How similar is similar? Exploring the binary and ternary solid solution landscapes of p-methyl/chloro/bromo-benzyl alcohols

The conceptual relationship between crystal reactivity, stability and metastability, solubility and morphology on the one hand and shape, charge distribution, chirality and distribution of functional groups over the molecular surfaces on the other hand is discussed, via a number of examples coming from three decades of research in the field of crystal engineering at the University of Bologna. The bottom-up preparation of mixed crystals, co-crystals and photoreactive materials starting from molecular building blocks across the borders of organic, organometallic and metalorganic chemistry is recounted.

Section: From Isomorphous Crystals To Solid Solutionsmentioning

confidence: 99%

Making crystals with a purpose; a journey in crystal engineering at the University of Bologna

Braga

Grepioni

Maini

et al. 2017

“…The efficacy of the 1:1 cocrystal-salt combination is enhanced in Valsartan (angiotensin receptor blocker) and Sacubitril (neprilsin inhibitor), Entresto (LCZ696 clinical candidate) (Jessup, 2014;McMurray et al, 2014), with a reduced risk of cardiovascular death during hospitalization of patients. Diverse applications of cocrystals and solid solutions and eutectics (multicomponent crystals) have been reported (Goldberg et al, 1966;Cherukuvada & Nangia, 2014;Braga et al, 2009;Romasanta et al, 2017;Mishra et al, 2015, Lusi, 2018.…”

Section: Figurementioning

confidence: 99%

Systematic synthesis of a 6-component organic-salt alloy of naftopidil, and pentanary, quaternary and ternary multicomponent crystals

Dandela

Tothadi

Marelli

et al. 2018

A 6-component organic-salt alloy of naftopidil with hydroxy-substituted benzoic acids is designed based on a recurrent supramolecular synthon and the replacement of coformer acids in the crystal lattice. Isostructurality of five binary salts leads to the crystallization of multicomponent salt alloys. One 6-component crystal, five 5-component, ten 4-component and ten 3-component organic-salt alloys of naftopidil with carboxylic acids are reported.

“…There have been attempts to achieve forms with Cl/Me interchange. Braga et al achieved a new polymorph of p-methylbenzyl alcohol, which is isomorphous with the crystal of p-chlorobenzyl alcohol, by hetero-seeding with a small quantity of the latter (Romasanta et al, 2017). Although there have been several case studies on isostructurality consisting of single-component forms, only a few examples of multicomponent forms are reported in the literature (Cinčić et al, 2008a;Fandaruff et al, 2015;Clarke et al, 2012;Galcera & Molins, 2009).…”

Section: Introductionmentioning

confidence: 99%

Isomorphism: `molecular similarity to crystal structure similarity' in multicomponent forms of analgesic drugs tolfenamic and mefenamic acid

Ranjan

Devarapalli

Kundu

et al. 2020

The non-steroidal anti-inflammatory drugs mefenamic acid (MFA) and tolfenamic acid (TFA) have a close resemblance in their molecular scaffold, whereby a methyl group in MFA is substituted by a chloro group in TFA. The present study demonstrates the isomorphous nature of these compounds in a series of their multicomponent solids. Furthermore, the unique nature of MFA and TFA has been demonstrated while excavating their alternate solid forms in that, by varying the drug (MFA or TFA) to coformer [4-dimethylaminopyridine (DMAP)] stoichiometric ratio, both drugs have produced three different types of multicomponent crystals, viz. salt (1:1; API to coformer ratio), salt hydrate (1:1:1) and cocrystal salt (2:1). Interestingly, as anticipated from the close similarity of TFA and MFA structures, these multicomponent solids have shown an isomorphous relation. A thorough characterization and structural investigation of the new multicomponent forms of MFA and TFA revealed their similarity in terms of space group and structural packing with isomorphic nature among the pairs. Herein, the experimental results are generalized in a broader perspective for predictably identifying any possible new forms of comparable compounds by mapping their crystal structure landscapes. The utility of such an approach is evident from the identification of polymorph VI of TFA from hetero-seeding with isomorphous MFA form I from acetone-methanol (1:1) solution. That aside, a pseudopolymorph of TFA with dimethylformamide (DMF) was obtained, which also has some structural similarity to that of the solvate MFA:DMF. These new isostructural pairs are discussed in the context of solid form screening using structural landscape similarity.