The Relevance of Crystal Forms in the Pharmaceutical Field: Sword of Damocles or Innovation Tools?

Abstract

This review is aimed to provide to an “educated but non-expert” readership and an overview of the scientific, commercial, and ethical importance of investigating the crystalline forms (polymorphs, hydrates, and co-crystals) of active pharmaceutical ingredients (API). The existence of multiple crystal forms of an API is relevant not only for the selection of the best solid material to carry through the various stages of drug development, including the choice of dosage and of excipients suitable for drug development and marketing, but also in terms of intellectual property protection and/or extension. This is because the physico-chemical properties, such as solubility, dissolution rate, thermal stability, processability, etc., of the solid API may depend, sometimes dramatically, on the crystal form, with important implications on the drug's ultimate efficacy. This review will recount how the scientific community and the pharmaceutical industry learned from the catastrophic consequences of the appearance of new, more stable, and unsuspected crystal forms. The relevant aspects of hydrates, the most common pharmaceutical solid solvates, and of co-crystals, the association of two or more solid components in the same crystalline materials, will also be discussed. Examples will be provided of how to tackle multiple crystal forms with screening protocols and theoretical approaches, and ultimately how to turn into discovery and innovation the purposed preparation of new crystalline forms of an API.

Polymorph Screening of the Antitumor Drug Ripretinib─Selective Preference of Dimer Synthons

“…Polymorphs are highly significant during drug development in the pharmaceutical industry, as they differ in several drug properties like melting point, density, solubility, chemical stability, shelf-life, and clinical profile. 1,2,4 A polymorph with the optimum drug properties is the most desirable solid form during formulation, followed by commercialization. Most often, an innovator commercializes a drug in its most stable crystalline phase to avoid phase transformation under storage conditions.…”

“…Polymorphs are defined as substances with minimum two crystalline packing arrangements of a given compound that are common for 50% of the active pharmaceutical ingredients (APIs). − In fact, polymorphism in APIs is familiar among the organic compounds and is often facilitated by flexibility in their crystal structures. Polymorphs are highly significant during drug development in the pharmaceutical industry, as they differ in several drug properties like melting point, density, solubility, chemical stability, shelf-life, and clinical profile. ,, A polymorph with the optimum drug properties is the most desirable solid form during formulation, followed by commercialization. Most often, an innovator commercializes a drug in its most stable crystalline phase to avoid phase transformation under storage conditions.…”

Crystallographic and Computational Analysis of the Solid-Form Landscape of Three Structurally Related Imidazolidine-2,4-dione Active Pharmaceutical Ingredients: Nitrofurantoin, Furazidin, and Dantrolene

“…Studies on solvate, solvate-hydrate, and hydrate formation, occurrence, and crystal structure analysis have been conducted on compounds having a rich solid-form landscape, for example, prolific solvate formers olanzapine, galunisertib, axitinib, and sulfathiazole as well as solvate-hydrate formers such as bosutinib and 3,5-dihydroxybenzoic acid. , The formation of multiple crystalline phases represents a possible strategy for altering the solid-state properties of pharmaceutical compounds and influencing the physicochemical and biopharmaceutical properties ( e.g. , the dissolution rate profile and hence bioavailability) without affecting the physiological action. , Therefore, considering the importance of solid crystalline forms and solvates in the pharmaceutical industry and their implication in the pharmaceutical development of small organic drug molecules, the large number of characterized solid forms for pharmaceutical compounds is not surprising. Currently, general observations from such studies allow one to conclude that the two main driving forces for formation of solvated crystalline phases of a substance are (a) the formation of host–guest interactions, typically strong hydrogen bonds, and (b) the solvent providing additional lattice stabilization via weak intramolecular interactions, decreasing void space, and improving crystal packing efficiency.…”

Effect of the Solvent on the Crystallographic and Magnetic Properties of rhenium(IV) Complexes Based on 2,2′-Bipyrimidine Ligand

“…The study on solvate formation in crystalline compounds is becoming increasingly a significant topic, given the academic and industrial interest in elucidating the properties and variations in morphology of different crystal forms [1,2]. Many times the crystallization solvent can explain the observed changes in physical properties of a crystalline material, and this investigation can assist in the ongoing efforts to improve the design of crystallization processes from solution [1][2][3][4][5].…”