Monohydrate Form Research Articles

Oral solid dosage form using alternate crystalline neratinib maleate anhydrous form: Pharmaceutical, bioequivalent, and clinical perspectives.

Neratinib (an active pharmaceutical ingredient [API]) is an irreversible pan-human epidermal growth factor receptor (HER) inhibitor used to treat HER2-positive breast cancer. The dosage form (marketed in the United States, China, Europe, and other regions) is a tablet for oral administration, and the brand product (NERLYNX) has patent protection for the crystalline neratinib maleate monohydrate form. This paper describes the product development using stable crystalline neratinib maleate anhydrous form, stability study, bioequivalence (BE) study of the products, and discussion of the adverse effects observed in the clinical study.

Polymeric additives to sustain the dissolution enhancement of niclosamide nanocrystals formed via freeze drying

Nanocrystal formation is an effective method to increase the dissolution of drug compounds with limited solubilities. Niclosamide is a sparingly soluble compound, and it also tends to become an even less soluble monohydrate upon contact with dissolution media. We utilized freeze drying to successfully generate niclosamide nanocrystals, which displayed rapid initial dissolution but also suffered from the expedited formation of the monohydrate. Therefore, we explored some pharmaceutically acceptable polymers to overcome the unfavorable anhydrate-to-monohydrate transformation. Poly(vinylpyrrolidone-co-vinyl acetate) (Mw 45000–70000) effectively retarded the monohydrate formation in a concentration-dependent manner, and 3–5% in the drug-polymer mixture was enough to sustain the enhanced initial dissolution of niclosamide nanocrystals. The area under the dissolution curve tripled due to the combined effect of the nanocrystal formation and the monohydrate inhibition. This study demonstrates an example of the one-pot freeze-drying process to form an optimized drug-additive mixture to realize the full potential of drug nanocrystals.

Effects of structure similar additive on the crystallization of L-phenylalanine from aqueous solution

A comprehensive understanding of the effect of structure similar additives on the nucleation and growth of amino acid in aqueous solution is of great significance for the crystallization of L-phenylalanine and industrial production of anhydrous L-phenylalanine. This paper mainly focuses on the influence of L-tyrosine on the crystallization process of L-phenylalanine by investigating the variation and typical phenomenon in solubility, metastable zone width, crystal nucleation and growth process, and crystal morphology. The results show that the existence of L-tyrosine can obviously increase the solubility and narrow the metastable zone of L-phenylalanine thus promote the nucleation process. Meanwhile, L-tyrosine can also selectively inhibit the formation of monohydrate and improve the purity of industry-favored anhydrous L-phenylalanine in the final product. In order to explore the inhibiting effect of L-tyrosine in crystallization process, the molecular configurations in two different crystallization states were simulated by using Molecular Dynamics.The results show that water and L-phenylalanine molecules tend to form anhydrous crystals when the addition proportion of L-tyrosine increases. The theoretical calculations are in good agreement with the experimental data. The conclusions of this paper will provide new ideas and effective controlling approaches for L-phenylalanine crystals’ morphology and amino acids’ crystallization process.

Preparation and characterization of fluconazole-loaded sodium caseinate matrix films for oral candidiasis

Sodium caseinates (SCs), which are milk proteins, can form micelle structures by self-assembly and can be applied as film-forming agents. The aim of this study was to investigate the physicochemical properties of SC films loaded with fluconazole (FCZ) for use as a drug delivery system with anticandidal activity. A tablet film-coating instrument was used for film production via the spraying method. FCZ molecules can interact with the SC micelles in films via hydrogen bond formation. The FCZ-loaded SC films with a 1:0.1 SC:FCZ ratio presented an amorphous form of FCZ and greater flexibility than films with higher loadings. The FCZ particles (in monohydrate form) can be embedded in the film matrix, resulting in changes in the thermal and mechanical properties. The film dissolution time and drug release rate increased with an increase in FCZ content. The released FCZ was efficient against Candida albicans and possessed mucoadhesive properties on porcine mucosa. In addition, the FCZ-loaded SC films still presented good stability under ambient conditions after 3-months of storage. This study indicates that FCZ-loaded SC films have strong potential for use in oral candidiasis treatment.

Eutectic mixtures containing the active pharmaceutical ingredient ezetimibe: Phase diagrams, solid state characterization and dissolution profiles

Cardiovascular disease represents the leading cause of death worldwide, according to the World Health Organization (WHO) report. One of the treatment strategies is the use of the drug ezetimibe (EZT). This drug is a cholesterol absorption inhibitor with low aqueous solubility, which affects its therapeutic efficacy. The purpose of this paper was to obtain eutectic materials of EZT with methylparaben (MPB), salicylic acid (SCA) and nicotinamide (NTM) coformers, and to study their phase diagrams, dissolution properties and hygroscopicity to assess possible enhancements. Phase and Tamman diagrams were constructed using differential scanning calorimetry (DSC) results. The eutectic materials were characterized by powder X-ray diffraction (PXRD) and polarized light optical microscopy (OM). The hygroscopicity of the materials was assessed at different relative humidities (RH) through dynamic vapor sorption (DVS). The dissolution study was conducted with the materials in powder form, with paddle dissolution, rotating at 50 rpm, in 900 mL of aqueous buffer solution at pH 6.8 and 37 °C. The phase diagrams demonstrated that EZT formed eutectic systems with eutectic molar fractions of 0.59, 0.67 and 0.69 for EZT-SCA, EZT-NTM and EZT-MPB, respectively. The three eutectic materials are characterized as microcrystalline conglomerates of their components. In terms of the hygroscopic behavior of EZT at different RHs, eutectic materials demonstrated lower susceptibility to monohydrate formation compared to the anhydrous form. In dissolution studies, EZT-SCA and EZT-MPB solubilized EZT in amounts 22 % higher than the pure drug in 15 min. On the other hand, EZT-NTM eutectic suppressed the dissolution of EZT down to 56 % at the same time. The results indicated the possibility of obtaining materials with enhanced properties using eutectic mixtures, with improved dissolution rates and hygroscopic stability.

Molecular Insights into Water-Chloride and Water-Water Interactions in the Supramolecular Architecture of Aconine Hydrochloride Dihydrate.

Despite the previous preparation of aconine hydrochloride monohydrate (AHM), accurate determination of the crystal's composition was hindered by severely disordered water molecules within the crystal. In this study, we successfully prepared a new dihydrate form of the aconine hydrochloride [C25H42NO9+Cl-·2(H2O), aconine hydrochloride dihydrate (AHD)] and accurately refined all water molecules within the AHD crystal. Our objective is to elucidate both water-chloride and water-water interactions in the AHD crystal. The crystal structure of AHD was determined at 136 K using X-ray diffraction and a multipolar atom model was constructed by transferring charge-density parameters to explore the topological features of key short contacts. By comparing the crystal structures of dihydrate and monohydrate forms, we have observed that both AHD and AHM exhibit identical aconine cations, except for variations in the number of water molecules present. In the AHD crystal, chloride anions and water molecules serve as pivotal connecting hubs to establish three-dimensional hydrogen bonding networks and one-dimensional hydrogen bonding chain; both water-chloride and water-water interactions assemble supramolecular architectures. The crystal packing of AHD exhibits a complete reversal in the stacking order compared to AHM, thereby emphasizing distinct disparities between them. Hirshfeld surface analysis reveals that H···Cl- and H···O contacts play a significant role in constructing the hydrogen bonding network and chain within these supramolecular architectures. Furthermore, topological analysis and electrostatic interaction energy confirm that both water-chloride and water-water interactions stabilize supramolecular architectures through electrostatic attraction facilitated by H···Cl- and H···O contacts. Importantly, these findings are strongly supported by the existing literature evidence. Consequently, navigating these water-chloride and water-water interactions is imperative for ensuring storage and safe processing of this pharmaceutical compound.

Effect of Hydration Forms and Polymer Grades on Theophylline Controlled-Release Tablet: An Assessment and Evaluation.

Drug release from controlled release delivery systems is influenced by various factors, including the polymer's grade and the drug's hydration form. This study aimed to investigate the impact of these factors on the controlled release of theophylline (THN). This research compares the monohydrate form found in branded products with the anhydrous form in generic equivalents, each formulated with different polymer grades. Quality control assessment was conducted alongside in vitro evaluation, complemented by various analytical techniques such as X-ray diffraction (XRD) and scanning electron microscopy (SEM). Additionally, thermal analyses using differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) were employed. Quality control assessments demonstrated that the generic tablets exhibited lower average weight and resistance force compared to the branded ones. In vitro tests revealed that generic tablets released contents within 120 min, compared to 720 min for the branded counterpart. Characterization using XRD and SEM identified disparities in crystallinity and particle distribution between the three samples. Additionally, the thermal analysis indicated consistent endothermic peaks across all samples, albeit with minor variations in heat flow and decomposition temperatures between the two products. This study demonstrated that variations in polymer grade and hydration form significantly impact THN release.

A mono-aquated di-pyridine-based Gd(III) complex as T1-weighted MRI probe with high relaxivity and stability

This study reports a new octadentate tricarboxylate appended ligand (H4dphta) with enhanced relaxivity and high stability towards Gd(III) complex as an MRI probe. The designed ligand was synthesized in multiple steps. Both, the ligand and its complex were characterized by spectroscopic techniques. Structural analysis of Gd(III) complex by single crystal XRD confirms its mono-hydrated form adopting distorted capped square antiprism geometry. Protonation constants of the ligand and the thermodynamic stability constant of the [Gd(Hdphta)] and [Gd(H2dphta)]+ species have been found as log K110 = 18.6(1) and log K111 = 24.8(1) at 25.0 °C, and I = 0.15 mol·L−1 NaClO4 by potentiometric method. The r1 relaxivity of the complex was found to be 4.63 mM−1s−1 at 1.41 T, 25 °C, and pH 7.4 in the HEPES buffer, which remained unaltered in the pH range of 4–10. The complex sustained its stability in the presence of different physiological anions (F−, HCO3−, HPO42−, C2O42−, CH3COO− and CH2(COO−)2) as supported by insignificant changes in longitudinal relaxivity (r1) at 1.41 T, 25 °C. The concentration-dependent contrast ability of [Gd(Hdphta)] is investigated by T1–weighted phantom images in a 3 T MRI scanner at 20 °C and pH 7.4. The cell viability has been evaluated using tissue culture in HEK cells.

Solid-State Phase Transformation of Monohydrate and Anhydrous Form II of Sitagliptin Phosphate into a Novel Anhydrous Form IV – Solvent-Driven, Temperature-Induced and Stress Testings

The solid form landscape of sitagliptin phosphate was systematically evaluated by differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), Fourier transform infrared spectroscopy (FTIR), Raman spectroscopy and X-ray powder diffraction (XRPD), supported by a plethora of auxiliary analytical techniques. The preformulation experiments resulted in the transition of sitagliptin phosphate monohydrate into a new anhydrous form (designated as form IV), obtained after recrystallization from absolute ethanol. The anhydrous form IV remained stable under stressed conditions (1 month at 25 °C/60 %RH and 40 °C/75 %RH). On the other hand, thermal heating (dehydration) of sitagliptin phosphate monohydrate resulted in conversion into another anhydrous form II. Form II was found to be metastable, because after melting, under exposure at 40 °C/75 %RH for 1 month, or when dissolved in absolute ethanol converted to the stable anhydrous form IV of sitagliptin phosphate. A monotropic relationship was found between both studied anhydrous forms. Intrinsic dissolution tests revealed differences in the dissolution rates between the monohydrate and the anhydrous forms of sitagliptin phosphate. This research corrects the record with an accurate chemical composition of the anhydrous form IV of sitagliptin phosphate that was previously regarded as a hemiethanolate. In addition, the crystal structure of anhydrous form II of sitagliptin phosphate has been solved and reported for the first time.

Pharmaceutical Evaluation of Levofloxacin Orally Disintegrating Tablet Formulation Using Low Frequency Raman Spectroscopy.

We evaluated the pharmaceutical properties of levofloxacin (LV) in the form of an orally disintegrating tablet (LVODT) to find a new usefulness of low frequency (LF) Raman spectroscopy. LVODT contained dispersed granules with diameters in the order of several hundred micrometers, which were composed of the active pharmaceutical ingredient (API), as confirmed by infrared (IR) microspectroscopy. On the contrary, the API and inactive pharmaceutical ingredients (non-APIs) were homogeneously distributed in LV tablet (LVT) formulations. Microscopic IR spectroscopy and thermal analyses showed that LVODT and LVT contained the API in different crystalline forms or environment around the API each other. Furthermore, powder X-ray diffraction showed that LVT contained a hemihydrate of the API, while LVODT showed a partial transition to the monohydrate form. This result was confirmed by microscopic LF Raman spectroscopy. Moreover, this method confirmed the presence of thin layers coating the outer edges of the granules that contained the API. Spectra obtained from these thin layers indicated the presence of titanium dioxide, suggesting that the layers coexisted with a polymer that masks the bitterness of API. The microscopic LF Raman spectroscopy results in this study indicated new applications of this method in pharmaceutical science.

Enhancement of Hydrate Stability through Substitutional Defects.

Cytosine monohydrate (CM) and anhydrate crystal forms reversibly interconvert under high temperatures or high humidity conditions. Here, we demonstrate through defect engineering the ability to expand the thermal stability range of CM through the targeted creation of quantifiable defects in low-level concentrations. Twelve different molecular dyes with a variety of core structures and charges were screened as potential dopants in CM. CM-dye phases prepared with Congo red (CR), Evans blue (EB), and Azocarmine G (AG) exhibited the highest inclusion levels (up to 1.1 wt %). In these doped isomorphous materials, each dye is presumed to substitute for 4-7 cytosine molecules within the low-rugosity (102) planes of the CM matrixes, thereby creating a quantifiable substitutional defect and an impediment to the cooperative molecular motions which enable the transformation to the anhydrate. Dehydration of materials with these engineered defects requires significantly higher temperatures and proceeds with slower kinetics compared to pure CM. The CM-dye phases also exhibit a reduction in the thermal expansion along key crystallographic axes and yield dehydration products with altered particle morphologies.

Dehydration of Niclosamide Monohydrate Polymorphs: Different Mechanistic Pathways to the Same Product.

Many active pharmaceutical ingredients (APIs) can crystallize as hydrates or anhydrates, the relative stability of which depends on their internal structures as well as the external environment. Hydrates may dehydrate unexpectedly or intentionally, though the molecular-level mechanisms by which such transformations occur are difficult to predict a priori. Niclosamide is an anthelmintic drug on the World Health Organization's "List of Essential Medicines" that crystallizes in two monohydrate forms: HA and HB. Through complementary time-resolved synchrotron powder X-ray diffraction and thermogravimetric kinetic studies, we demonstrate that the two monohydrates dehydrate via distinctly different solid state pathways yet yield the same final anhydrate phase. Water loss from HA via diffusion yields an isomorphous desolvate intermediate which can rearrange to at least two different polymorphs, only one of which exhibits long-term stability. In contrast, dehydration of HB proceeds via a surface nucleation process where simultaneous water loss and product formation occur with no detectable crystalline intermediates. Comparative analysis of the two systems serves to highlight the complex relationship between lattice structure and solid state dehydration processes.

Life-cycle analysis of battery metal recycling with lithium recovery from a spent lithium-ion battery

Demand for critical materials (nickel, cobalt, manganese [NCM], and lithium) for use in batteries is increasing rapidly due to the expansion of the battery-electric vehicles market. Battery metal recycling (BMR) is an important technology that can potentially realize environmental and economic benefits in cathode active material (LiNixMnyCozO2) production using recycled materials. While current major battery recycling technologies recover cathode materials (NCM) and other metals (steel, aluminum, copper, etc.) from the spent battery, the lithium (Li) recovery rate is less than 1% in the world. In this study, we analyze the environmental benefits of a BMR process that recovers lithium in the form of lithium hydroxide monohydrate (LiOH∙H2O) along with other cathode materials. Using life-cycle analysis (LCA), we evaluate the life-cycle greenhouse gas (GHG) emissions, criteria air pollutant emissions, and water consumption of the new BMR technology in terms of lithium hydroxide production and cathode active material production. The LCA results show that the life-cycle GHG emissions recycled LiOH are 37–72% lower than those of virgin LiOH production from Chilean brine and Australian ore, respectively. In addition, the life-cycle GHG emissions of NCM811 produced using the recycled materials are 40–48% lower compared to virgin cathode active material production. Furthermore, recovering lithium from the spent batteries reduces associated air pollutant emissions and water consumption relative to using the virgin materials or materials from other recycling technologies without LiOH recovery.

Dose-Dependent Dual Effect ofMorus nigraL. Extract on Urinary Parameters of Hypertensive Rats.

This study investigated the diuretic and antiurolithic effects of the hydroalcoholic extract obtained from Morus nigra L. leaves (HEMN) in female hypertensive rats. The rats were treated orally with vehicle (VEH), hydrochlorothiazide (HCTZ), or HEMN. After 8-h, the urine was analyzed. Besides, the precipitation of calcium oxalate (CaOx) was induced in the urine. The HEMN, at a dose of 0.03 mg/g, increased the volume of urine compared to the VEH-treated group and increased the urinary content of Cl-, without altering the excretion of Na+ and K+. Besides, HENM reduced the elimination of Ca2+ in the urine. On the other hand, at a dose of 0.1 mg/g, it significantly reduced the volume of urine excreted, thus suggesting an antidiuretic effect dependent on the dose used. Similarly, HEMN at concentrations of 1 and 3 mg/mL reduced CaOx crystals' formation in monohydrate and dihydrate forms. However, with the increase in the concentration of HEMN to 10 mg/mL, a significant increase in the formation of CaOx crystals was found. In conclusion, M. nigra extract has a dose-dependent dual effect on urinary parameters, which may have a diuretic and antiurolithic effect at lower doses or the opposite effect at higher doses.

Characterization and Interconversion of Two Crystal Forms of NEt-3IB, a Retinoid X Receptor Agonist.

Retinoid X receptor (RXR) agonist NEt-3IB (1) is a candidate for the treatment of inflammatory bowel disease (IBD), and we have established a process synthesis of 1 in which the final product is obtained by recrystallization from 70% EtOH. However, we found that there are two crystal forms of 1. Here, to characterize and clarify the relationship between them, we conducted thermogravimetry, powder X-ray diffraction, and single crystal X-ray diffraction. The crystal forms were identified as the monohydrate form I and anhydrate form II. The crystal form I, obtained as a stable form by our established synthesis, was easily dehydrated simply by drying to afford the form II', which was similar to the crystal form II obtained by recrystallization from anhydrous EtOH. Storage of the form II' in air regenerated the form I. The molecular conformations of 1 in the crystals of the two forms are similar, and they can be reversibly interconverted. The solubility of the monohydrate form I and anhydrate form II was examined and the former was found to be less soluble than the latter. Thus, form I may be superior to form II for targeting IBD, because of higher delivery to the lower gastrointestinal tract and reduction of systemic side effects associated with lower absorption due to lower water solubility.

Bioprospecting of desert actinobacteria with special emphases on griseoviridin, mitomycin C and a new bacterial metabolite producing Streptomyces sp. PU-KB10–4

BackgroundBioprospecting of actinobacteria isolated from Kubuqi desert, China for antibacterial, antifungal and cytotoxic metabolites production and their structure elucidation.ResultsA total of 100 actinobacteria strains were selectively isolated from Kubuqi desert, Inner Mongolia, China. The taxonomic characterization revealed Streptomyces as the predominant genus comprising 37 different species, along with the rare actinobacterial genus Lentzea. The methanolic extracts of 60.8% of strains exhibited potent antimicrobial activities against Staphylococcus aureus, Micrococcus luteus, Bacillus subtilis, Escherichia coli, Salmonella enterica, Saccharomyces cerevisiae and high to mild in vitro cytotoxicity against PC3 (prostate cancer) and A549 (lung carcinoma) cell lines. The metabolomics analysis by TLC, HPLC-UV/vis, HPLC-MS and NMR showed the presence of compounds with molecular weights ranging from 100 to 1000 Da. The scale-up fermentation of the prioritized anti-Gram-negative strain PU-KB10–4 (Streptomyces griseoviridis), yielded three pure compounds including; griseoviridin (1; 42.0 mgL− 1) with 20 fold increased production as compared to previous reports and its crystal structure as monohydrate form is herein reported for the first time, mitomycin C (2; 0.3 mgL− 1) and a new bacterial metabolite 4-hydroxycinnamide (3; 0.59 mgL− 1).ConclusionsThis is the first report of the bioprospecting and exploration of actinobacteria from Kubuqi desert and the metabolite 4-hydroxycinnamide (3) is first time isolated from a bacterial source. This study demonstrated that actinobacteria from Kubuqi desert are a potential source of novel bioactive natural products. Underexplored harsh environments like the Kubuqi desert may harbor a wider diversity of actinobacteria, particularly Streptomyces, which produce unique metabolites and are an intriguing source to develop medicinally valuable natural products.

Experimental Study on the Manufacturing of Functional Paper with Modified by N-Methylmorpholine-N-oxide Surfaces.

The manufacturing of paper with new functional properties is a current problem today. A method of modifying the surface layer of paper by the partial dissolution of cellulose on its surface is proposed. N-Methylmorpholine-N-oxide (NMMO) is proposed for use as a solvent, the regeneration of which provides an environmentally friendly process. It was shown that among the possible hydrate forms of the solvent, the monohydrate and higher-melting forms are optimal for modifying the paper surface. The temperature-time modes of processing were revealed and the weight gain and density increase in the course of modification were estimated. The structural and morphological features of the original and modified paper were studied by X-ray imaging and scanning microscopy. The NMMO surface treatment makes it possible to vary the air permeability of the paper, making it practically non-permeable. The capillary and pore system were radically transformed after the partial dissolution of cellulose and its coagulation, as the formed cellulose film isolates them, which leads to a decrease in surface absorbency. The processing conditions allowing for the optimization of the optical and strength properties of the modified paper samples are revealed. The resulting paper with a modified N-methylmorpholine-N-oxide surface layer can be used for printing valuable documents.

Thermal characteristics of crystalline and amorphous 2′-fucosyllactose, a human milk oligosaccharide

The thermal characteristics of crystalline and amorphous forms of a human milk oligosaccharide, 2ʹ-fucosyllactose (2ʹ-FL), were investigated by differential scanning calorimetry and thermogravimetric analysis, and compared with the two forms of α-lactose monohydrate. Crystalline 2ʹ-FL (87.48% crystallinity according to X-ray diffraction) showed dehydration at 143.4 °C (close to lactose) and melting at 230.6 °C (the same as β-lactose crystal). Amorphous 2ʹ-FL showed glass transition at 127.6 °C and crystallisation at 192.8 °C, which were much higher than the corresponding temperatures for amorphous lactose. 2ʹ-FL showed thermal decomposition at temperatures about 10 °C higher (210–212 °C) than lactose, indicating the higher thermal stability of 2ʹ-FL. Amorphous 2ʹ-FL showed sharp decreases in glass transition (127.6 °C to 36.5 °C) and crystallisation (192.8 °C to 103.4 °C) temperatures with increasing water activity (aw) from 0 to 0.53, above which no glass transition or crystallisation was observed.

A molecular understanding of citrate adsorption on calcium oxalate polyhydrates.

Calcium oxalate precipitation is a common pathological calcification in the human body, whereby crystallite morphology is influenced by the chelating properties of biological ions such as citrate. It has been suggested that citrate could steer oxalate formation towards its dihydrated form and away from the monohydrated form, which was identified as a major cause for disease. To assess the influence of the citrate ion on the resulting calcium oxalate, surface energies were calculated at the dispersion-corrected density functional level of theory for both monohydrated and dihydrated calcium oxalate. Different adsorption geometries were considered by varying the attacking angle of citrate as well as by considering the citrate ion on top of an adsorbed water layer or penetrating the water layer. The obtained results were compared to ab initio molecular dynamics simulations and experimental scanning electron microscope images. A strong preference for citrate adsorption on calcium oxalate dihydrate was observed, suggesting medical applications for the treatment of such pathological calcifications.

Design, Preparation, Characterization and Evaluation of Five Cocrystal Hydrates of Fluconazole with Hydroxybenzoic Acids.

To modulate the physicochemical properties of fluconazole (FLZ), a multifunctional antifungal drug, the crystal engineering technique was employed. In this paper, five novel cocrystal hydrates of FLZ with a range of phenolic acids from the GRAS list, namely, 2,4-dihydroxybenzoic acid (24DHB), 3,4-dihydroxybenzoic acid (34DHB, form I and form II), 3,5-dihydroxybenzoic acid (35DHB), and 3,4,5-trihydroxybenzoic acid (345THB) were disclosed and reported for the first time. Crystals of these five hydrates were all obtained for single-crystal X-ray diffraction (SCXRD) analysis. Robust (hydroxyl/carboxyl) O-H. . . Narom hydrogen bonds between acids and FLZ triazolyl moiety were observed to be dominant in guiding these crystal forms. The water molecule plays the role of supramolecular "linkage" in the strengthening and stabilization of these hydrates by interacting with FLZ and acids through O-H. . . O hydrogen bonds. In particular, the formation of FLZ-34DHB-H2O (1:1:1) significantly reduces hygroscopicity and hence improves the stability of FLZ, the latter of which is unstable and easily transforms into its monohydrate form. Increased initial dissolution rates were observed in the obtained cocrystal forms, and an enhanced intrinsic dissolution rate was obtained in FLZ-35DHB-H2O (1:1:1) in comparison with commercialized FLZ form II.