Surface functionalization in combination with confinement for crystallization from undersaturated solutions

Crystallization from undersaturated solutions was demonstrated using functionalized nanoporous silica (Zorbax® chromatographic media). The silica matrix acts as a source of bound groups within the nanopores which act to reduce the solubility within the small pore volume resulting in the formation of nanocrystals within the pores. Experiments were conducted within sealed capillaries which were monitored via X-ray powder diffraction. Experiments were conducted for a number of solutes and concentrations and clearly demonstrated a critical concentration in the undersaturated region below which crystals would not form. Concentrations above this critical concentration would form crystals. Batch experiments confirmed that the crystallization yield could be calculated from the difference between the initial concentration before the addition of Zorbax® and the critical (effective saturation) concentration.United States. Defense Advanced Research Projects Agency (Grant W911NF-16-2-0023)Novartis-MIT Center for Continuous Manufacturin

Two-Stage Crystallizer Design for High Loading of Poorly Water-Soluble Pharmaceuticals in Porous Silica Matrices

While porous silica supports have been previously studied as carriers for nanocrystalline forms of poorly water-soluble active pharmaceutical ingredients (APIs), increasing the loading of API in these matrices is of great importance if these carriers are to be used in drug formulations. A dual-stage mixed-suspension, mixed-product removal (MSMPR) crystallizer was designed in which the poorly soluble API fenofibrate was loaded into the porous matrices of pore sizes 35 nm-300 nm in the first stage, and then fed to a second stage in which the crystals were further grown in the pores. This resulted in high loadings of over 50 wt % while still producing nanocrystals confined to the pores without the formation of bulk-sized crystals on the surface of the porous silica. The principle was extended to another highly insoluble API, griseofulvin, to improve its loading in porous silica in a benchtop procedure. This work demonstrates a multi-step crystallization principle API in porous silica matrices with loadings high enough to produce final dosage forms of these poorly water-soluble APIs

Confined crystallization of fenofibrate in nanoporous silica

Producing stable nanocrystals confined to porous excipient media is a desirable way to increase the dissolution rate and improve the bioavailability of poorly water soluble pharmaceuticals. The poorly soluble pharmaceutical fenofibrate was crystallized in controlled pore glass (CPG) of 10 different pore sizes between 12 nm and 300 nm. High drug loadings of greater than 20 wt% were achieved across all pore sizes greater than 20 nm. Nanocrystalline fenofibrate was formed in pore sizes greater than 20 nm and showed characteristic melting point depressions following a Gibbs–Thomson relationship as well as enhanced dissolution rates. Solid-state Nuclear Magnetic Resonance (NMR) was employed to characterize the crystallinity of the confined molecules. These results help to advance the fundamental understanding of nanocrystallization in confined pores.Novartis-MIT Center for Continuous ManufacturingNational Institute for Biomedical Imaging and Bioengineering (U.S.) (Grant EB-002026)Natural Sciences and Engineering Research Council of Canada (Banting Postdoctoral Fellowship

Nanocrystallization confined to porous matrices with and without surface functionalization effects

This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections.Thesis: Ph. D., Massachusetts Institute of Technology, Department of Chemical Engineering, 2018Cataloged from student-submitted PDF version of thesis.Includes bibliographical references (pages 147-153).Poorly water-soluble active pharmaceutical ingredients (APIs), which represent a major fraction of the molecules in drug discovery and development, are a challenge to the pharmaceutical industry given their low bioavailability. One way to address this issue is to generate nanocrystals of these APIs. Nanocrystals have a significantly increased surface area to volume ratio as compared to standard micron-sized crystals, which results in improved solubility and dissolution rates. There already exist some industrially relevant techniques for producing pharmaceutical nanocrystals, which typically exploit contact forces and high pressures to bring crystals of a normal micron range down to the nanocrystal scale. However, these techniques are often plagued with challenges such as low production rates, high energy input, and issues with stabilization and control over the final crystalline form produced.Because of this, techniques which produce nanocrystals in the desired size range from the start are gaining interest. In this work, crystallization in confinement is used to produce stable pharmaceutical nanocrystals of a well-controlled size. Rigid, nanoporous silica matrices were used to confine crystallization volumes to the nanoscale, resulting in the formation of nanocrystals within these pores. The technique was demonstrated across a wide range of pore sizes, and using several poorly water-soluble APIs. When the principles were extended to a two-stage continuous crystallizer setup, the loadings of API in these porous matrices were improved to over 50 weight percent. When these drug loaded porous silicas were tested in a dissolution rate apparatus, the resulting dissolution profiles showed dramatic improvements as compared to the dissolution of bulk micron-sized crystals.In the later stages of this research, porous silica with surface functionalization was used rather than bare porous matrices. Herein, it was demonstrated that, at the small pore volumes present in these systems, the surface functionalization from the media may contribute enough functional group interaction to the solvent-solute system for the solubility of a dissolved API within these pores to change. Thus, through the combination of surface functionalization and confinement effects, this work demonstrated nanocrystallization from undersaturated API solutions using functionalized nanoporous matrices.by Leia M. Dwyer.Ph. D.Ph.D. Massachusetts Institute of Technology, Department of Chemical Engineerin