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Within each molecular family there is substantial variation in cocrystal tendency, leading to considerable scope for selective cocrystal precipitation to assist in the separation of complex mixtures of these natural product families. Theophylline (C\n                    <jats:sub>7<\/jats:sub>\n                    H\n                    <jats:sub>8<\/jats:sub>\n                    N\n                    <jats:sub>4<\/jats:sub>\n                    O\n                    <jats:sub>2<\/jats:sub>\n                    ) follows caffeine and theacrine in forming a substantial number of flavonoid cocrystals \u2013 six in total, of which three were reported previously. By contrast, the 8-halo-substituted analogues 8-\n                    <jats:italic>X<\/jats:italic>\n                    -Tph [\n                    <jats:italic>X<\/jats:italic>\n                    \u00a0= Cl (C\n                    <jats:sub>7<\/jats:sub>\n                    H\n                    <jats:sub>7<\/jats:sub>\n                    ClN\n                    <jats:sub>4<\/jats:sub>\n                    O\n                    <jats:sub>2<\/jats:sub>\n                    ), Br (C\n                    <jats:sub>7<\/jats:sub>\n                    H\n                    <jats:sub>7<\/jats:sub>\n                    BrN\n                    <jats:sub>4<\/jats:sub>\n                    O\n                    <jats:sub>2<\/jats:sub>\n                    )] form cocrystals with just myricetin (C\n                    <jats:sub>15<\/jats:sub>\n                    H\n                    <jats:sub>10<\/jats:sub>\n                    O\n                    <jats:sub>8<\/jats:sub>\n                    ) and kaempferol (C\n                    <jats:sub>15<\/jats:sub>\n                    H\n                    <jats:sub>10<\/jats:sub>\n                    O\n                    <jats:sub>6<\/jats:sub>\n                    ). Weakening of the acceptor capability of the alkaloid N9 atom upon proximal halo substitution may play a role in the reduced tendency of 8-\n                    <jats:italic>X<\/jats:italic>\n                    -Tph towards cocrystal formation, since improved packing efficiency is not a key factor in the formation of these cocrystals. Most of the cocrystal phases may be conveniently prepared with good yield and purity through either liquid-assisted grinding (LAG) or microwave-assisted cocrystallization from 1-butanol.\n                  <\/jats:p>","DOI":"10.1107\/s2053229626006637","type":"journal-article","created":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T13:52:58Z","timestamp":1783432378000},"page":"414-426","update-policy":"https:\/\/doi.org\/10.1107\/cm_01","source":"Crossref","is-referenced-by-count":1,"title":["Effect of molecular perturbation on cocrystal formation: theophylline and its 8-halo analogues with flavonoids"],"prefix":"10.1107","volume":"82","author":[{"given":"Weijian","family":"Ye","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3370-0332","authenticated-orcid":true,"given":"Herman H-Y.","family":"Sung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8743-401X","authenticated-orcid":true,"given":"Ian D.","family":"Williams","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"329","published-online":{"date-parts":[[2026,7,7]]},"reference":[{"key":"oj3040_bb1","doi-asserted-by":"crossref","first-page":"1381","DOI":"10.1039\/C9CE01886G","volume":"22","author":"Ahuja","year":"2020","journal-title":"CrystEngComm"},{"key":"oj3040_bb2","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1107\/S2053273314022207","volume":"71","author":"Bourhis","year":"2015","journal-title":"Acta Cryst. 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