><mi>S</mi><mn>0</mn><mi>c</mi></msubsup></mrow></semantics></math></inline-formula>) of drug-like molecules. Based on the thermodynamic principles, the crystalline solubility LLPS concentration melting point (<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mrow><msub><mi>T</mi><mi>m</mi></msub></mrow></semantics></math></inline-formula>) equation (CLME) was derived (<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mrow><mi>l</mi><mi>o</mi><msub><mi>g</mi><mrow><mn>10</mn></mrow></msub><msubsup><mi>S</mi><mn>0</mn><mi>C</mi></msubsup><mo>=</mo><mi>l</mi><mi>o</mi><msub><mi>g</mi><mrow><mn>10</mn></mrow></msub><msubsup><mi>S</mi><mn>0</mn><mrow><mi>L</mi><mi>L</mi><mi>P</mi><mi>S</mi></mrow></msubsup><mo>−</mo><mn>0.0095</mn><mfenced><mrow><msub><mi>T</mi><mi>m</mi></msub><mo>−</mo><mn>310</mn></mrow></mfenced></mrow></semantics></math></inline-formula> for 310 K). The <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mrow><msubsup><mi>S</mi><mn>0</mn><mrow><mi>L</mi><mi>L</mi><mi>P</mi><mi>S</mi></mrow></msubsup></mrow></semantics></math></inline-formula> values of 31 drugs were newly measured by simple bulk phase pH-shift or solvent-shift precipitation tests coupled with laser-assisted visual turbidity detection. To ensure the precipitant was not made crystalline at <10 s, the precipitation tests were also performed under the polarized light microscope. The calculated and observed <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mrow><msub><mrow><mi>log</mi></mrow><mrow><mn>10</mn></mrow></msub><msubsup><mi>S</mi><mn>0</mn><mi>C</mi></msubsup></mrow></semantics></math></inline-formula> values showed a good correlation (root mean squared error: 0.40 log unit, absolute average error: 0.32 log unit).https://www.mdpi.com/1999-4923/14/12/2560liquid–liquid phase separationintrinsic solubilitymelting pointdrug-like |
| spellingShingle | Taiga Uekusa Tomohiro Watanabe Daiju Watanabe Kiyohiko Sugano Thermodynamic Correlation between Liquid–Liquid Phase Separation and Crystalline Solubility of Drug-Like Molecules Pharmaceutics liquid–liquid phase separation intrinsic solubility melting point drug-like |
| title | Thermodynamic Correlation between Liquid–Liquid Phase Separation and Crystalline Solubility of Drug-Like Molecules |
| title_full | Thermodynamic Correlation between Liquid–Liquid Phase Separation and Crystalline Solubility of Drug-Like Molecules |
| title_fullStr | Thermodynamic Correlation between Liquid–Liquid Phase Separation and Crystalline Solubility of Drug-Like Molecules |
| title_full_unstemmed | Thermodynamic Correlation between Liquid–Liquid Phase Separation and Crystalline Solubility of Drug-Like Molecules |
| title_short | Thermodynamic Correlation between Liquid–Liquid Phase Separation and Crystalline Solubility of Drug-Like Molecules |
| title_sort | thermodynamic correlation between liquid liquid phase separation and crystalline solubility of drug like molecules |
| topic | liquid–liquid phase separation intrinsic solubility melting point drug-like |
| url | https://www.mdpi.com/1999-4923/14/12/2560 |
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