Role of Self-Assembled Surface Functionalization on Nucleation Kinetics and Oriented Crystallization of a Small-Molecule Drug: Batch and Thin-Film Growth of Aspirin as a Case Study.

Fiora Artusio,Andrea Valsesia,Giacomo Ceccone,Francesco Fumagalli,Roberto Pisano

doi:10.1021/acsami.1c00460

Fiora Artusio, Andrea Valsesia + Show 3 more

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https://doi.org/10.1021/acsami.1c00460

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Abstract

The present paper assesses the heterogeneous nucleation of a small-molecule drug and its relationship with the surface chemistry of engineered heteronucleants. The nucleation of aspirin (ASA) was tuned by different functional groups exposed by self-assembled monolayers (SAMs) immobilized on glass surfaces. Smooth topographies and defect-free surface modification allowed the deconvolution of chemical and topographical effects on nucleation. The nucleation induction time of ASA in batch crystallization was mostly enhanced by methacrylate and amino groups, whereas it was repressed by thiol groups. In this perspective, we also present a novel strategy for the evaluation of surface–drug interactions by confining drug crystallization to thin films and studying the preferential growth of crystal planes on different surfaces. Crystallization by spin coating improved the study of oriented crystallization, enabling reproducible sample preparation, minimal amounts of drug required, and short processing time. Overall, the acid surface tension of SAMs dictated the nucleation kinetics and the extent of relative growth of the ASA crystal planes. Moreover, the face-selective action of monolayers was investigated by force spectroscopy and attributed to the preferential interaction of exposed groups with the (100) crystal plane of ASA.

Highlights

The industrial manufacturing of drugs often involves crystallization steps for the isolation, purification, or delivery of active pharmaceutical ingredients (APIs).[1]
self-assembled monolayers (SAMs) guaranteed fine functionalization coupled to very low roughness to deconvolute the influence of surface chemistry on API nucleation from morphological effects, as much as physically possible
SAMs effectively tuned ASA nucleation kinetics during batch crystallization, being either nucleation promoters or inhibitors according to their surface hydrophobicity

Summary

Introduction

The industrial manufacturing of drugs often involves crystallization steps for the isolation, purification, or delivery of active pharmaceutical ingredients (APIs).[1] Being one of the most widespread unit operations, crystallization nowadays represents a relevant percentage of the drug manufacturing process in terms of time and cost. Crystallization opens access to an easy-to-handle and stable product and strongly affects the final product properties, such as flowability, biological activity, and tableting.[2] Such features are directly correlated with the crystal form, habit, and size, which result from the crystallization step. Many different approaches have been recently proposed to achieve a higher degree of control over the process and ensure the meeting of strict pharmaceutical quality constraints. Crystallization confinement, crystal size, and density control are just a few examples of the application of such a technique.[3]

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