Exploring the Formation of Multiple Layer Hydrates for a Complex Pharmaceutical Compound (original) (raw)
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Molecular pharmaceutics, 2014
Morphine, codeine, and ethylmorphine are important drug compounds whose free bases and hydrochloride salts form stable hydrates. These compounds were used to systematically investigate the influence of the type of functional groups, the role of water molecules, and the Cl(-) counterion on molecular aggregation and solid state properties. Five new crystal structures have been determined. Additionally, structure models for anhydrous ethylmorphine and morphine hydrochloride dihydrate, two phases existing only in a very limited humidity range, are proposed on the basis of computational dehydration modeling. These match the experimental powder X-ray diffraction patterns and the structural information derived from infrared spectroscopy. All 12 structurally characterized morphinane forms (including structures from the Cambridge Structural Database) crystallize in the orthorhombic space group P212121. Hydrate formation results in higher dimensional hydrogen bond networks. The salt structure...
Factors affecting crystallization of hydrates
Journal of Pharmacy and Pharmacology, 2010
Objectives To provide a comprehensive understanding of the competing thermodynamic and kinetic factors governing the crystallization of various hydrate systems. The ultimate goal is to utilize this understanding to improve the control over the unit operations involving hydrate formation, as well as to optimize the bioavailability of a given drug product. Key findings The thermodynamic and kinetic factors that govern hydrate crystallization are introduced and the current status of the endeavour to gain a mechanistic understanding of the phenomena that occur during the crystallization of different hydrate systems is discussed. The importance of hydrate investigation in the pharmaceutical field is exemplified by examining two specific hydrate systems: the polymorphic hydrate system and hydrates of pharmaceutical salts. Summary This review identifies the factors that are of critical importance in the investigation of anhydrate/hydrate systems. This knowledge can be used to control the phase transformation during pharmaceutical processing and storage, as well as in building a desired functionality for the final formulation.
Molecular simulations as a tool for selection of kinetic hydrate inhibitors
Molecular Simulation, 2005
The possible effects of tour different functional groups that operate in kinetic hydrate inhibitors have been examined by molecular dynamics simulations, with focus on their possible effects at the hydrate surface. New simulations for models of PVCAP (Poly(N-vinylprolactam)) and another functional group that takes part in the inhibitor VC-713 are presented and discussed in relation to previously published results for PVP (Poly(N-vinylpyrrolidine)). A modified version of the PVCAP polymer is also suggested. In addition a monomer of the polymer chitosan is also simulated. Simulated results are discussed in relation to observations from experiments on real systems. For the model systems in this study we find that PVPCAP has more favourable interaction properties with hydrate water than PVP and should, according to the simulations presented in this paper, have better properties as a kinetic hydrate inhibitor than PVP. A modified version of the PVP monomer, where a hydroxyl group is added to the ring, increases the attachment to the hydrate surface further. In VC-713 a third group is alternating with PVP monomers and PVCAP monomers as the functional groups attached to the paraffinic backbone. The simulations of this particular group indicate favourable interactions between hydrate water and for the limited monomer simulated in this study, practically all coloumbic interaction between this group and water is devoted to connections with the hydrate crystal. A monomer of chitosan is also simulated and although this monomer has strong attachment energy to the hydrate surface it also has very favourable interactions with liquid water. It is, therefore, somewhat unclear whether this polymer would have a sufficient attachment to a hydrate in the competition with a liquid water environment.
Thermodynamics of non-stoichiometric pharmaceutical hydrates
International journal of pharmaceutics, 2005
Different physical and mathematical models of non-stoichiometric hydrates derived form previous work in inorganic hydrates are reviewed. A theoretical link between the order of water molecules in the hydrate and the shape of the isotherm is outlined. The comparison of the models with sorption isotherms and structural data of well-known cases from the literature and one in-house case shows that the model can fit many experimental situations and is in good agreement with qualitative assessments of the order in the hydrates.
Hydration studies of a simple molecular solid
CrystEngComm, 2012
This paper presents novel information on the thermal dehydration and rehydration of the molecular solid, Oxalic Acid Dihydrate. Although the procedure of the overall decomposition process is welldefined, the structural basis and mechanism of the dehydration process has been poorly studied. We show that the dehydration occurs in a planar manner, with a resultant semi-topotactic relationship between hydrated and dehydrated structures, reflected in the molecular packing. During rehydration, the reconstruction of the phase can be seen to occur at a 3-dimensional phase boundary reaction front, i.e. a recrystallisation of the dihydrate on the surface of the reactant product, with the topotactic relationship leading to texturing and possibly epitaxial relationships between partially dehydrated and rehydrated structures. The proposed mechanism is shown to be consistent with the measured kinetics of the process.
Molecular dynamics simulations for selection of kinetic hydrate inhibitors
Journal of Molecular Graphics and Modelling, 2005
Natural gas hydrates are ice-like structures composed of water and gas molecules that have long been a problem in petroleum industry. Heavy cost of alcohol and glycol injection has spurred an interest in called 'kinetic inhibitors' able to slow down the hydrate formation rather than prevent it. Since it is not possible to compare directly the macroscopic effects of different inhibitors on the kinetics of hydrate formation in computer experiments, a scheme capable of culling the list of candidates for experimental testing was proposed earlier [B. Kvamme, G. Huseby, O.K. Førrisdahl, Molecular dynamics simulations of PVP kinetic inhibitor in liquid water and hydrate/liquid water systems, Mol. Phys. 90 (1997) 979-991]. Molecular dynamics simulations were implemented to test several kinetic inhibitors in a multiphase water-hydrate system with rigid hydrate interface. In addition, a long-scale run was implemented for a system where the hydrate was free to melt and reform. Our conclusion that PVCap will outperform PVP as a kinetic hydrate inhibitor is supported by experimental data. We demonstrate that numerical experiments can be a valuable tool for selecting kinetic inhibitors as well as provide insight into mechanisms of kinetic inhibition and hydrate melting and reformation. #
Pharmaceutical Hydrates Analysis—Overview of Methods and Recent Advances
Pharmaceutics, 2020
This review discusses a set of instrumental and computational methods that are used to characterize hydrated forms of APIs (active pharmaceutical ingredients). The focus has been put on highlighting advantages as well as on presenting some limitations of the selected analytical approaches. This has been performed in order to facilitate the choice of an appropriate method depending on the type of the structural feature that is to be analyzed, that is, degree of hydration, crystal structure and dynamics, and (de)hydration kinetics. The presented techniques include X-ray diffraction (single crystal X-ray diffraction (SCXRD), powder X-ray diffraction (PXRD)), spectroscopic (solid state nuclear magnetic resonance spectroscopy (ssNMR), Fourier-transformed infrared spectroscopy (FT-IR), Raman spectroscopy), thermal (differential scanning calorimetry (DSC), thermogravimetric analysis (TGA)), gravimetric (dynamic vapour sorption (DVS)), and computational (molecular mechanics (MM), Quantum Me...
Pharmaceutical Research, 2013
Purpose To understand the transformation pathways amongst anhydrate/hydrate solid forms of sodium naproxen and to highlight the importance of a polymorphic dihydrate within this context. Methods Multi-temperature dynamic vapour sorption (DVS) analysis combined with variable-humidity X-ray powder diffraction (XRPD) to establish the transformation pathways as a function of temperature and humidity. XRPD and thermogravimetric analysis (TGA) to characterise bulk samples. Monitoring of in-situ dehydration using solid-state 13 C CP/MAS spectroscopy. Results At 25°C, anhydrous sodium naproxen (AH) transforms directly to one dihydrate polymorph (DH-II). At 50°C, AH transforms stepwise to a monohydrate (MH) then to the other dihydrate polymorph (DH-I). DH-II transforms to a tetrahydrate (TH) more readily than DH-I transforms to TH. Both dihydrate polymorphs transform to the same MH. Conclusions The properties of the polymorphic dihydrate control the transformation pathways of sodium naproxen.
Proceedings of the 7th …, 2011
Over the past decade, low dosage hydrate inhibitors (LDHIs) which include anti-agglomerants (AAs) and kinetic hydrate inhibitors (KHIs) have seen increasing use as a cost effective technology for gas hydrate control in the oil and gas industry, offering significant CAPEX/OPEX advantages when compared with traditional thermodynamic inhibitors (e.g. methanol, glycols). While AAs prevent agglomeration/plugging, KHIs are primarily understood to be nucleation inhibitors, inducing an extended 'induction time' at a specific subcooled condition before hydrate nucleation can proceed to growth. The best known KHIs are water soluble poly-n-vinylamides such as poly-n-vinylcaprolactam (PVCap), poly-n-vinylpyrrolidone (PVP) and related polymers. As KHIs are seen primarily as 'nucleation delayers', evaluation is typically undertaken through measurement of induction times as a function of various parameters at the conditions of interest. However, as nucleation is stochastic by nature, obtaining repeatable/transferrable data is often highly problematic and time-consuming, making robust evaluation difficult. Here, we demonstrate that less well investigated aspect of KHI polymers their ability to inhibit crystal growth is considerably simpler to quantify than nucleation inhibition. Beginning at low aqueous concentrations (e.g. > 0.1 mass% aqueous), PVCap and other KHI polymers induce a number of highly repeatable, well-defined hydrate crystal growth inhibition (CGI) regions as a function of subcooling. Discernible by step changes in relative growth rates − commonly by an order of magnitude − CGI regions range from complete inhibition (even hydrate dissociation), through severely to moderately reduced growth rates, ultimately to final rapid/catastrophic growth as subcooling increases. Closely related to induction time data, CGI regions are readily measureable using conventional hydrate laboratory equipment, with subcooling extents − which it is speculated are polymer crystal surface absorption related phenomena providing a means to assess KHIs more rapidly and reliably, while giving a increased confidence in performance under worst case scenario (hydrate present) field conditions.
Monte Carlo Studies on Water in the dCpG/Proflavin Crystal Hydrate
Journal of Biomolecular Structure and Dynamics, 1983
The extensive water network identified in the crystallographic studies of the dCpG/Proflavin hydrate by Neidle, Berman and Shieh (Nature 288, 129, 1980) forms an ideal test case for a) assessing the accuracy of theoretical calculations on nucleic acidwater systems based on statistical thermodynamic computer simulation, and b) the possible use of computer simulation in predicting the water positions in crystal hydrates for use in the further refine-1 ment and interpretation of diffraction data. Monte Carlo studies have been carried out on water molecules in the unit cell of dCpG/ proflavin, with the nucleic acid complex fixed and the condensed phase environment of the system treated by means of periodic boundary, conditions. Intermolecular interactions are described by potential functions representative of quantum mechanical calculations developed by Clementi and coworkers, and widely used in recent studies of the aqueous hydration of various forms of DNA fragments. The results are analyzed in terms of hydrogen bond topology, hydrogen bond distances and energies, mean water positions, and water crystal probability density maps. Detailed comparison of calculated and experimentally observed results are given, and the sensitivity of results to choice of potential is determined by comparison with simulation results based on a set of empirical potentials.