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Context: Isoniazid (INH) is one of the medications most used for tuberculosis (TB) treatment. However, long-term continuous therapy can cause hepatotoxicity and peripheral neuritis. The degradation of INH is an important aspect of the research in the field of drug stability as well as drug formulation for controlling release. It is thought that tautomerization, hydrolysis as well as nucleophilic substitutions can cause decrease in INH as non-enzymatic degradation. Therefore, it is crucial to understand the mechanisms and energies of the major reactions in order to provide reference for future drug formulation and application. This study is an effort to understand the kinetic and thermodynamic properties of the non-enzymatic degradation reactions. The chemical reaction phenomena are investigated using the density functional theory (DFT) method. This study shows that major degradation of INH can be done via tautomerization followed by hydrolysis. The general trends in nucleophilic degradation presented here are consistent with experimental pKa of nucleophiles. Methods: All DFT calculations were performed using the Gaussian Software Packages (Gaussian 09 revision B.01 and GaussView 5.0.8). MOLEKEL 4.3 software was utilized to visualize the molecular graphics of all relevant species. The optimized molecular geometries were calculated using B3LYP/6–311 + G(d,p) level in the gas phase. The IEF-PCM/B3LYP/6–311 + G(d,p) level was selected for single-point and frequency calculations in aqueous media. [ABSTRACT FROM AUTHOR]

[Display omitted] Co-crystallization of active pharmaceutical ingredients (API) with co-formers can induce synergistic effects on cytotoxicity; however, the underlying mechanism is unclear. Here, cell metabolomics was used to gain insight into the mechanisms of synergistic effect from API and co-former in co-crystal. The 5-Fluorouracil-phenylalanine co-crystal system was selected as the model owing to the apparent difference of cytotoxicity occurring between co-crystal and physical mixture of two components (PM). The cytotoxicity of 5-FU, PM and co-crystal on B16 cells were evaluated by MTT assay. Based on the IC 50 values from MTT assays, the cytotoxicity mechanism of 5-FU, PM and co-crystal was evaluated using a comprehensive non-targeted metabolomics strategy based on multivariate data analysis and statistics using UHPLC-Q-TOF-MS/MS platform with IDA data acquisition. Co-crystal showed higher cytotoxicity than PM against B16 cells. In the cell metabolomics study, a total of 12 differential metabolites were found. Pathway analysis indicated that differences in purine and glycerophospholipid metabolism occurred between PM and co-crystal. The downregulated deoxyguanosine diphosphate and adenosine diphosphate in the purine metabolism and downregulated L-glycerophosphocholine and upregulated C16-dihydroceramide in the glycerophospholipid metabolism were associated with cellular antiproliferation and apoptosis, which directly influenced the cytotoxicity. Cell metabolomics was used to investigate the cytotoxicity mechanism of the pharmaceutical co-crystal, providing an effective and innovative method for clarifying the synergistic mechanism of API and CCF in co-crystal. [ABSTRACT FROM AUTHOR]

A pharmaceutical co-crystal (named as APAP-NICO) was prepared at 25 °C by using acetaminophen (APAP) as the drug active ingredient and nicotinamide (NICO) as the eutectic substance. The monomer and eutectic were characterized by infrared spectrometer (IR), scanning electron microscope (SEM), X-ray powder diffractometer (XRD), high performance liquid chromatography (HPLC), and thermogravimetric (TG) analyzer. The stoichiometric ratio of APAP to NICO was determined to be 1:1 by two methods. This experiment involves a number of cutting-edge analysis methods that will help students to improve their hands-on ability and data analysis ability. [ABSTRACT FROM AUTHOR]

The pharmaceutical co-crystal has attracted increasing interest due to the improvement of physicochemical properties of active pharmaceutical ingredients. The characterization of pharmaceutical co-crystal is an integral part of the pharmaceutical field. In this paper, the low-frequency vibrational properties for carbamazepine co-crystals with nicotinamide and saccharin (CBZ-NIC and CBZ-SAC) have been characterized by combining the THz spectroscopy with low-wavenumber Raman spectroscopy. The experiment results show that, compared with the individual constituents, CBZ-NIC and CBZ-SAC co-crystals not only have different characteristic absorption peaks in the 0.3-2.5 THz region, but also have significant low-wavenumber Raman characteristic peaks in 0–100 cm−1. Density functional theory was performed to simulate the terahertz and low-wavenumber Raman spectra of the two co-crystals, where the calculation agreed well with the measured vibrational peak positions. The vibrational modes of CBZ-NIC and CBZ-SAC co-crystals were assigned through comparing theoretical results with the experimental spectra. Meanwhile, the low-frequency infrared and/or Raman active of characteristic peaks for such co-crystals were discussed. The results indicate the combination of THz spectroscopy and low-wavenumber Raman spectroscopy can provide more comprehensive low-frequency vibrational information for pharmaceutical co-crystals, such as collective vibration and skeleton vibration, which could play an important role in pharmaceutical science. [ABSTRACT FROM AUTHOR]

• NTG is a BCS class II drug, almost insoluble in water, with limited oral bioavailability. • NTG-INA co-crystal prepared through solvent evaporation with ultrasound. • Co-crystals were characterized via DSC, FTIR, XRPD, SEM, and SCXRD. • Equilibrium solubility of the co-crystal was more than twice that of NTG. Nateglinide (NTG) is clinically used to treat type II diabetes. NTG is a Biopharmaceutics Classification System class II drug and is thus almost insoluble in water, limiting its oral bioavailability. The solubility of drugs can be increased through various methods; however, these methods have several limitations. Therefore, this study used solvent evaporation combined with the ultrasonic method to prepare an NTG-isonicotinamide (INA) co-crystal to improve the solubility of NTG and characterized the co-crystal using scanning electron microscopy, differential scanning calorimetry, X-ray powder diffraction, single-crystal X-ray diffraction (SCXRD), and Fourier transform infrared spectroscopy. The SCXRD results demonstrate that the newly formed crystal material belongs to the P2 1 monoclinic crystal system. A single crystal was formed by NTG and INA in a stoichiometric ratio of 2:2; the crystallographic information is as follows: a = 8.9552 Å, b = 12.6413 Å, c = 21.5877 Å, α=90°, β=98.463 (6)°, γ=90°, Z = 4, R 1 =0.0712, and wR 2 =0.1284. The equilibrium solubility of the co-crystal was more than twice that of NTG, suggesting that it is suitable for further research on its bioavailability and improvement in clinical application. [Display omitted] [ABSTRACT FROM AUTHOR]

The pharmaceutical co-crystal has attracted increasing interest due to the improvement of physicochemical properties of active pharmaceutical ingredients. The characterization of pharmaceutical co-crystal is an integral part of the pharmaceutical field. In this paper, the low-frequency vibrational properties for carbamazepine co-crystals with nicotinamide and saccharin (CBZ-NIC and CBZ-SAC) have been characterized by combining the THz spectroscopy with low-wavenumber Raman spectroscopy. The experiment results show that, compared with the individual constituents, CBZ-NIC and CBZ-SAC co-crystals not only have different characteristic absorption peaks in the 0.3-2.5 THz region, but also have significant low-wavenumber Raman characteristic peaks in 0–100 cm−1. Density functional theory was performed to simulate the terahertz and low-wavenumber Raman spectra of the two co-crystals, where the calculation agreed well with the measured vibrational peak positions. The vibrational modes of CBZ-NIC and CBZ-SAC co-crystals were assigned through comparing theoretical results with the experimental spectra. Meanwhile, the low-frequency infrared and/or Raman active of characteristic peaks for such co-crystals were discussed. The results indicate the combination of THz spectroscopy and low-wavenumber Raman spectroscopy can provide more comprehensive low-frequency vibrational information for pharmaceutical co-crystals, such as collective vibration and skeleton vibration, which could play an important role in pharmaceutical science.

Resveratrol (RSV) and polydatin (PD) have been widely used to treat several chronic diseases, such as atherosclerosis, pulmonary fibrosis, and diabetes, among several others. However, their low solubility hinders their further applications. In this work, we show that the solubility of PD can be boosted via its co-crystallization with L-proline (L-Pro). Two different phases of co-crystals, namely the RSV-L-Pro (RSV:L-Pro = 1:2) and PD-L-Pro (PD:L-Pro = 1: 3), have been prepared and characterized. As compared to the pristine RSV and PD, the solubility and dissolution rates of PD-L-Pro in water (pH 7.0) exhibited a 15.8% increase, whereas those of RSV-L-Pro exhibited a 13.8% decrease. A 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay of pristine RSV, PD, RSV-L-Pro, and PD-L-Pro against lung cancer cell line A549 and human embryonic kidney cell line HEK-293 indicated that both compounds showed obvious cytotoxicity against A549, but significantly reduced cytotoxicity against HEK-293, with PD/PD-L-Pro further exhibiting better biological safety than that of RSV/RSV-L-Pro. This work demonstrated that the readily available and biocompatible L-Pro can be a promising adjuvant to optimize the physical and chemical properties of RSV and PD to improve their pharmacokinetics.

Puerarin (PUE) is a Chinese traditional medicine known to enhance glucose uptake into the insulin cells to downregulate the blood glucose levels in the treatment of type II diabetes. Nevertheless, the bioavailability of pristine PUE is limited due to its poor solubility and low intestinal permeability. In this work, we demonstrate that the solubility of PUE can be significantly enhanced via its co-crystallization with L-Proline (PRO). Two crystalline phases, namely, the solvate-free form [PUE][PRO] (I) and the solvated form [PUE]2[PRO]∙EtOH∙(H2O)2 (II) are isolated. These two phases are characterized by single-crystal X-ray diffraction (SCXRD), powder X-ray diffraction (PXRD), Fourier-transformed infrared (FT-IR) spectra, nuclear magnetic resonance (NMR), and thermogravimetric analysis in association with differential scanning calorimetry (TGA-DSC). The solubility and dissolution rate of both I and II in water, gastrointestinal tract at pH 1.2, and phosphate buffer at pH 6.8 indicates a nearly doubled increase as compared to the pristine PUE. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay of pristine PUE, I and II against murine colon cancer cell lines CT-26 and human kidney cell lines HEK-293 indicated that neither compound exhibits obvious cytotoxicity after 24 h. This work showcases that the readily available and biocompatible PRO can be a promising adjuvant to enhance the physicochemical properties of PUE toward orally administered drug formulation with improved pharmacokinetics.

Tenofovir alafenamide (TAF) is a prodrug of tenofovir as a potent nucleotide reverse transcriptase inhibitor. It serves as the key component of Genvoya® for the first-line treatment of human immunodeficiency virus infection (HIV) and is the active component of Vemlidy® for the treatment of chronic hepatitis B. Vemlidy® is also a monotherapeutic regimen formulated as TAF hemifumarate (1; TAF:fumarate = 2:1). In this work, we report for the first time the single-crystal structure of TAF fumarate hemihydrate (2, TAF:fumarate:H2O = 2:2:1). Compound 2 is initially documented as a salt in which one proton of the fumaric acid migrates to the amine group of the adenine moiety in TAF. It was recently proposed that ca. 20–30% proton is transferred to the N atom on the aromatic adenine backbone. We herein provide definitive single-crystal X-ray diffraction results to confirm that 2, though phase pure, is formed as a mixture of co-crystal (75%) and salt (25%). It features two pairs of TAF fumarates, wherein one of the four H atoms on the fumaric acid is transferred to the N atom of the adjacent adenine moiety while the other three carboxylates remain in their intrinsic acid form. Compound 2 is a metastable phase during the preparation of 1 and can be isolated by halting the reaction during the refluxing of TAF and fumaric acid in acetonitrile (MeCN). Our report complements the previous characterizations of TAF monofumarate, and its elusive structural patterns are finally deciphered.

Multi-component crystals have been studied during recent years from the applications points of view. Particularly are useful in the case of pharmaceutical co-crystals due they play a significant role in the development of new drugs. These materials are considered good alternatives to existing pharmaceutical formulations, as they may help to improve pharmacological properties such assolubility, stability and bioavailability. Single-crystal X-ray diffraction was used to examine the nature of non-covalent interactions in the multi-component crystal (RS)-nipecotic: oxalic acid: water (1:1:1). All three entities are linked by intermolecular interactions. The crystals are orthorhombic, space group Pbca, with a = 11.184(4) Å, b = 11.895(4) Å, c = 16.781(6) Å, V = 2232.4(1) ų, Z = 8. In this structure, an ionic ensemble assisted by hydrogen bonds, the molecules are connected by O--H···O and N--H···O hydrogen bonds, forming linearsemi-oxalate--semi-oxalate chains with intercalated R and S nipecotic molecules. The combination of these intermolecular interactions leads to the formation of a molecular assembly which can be described as a two-dimensional bilayer-like arrangement. [ABSTRACT FROM AUTHOR]

Two novel pharmaceutical co-crystals of anti-inflammatory drug flufenamic acid (FFA) with 2-chloro-4-nitrobenzoic acid (CNB) and ethenzamide (ETZ) have been synthesized by solvent evaporation method as well as by solvent drop-assisted grinding method. The synthesized co-crystals were characterized thoroughly by various spectroscopic methods and crystal structures were determined by single-crystal x-ray diffraction technique. In FFA-CNB co-crystal, robust supramolecular acid-acid homosynthon was observed. FFA-ETZ co-crystal is formed via robust supramolecular acid-amide heterosynthon. In FTIR spectra, a significant shift in the carbonyl stretching frequency was observed for the co-crystals due to the presence of intermolecular hydrogen bond. 1 H nuclear magnetic resonance study suggests the presence of hydrogen bond in the solution state of FFA-ETZ co-crystal; however, it was absent for FFA-CNB co-crystal. Solubility study in Millipore water revealed that the solubility of FFA is increased by 2-fold when it is in the form of FFA-CNB co-crystal and no increment in the solubility of FFA was observed in FFA-ETZ co-crystal. About 5-fold increment in the solubility of FFA was observed in both the co-crystals in 0.1 N HCl (pH 1) solution. The synthesized co-crystals were found to be non-hygroscopic at ∼75% relative humidity and stable for a period of 6 months at ambient temperature (∼25°C). [ABSTRACT FROM AUTHOR]

Pharmaceutical salts of BCS class II second line anti-tuberculosis drug ethionamide (ETH) with various counter ions namely, 2-chloro-4-nitrobenzoic acid (CNB), 2,6-dihydroxybenzoic acid (2,6HBA), 2,3-dihydroxybenzoic acid (2,3HBA) and 2,4-dinitrobenzoic acid (DNB) were synthesized by crystal engineering approach. All the synthesized salts were characterized by various spectroscopic (NMR, FT-IR,), thermal (DSC & TGA) and PXRD techniques. The crystal structure of the synthesized salts was determined by single-crystal X-ray diffraction techniques. All the reported salts, except ETH-2,3HBA exhibited charge assisted acid pyridine heterosynthon. In ETH-2,3HBA hydoxyl pyridine heterosynthon is observed. In ETH-CNB salt, both ionic and neutral acid pyridine heterosynthon were observed in the asymmetric unit. ETH-DNB salt consists of both partial and complete proton transfer from DNB to ETH in the asymmetric unit. All the synthesized salts were found to be non-hygroscopic at accelerated humid condition (~ 75% RH). Solubility experiment has been performed in purified water and in 0.1 N HCl (pH = 1) solution and found that the solubility of ETH-CNB salt was about eight-fold higher soluble than ETH in purified water. The solubility of synthesized salts follows the order of ETH < ETH-2,3HBA < ETH-2,6HBA < ETH-CNB in purified water. [ABSTRACT FROM AUTHOR]

6-Mercaptopurine (6-MP) is a clinically important antitumor drug. The commercially available form was provided as monohydrate and belongs to BCS class II category. Co-crystallization screening by reaction crystallization method (RCM) and monitored by powder X-ray diffraction led to the discovery of a new co-crystal formed between 6-MP and isonicotinamide (co-crystal 1 ). Co-crystal 1 was thoroughly characterized by X-ray diffraction, FT-IR and Raman spectroscopy, and thermal analysis. Noticeably, the in vitro and in vivo studies revealed that co-crystal 1 possesses improved dissolution rate and superior bioavailability on animal model. [ABSTRACT FROM AUTHOR]

Understanding the intermolecular interactions is central to crystal engineering and is pivotal in designing of the new materials. Of recent we have reported sulfonate-pyridinium interaction as robust synthon and herein we utilize the interaction to develop molecular complexes: [(ISN–I3C–H)+(5-SSA-H)ˉ] (1), [(ISN-pV-H)+(5-SSA-H)ˉ.MeOH·H 2 O] (2), and [(ISN-oV-H)+(5-SSA-H)ˉ.H 2 O] (3). 1–3 have been obtained by reaction of isoniazid derivatives: ((1H-indol-3-yl)methylene)isonicotinohydrazide (ISN–I3C), isonicotinic acid (4-hydroxy-3-methoxy-benzylidene)-hydrazide (ISN-pV) and isonicotinic acid (2-hydroxy-3-methoxy-benzylidene)-hydrazide (ISN-oV) with 5-sulfosalicylic acid (5-SSA-2H). Molecular salts 1 and 2 manifest direct charge assisted sulfonate-pyridinium interaction, while, in 3, the synthon is masked by lattice water. The Schiff base cations in 1 and 2 stack together through strong π-interactions forming 2-dimensional layers and 1-dimensional tapes, respectively, which, in turn, are bridged by the organo-sulfonate anions into a 3-dimensional ionic solids. While the crystal formers in 3, the hydrogen bonds are utilized to form three molecule thick sheets, which aggregate through C–H⋯O and π-π interactions to form a 3-dimensional supramolecule. Hirshfeld studies corroborate with structural studies and validate that reciprocal O–H/H–O interactions are the chief intermolecular interactions in these oxygen rich compounds while weak dispersive H–H contacts are the second dominant interactions responsible for the molecular packing. Framework energy, as well as individual contribution of columbic, potential and dispersive forces towards molecular packing, are visualized through framework energy analyses of 1–3, which also substantiate that very robust sulfonate-pyridinium contact is not the strongest intermolecular contact. The resultant multi-component crystals exhibit enhanced optical properties, which are attributed to proton transfer and/or π-stacking interactions. The band gap values of 1–3 observed in the Tauc plots corroborate with charge transfer interactions. The products also exhibit enhanced solubility in methanol, higher than the isoniazid derivatives, and the thermal stability up to 240 ​°C. The molecular salts have also been screened for preliminary biological studies. [Display omitted] • Pharmaceutical co-crystal. • Supramolecular synthon. • Hydrogen bond. • Crystal engineering. [ABSTRACT FROM AUTHOR]

Crystal engineering has evolved in such a manner that it is now synonymous with the paradigm of supramolecular synthesis, that is, it invokes self-assembly of existing molecules to generate a wide range of new solid forms without the need to break or form covalent bonds. This review addresses how crystal engineering has been applied to active pharmaceutical ingredients, API's, with emphasis upon how pharmaceutical co-crystals, a long known but little explored alternative to the four traditionally known forms of API, can be generated in a rational fashion. Case studies on Carbamazepine (CBZ) and Piracetam are presented which illustrate the relative ease with which pharmaceutical co-crystals can be prepared and their diversity in terms of composition and physical properties. &copy 2006 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 95:499–516, 2006 [ABSTRACT FROM AUTHOR]

Resveratrol (RSV) and polydatin (PD) have been widely used to treat several chronic diseases, such as atherosclerosis, pulmonary fibrosis, and diabetes, among several others. However, their low solubility hinders their further applications. In this work, we show that the solubility of PD can be boosted via its co-crystallization with L-proline (L-Pro). Two different phases of co-crystals, namely the RSV-L-Pro (RSV:L-Pro = 1:2) and PD-L-Pro (PD:L-Pro = 1: 3), have been prepared and characterized. As compared to the pristine RSV and PD, the solubility and dissolution rates of PD-L-Pro in water (pH 7.0) exhibited a 15.8% increase, whereas those of RSV-L-Pro exhibited a 13.8% decrease. A 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay of pristine RSV, PD, RSV-L-Pro, and PD-L-Pro against lung cancer cell line A549 and human embryonic kidney cell line HEK-293 indicated that both compounds showed obvious cytotoxicity against A549, but significantly reduced cytotoxicity against HEK-293, with PD/PD-L-Pro further exhibiting better biological safety than that of RSV/RSV-L-Pro. This work demonstrated that the readily available and biocompatible L-Pro can be a promising adjuvant to optimize the physical and chemical properties of RSV and PD to improve their pharmacokinetics. [ABSTRACT FROM AUTHOR]

Puerarin (PUE) is a Chinese traditional medicine known to enhance glucose uptake into the insulin cells to downregulate the blood glucose levels in the treatment of type II diabetes. Nevertheless, the bioavailability of pristine PUE is limited due to its poor solubility and low intestinal permeability. In this work, we demonstrate that the solubility of PUE can be significantly enhanced via its co-crystallization with L-Proline (PRO). Two crystalline phases, namely, the solvate-free form [PUE][PRO] (I) and the solvated form [PUE]2[PRO]∙EtOH∙(H2O)2 (II) are isolated. These two phases are characterized by single-crystal X-ray diffraction (SCXRD), powder X-ray diffraction (PXRD), Fourier-transformed infrared (FT-IR) spectra, nuclear magnetic resonance (NMR), and thermogravimetric analysis in association with differential scanning calorimetry (TGA-DSC). The solubility and dissolution rate of both I and II in water, gastrointestinal tract at pH 1.2, and phosphate buffer at pH 6.8 indicates a nearly doubled increase as compared to the pristine PUE. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay of pristine PUE, I and II against murine colon cancer cell lines CT-26 and human kidney cell lines HEK-293 indicated that neither compound exhibits obvious cytotoxicity after 24 h. This work showcases that the readily available and biocompatible PRO can be a promising adjuvant to enhance the physicochemical properties of PUE toward orally administered drug formulation with improved pharmacokinetics. [ABSTRACT FROM AUTHOR]

Tenofovir alafenamide (TAF) is a prodrug of tenofovir as a potent nucleotide reverse transcriptase inhibitor. It serves as the key component of Genvoya® for the first-line treatment of human immunodeficiency virus infection (HIV) and is the active component of Vemlidy® for the treatment of chronic hepatitis B. Vemlidy® is also a monotherapeutic regimen formulated as TAF hemifumarate (1; TAF:fumarate = 2:1). In this work, we report for the first time the single-crystal structure of TAF fumarate hemihydrate (2, TAF:fumarate:H2O = 2:2:1). Compound 2 is initially documented as a salt in which one proton of the fumaric acid migrates to the amine group of the adenine moiety in TAF. It was recently proposed that ca. 20–30% proton is transferred to the N atom on the aromatic adenine backbone. We herein provide definitive single-crystal X-ray diffraction results to confirm that 2, though phase pure, is formed as a mixture of co-crystal (75%) and salt (25%). It features two pairs of TAF fumarates, wherein one of the four H atoms on the fumaric acid is transferred to the N atom of the adjacent adenine moiety while the other three carboxylates remain in their intrinsic acid form. Compound 2 is a metastable phase during the preparation of 1 and can be isolated by halting the reaction during the refluxing of TAF and fumaric acid in acetonitrile (MeCN). Our report complements the previous characterizations of TAF monofumarate, and its elusive structural patterns are finally deciphered. [ABSTRACT FROM AUTHOR]