Crystallization from the Gas Phase: Morphology Control, Co-Crystal and Salt Formation

Ciaran O’Malley,Patrick Mcardle,Andrea Erxleben

doi:10.3390/iecp2020-08797

Abstract

Multicomponent crystallisation is a widely studied technique in pharmaceutical chemistry to enhance physical properties of API’s such as solubility, stability and bioavailability without chemically modifying the drug moiety itself. Methods to produce multicomponent crystals are varied with solution crystallisation being the predominant method. Crystal morphologies also influence an API’s properties with needle shaped crystals dissolving slower and possessing poor flow properties compared to a more equant block shape. In this paper, we discuss the preparation of co-crystals and co-crystal salts of two poorly soluble drugs, pyrimethamine and diflunisal. In particular, we compare production of multicomponent crystals via cosublimation with the more common methods of mechanical grinding and solution crystallisation. Samples are sublimed on a laboratory scale from both ends of standard 15 × 160 mm test tubes sealed under vacuum with two heaters were used to equalize the sublimation rates of the components. We show that a range of multicomponent pharmaceutical crystals can be prepared that are not accessible via solution crystallisation, including polymorphs and ansolvates. In addition to binary systems, ternary crystals can also be obtained via this technique. Various diflunisal co-crystals crystallise as thin needles and we describe the use of tailor-made additives to obtain unprecedented morphology control of gas phase crystal growth. Finally, we discuss the formation of co-crystal salts in the absence of solvent. Salt formation was observed to occur during gas phase crystallisations in accordance with the pKa rule of 3 and modelling studies were carried out to understand the nature of proton transfer in these crystals in the absence of a solvent.

Highlights

31 Co-crystals, i.e. crystals containing two or more molecular components that crystallise together in the same crystal structure, are extensively studied in the field of pharmaceutical chemistry to enhance the physical properties of API’s without chemical modification of the drug molecule itself[1,2,3]
Sublimation is a much less common technique for co-crystal formation with only a limited number of examples available in the literature but can provide a much greener alternative to crystal growth avoiding solvent needed for growth from solution which can
It can be noted that many solvates were identified during this study and co-crystallisation 93 from the gas phase was carried out to prevent solvate formation

Summary

Introduction

31 Co-crystals, i.e. crystals containing two or more molecular components that crystallise together in the same crystal structure, are extensively studied in the field of pharmaceutical chemistry to enhance the physical properties of API’s without chemical modification of the drug molecule itself[1,2,3]. Properties such as dissolution rate, solubility, processability, stability and bioavailability can be modified in such a manner. The successful use of tailor made additives and an apparatus constructed of inexpensive and commercially available components to obtain morphology control and improve the quality of crystal growth from the gas phase is described

Methods

Results

Discussion

Conclusion