Supramolecular hydrogen-bonding patterns in 1:1 cocrystals of 5-fluorouracil with 4-methylbenzoic acid and 3-nitrobenzoic acid

Abstract

The design of a pharmaceutical cocrystal is based on the identification of specific hydrogen-bond donor and acceptor groups in active pharmaceutical ingredients (APIs) in order to choose a `complementary interacting' molecule that can act as an efficient coformer. 5-Fluorouracil (5FU) is a pyrimidine derivative with two N-H donors and C=O acceptors and shows a diversity of hydrogen-bonding motifs. Two 1:1 cocrystals of 5-fluorouracil (5FU), namely 5-fluorouracil-4-methylbenzoic acid (5FU-MBA), CHFNO·CHO, (I), and 5-fluorouracil-3-nitrobenzoic acid (5FU-NBA), CHFNO·CHNO, (II), have been prepared and characterized by single-crystal X-ray diffraction. In (I), the MBA molecules form carboxylic acid dimers [R(8) homosynthon]. Similarly, the 5FU molecules form two types of base pair via a pair of N-H...O hydrogen bonds [R(8) homosynthon]. In (II), 5FU interacts with the carboxylic acid group of NBA via N-H...O and O-H...O hydrogen bonds, generating an R(8) ring motif (heterosynthon). Furthermore, the 5FU molecules form base pairs [R(8) homosynthon] via N-H...O hydrogen bonds. Both of the crystal structures are stabilized by C-H...F interactions.

Supramolecular architectures in two 1:1 cocrystals of 5-fluorouracil with 5-bromothiophene-2-carboxylic acid and thiophene-2-carboxylic acid

“…This leads to the formation of a supramolecular ribbon of 5FU molecules parallel to the (013) plane. Similar types of R 2 2 (8) homosynthons (N-HÁ Á ÁO) and ribbons are observed in 5-fluorouracil-3-hydroxybenzoic acid, 5-fluorouracil-4-aminobenzoic acid and 5-fluorouracil-cinnamic acid (Dai et al, 2016), and 5-fluorouracil-4-methyl-benzoic acid (Mohana et al, 2017). In cocrystal (I), the supramolecular ribbon also contains an R 2 3 (9) motif involving N-HÁ Á ÁO and C-HÁ Á ÁO hydrogen bonds, generating a quadruple DADA (D is a donor and A is an acceptor) array of hydrogen bonds.…”

“…The 5FU molecules are connected through a pair of N1-H1Á Á ÁO1 i and N3-H3Á Á ÁO1 ii hydrogen bonds to form an R 2 2 (8) dimeric homosynthon (see Table 3 for details and symmetry codes). Similar types of R 2 2 (8) homosynthons (N-HÁ Á ÁO) and ribbons are observed in 5-fluorouracil-3-hydroxybenzoic acid, 5-fluorouracil-4-aminobenzoic acid and 5-fluorouracil-cinnamic acid (Dai et al, 2016), and 5-fluorouracil-4-methylbenzoic acid (Mohana et al, 2017). This leads to the formation of a supramolecular ribbon of 5FU molecules parallel to the (021) plane.…”

“…Various crystal structures of 5-fluorourcil have been reported in the literature (Fallon, 1973;Hulme & Tocher, 2004a,b,c, 2005aBarnett et al, 2006;Delori et al, 2013;Li et al, 2014;Dai et al, 2016). In our previous work, the structures of 5-fluorouracil-4-methylbenzoic acid and 5-fluorouracil-3nitrobenzoic acid (Mohana et al, 2017) have been reported. The carboxylic acid group can form dimers via a pair of O-HÁ Á ÁO hydrogen bonds [R 2 2 (8) motif, supramolecular homosynthon].…”

Preparation and Characterization of Oxidized Inulin Hydrogel for Controlled Drug Delivery

“…The release of 5FU from the hydrogels was dependent on the crosslinking density and pH of the release media. The FTIR result for the 5FU-loaded hydrogels show that the 5FU amine group and inulin polymer hydroxyl may have formed a hydrogen bond interaction [71,83,84]. This polymer–drug interaction may have resulted in slow drug release from the hydrogel due to entrapment of the remaining drug in the gel network (Figure 2C,D).…”

Engineering Cocrystals of Poorly Water-Soluble Drugs to Enhance Dissolution in Aqueous Medium

“…Newman [ 133 ] has summarized various methods reported in the literature to obtain various solid forms such as polymorphs, salts, cocrystals and amorphous solid dispersions [ 133 ]. Though hydrogen-bonding motif structures play a significant role in stabilizing the crystal structures of cocrystals [ 134 , 135 , 136 , 137 , 138 , 139 ], in some cases, evaluation of crystal structures of some cocrystals synthesized using techniques such as Solution crystallization, mechanocrystallization and hot-stage microscopy showed that these cocrystals do not possess hydrogen-bonding motifs as given by Crystal Engineering principles [ 124 ]. Therefore, a suitable coformer screening technique is highly essential for a cocrystallization process.…”