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Solid solutions of pharmaceutical compounds: a new crystal engineering strategy for drug formulations
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Date
2025-12
Abstract
Crystal engineering aims at the design and synthesis of crystalline materials with desired solid-state properties. A strategy to achieve this ambitious objective involves the combination of multiple molecular ingredients to modify crystal structures of the parent compounds, which affects physicochemical properties such as solubility, dissolution rate, thermal stability, morphology, conductivity, mechanical and photophysical properties. The resulting materials can find applications in various industrial sectors: from pharmaceutical and agrochemicals, to semiconductors and optoelectronics. As most multicomponent materials have a fixed chemical composition, hence optimization of properties involves the synthesis and characterization of many materials and selection of the best for the scope at hand. In contrast, solid solutions are multicomponent systems in which the stoichiometry can be varied in continuum, allowing a continuous variation of the physicochemical properties. This feature allows the fine tuning of materials’ composition and properties. Since solid solutions of organic molecules are an underexplored area of materials chemistry, the purpose of my PhD is to deepen the knowledge on organic molecular solid solutions, focusing on pharmaceutical compounds. In the course of this crystal engineering work, the design and synthesis of solid solutions of pharmaceutical interest was addressed, whose crystalline structures and properties were studied.
In the first chapter, a solid solution of tolbutamide and chlorpropamide, two hypoglycemic drugs characterized by low aqueous solubility, has been synthesized by different methods which led to the discovery of a rare case of polymorphic solid solution. At any stoichiometry, two crystal forms were isolated that are kinetically stable at room temperature from a few months to over a year. Dissolution tests certify the solubility advantage of the solid solution over the pure drugs as well as their physical mixtures.
The second chapter is dedicated to a solid form screening of theophylline and sulfuric acid that led to a collection of new crystals including three anhydrous sulfate salts and two hydrated forms. The new structures were determined and their stability investigated, suggesting multiple modes of movement for the ions in the solids state. The anhydrous form II exhibits unusually large anisotropic linear thermal expansion; additionally, thermal dehydration of the dihydrate salt occurs in a salient, rocket-like manner that may be caused by the sudden release of water vapor trapped inside the particles.
The findings of this study were exploited for the design of a solid solution of caffeine and theophylline that was realised as sulfate salt hydrate: here the two xanthines enter the structure with one and two equivalents of water respectively, creating a novel type of non-stoichiometric hydrate. The solid solution is more thermally stable and enables an increased dissolution rate in water for caffeine and theophylline than the respective hydrated sulfate salts; however, the solid solution shows reduced permeability of caffeine through a skin-mimetic membrane when tested against the physical mixture of the parent salts.
In the last experimental chapter, a crystal engineering screening was conducted to produce a solid solution mixing the nootropic drugs piracetam and oxiracetam. Despite their different H-bond capabilities, multiple solid solutions were obtained whose structure depends on the components’ ratio. The crystal form is controlled when enantiopure oxiracetam is used or when both drugs are co-crystallized with either a molecular coformer (gallic acid) or an inorganic salt (MgCl2) to produce co-crystalline and ionic co-crystalline solid solutions. Thermal and humidity stability of each form is discussed as well as the solubility profile of the gallic acid co-crystal solid solution, suggesting that the solid-state landscape of solid solutions could be as rich as that of other solid forms.
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Peer-reviewed
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University of Limerick
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Spoletti_2025_Solid.pdf
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Sustainable Development Goals
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Attribution-NonCommercial-ShareAlike 4.0 International