Deniz Erdemir

Nucleation of Crystals from Solution: Classical and Two-Step Models

Crystallization is vital to many processes occurring in nature and in the chemical, pharmaceutical, and food industries. Notably, crystallization is an attractive isolation step for manufacturing because this single process combines both particle formation and purification. Almost all of the products based on fine chemicals, such as dyes, explosives, and photographic materials, require crystallization in their manufacture, and more than 90% of all pharmaceutical products contain bioactive drug substances and excipients in the crystalline solid state. Hence control over the crystallization process allows manufacturers to obtain products with desired and reproducible properties. We judge the quality of a crystalline product based on four main properties: size, purity, morphology, and crystal structure. The pharmaceutical industry in particular requires production of the desired crystal form (polymorph) to assure the bioavailability and stability of the drug substance. In solution crystallization, nucleation plays a decisive role in determining the crystal structure and size distribution. Therefore, understanding the fundamentals of nucleation is crucial to achieve control over these properties. Because of its analytical simplicity, researchers have widely applied classical nucleation theory to solution crystallization. However, a number of differences between theoretical predictions and experimental results suggest that nucleation of solids from solution does not proceed via the classical pathway but follows more complex routes. In this Account, we discuss the shortcomings of classical nucleation theory and review studies contributing to the development of the modern two-step model. In the two-step model that was initially proposed for protein crystallization, a sufficient-sized cluster of solute molecules forms first, followed by reorganization of that cluster into an ordered structure. In recent experimental and theoretical studies, we and other researchers have demonstrated the applicability of the two-step mechanism to both macromolecules and small organic molecules, suggesting that this mechanism may underlie most crystallization processes from solutions. Because we have observed an increase in the organization time of appropriate lattice structures with greater molecular complexity, we propose that organization is the rate-determining step. Further development of a clearer picture of nucleation may help determine the optimum conditions necessary for the effective organization within the clusters. In addition, greater understanding of these processes may lead to the design of auxiliaries that can increase the rate of nucleation and avoid the formation of undesired solid forms, allowing researchers to obtain the final product in a timely and reproducible manner.

Crystal Polymorphism in Chemical Process Development

Polymorphism in molecular crystals is a prevalent phenomenon and is of great interest to the pharmaceutical community. The solid-state form is a key quality attribute of a crystalline product. Inconsistencies in the solid phase produced during the manufacturing and storage of drug substances and drug products may have severe consequences. It is essential to understand the solid-state behavior of the drug and to judiciously select the optimal solid form for development. This review highlights the pervasiveness and relevance of polymorphism and describes solid form screening and selection processes. Moreover, case studies on controlling polymorphs from a chemical development perspective are provided.

A novel co-processing method to manufacture an API for extended release formulation via formation of agglomerates of active ingredient and hydroxypropyl methylcellulose during crystallization

Abstract A novel process for generating agglomerates of active pharmaceutical ingredient (API) and polymer by swelling the polymer in a water/organic mixture has been developed to address formulation issues resulting from a water sensitive, high drug load API with poor powder properties. Initially, the API is dissolved in water, following which hydroxypropyl methylcellulose (HPMC) is added, resulting in the imbibing of water, along with the dissolved API, into the HPMC matrix. The addition of acetone and isopropyl acetate (anti-solvents) then causes the API to crystallize inside and on the surface of HPMC agglomerates. The process was scaled up to 20 kg scale. The agglomerates of API and HPMC generated by this process are ∼350 µm diameter, robust, and have significantly better flow than the API as measured by Erweka flow testing. These agglomerates exhibit improved bulk density, acceptable chemical stability, and high compressibility. The agglomerates process well through roller compaction and tableting, with no flow or sticking issues. This process is potentially adaptable to other APIs with similar attributes.