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PURPOSE: Employing polymer additives is an effective strategy to realize the manipulation of polymorphic transformation. However, the manipulation mechanism is still not clear, which limit the precise selection of polymeric excipients and the development of pharmaceutical formulations. METHODS: The solubility of cimetidine (CIM) in acetonitrile/water mixtures were measured. And the polymorphic transformation from CIM form A to form B with the addition of different polymers was monitored by Raman spectroscopy. Furthermore, the manipulation effect of polymers was determined based on the results of experiments and molecular simulations. RESULTS: The solubility of form A is consistently higher than that of form B, which indicate that form B is the thermodynamically stable form within the examined temperature range. The presence of polyvinylpyrrolidone (PVP) of a shorter chain length could have a stronger inhibitory effect on the phase transformation process of metastable form, whereas polyethylene glycol (PEG) had almost no impact. The nucleation kinetics experiments and molecular dynamic simulation results showed that only PVP molecules could significantly decrease the nucleation rate of CIM, due to the ability of reducing solute molecular diffusion and solute-solute molecular interaction. A combination of crystal growth rate measurements and calculations of the interaction energies between PVP and the crystal faces of CIM indicate that smaller molecular weight PVP can suppress crystal growth more effectively. CONCLUSION: PVP K16-18 has more impact on the stabilization of CIM form A and inhibition of the phase transformation process. The manipulation mechanism of polymer additives in the polymorphic transformation of CIM was proposed.
ABSTRACT
PURPOSE: Pradofloxacin is an important antibiotic with poor physical stability. At present, there is no systematic study on its polymorphic form. The purpose of this study is to develop new crystal forms to improve the stability of Pradofloxacin and systematically study the crystal transformation relationships to guide industrial production. METHOD: In this work, three solvent-free forms (Form A, Form B and Form C), a new dimethyl sulfoxide solvate (Form PL-DMSO) and a new hydrate (Form PL-H) were successfully obtained and the single crystal data of Form A, Form B and Form PL-DMSO were solved for the first time. Various solid state analysis techniques and slurry experiments have been used to evaluate the stability and determine phase transformation relationships of five crystal forms, the analysis of crystal structure provided theoretical support for the results. RESULT: The water vapor adsorption and desorption experiences of Forms A, B, C and Form PL-H were studied, and the results show that the new hydrate has good hygroscopic stability and certain development potential. The thermal stability of different forms was determined by thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) and the crystal structure shows that there are more hydrogen bonds and C - H···π interactions in form B, which is the reason why Form B is more stable than form A. Finally, the phase transformation relationships of the five crystal forms were systematically studied and discussed. CONCLUSION: These results are helpful to provide guiding methods in the production and storage of pradofloxacin.
Subject(s)
Dimethyl Sulfoxide , Fluoroquinolones , Crystallization/methods , Anti-Bacterial Agents , Calorimetry, Differential Scanning , Drug Stability , X-Ray DiffractionABSTRACT
Ultrasound-mediated method, which can effectively disperse agglomerates or even eliminate agglomeration, has received more and more attentions in industrial crystallization. However, the ultrasound-mediated de-agglomeration mechanism has not been well understood, and no general conclusions have been drawn. In this study, the crystallization and de-agglomeration process of ceftezole sodium agglomerates under ultrasound irradiation were systematically investigated. Kapur function was selected to investigate the de-agglomeration process under different ultrasonic powers. The results revealed that ultrasound could efficiently inhibit agglomeration. Besides, the de-agglomeration of large sized agglomerate particles was found to be easier to occur in comparison with small sized particles due to its higher specific breakage rate. Finally, the de-agglomeration mechanism under ultrasonic irradiation was proposed on the basis of the calculated cumulative breakage functions.
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Increasing evidence has shown that nucleation pathways involving disordered pre-nucleation species exist in the nucleation process of many types of solid state products, especially inorganic solid state products. Studying the thermodynamic and kinetic properties of these pre-nucleation species is crucial to understand and control the nucleation process of solid state products. In this work, the evolution pathway of molecular or supramolecular structures during the nucleation process was investigated by using 2-cyano-4'-methylbiphenyl (OTBN) as a model compound. In the resultant solutions, similar pre-nucleation clusters were analyzed and characterized by dynamic light scattering (DLS), small-angle X-ray scattering (SAXS) and nanoparticle tracking analysis (NTA). It was found that the clusters were disordered and liquid-like and did not represent any of the known OTBN condensed phases. They were of interest since they may be the key sites for the formation of new crystal nuclei of OTBN. It was demonstrated that the change in the solvation effect would drive the pre-nucleation clusters to exhibit very different structures. How the clusters vary with concentration and temperature, and how they differ before and after nucleation have been systematically studied. In addition, the molecular dynamics of the evolution of clusters, the effect of initial mixing process on clusters and the nucleation dynamics were also investigated. The results suggested that the pre-nucleation clusters played a key role in the process of crystallization of organic small molecules, indicating that the dynamics of nucleation could be regulated by changing the structure and size of the pre-nulceation clusters.
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BACKGROUND: In the pharmaceutical field, it is vital to ensure a consistent product containing a single solid-state form of the active pharmaceutical ingredient (API) in the drug product. However, some APIs are suffering from the risk of transformation of their target forms during processing, formulation and storage. METHODS: The purpose of this review is to summarize the relevant category of excipients and demonstrate the availability and importance of using excipients as a key strategy to manipulate pharmaceutical polymorphic transformation. RESULTS: The excipient effects on solvent-mediated phase transformations, solid-state transitions and amorphous crystallization are significant. Common pharmaceutical excipients including amino acids and derivatives, surfactants, and various polymers and their different manipulation effects were summarized and discussed. CONCLUSION: Appropriate use of excipients plays a role in manipulating polymorphic transformation process of corresponding APIs, with a promising application of guaranteeing the stability and effectiveness of drug dosage forms.
Subject(s)
Excipients , Pharmaceutical Preparations , Chemistry, Pharmaceutical , Crystallization , Drug StabilityABSTRACT
Removal of contaminants in wastewater, such as heavy metals, has become a severe problem in the world. Numerous technologies have been developed to deal with this problem. As an emerging technology, nanotechnology has been gaining increasing interest and many nanomaterials have been developed to remove heavy metals from polluted water, due to their excellent features resulting from the nanometer effect. In this work, novel nanomaterials, including carbon-based nanomaterials, zero-valent metal, metal-oxide based nanomaterials, and nanocomposites, and their applications for the removal of heavy metal ions from wastewater were systematically reviewed. Their efficiency, limitations, and advantages were compared and discussed. Furthermore, the promising perspective of nanomaterials in environmental applications was also discussed and potential directions for future work were suggested.
ABSTRACT
Recyclable nanomaterials are in great need to develop clean technology for applications in the removal of water contaminants. In this work, easily separable montmorillonite/Fe3O4/humic acid (MFH) nanocomposites were fabricated through a facile hydrothermal route. It was found the adsorption ability and stability of MFH was significantly enhanced due to the synergistic effects between montmorillonite, Fe3O4 nanoparticles and humic acid. The MFH nanocomposites are highly efficient and recyclable as they can remove at least 82.3% of Cr(VI) and 95.1% of aniline in six consecutive runs. The adsorption mechanism was investigated by analyzing the kinetic parameters of pseudo first-order, pseudo second-order, and intraparticle diffusion models and describing the equilibrium isotherms of Langmuir and Freundlich models. Results indicated different adsorption mechanisms of Cr(VI) and aniline by MFH. The readily synthesized MFH nanocomposites can act as effective and practical materials for environmental applications.
