Highly Efficient Production of Desired Solid Forms of Drugs with Improved Mechanical Properties via an Organic Solvent-Free Sublimation Process

Abstract

The pharmaceutical industry is required to constantly broaden its development areas and accelerate technical transformation because of the continued global rise in medicine consumption. However, the usage of organic solvents in pharmaceutical production results in up to 20 million tons annually of chemical waste, causing a serious environmental problem. Here, we proposed a solvent-free sustainable chemical technology, sublimation crystallization, for highly efficient screening and preparation of pharmaceutical solid forms (i.e., polymorphs), which eliminates the wastes associated with solvent use from the source. By adjusting the parameters of sublimation crystallization, we have obtained multiple polymorphs of several important drugs, including the antituberculosis drug pyrazinamide (PZA) and nonsteroidal anti-inflammatory drugs (NSAIDs), flufenamic acid (FFA) and mefenamic acid, particularly γ form of PZA and polymorphs IV and VII of FFA, which are difficult to produce from conventional solution crystallization methods. Mechanical property measurements from both powder and single crystal tests reveal that the γ form of PZA readily prepared by sublimation crystallization has the most excellent tabletability properties. In situ crystal growth observations indicate a direct vapor-to-crystal growth mechanism for the sublimation crystallization process consistent with conventional vapor phase deposition. Furthermore, the governing factors and growth mechanisms of sublimation and solution crystallization processes were analyzed and discussed, and it was found that the rate-limiting step of crystal growth is the surface-integration process in solution crystallization, whereas it becomes the surface diffusion process in sublimation crystallization. Overall, our developed sublimation crystallization provides a promising green technology for the development and production of (new) drugs, broadening the thinking behind the development of sustainable chemicals.

Polymorphic Development Strategy for Rapid Pesticide Release: A Case Study of Spirotetramat

“…Spirotetramat has only been reported in two solid forms, amorphous and form I, which have been documented in the CCDC or patent databases . Although screening methods for crystal systems are comprehensive, − no other new crystal forms of spirotetramat have been reported in the literature to date. Melt crystallization combines a high driving force with low nucleation and growth rates, making it possible to access regions of the potential energy landscape that are inaccessible to solution growth. , This approach may facilitate the development of polymorphs for active pesticide ingredients .…”

Efficient Screening of Pharmaceutical Cocrystals by Microspacing In-Air Sublimation

“…Melting methods have been reported for the screening of cocrystals and polymorph exploration, though this method has limits due to the requirements of the drug’s thermal stability. By contrast, sublimation is a solvent-free method, and the use of a vacuum can prevent thermolabile materials from decomposing . However, the complexity of pressure, temperature gradient, feeding ratio, and gas flow rate factors made its application somewhat inconvenient.…”