Crystallization of Metastable Polymorphs of Phenobarbital by Isomorphic Seeding

Abstract

Six metastable polymorphs (V, VII-XI) of phenobarbital (Pbtl) were produced by melt crystallization via seeding with corresponding isomorphic barbiturate homologues, following the teachings of earlier thermoanalytical studies of isopolymorphic relationships and utilizing the melting phase diagrams of Pbtl admixtures with various 5,5-substituted barbituric acid derivatives. The Pbtl forms and their solid solutions were analyzed with hot-stage microscopy, powder X-ray diffraction, and infrared spectroscopy. The crystal structures of several isomorphic homologues were determined to assess the structural features of the metastable Pbtl polymorphs. In contrast to Pbtl-V, VIII, and IX, which could be isolated as a single component phase, Pbtl-VII, X, and XI could only be stabilized in the presence of one of the isomorphic additives. Form Pbtl-V, the most stable form among the six metastable polymorphs, is structurally similar to Pbtl-IV and was crystallized by seeding with co-crystals of Pbtl/rutonal (3:1). Pbtl-VII was obtained as a stabilized intermediate phase from the system dipropylbarbital/Pbtl. Pbtl-VIII occurs on seeding with alphenal (Alp) form I. The structure analysis of this orthorhombic Alp modification revealed the presence of N-H • • • OdC hydrogen bonded layers. Pbtl-IX and X show isomorphic relationships to a rich variety of different barbiturate structures, all based on the same pair of H-bonded ribbon chains. The packing features of Pbtl-IX were deduced from the isomorphic structures of amytal-II and soneryl-I. Pbtl-X is isomorphic to both amytal-I and phanodorm-II. The existence of form XI was confirmed via the solid solutions of Pbtl/Alp and Pbtl/dipropylbarbital. This study conveys some of the basic principles of isomorphic additives on the formation of specific polymorphs or the stabilization of unstable crystal forms, which are not detectable in solvent or melt crystallization experiments of the pure compound. † Dedicated to Emer. Prof. Maria Kuhnert-Brandsta ¨tter on the occasion of her 90th birthday.

Problems, potentials and future of industrial crystallization

“…However, these methods are difficult to control in terms of avoiding the formation of more than one polymorph [45,46]. Moreover, the isolation of a metastable polymorph is difficult and challenging before it undergoes a solvent-mediated phase transformation to the more stable form.…”

Polymorphism and Solvatomorphism 2009

“…25 It was concluded that for systems in which isomorphic structural relationships are known to exist, appropriately chosen additives can be used to stabilize unstable crystal forms that are unable to be isolated during conventional solvent or melt crystallization experiments. N-(1-naphthyl)-succinimide was used as a model case to test the relative merits of a "quenched nucleation" protocol and conventional homogeneous nucleation procedures, with different polymorphic outcomes being observed depending on the procedure followed.…”

Emerging role of primary heterogeneous nucleation in pharmaceutical crystallization

“…Zencirciet al investigated the crystallization of the phenobarbital using a variety of structurally related compounds as heterosurface (Zencirci et al, ). They were able to identify six metastable polymorphs of Phenobarbital (Form V and VII to XI) which were not reported previously by either solution crystallization or melt crystallization.…”

“…Only two polymorphic forms of the sulfamethoxazone were known till Price et al recently discovered two more polymorphs III and IV using diverse polymer library as heterosurface (Price et al, ). Phenobarbital was discovered in 1912 and exists in 11 polymorphic forms, wherein, six novel polymorphs were discovered recently using isomorphous heterosurfaces (Zencirci et al, ). Fenofibrate is one of the blockbuster antihyperlipidemic agents identified with two novel polymorphs when crystallization was attempted with pharmaceutically relevant excipients like talc (Tipduangta et al, ) and HPMC (Shi et al, ) as heterosurfaces.…”