Quantitative plane-resolved crystal growth and dissolution kinetics by coupling in situ optical microscopy and diffusion models : the case of salicylic acid in aqueous solution

The growth and dissolution kinetics of salicylic acid crystals are investigated in situ by focusing on individual microscale crystals. From a combination of optical microscopy and finite element method (FEM) modeling, it was possible to obtain a detailed quantitative picture of dissolution and growth dynamics for individual crystal faces. The approach uses real-time in situ growth and dissolution data (crystal size and shape as a function of time) to parametrize a FEM model incorporating surface kinetics and bulk to surface diffusion, from which concentration distributions and fluxes are obtained directly. It was found that the (001) face showed strong mass transport (diffusion) controlled behavior with an average surface concentration close to the solubility value during growth and dissolution over a wide range of bulk saturation levels. The (1̅10) and (110) faces exhibited mixed mass transport/surface controlled behavior, but with a strong diffusive component. As crystals became relatively large, they tended to exhibit peculiar hollow structures in the end (001) face, observed by interferometry and optical microscopy. Such features have been reported in a number of crystals, but there has not been a satisfactory explanation for their origin. The mass transport simulations indicate that there is a large difference in flux across the crystal surface, with high values at the edge of the (001) face compared to the center, and this flux has to be redistributed across the (001) surface. As the crystal grows, the redistribution process evidently can not be maintained so that the edges grow at the expense of the center, ultimately creating high index internal structures. At later times, we postulate that these high energy faces, starved of material from solution, dissolve and the extra flux of salicylic acid causes the voids to close

FDA Critical Path Initiatives: Opportunities for Generic Drug Development

FDA’s critical path initiative documents have focused on the challenges involved in the development of new drugs. Some of the focus areas identified apply equally to the production of generic drugs. However, there are scientific challenges unique to the development of generic drugs as well. In May 2007, FDA released a document “Critical Path Opportunities for Generic Drugs” that identified some of the specific challenges in the development of generic drugs. The key steps in generic product development are usually characterization of the reference product, design of a pharmaceutically equivalent and bioequivalent product, design of a consistent manufacturing process and conduct of the pivotal bioequivalence study. There are several areas of opportunity where scientific progress could accelerate the development and approval of generic products and expand the range of products for which generic versions are available, while maintaining high standards for quality, safety, and efficacy. These areas include the use of quality by design to develop bioequivalent products, more efficient bioequivalence methods for systemically acting drugs (expansion of BCS waivers, highly variable drugs), and development of new bioequivalence methods for locally acting drugs

Sensitivity of morphology prediction to the force field: paracetamol as an example

The growth morphology of paracetamol is known to show a strong supersaturation dependence. Most morphology prediction methods, like the attachment energy method, cannot include this dependence in their prediction. Monte Carlo simulations are able to use the supersaturation as an input parameter and can also include the growth mechanism. This makes the Monte Carlo technique a powerful tool to study the growth of organic crystals. Some studies in the literature show that the attachment energy method is only weakly influenced by the force field used to calculate the attachment energies. The present paper presents the sensitivity of the Monte Carlo simulation results to the force field and charge set using paracetamol as a case study. The force field and atomic point charges are found to influence the results to a large extent. This is due to subtle differences in step energies that determine the growth rates of the crystal faces

Influence of solution speciation of impurities on polymorphic nucleation in glycine

10.1021/cg060570wCrystal Growth and Design81179-18

Design of a device for simultaneous particle size and electrostatic charge measurement of inhalation drugs

10.1007/s11095-008-9660-xPharmaceutical Research25112488-2496PHRE