Crystallization formulation considerations

A set of principles governing the structure of complex ionic crystals, based upon the assumption of a coordinated arrangement of anions about each cation at the comers of an approximately regular polyhedron, is formulated with the aid of considerations based upon the crystal energy. Included in the set is a new electrostatic principle which is of wide application and considerable power. 

With the exception of single-crystal transmission work, most solids are too opaque to permit the conventional use of ultraviolet/visible (UV/VIS) electronic spectroscopy. As a result, such work must be performed through the use of diffuse reflection techniques [8-10]. Important work has been conducted in which UV/VIS spectroscopy has been used to study the reaction pathways of various solid state reactions. Other applications have been made in the fields of color measurement and color matching, areas which can be of considerable importance when applied to the coloring agents used in formulations. 

To understand how chirality is expressed, it is important to first describe the different thermotropic mesophase assemblies which can be formed by chiral discotics. Even though expression of chirality has been observed in thermotropic mesophases, the chiral expression occurs in a rather uncontrolled manner, and systems which are suitable for applications, for example, easily switchable columns/ferroelectric discotic liquid crystals, consequently have not yet been developed. Hence, the assembly of discotics in solution has received considerable attention. Supramolecular assemblies of discotic molecules in solution are still in their infancy and have not yet found commercial application, but they are of fundamental importance since they allow a detailed and focused investigation of the specific interactions that are required to express chirality at higher levels of organization. As such, the fundamental knowledge acquired from supramolecular assemblies in solution might formulate the design criteria for thermotropic chiral discotic mesophases and provide the necessary tools for the creation of functional systems. 

Samples of the Form I API were formulated in the laboratory to understand the precipitation issue. It was quickly discovered that the laboratory process now produced material with the same precipitation problems as the capsules from the manufacturing plant. Despite considerable effort the From II precipitate could not be avoided. It is suspected that the laboratory equipment had become contaminated with trace quantities of the Form II crystals and these promoted the transformation of Form I material into the thermodynamically stable Form II. 

Buffers for lyophilized formulations need additional consideration. Some buffers like sodium phosphate can crystallize out of the protein amorphous phase during freezing resulting in rather large shifts in pH. Other common buffers such as acetate and imidazole should be avoided since they may sublime or evaporate during the lyophilization process, thereby shifting the pH of formulation during lyophilization or after reconstitution. 

If Form I could no longer be prepared reproducibly, then Abbott needed to be able to develop a viable formulation of Form II. Both plans were fully executed. After considerable work, the process group discovered a number of contributing factors to the appearance of Form II. Ultimately, the solution to the problem was a simple one batches of ritonavir were seeded with Form I crystals to encourage precipitation of the desired polymorph. 

---