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The active pharmaceutical ingredient (API) doxycycline (DOX) is a broad-spectrum antibiotic mainly used in the treatment of respiratory and urinary tract infections and, like many drugs, its efficacy may be affected by the crystal form. Up to now, only the crystal structure of doxycycline hyclate (DOX$HYC) (generic name of brand names such as DORYXÒ, PERIOSTATÒ, ATRIDOXÒ, and VIBRAMYCINÒ) has been reported. This study presents the single-crystal X-ray diffractometry structural characterisation of another crystal form, doxycycline monohydrate (DOX$H 2 O) (generic name of brand names such as MONODOXÒ and ORACEAÒ). The DOX$H 2 O structure was compared with the known DOX$HYC one in terms of intra-and intermolecular geometries, and their melting temperature, water solubility and dissolution rate were measured. These data allowed us to establish relationships between solid state properties related to the pharmaceutical performance of the two DOX crystal variants and their supramolecular structures for the first time. Both hyclate and monohydrate forms crystallise the DOX molecules as zwitterions in which their dimethylamine groups are protonated and one of their hydroxyl groups is deprotonated. Whereas two conformers were observed in the DOX$HYC (i.e., the amine group is next to the enolate in one of them (T1) and beside the carbonyl in the other one (T2)), only one (T2) was found in DOX$H 2 O. Additionally, in the hyclate form, the presence of ethanol in the crystal lattice could be related to a rotation around the C-C bond of the amide group, directing the oxygen toward the amine group in one (T1) of the two conformers present in this solid state phase. Meanwhile, in the other crystallographically independent molecule (T2), the amide nitrogen is on the same side as the amine. However, only the conformer similar to T1 in DOX$HYC was observed in DOX$H 2 O. The crystal packing of DOX$H 2 O was stabilised by several intermolecular hydrogen bonds, with each drug entity interacting with another two DOX and three water molecules in such a way that a compact supramolecular network was formed. This structure was saturated in terms of hydrogen bonding, which could be related to its lower solubility and dissolution rate relative to DOX$HYC.

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Doxycycline (DOX) is a tetracycline class drug that is used worldwide as a broad-spectrum antibiotic. Although its clinical importance and use have been known since the 1960s, only four crystal forms have been reported until now. These are doxycycline hyclate (DOX.HYC), which is a hydrochloride salt hemiethanolate-hemihydrate; its isomorphous hydrobromide, hydrochloride salt dihydrate (DOX·HCl·2H2O); and doxycycline monohydrate (DOX·H2O). Here we report the preparation of two new multicomponent molecular crystal forms of doxycycline and their crystal structure determination along with their melting temperature, aqueous solubility, and time-dependent dissolution profile. These crystal forms are a hydronitrate salt hemihydrate (DOX·HNO3·0.5H2O) and an acetic acid solvate dihydrate (DOX·HAc·2H2O). The two new doxycycline crystal forms were compared with known forms, including DOX·HCl·2H2O, the structure of which was redetermined in this work. The structural variability of the protonation patterns, tautomerism of the keto–enolate moieties, and conformation of the amide groups was observed for these compounds. While intramolecular rings assembled through resonance-assisted hydrogen bond (RAHB) were observed in both fused keto–enol moieties of all structures, DOX·HCl·2H2O and DOX·HNO3·0.5H2O have another RAHB encompassing the protonated amide carbonyl oxygen and the enolate oxygen. These two crystal forms have a net positive charge on their drug molecule as DOX·HYC. They crystallize with the N,N -dimethylamine and amide carbonyl groups protonated and the neighboring hydroxyl group deprotonated. DOX, by contrast, crystallizes as a zwitterion in DOX·HAc·2H2O similarly to DOX·H2O. Their amide carbonyl oxygens are not protonated, which differs from the salt forms. DOX·HNO3·0.5H2O presents as two tautomers that are similar to those of DOX·HYC, namely, T1, in which the enolate oxygen is next to the protonated amine group, and T2, with the carbonyl oxygen close to the protonated amine group. These tautomers also differ in their amide conformations due to a rotation of ca. 180° on the C–C bond axis of the amide group, which directs the protonated carbonyl oxygen toward the enolate oxygen. DOX·HCl·2H2O has only one T1-like tautomer and therefore only one amide conformation similar to that of T1. A T1-like keto–enolate tautomer is present in DOX·HAc·2H2O, which exhibits an amide conformation similar to that of T2. Thermal (DSC and TG) and infrared analysis and equilibrium solubility, dissolution profiles, and forced degradation studies were performed to both new and known DOX forms. The results were correlated with their structural features. DOX·HNO3·0.5H2O was the most soluble form. This new form was also more stable than the commercial DOX·HYC in the oxidation test and more stable than commercial DOX·H2O against acid and basic hydrolysis and in the photostability study. DOX·HNO3·0.5H2O and DOX·HYC (commercial form) were observed to have similar drug release behaviors from capsules (F2 > 50) and therefore they could be i...

For the first time, crystals of suitable size for X-ray diffractometry structure determination of an important anti-HIV drug were prepared under solvothermal conditions. In this study, the crystal structure of didanosine (2 0 ,3 0 -dideoxyinosine, ddI) in the form of a hydrate was determined using single-crystal X-ray diffractometry. Powder X-ray diffraction analysis revealed that the solid-state phase of the drug incorporated into pharmaceutical solid dosage forms is isostructural to the solvothermally prepared ddI material, even though they do not exhibit an identical chemical composition due to different water fractions occupying hydrophobic channels formed within the crystal lattice. Two ddI conformers are present in the structure, in agreement with a previous structure elucidation attempt. Concerning the keto-enol equilibrium of ddI, our crystal data and vibrational characterizations by Fourier transform infrared (FTIR) and FT-Raman spectroscopy techniques were conclusive to state that both conformers exist in the keto form, contrary to solid-state NMR spectroscopic assignments that suggested ddI molecules occur as enol tautomers. In addition, characterizations by thermal (differential scanning calorimetry) and spectroscopic techniques allowed us to understand the structural similarities and the differences related to the hydration pattern of the nonstoichiometric hydrates.

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