J.H. ter Horst

Isonicotinamide self-association: the link between solvent and polymorph nucleation

We show that, in a controlled and reproducible way, specific solvents lead to specific polymorphic forms of isonicotinamide. We argue on the basis of Raman and FTIR spectroscopy that the hydrogen bonding in solution kinetically drives the nucleation towards a specific form. This generally may lead to good understanding and control of polymorphism and crystal nucleation.

The influence of a solvent on the crystal morphology of RDX

A solvent can have a large influence on the crystal morphology. A molecular modeling technique based on the adsorption of solvent molecules on a crystal surface has been used to predict the influence of a solvent on the morphology of RDX. The predicted morphology has been compared with the experimentally found morphology of RDX crystallized from several solvents by cooling crystallization.

A thermodynamic based approach on the investigation of a diflunisal pharmaceutical co-crystal with improved intrinsic dissolution rate

A thermodynamic based approach is used to investigate diflunisal+nicotinamide binary and solution mixtures. A 2:1 co-crystal could be prepared by liquid assisted ball mill grinding and by solution crystallization from ethanol. The diflunisal+nicotinamide+ethanol ternary phase diagram points out conditions for co-crystal scaling-up. From the diflunisal+nicotinamide binary phase diagram, besides identification of the co-crystal stoichiometry, two additional useful binary compositions, eutectic mixtures, were characterized. From a solution enthalpy based approach, the enthalpic stabilization of the co-crystal relative to the pure solid components is quantified. Intrinsic dissolution rate, IDR, in test conditions consistent with USP requirements, including those referred in the diflunisal tablet monograph, were carried out, indicating that the co-crystal improves diflunisal IDR by about 20%. The systematic study of diflunisal+nicotinamide mixtures presented in this work is of particular interest due to the relevance of diflunisal, both as a non-steroidal anti-inflammatory drug and also due to the potentiality of orally administrated diflunisal in familial amyloid polyneuropathy.

Molecular modelling of the transport behaviour of C3 and C4 gases through the zeolite DD3R

Abstract The all-silica zeolite deca-dodecasil 3R (DD3R) has a two-dimensional pore structure which might be used for separation of gas mixtures of small molecules in a zeolite packed bed or membrane configuration. The DD3R pore structure exists of large cages connected by narrow 8-membered oxygen rings. A specially developed and computationally efficient molecular modelling method is used to determine the permeability of a number of gaseous C 3 and C 4 hydrocarbon compounds in a DD3R zeolite membrane. The permeability is determined by the solubility coefficient and the diffusion coefficient. The solubility coefficient is determined from the adsorption energy of a gas molecule in the DD3R cage. The diffusion coefficient is determined from the energy barrier for diffusion which is the energy difference of the gas molecule in the ring and in the cage. High permeabilities and selectivities for the compounds trans -1,3-butadiene and propene were determined.

The role of temperature in nucleation processes.

Heat and mass transfers are coupled processes, also in nucleation. In principle, a nucleating cluster would have a different temperature compared to the surrounding supersaturated old phase because of the heat release involved with attaching molecules to the cluster. In turn a difference in temperature across the cluster surface is a driving force for the mass transfer to and from the cluster. This coupling of forces in nonisothermal nucleation is described using mesoscopic nonequilibrium thermodynamics, emphasizing measurable heat effects. An expression was obtained for the nonisothermal nucleation rate in a one-component system, in the case where a temperature difference exists between a cluster distribution and the condensed phase. The temperature is chosen as a function of the cluster size only, while the temperature of the condensed phase is held constant by a bath. The generally accepted expression for isothermal stationary nucleation is contained as a limiting case of the nonisothermal stationary nucleation rate. The equations for heat and mass transport were solved for stationary nucleation with the given cluster distribution and with the temperature controlled at the boundaries. A factor was defined for these conditions, determined by the heat conductivity of the surrounding phase and the phase transition enthalpy, to predict the deviation between isothermal and nonisothermal nucleation. For the stationary state described, the factor appears to give small deviations, even for primary nucleation of droplets in vapor, making the nonisothermal rate smaller than the isothermal one. The set of equations may lead to larger and different thermal effects under different boundary conditions, however.

Molecular modelling of the crystallization of polymorphs. Part I: The morphology of HMX polymorphs

A molecular modelling procedure for the prediction of interfacial energies between polymorphs and solvents is under development. The first step in such a procedure must be to determine and investigate the structure of the possible morphologically important crystal surfaces. This is done for two of the experimentally readily obtained polymorphs β-HMX and α-HMX (cyclotetramethylene tetramine) by means of a periodic bond chain analysis.

Adsorption behaviour of polyelectrolytes on calcium fluoride: Part II: molecular modeling of the adsorption behaviour☆

Abstract Molecular modeling techniques were used to find an explanation for the observed adsorption behaviour of polyelectrolytes on CaF 2 . The adsorption energies of polyacrylate (PA) and polymaleate (PM) on calcium fluoride (CaF 2 ) were calculated at different pH values. It was found that the adsorption energy becomes less negative at higher pH values, indicating that the surface concentration plateau value of the polyelectrolytes decreases with increasing pH. This finding is in agreement with the observations.

Cold plasma synthesis of high quality organic nanoparticles at atmospheric pressure

Atmospheric pressure cold surface dielectric barrier discharge (SDBD) plasma was used for the first time to produce nano-sized organic crystals. Nano-sized particles can have beneficial product properties, such as improved internal quality and dissolution rate, compared to conventionally sized crystalline products. In cold plasma crystallization a nebulizer system sprays the solution aerosol into the plasma with the help of a carrier gas. The plasma heats and charges the droplets causing solvent evaporation and coulomb fission to occur, after which nucleation and crystal growth commence within the small, confined volume offered by the small droplets. As a result nano-sized crystals are produced. The operation conditions of SDBD plasma to produce nano-sized crystals of the energetic material RDX were determined by scanning electron microscopy, and the product was investigated with X-ray powder diffraction and sensitivity tests. The sensitivity tests indicated that the nano-sized product had reduced sensitivity for friction, indicating a higher internal quality of the crystalline product.

Co-crystals of diflunisal and isomeric pyridinecarboxamides – a thermodynamics and crystal engineering contribution

Diflunisal is an anti-inflammatory, non-steroidal drug, class II of the Biopharmaceutical Classification System, which has recently been the subject of renewed interest due to its potential for use in the oral therapy of familial amyloid polyneuropathy. In this study, a thermodynamics based approach is used to investigate binary mixtures (diflunisal + picolinamide and diflunisal + isonicotinamide) in order to identify solid forms that are potentially useful to improve the biopharmaceutical performance of this active pharmaceutical ingredient. Special emphasis is placed on the research of co-crystals and on the influence of structural changes in the pyridinecarboxamide co-former molecules for co-crystal formation with diflunisal. The thermodynamics based methodology described by ter Horst et al. in 2010 indicates that the formation of co-crystals is thermodynamically feasible for both systems. The binary solid–liquid phase diagrams were built and allowed unequivocal identification of the formation of co-crystals of diflunisal with each of the two isomers and also their stoichiometry of 1 : 1, (diflunisal : co-former) in the case of pyridine-2-carboxamide (picolinamide) and (2 : 1) for pyridine-4-carboxamide (isonicotinamide). Two binary eutectic mixtures, potentially relevant for pharmaceutical application, were also identified. Infrared spectroscopy allowed the identification of the acid⋯N-pyridine heterosynthon in the three co-crystals formed by diflunisal with the isomeric pyridinecarboxamides. However, the results clearly differentiated pyridine-2-carboxamide from pyridine-3-carboxamide and pyridine-4-carboxamide, that share similar crystalline arrangements, at least with respect to the supramolecular synthons.

ADSORPTION BEHAVIOUR OF POLYELECTROLYTES ON CALCIUM FLUORIDE. PART I : INFLUENCE OF THE PH AND THE IONIC STRENGTH ON THE ADSORPTION ISOTHERMS

Abstract The adsorption behaviour of weak polyelectrolytes onto CaF 2 crystals has been investigated to support the research on the mechanism of growth retardation. Adsorption isotherms and surface concentration plateau values of three kinds of poly(phosphino)acrylate, a polyacrylate and a polymaleate were determined at different pH values in pure water and at a higher ionic strength. It was found that the surface concentration plateau values decrease with decreasing pH. The addition of an indifferent salt makes the polyelectrolytes more flexible due to partial screening of the polyelectrolyte charge.