Nucleation and growth of polymorphs of barbital on chemically modified surfaces in microfluidic channels
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Nucleation and growth of polymorphs of barbital on chemically modified surfaces in microfluidic channels John C. MacDonald*, Kasim Biyikli, Branko Zugic, Garrett Ebersole and Joshua Allor Department of Chemistry & Biochemistry, Worcester Polytechnic Institute, Worcester, MA, USA ABSTRACT Crystallization experiments have been carried out in microfluidic devices to screen for polymorphs by crystallization on a range of surfaces. These devices consist of PDMS (polydimethylsiloxane) patterned with microchannels and then bonded to self-assembled monolayers (SAMs) of organic molecules on gold substrates. Barbital was crystallized in microchannels over five different SAMs functionalized with polar and nonpolar organic groups. Growth of polymorphs was examined under thermodynamic conditions from solutions at room temperature and under kinetic conditions by rapid cooling. The results of these experiments and the influence of chemically modified surfaces in microchannels in controlling polymorphism are discussed. INTRODUCTION Crystallization of drug molecules from solution as polymorphs—that is, different crystal forms in which the molecules adopt alternate packing arrangements—remains a persistent problem for crystal engineering.1,2 Polymorphism is particularly problematic in the development of pharmaceuticals because polymorphs of a single compound legally are classified as different drugs. Thus, there is a need to develop methods to screen for the incidence of polymorphs and control which polymorphs form. While considerable effort has been spent investigating how factors such as concentration, temperature, solvent and pH influence nucleation and growth of polymorphs, considerably less is known about the influence of thin molecular films such as selfassembled monolayers (SAMs) in this regard. While crystallization of inorganic minerals,3-9 organic compounds10-14 and proteins15,16 on SAMs, langmuir layers and other substrates have been reported, few studies have focused on the use of SAMs in controlling the incidence of polymorphs.17,18 Fewer studies still have focused on the use of microfluidic devices to carry out crystallization on small quantities of solution (e.g., nanoliters) in microchannels,19,20 although control of polymorphism has been studied in micropores and capillaries recently.21-23 Consequently, we are investigating whether nucleation and growth of polymorphs of pharmaceuticals such as barbital (5,5’-diethylbarbituric acid) can be promoted and controlled on chemically modified surfaces in microchannels. We have begun to investigate microfluidic devices that contain multiple channels as a means to develop high throughput methods24 to screen for polymorphism. Goals of this research include determining (1) if crystals of barbital will nucleate selectively on SAMs in microchannels, (2) if nucleation of polymorphs occurs preferentially in microchannels on surfaces functionalized with a range of hydrophobic and hydrophilic organic groups, (3) whether the incidence of specific polymorphs (particularl
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